Recent Progress in the Synthesis of Drugs and ... - MDPI

Citation: Bastrakov, M.;

Starosotnikov, A. Recent Progress in

the Synthesis of Drugs and Bioactive

Molecules Incorporating

Nitro(het)arene Core. Pharmaceuticals

2022, 15, 705. https://doi.org/

10.3390/ph15060705

Academic Editors: Patrice Vanelle

and Nicolas Primas

Received: 28 April 2022

Accepted: 31 May 2022

Published: 3 June 2022

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in

published maps and institutional affil-

iations.

Copyright: © 2022 by the authors.

Licensee MDPI, Basel, Switzerland.

This article is an open access article

distributed under the terms and

conditions of the Creative Commons

Attribution (CC BY) license (https://

creativecommons.org/licenses/by/

4.0/).

pharmaceuticals

Review

Recent Progress in the Synthesis of Drugs and BioactiveMolecules Incorporating Nitro(het)arene CoreMaxim Bastrakov * and Alexey Starosotnikov

N.D. Zelinsky Institute of Organic Chemistry RAS, Leninsky Prosp. 47, Moscow 19991, Russia; [email protected]* Correspondence: [email protected]

Abstract: Aromatic nitro compounds play a unique role in the synthesis of drugs and pharmaceu-tically oriented molecules. This field of organic chemistry continues to be in demand and relevant.A significant number of papers are published annually on new general methods for the synthesisof nitrodrugs and related biomolecules. This review is an analysis of the literature on methods forthe synthesis of both new and already-known aromatic and heteroaromatic nitrodrugs covering theperiod from 2010 to the present.

Keywords: nitro group; arenes; heterocycles; drugs; biological activity

1. Introduction

The synthesis and study of biologically active compounds remains one of the mostimportant and developing areas of organic and medicinal chemistry. Aromatic nitro com-pounds of both natural and synthetic origin constitute a broad class of organic moleculesthat exhibit a wide range of biological activities and are being used as drugs [1,2]. Thespectrum of activity directly depends on the nature and mutual arrangement of substituentsin a molecule. A significant number of papers are published annually not only on toxicityand metabolism of nitrodrugs and related biomolecules, but also on new general meth-ods for their synthesis [3–6]. These studies are driven by the need to reduce costs andenvironmental impact during industrial production.

This review is an analysis of the literature on methods for the synthesis of both newand previously known aromatic and heteroaromatic nitrodrugs covering the period from2010 to the present.

2. Nitrobenzene Derivatives

Acenocoumarol is an anticoagulant that acts as a vitamin K antagonist (similar towarfarin). It is a coumarin-based generic drug and is sold under many brand namesaround the world. Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketonesis a straightforward method to access warfarin analogues. Basically, acenocoumarol hasbeen prescribed as racemate; however, both enantiomers are also described. Each of themdemonstrates different activity and metabolism. In the last few years, a number of newmethods for the syntheses of acenocoumarol as well as other nitro-containing warfarinderivatives using organocatalysis have been published, leading to enantiomerically pureMichael adducts [7] (Scheme 1).

Other organocatalysts can be used in these reactions, such as 2-amino-DMAP/ proli-namide [8], α-helical peptide foldamer [9], enantiomerically pure (S,S)-diphenylethylenediamine [10], and binaphthyl-modified 1,2-diphenylethylenediamine [11]. In addition, Vaccaroet al. proposed a method for the synthesis of warfarin derivatives (including aceno-coumarol) using polystyrene-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as acatalyst [12].

Pharmaceuticals 2022, 15, 705. https://doi.org/10.3390/ph15060705 https://www.mdpi.com/journal/pharmaceuticals

https://doi.org/10.3390/ph15060705

https://doi.org/10.3390/ph15060705

https://creativecommons.org/

https://creativecommons.org/licenses/by/4.0/

https://creativecommons.org/licenses/by/4.0/

https://www.mdpi.com/journal/pharmaceuticals

https://www.mdpi.com

https://orcid.org/0000-0003-2145-5146

https://orcid.org/0000-0003-1900-4805

https://doi.org/10.3390/ph15060705

https://www.mdpi.com/journal/pharmaceuticals

https://www.mdpi.com/article/10.3390/ph15060705?type=check_update&version=3

Pharmaceuticals 2022, 15, 705 2 of 24Pharmaceuticals 2022, 15, x FOR PEER REVIEW 2 of 25

O

OH

OMe+

O

OH

O

Me

OO

NO2

NO2

acenocoumarol98% (99 ee)

Ph Ph

H2N NHPPh2

O10% L, 20% 4-CH3C6H4CO2H

toluene, 72 rt

L

Scheme 1. Synthesis of enantiomerically pure (R)-acenocoumarol.

Other organocatalysts can be used in these reactions, such as 2-amino-DMAP/prolinamide [8], α-helical peptide foldamer [9], enantiomerically pure (S,S)-diphenylethylenediamine [10], and binaphthyl-modified 1,2-diphenylethylenediamine [11]. In addition, Vaccaro et al. proposed a method for the synthesis of warfarin derivatives (including acenocoumarol) using polysty-rene-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst [12].

Antibiotics of the amphinicol group have been of interest to researchers for several decades due to their wide spectrum of activities against Gram-positive and Gram-negative bacteria. Among the representatives of the amphinicol group, there are nitrogroup-containing compounds. Recently, Chen et al. proposed two methods for the synthesis of azidamphinicol and chloramifinicol. The reactions proceed with high ste-reo- and enantioselectivity. The first method is based on two key steps: urea-catalyzed aldol condensation of p-nitrobenzaldehyde and isocyanatomalonic ester leading to chiral oxazolidinone. Further decarboxylation of this compound occurs in a continuous flow reactor with the formation of trans-monoester of oxazolidinone with two adjacent stere-ocenters, which leads to syn-vicinal amino alcohols of the amphinicol family [13] (Scheme 2).

O2N

OCO2Et

EtO2C

OCN NHO

CO2EtCO2Et

O

O2N

NHO

CO2Et

O

O2N

OH

NH

OH

O2NO

R1

R2

R1=R2=Cl ( (-)-chloramphenicol), 70%, 97%eeR1=H, R2=N3

((-)-azidamphenicol) 75%, 97%ee60%, 97% ee 69%, 97% ee

continuos-flowdecarboxylationurea catalyst,

CHCl3, -60oC

Scheme 2. Synthesis of amphinicol derivatives.

The key step of the second method is the Henri reaction catalyzed by the cop-per(II)-chiral biphenyl-substituted amino alcohol complex, which ultimately leads to 2-amino-1,3-diol, which undergoes multistep continuous-flow transformations, which also afford enantiomerically pure antibiotics of the amphinicol group [14].

The biosynthesis of chloramphinicol is another modern approach to this antibiotic. In 2012 and 2014, two research groups independently published articles on the biosyn-thesis of chloramphinicol. The key step in biosynthetic transformations is the en-zyme-catalyzed N-oxidation of the amino group [15,16].

A four-step method for the synthesis of (-)-chloramphenicol was described by J. Dixon. It is based on the enantio- and diastereoselective aldol reaction of isocyanoace-tates, with p-nitrobenzaldehyde catalyzed by Ag2O and aminophosphine ligands [17] (Scheme 3).


Antibiotics of the amphinicol group have been of interest to researchers for sev-eral decades due to their wide spectrum of activities against Gram-positive and Gram-negative bacteria. Among the representatives of the amphinicol group, there are nitrogroup-containing compounds. Recently, Chen et al. proposed two methods for the synthesis ofazidamphinicol and chloramifinicol. The reactions proceed with high stereo- and enantios-electivity. The first method is based on two key steps: urea-catalyzed aldol condensation ofp-nitrobenzaldehyde and isocyanatomalonic ester leading to chiral oxazolidinone. Furtherdecarboxylation of this compound occurs in a continuous flow reactor with the forma-tion of trans-monoester of oxazolidinone with two adjacent stereocenters, which leads tosyn-vicinal amino alcohols of the amphinicol family [13] (Scheme 2).

Pharmaceuticals 2022, 15, x FOR PEER REVIEW 2 of 25

O

OH

OMe+

O

OH

O

Me

OO

NO2

NO2

acenocoumarol98% (99 ee)

Ph Ph

H2N NHPPh2

O10% L, 20% 4-CH3C6H4CO2H

toluene, 72 rt

L


Other organocatalysts can be used in these reactions, such as 2-amino-DMAP/prolinamide [8], α-helical peptide foldamer [9], enantiomerically pure (S,S)-diphenylethylenediamine [10], and binaphthyl-modified 1,2-diphenylethylenediamine [11]. In addition, Vaccaro et al. proposed a method for the synthesis of warfarin derivatives (including acenocoumarol) using polysty-rene-supported 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as a catalyst [12].

Antibiotics of the amphinicol group have been of interest to researchers for several decades due to their wide spectrum of activities against Gram-positive and Gram-negative bacteria. Among the representatives of the amphinicol group, there are nitrogroup-containing compounds. Recently, Chen et al. proposed two methods for the synthesis of azidamphinicol and chloramifinicol. The reactions proceed with high ste-reo- and enantioselectivity. The first method is based on two key steps: urea-catalyzed aldol condensation of p-nitrobenzaldehyde and isocyanatomalonic ester leading to chiral oxazolidinone. Further decarboxylation of this compound occurs in a continuous flow reactor with the formation of trans-monoester of oxazolidinone with two adjacent stere-ocenters, which leads to syn-vicinal amino alcohols of the amphinicol family [13] (Scheme 2).


The key step of the second method is the Henri reaction catalyzed by the cop-per(II)-chiral biphenyl-substituted amino alcohol complex, which ultimately leads to 2-amino-1,3-diol, which undergoes multistep continuous-flow transformations, which also afford enantiomerically pure antibiotics of the amphinicol group [14].

The biosynthesis of chloramphinicol is another modern approach to this antibiotic. In 2012 and 2014, two research groups independently published articles on the biosyn-thesis of chloramphinicol. The key step in biosynthetic transformations is the en-zyme-catalyzed N-oxidation of the amino group [15,16].

A four-step method for the synthesis of (-)-chloramphenicol was described by J. Dixon. It is based on the enantio- and diastereoselective aldol reaction of isocyanoace-tates, with p-nitrobenzaldehyde catalyzed by Ag2O and aminophosphine ligands [17] (Scheme 3).


The key step of the second method is the Henri reaction catalyzed by the copper(II)-chiral biphenyl-substituted amino alcohol complex, which ultimately leads to 2-amino-1,3-diol, which undergoes multistep continuous-flow transformations, which also affordenantiomerically pure antibiotics of the amphinicol group [14].

The biosynthesis of chloramphinicol is another modern approach to this antibiotic. In2012 and 2014, two research groups independently published articles on the biosynthesisof chloramphinicol. The key step in biosynthetic transformations is the enzyme-catalyzedN-oxidation of the amino group [15,16].

A four-step method for the synthesis of (-)-chloramphenicol was described by J. Dixon.It is based on the enantio- and diastereoselective aldol reaction of isocyanoacetates, withp-nitrobenzaldehyde catalyzed by Ag2O and aminophosphine ligands [17] (Scheme 3).


Scheme 3. Dixon’s synthesis of (-)-chloramphenicol.

Dantrolene is a muscle relaxant, the mechanism of action of which is based on the blockade of ryanodine receptors (calcium channels of the sarcoplasmic reticulum of my-ocytes). This drug has been used since 1973 [18]. The original patent synthesis started with p-nitroaniline, which undergoes diazotization followed by a copper(II) chloride catalyzed arylation with furfural (essentially a modified Meerwein arylation). This then reacts with 1-aminohydantoin to form the final product [19].

The current literature describes several new methods for the multigram-scale syn-thesis of dantrolene [20–22]. The authors proposed new catalytic systems at the arylation step. In this case, both p-nitroanaline or p-nitrohalogenobenzenes can be used as starting compounds (Scheme 4, Table 1).

H2N NO2 OO+

1. Conditions*

2.HN

NO

O

NH2*HCl

NO2

O

NNHN

O

O

dantrolene*- see Table 1 Scheme 4. Synthesis of dantrolene.

Table 1. Reagents and conditions.

* Conditions Yield, % Ref. AcOK (2 eqviv.), DMA, 12 h, 150 °C

bis{1,3-bis(2,6-diisopropylphenyl)-2,4 -diphenylimidazolium}bromobridged Pd(II) dimer

52 [20]

K2CO3, AcOH, DMA, 12 h, 130 °C

N N

PdN

Cl

PhPh

MeO Cl

ClPh Ph

51 [21]

t-BuONO, MeCN, r.t. ascorbic acid (10 mol%)

41 [22]

Entacapone is a nitrocatechol derivative and an inhibitor of cate-chol-O-methyltransfarase, and is used in the treatment of Parkinson’s disease as an ad-junct to levodopa/carbidopa therapy. It was developed by Orion Pharma and is marketed by Novartis under the trade name Comtan in the United States. To date, several ap-proaches to entacapone have been described. Harisha et al. described its synthesis from 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide using amine-mediated demethylation [23,24]. An industrial method for the synthesis of entacapone via a Knoevenagel reaction of 2-cyano-3-(3-methoxy 4-hydroxy-5-nitrophenyl)acrylic acid was reported by Guo [25]. Fu and coworkers proposed another method starting from


Dantrolene is a muscle relaxant, the mechanism of action of which is based on theblockade of ryanodine receptors (calcium channels of the sarcoplasmic reticulum of my-ocytes). This drug has been used since 1973 [18]. The original patent synthesis started withp-nitroaniline, which undergoes diazotization followed by a copper(II) chloride catalyzedarylation with furfural (essentially a modified Meerwein arylation). This then reacts with1-aminohydantoin to form the final product [19].

Pharmaceuticals 2022, 15, 705 3 of 24

The current literature describes several new methods for the multigram-scale syn-thesis of dantrolene [20–22]. The authors proposed new catalytic systems at the arylationstep. In this case, both p-nitroanaline or p-nitrohalogenobenzenes can be used as startingcompounds (Scheme 4, Table 1).

Scheme 4. Synthesis of dantrolene. *—see Table 1.


* Conditions Yield, % Ref.

AcOK (2 eqviv.), DMA, 12 h, 150 ◦Cbis{1,3-bis(2,6-diisopropylphenyl)-2,4

-diphenylimidazolium}bromobridged Pd(II) dimer52 [20]

K2CO3, AcOH, DMA, 12 h, 130 ◦C



Dantrolene is a muscle relaxant, the mechanism of action of which is based on the blockade of ryanodine receptors (calcium channels of the sarcoplasmic reticulum of my-ocytes). This drug has been used since 1973 [18]. The original patent synthesis started with p-nitroaniline, which undergoes diazotization followed by a copper(II) chloride catalyzed arylation with furfural (essentially a modified Meerwein arylation). This then reacts with 1-aminohydantoin to form the final product [19].

The current literature describes several new methods for the multigram-scale syn-thesis of dantrolene [20–22]. The authors proposed new catalytic systems at the arylation step. In this case, both p-nitroanaline or p-nitrohalogenobenzenes can be used as starting compounds (Scheme 4, Table 1).

H2N NO2 OO+

1. Conditions*

2.HN

NO

O

NH2*HCl

NO2

O

NNHN

O

O

dantrolene*- see Table 1 Scheme 4. Synthesis of dantrolene.


* Conditions Yield, % Ref. AcOK (2 eqviv.), DMA, 12 h, 150 °C

bis{1,3-bis(2,6-diisopropylphenyl)-2,4 -diphenylimidazolium}bromobridged Pd(II) dimer

52 [20]

K2CO3, AcOH, DMA, 12 h, 130 °C

N N

PdN

Cl

PhPh

MeO Cl

ClPh Ph

51 [21]

t-BuONO, MeCN, r.t. ascorbic acid (10 mol%)

41 [22]

Entacapone is a nitrocatechol derivative and an inhibitor of cate-chol-O-methyltransfarase, and is used in the treatment of Parkinson’s disease as an ad-junct to levodopa/carbidopa therapy. It was developed by Orion Pharma and is marketed by Novartis under the trade name Comtan in the United States. To date, several ap-proaches to entacapone have been described. Harisha et al. described its synthesis from 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide using amine-mediated demethylation [23,24]. An industrial method for the synthesis of entacapone via a Knoevenagel reaction of 2-cyano-3-(3-methoxy 4-hydroxy-5-nitrophenyl)acrylic acid was reported by Guo [25]. Fu and coworkers proposed another method starting from

51 [21]

t-BuONO, MeCN, r.t.ascorbic acid (10 mol%) 41 [22]

Entacapone is a nitrocatechol derivative and an inhibitor of catechol-O-methyltransfarase,and is used in the treatment of Parkinson’s disease as an adjunct to levodopa/carbidopatherapy. It was developed by Orion Pharma and is marketed by Novartis under thetrade name Comtan in the United States. To date, several approaches to entacaponehave been described. Harisha et al. described its synthesis from 2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide using amine-mediated demethylation [23,24].An industrial method for the synthesis of entacapone via a Knoevenagel reaction of 2-cyano-3-(3-methoxy 4-hydroxy-5-nitrophenyl)acrylic acid was reported by Guo [25]. Fuand coworkers proposed another method starting from p-vanillin [26]. Srikanth et al. [27]reported on the condensation of 3,4-hydroxy-5-nitrobenzaldehyde with 2-cyanoacetic acid(Scheme 5).


p-vanillin [26]. Srikanth et al. [27] reported on the condensation of 3,4-hydroxy-5-nitrobenzaldehyde with 2-cyanoacetic acid (Scheme 5).

OHOMe

I

OHOMeO2N

O

NEt2CN

OHOHO2N

O

NEt2CN

HOOH

O2NO

HOOH

O2N

CN

O

Cl

Entacaponei: Pd(Ph3P)4

(8 mol%), Ph3P (12 mol%), TEA, DMF, 95-100oC

ii: HNO3/H2SO4, r.t.

iii: AlCl3, Py, DCM, reflux, (55%)iv: Et2NH, 0oC, (65%)

i, ii iii iv

Scheme 5. Fu’s and Srikanth’s methods for the synthesis of entacapone.

In addition, preparation of entacapone from 4-iodo-2-methoxyphenol with 2-cyano-N,N-diethylacrylamide using a Pd-catalyzed Heck reaction as a key step was described [28].

Flutamide (4-nitro-3-trifluoromethylisobutyranilide) is a nonsteroidal antiandrogen (NSAA) that is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions such as acne, excessive hair growth, and high androgen levels in women. In addition to previously published studies [29–32], a convenient and economically beneficial method was developed by S. Rahbar et al. [33] (Scheme 6). Ac-cording to the procedure, benzotrifluoride was first nitrated, and the product was re-duced and acylated in one pot in the presence of iron powder and isobutyric acid to produce 3-trifluoroisobutyranilide. Finally, flutamide was produced via further nitration.

CF3 CF3

NO2

CF3

O

i-Pr

CF3

O

i-Pr

O2NHNO3/H2SO4 HNO3/H2SO4Fe, i-PrCO2H

94% 81% 85%

reflux

flutamide

NH

NH

Scheme 6. Synthesis of flutamide.

General methods for the synthesis of structurally close arylamides using metal complex catalysis have been described recently [34,35]. According to the proposed methods, it is possible to synthesize 3-trifluoroisobutyranilide, a key intermediate in the synthesis of flutamide, in high yields.

Another synthesis of flutamide was described in 2016 by Ren et. al. [36]. The target compound was synthesized via trifluoromethylation of the corresponding nitro com-pound.

Iniparib, a drug for cancer treatment, has been known since 2009. In 2013, its syn-thesis was published by Divi et al. [37] (Scheme 7). It is noteworthy that the proposed scheme allowed the researchers to obtain the product with virtually no impurities.

MeOH/H2SO4

I

O2N CO2H

70oC I

O2N CO2Me

85%

MeOH, -15oC

NH3

I

O2N CONH2

95%

Iniparib Scheme 7. Scheme of the synthesis of iniparib.

Later, the final step of this synthetic scheme was optimized in a patent [38]. In addition, a two-step synthesis of iniparib based on 4-bromobenzonitrile was de-

scribed recently. The key step of the proposed synthesis was the iodination of the corre-sponding aryl bromide using metal complex catalysis [39] (Scheme 8).



Flutamide (4-nitro-3-trifluoromethylisobutyranilide) is a nonsteroidal antiandrogen(NSAA) that is used primarily to treat prostate cancer. It is also used in the treatment of


androgen-dependent conditions such as acne, excessive hair growth, and high androgenlevels in women. In addition to previously published studies [29–32], a convenient andeconomically beneficial method was developed by S. Rahbar et al. [33] (Scheme 6). Ac-cording to the procedure, benzotrifluoride was first nitrated, and the product was reducedand acylated in one pot in the presence of iron powder and isobutyric acid to produce3-trifluoroisobutyranilide. Finally, flutamide was produced via further nitration.



OHOMe

I

OHOMeO2N

O

NEt2CN

OHOHO2N

O

NEt2CN

HOOH

O2NO

HOOH

O2N

CN

O

Cl





i, ii iii iv




CF3 CF3

NO2

CF3

O

i-Pr

CF3

O

i-Pr


94% 81% 85%

reflux

flutamide

NH

NH





MeOH/H2SO4

I

O2N CO2H

70oC I

O2N CO2Me

85%

MeOH, -15oC

NH3

I

O2N CONH2

95%





General methods for the synthesis of structurally close arylamides using metal complexcatalysis have been described recently [34,35]. According to the proposed methods, it ispossible to synthesize 3-trifluoroisobutyranilide, a key intermediate in the synthesis offlutamide, in high yields.

Another synthesis of flutamide was described in 2016 by Ren et. al. [36]. The targetcompound was synthesized via trifluoromethylation of the corresponding nitro compound.

Iniparib, a drug for cancer treatment, has been known since 2009. In 2013, its synthesiswas published by Divi et al. [37] (Scheme 7). It is noteworthy that the proposed schemeallowed the researchers to obtain the product with virtually no impurities.



OHOMe

I

OHOMeO2N

O

NEt2CN

OHOHO2N

O

NEt2CN

HOOH

O2NO

HOOH

O2N

CN

O

Cl





i, ii iii iv




CF3 CF3

NO2

CF3

O

i-Pr

CF3

O

i-Pr


94% 81% 85%

reflux

flutamide

NH

NH





MeOH/H2SO4

I

O2N CO2H

70oC I

O2N CO2Me

85%

MeOH, -15oC

NH3

I

O2N CONH2

95%




Scheme 7. Scheme of the synthesis of iniparib.

Later, the final step of this synthetic scheme was optimized in a patent [38].In addition, a two-step synthesis of iniparib based on 4-bromobenzonitrile was de-



Scheme 8. Synthesis of iniparib from 4-bromobenzonitrile.

The interest of researchers in dihydropyridine derivatives (including those con-taining nitro) has not weakened to date due to new types of activities revealed: anticon-vulsant [40], antioxidant, anti-inflammatory, and antiulcer [41]. Nifedipine is a calci-um-channel blocker of the dihydropyridine type that has been used since the last century [42] as a medicine for the treatment of diseases such as angina, high blood pressure (in-cluding during pregnancy), Raynaud’s phenomenon, and premature labor.

New methods for assembling the dihydropyridine ring are regularly published; these can be used in the synthesis of nifedepine. For example, Siddaiah et al. published a modified Hantzsch PEG-mediated, catalyst-free synthesis under solvent-free conditions [43] (Scheme 9).

NO2

O

Me OMe

O O+

NH4OAcPEG-400

75oC, 2-3h NH

MeO2C CO2MeNO2

92%Nifedipine

Scheme 9. Modified Hantzsch synthesis of nifedipine.

In addition, methods for the synthesis of nifedipine using new composite catalysts [44] and ionic liquids [45] were described.

Nifekalant is a class III antiarrhythmic agent approved in Japan for the treatment of arrhythmias and ventricular tachycardia. Earlier, a method for the synthesis of nifecalant hydrochloride using dimethylurea as a starting material was described [46]. This method had a number of disadvantages: low yield (about 30%), high cost, and the use of corrosive reagents such as phosphorus oxychloride and sodium hydride in the preparation; these are harmful to the environment and are not conducive to industrial production. In 2013, Yi et al. published a new synthetic method on an industrial scale to produce nifecalant based on 6-amino-1,3-dimethyluracil. This method features a high yield and purity of the product, simple operation, and environmental tolerance of the used reagents [47] (Scheme 10).

N N

O

O NH2N

NO

O

NH NH OH

NO2

TsO

MeOH, NaOH, reflux, 1h

N

NO

O

NH N OH

NO2

Nifecalant

90%

Scheme 10. A method for the synthesis of nifecalant by Yi.


The interest of researchers in dihydropyridine derivatives (including those containingnitro) has not weakened to date due to new types of activities revealed: anticonvulsant [40],antioxidant, anti-inflammatory, and antiulcer [41]. Nifedipine is a calcium-channel blockerof the dihydropyridine type that has been used since the last century [42] as a medicine forthe treatment of diseases such as angina, high blood pressure (including during pregnancy),Raynaud’s phenomenon, and premature labor.

New methods for assembling the dihydropyridine ring are regularly published; thesecan be used in the synthesis of nifedepine. For example, Siddaiah et al. published amodified Hantzsch PEG-mediated, catalyst-free synthesis under solvent-free conditions [43](Scheme 9).






NO2

O

Me OMe

O O+

NH4OAcPEG-400

75oC, 2-3h NH

MeO2C CO2MeNO2

92%Nifedipine




N N

O

O NH2N

NO

O

NH NH OH

NO2

TsO


N

NO

O

NH N OH

NO2

Nifecalant

90%

Scheme 10. A method for the synthesis of nifecalant by Yi.


In addition, methods for the synthesis of nifedipine using new composite catalysts [44]and ionic liquids [45] were described.

Nifekalant is a class III antiarrhythmic agent approved in Japan for the treatment ofarrhythmias and ventricular tachycardia. Earlier, a method for the synthesis of nifecalanthydrochloride using dimethylurea as a starting material was described [46]. This methodhad a number of disadvantages: low yield (about 30%), high cost, and the use of corrosivereagents such as phosphorus oxychloride and sodium hydride in the preparation; these areharmful to the environment and are not conducive to industrial production. In 2013, Yi et al.published a new synthetic method on an industrial scale to produce nifecalant based on6-amino-1,3-dimethyluracil. This method features a high yield and purity of the product,simple operation, and environmental tolerance of the used reagents [47] (Scheme 10).





NO2

O

Me OMe

O O+

NH4OAcPEG-400

75oC, 2-3h NH

MeO2C CO2MeNO2

92%Nifedipine




N N

O

O NH2N

NO

O

NH NH OH

NO2

TsO


N

NO

O

NH N OH

NO2

Nifecalant

90%

Scheme 10. A method for the synthesis of nifecalant by Yi. Scheme 10. A method for the synthesis of nifecalant by Yi.

Nilutamide is a nonsteroidal antiandrogen (NSAA) that is used in the treatment ofprostate cancer. It has also been studied as a component of feminizing hormone therapyfor transgender women and to treat acne and seborrhea in women. Nilutamide was firstdescribed in 1977 and introduced for medical use in 1987 in France [48]. However, interestin this compound has not weakened, even today. In 2010, a general method for the synthesisof nilutamide was published (this patent was later republished in 2021) via a reaction ofhaloarene with N-trimethylsilyl imidazoline-1,3-dione [49] (Scheme 11).


Nilutamide is a nonsteroidal antiandrogen (NSAA) that is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. Nilutamide was first described in 1977 and introduced for medical use in 1987 in France [48]. However, inter-est in this compound has not weakened, even today. In 2010, a general method for the synthesis of nilutamide was published (this patent was later republished in 2021) via a reaction of haloarene with N-trimethylsilyl imidazoline-1,3-dione [49] (Scheme 11).

F

CF3NO2

HN

NOO

Si(CH3)3

+ CsF, DMF

60oC,16h

N

CF3NO2

HN

O O

Nilutamide

71%

Scheme 11. Synthesis of nilutamide.

According to the authors of the patent, this method is simpler, faster, and cheaper to implement; provides high yields; and avoids toxic heavy-metal contamination compared to the methods described earlier.

N-(4-nitro-2-phenoxyphenyl)methanesulfonamide (nimesulide) is a well-known brain cyclooxygenase (COX) inhibitor with increased selectivity for COX-2, which was reported to play a role in the physiological control of synaptic plasticity and neurological disorders, including cerebrovascular and neurodegenerative disorders such as Alz-heimer’s and Parkinson’s diseases. In 2010, analogs of nimesulide containing methoxy substituents in the phenyl ring were designed, synthesized, and evaluated for potential as radioligands for brain COX-2 imaging. The synthesis of nimesulide analogs was based on the copper-mediated arylation of phenolic derivatives [50] (Scheme 12).

Scheme 12. Synthesis of nimesulide and its analogs.

In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening as-say demonstrated that methoxy analogs of nimesulide also demonstrated an inhibition ability toward the COX-2 enzyme.

One more nitro-group-containing drug is 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC. NTBC is used to slow the effects of hereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients. It was approved by the FDA and EMA in January 2002 and Feb-ruary 2005, respectively. Unfortunately, one of the problems of the actual drug formula-tion (i.e., Orfadin® capsules) is its chemical instability. After opening, the drug can be used only for 2 months and must be stored at a temperature not exceeding 25 °C. This negatively affects the cost of the drug. In 2016, an improved method for the synthesis and purification of NTBC was proposed that allows the target product to be obtained with a stability of at least 6 months [51] (Scheme 13). The extreme stability of the drug is associ-



According to the authors of the patent, this method is simpler, faster, and cheaper toimplement; provides high yields; and avoids toxic heavy-metal contamination comparedto the methods described earlier.

N-(4-nitro-2-phenoxyphenyl)methanesulfonamide (nimesulide) is a well-known braincyclooxygenase (COX) inhibitor with increased selectivity for COX-2, which was reportedto play a role in the physiological control of synaptic plasticity and neurological disorders,including cerebrovascular and neurodegenerative disorders such as Alzheimer’s andParkinson’s diseases. In 2010, analogs of nimesulide containing methoxy substituents inthe phenyl ring were designed, synthesized, and evaluated for potential as radioligandsfor brain COX-2 imaging. The synthesis of nimesulide analogs was based on the copper-mediated arylation of phenolic derivatives [50] (Scheme 12).


Nilutamide is a nonsteroidal antiandrogen (NSAA) that is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. Nilutamide was first described in 1977 and introduced for medical use in 1987 in France [48]. However, inter-est in this compound has not weakened, even today. In 2010, a general method for the synthesis of nilutamide was published (this patent was later republished in 2021) via a reaction of haloarene with N-trimethylsilyl imidazoline-1,3-dione [49] (Scheme 11).

F

CF3NO2

HN

NOO

Si(CH3)3

+ CsF, DMF

60oC,16h

N

CF3NO2

HN

O O

Nilutamide

71%


According to the authors of the patent, this method is simpler, faster, and cheaper to implement; provides high yields; and avoids toxic heavy-metal contamination compared to the methods described earlier.

N-(4-nitro-2-phenoxyphenyl)methanesulfonamide (nimesulide) is a well-known brain cyclooxygenase (COX) inhibitor with increased selectivity for COX-2, which was reported to play a role in the physiological control of synaptic plasticity and neurological disorders, including cerebrovascular and neurodegenerative disorders such as Alz-heimer’s and Parkinson’s diseases. In 2010, analogs of nimesulide containing methoxy substituents in the phenyl ring were designed, synthesized, and evaluated for potential as radioligands for brain COX-2 imaging. The synthesis of nimesulide analogs was based on the copper-mediated arylation of phenolic derivatives [50] (Scheme 12).


In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening as-say demonstrated that methoxy analogs of nimesulide also demonstrated an inhibition ability toward the COX-2 enzyme.

One more nitro-group-containing drug is 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC. NTBC is used to slow the effects of hereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients. It was approved by the FDA and EMA in January 2002 and Feb-ruary 2005, respectively. Unfortunately, one of the problems of the actual drug formula-tion (i.e., Orfadin® capsules) is its chemical instability. After opening, the drug can be used only for 2 months and must be stored at a temperature not exceeding 25 °C. This negatively affects the cost of the drug. In 2016, an improved method for the synthesis and purification of NTBC was proposed that allows the target product to be obtained with a stability of at least 6 months [51] (Scheme 13). The extreme stability of the drug is associ-


In vitro inhibition studies using a colorimetric COX (ovine) inhibitor-screening assaydemonstrated that methoxy analogs of nimesulide also demonstrated an inhibition abilitytoward the COX-2 enzyme.

One more nitro-group-containing drug is 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, also known as nitisinone or NTBC. NTBC is used to slow the effects ofhereditary tyrosinemia type 1 (HT-1) in adult and pediatric patients. It was approved by theFDA and EMA in January 2002 and February 2005, respectively. Unfortunately, one of theproblems of the actual drug formulation (i.e., Orfadin® capsules) is its chemical instability.After opening, the drug can be used only for 2 months and must be stored at a temperaturenot exceeding 25 ◦C. This negatively affects the cost of the drug. In 2016, an improvedmethod for the synthesis and purification of NTBC was proposed that allows the targetproduct to be obtained with a stability of at least 6 months [51] (Scheme 13). The extremestability of the drug is associated with the high purity of the product. The synthesis wasaccomplished according to a known scheme; however, the authors changed the reactionconditions and the purification process of the target compound.


ated with the high purity of the product. The synthesis was accomplished according to a known scheme; however, the authors changed the reaction conditions and the purifica-tion process of the target compound.

Scheme 13. Improved method for the synthesis of nitisinone.

Nitrendipine is another representative of dihydropyridine derivatives used as a calcium-channel blocker. Recently, a number of studies of nitrendipine analogs have been carried out, including studies of their antihypertensive activity [52,53]. In 2011, Zhou et al. reported on the synthesis of nitrendipine analogs based on m-nitrobenzaldehyde. The transformations take place according to Scheme 14 below.

NO2

OMe OMe

O O

AcOH, piperidine

NO2

CO2MeMe

O

Me OR

ONH2

EtOH, reflux NH

NO2

Me

MeO2C CO2R

Me

R = Et (nitrendipine), 86%60-86% yield

Scheme 14. Synthesis of nitrendipine.

The synthesized compounds showed significant antihypertensive activity at the level of nitrendipine or higher.

Modified synthesis of nifedipine and nitrendipne through a three-component Hantzsch reaction has been described under catalysis of either micellar heteropoly acids [54] or nanoscale metal oxides [55] (Scheme 15).

H

O

O2NMe OMe(Et)

O ONH3

NH

CO2Me(Et)MeO2C

Me Me

NO2

CuO (Al2O3)+

67% (nifedipine)50% (nitrendipine)

Scheme 15. Modified Hantzsch synthesis of nifedipine and nitrendipne.

Nitrocefin is a cephalosporin that can be used to detect whether a bacteria produces beta-lactamase; i.e., to detect bacterial resistance. The detection of bacterial resistance can help to avoid overtreatment and treatment errors, thereby improving the efficiency and quality of treatment, reducing the suffering of patients, and reducing the cost of treat-ment. In 2016, Wang et al. [56] proposed an improved method for the synthesis of nitro-cefin in seven steps by using 7-aminocephalosporanic acid (7-ACA) as a starting material (Scheme 16). 7-ACA is a key intermediate for cephalosporins and has been industrialized at a low market price. The new method has a simple operation, an easy reaction, con-venient product purification, a high yield, easy industrialization, and a low production cost.


Nitrendipine is another representative of dihydropyridine derivatives used as acalcium-channel blocker. Recently, a number of studies of nitrendipine analogs havebeen carried out, including studies of their antihypertensive activity [52,53]. In 2011, Zhouet al. reported on the synthesis of nitrendipine analogs based on m-nitrobenzaldehyde. Thetransformations take place according to Scheme 14 below.






NO2

OMe OMe

O O

AcOH, piperidine

NO2

CO2MeMe

O

Me OR

ONH2

EtOH, reflux NH

NO2

Me

MeO2C CO2R

Me





H

O

O2NMe OMe(Et)

O ONH3

NH

CO2Me(Et)MeO2C

Me Me

NO2

CuO (Al2O3)+





The synthesized compounds showed significant antihypertensive activity at the levelof nitrendipine or higher.

Modified synthesis of nifedipine and nitrendipne through a three-component Hantzschreaction has been described under catalysis of either micellar heteropoly acids [54] ornanoscale metal oxides [55] (Scheme 15).





NO2

OMe OMe

O O

AcOH, piperidine

NO2

CO2MeMe

O

Me OR

ONH2

EtOH, reflux NH

NO2

Me

MeO2C CO2R

Me





H

O

O2NMe OMe(Et)

O ONH3

NH

CO2Me(Et)MeO2C

Me Me

NO2

CuO (Al2O3)+





Nitrocefin is a cephalosporin that can be used to detect whether a bacteria producesbeta-lactamase; i.e., to detect bacterial resistance. The detection of bacterial resistancecan help to avoid overtreatment and treatment errors, thereby improving the efficiencyand quality of treatment, reducing the suffering of patients, and reducing the cost oftreatment. In 2016, Wang et al. [56] proposed an improved method for the synthesis ofnitrocefin in seven steps by using 7-aminocephalosporanic acid (7-ACA) as a startingmaterial (Scheme 16). 7-ACA is a key intermediate for cephalosporins and has beenindustrialized at a low market price. The new method has a simple operation, an easyreaction, convenient product purification, a high yield, easy industrialization, and a lowproduction cost.


N

SH2N

O

OHO

O

O

N

SHN

O

OO

OHO

S

Ph Ph

N

SHN

O

OO

BrO

S

Ph Ph

PPh3

AcOEt N

SHN

O

OO

P+Ph3Br-O

S

Ph Ph

CHO

O2N NO2

N

SHN

O

OHO

OS NO2

NO2

PBr3

THF

1.Na2CO3, DCM

+2.TFA, PhOMe, DCM

100%

76%

70%Nitrocefine

7-ACA

Scheme 16. Wang’s synthesis of nitrocefin.

Another important nitro-containing drug described in the last decade is opicapone. This compound was approved for use in 2016, and is prescribed for people with Parkin-son’s disease. Opicapon restores dopamine levels in the parts of the brain responsible for movement and coordination. The synthesis of opicapone and its intermediates has been recently described in a number of patents. Nabold et al. [57] published a new route for the synthesis of opicapone as shown in the following Scheme 17.

N

CNMe

OHMe N

Me

ClMe

ClCl

NOHHO

MeO

NO2

CN

87%

Et3N, toluene, 110oC N

N

ONMe

Cl

Cl

Me

MeO OH

NO2

50%

1. AlCl3, Py, NMP

2. AcOH, H2O2, r.t.

N

N

ONMe

Cl

Cl

Me

HO OH

95%O

opicapone

NO2

Scheme 17. Synthesis of opicapone.

In addition, Sathe et al. patented a process for the preparation of opicapone that overcame the disadvantages of previously known methods [58].

Notably, the structural nitro analogs of opicapone were investigated as selective in-hibitors of the catechol-O-methyltransferase (COMT) enzyme. They were found to have a reduced toxicity risk, and were endowed with a longer duration of inhibition than opi-capone [59].

Phosphate esters have been found in a variety of biological molecules, such as nu-cleic acids, proteins, carbohydrates, lipids, coenzymes and steroids. In this regard, new approaches to the synthesis of their derivatives are relevant and in demand. Paraoxon is one of the representatives of organophosphates; it acts as a cholinesterase inhibitor. During the last decade, several papers were published on new general methods of syn-thesis of organophosphates, including paraoxon. The key reactions are based on the in-teraction of phenols with phosphates and phosphites. The methods differ in the reaction conditions: electrolysis [60], a LiI/TBHP-mediated oxidative cross-coupling reaction [61], or interaction in the presence Tf2O/Py [62] (Scheme 18).


Another important nitro-containing drug described in the last decade is opicapone.This compound was approved for use in 2016, and is prescribed for people with Parkinson’sdisease. Opicapon restores dopamine levels in the parts of the brain responsible formovement and coordination. The synthesis of opicapone and its intermediates has been


recently described in a number of patents. Nabold et al. [57] published a new route for thesynthesis of opicapone as shown in the following Scheme 17.


N

SH2N

O

OHO

O

O

N

SHN

O

OO

OHO

S

Ph Ph

N

SHN

O

OO

BrO

S

Ph Ph

PPh3

AcOEt N

SHN

O

OO

P+Ph3Br-O

S

Ph Ph

CHO

O2N NO2

N

SHN

O

OHO

OS NO2

NO2

PBr3

THF

1.Na2CO3, DCM

+2.TFA, PhOMe, DCM

100%

76%

70%Nitrocefine

7-ACA


Another important nitro-containing drug described in the last decade is opicapone. This compound was approved for use in 2016, and is prescribed for people with Parkin-son’s disease. Opicapon restores dopamine levels in the parts of the brain responsible for movement and coordination. The synthesis of opicapone and its intermediates has been recently described in a number of patents. Nabold et al. [57] published a new route for the synthesis of opicapone as shown in the following Scheme 17.

N

CNMe

OHMe N

Me

ClMe

ClCl

NOHHO

MeO

NO2

CN

87%

Et3N, toluene, 110oC N

N

ONMe

Cl

Cl

Me

MeO OH

NO2

50%

1. AlCl3, Py, NMP

2. AcOH, H2O2, r.t.

N

N

ONMe

Cl

Cl

Me

HO OH

95%O

opicapone

NO2


In addition, Sathe et al. patented a process for the preparation of opicapone that overcame the disadvantages of previously known methods [58].

Notably, the structural nitro analogs of opicapone were investigated as selective in-hibitors of the catechol-O-methyltransferase (COMT) enzyme. They were found to have a reduced toxicity risk, and were endowed with a longer duration of inhibition than opi-capone [59].

Phosphate esters have been found in a variety of biological molecules, such as nu-cleic acids, proteins, carbohydrates, lipids, coenzymes and steroids. In this regard, new approaches to the synthesis of their derivatives are relevant and in demand. Paraoxon is one of the representatives of organophosphates; it acts as a cholinesterase inhibitor. During the last decade, several papers were published on new general methods of syn-thesis of organophosphates, including paraoxon. The key reactions are based on the in-teraction of phenols with phosphates and phosphites. The methods differ in the reaction conditions: electrolysis [60], a LiI/TBHP-mediated oxidative cross-coupling reaction [61], or interaction in the presence Tf2O/Py [62] (Scheme 18).


In addition, Sathe et al. patented a process for the preparation of opicapone thatovercame the disadvantages of previously known methods [58].

Notably, the structural nitro analogs of opicapone were investigated as selectiveinhibitors of the catechol-O-methyltransferase (COMT) enzyme. They were found to havea reduced toxicity risk, and were endowed with a longer duration of inhibition thanopicapone [59].

Phosphate esters have been found in a variety of biological molecules, such as nu-cleic acids, proteins, carbohydrates, lipids, coenzymes and steroids. In this regard, newapproaches to the synthesis of their derivatives are relevant and in demand. Paraoxon isone of the representatives of organophosphates; it acts as a cholinesterase inhibitor. Duringthe last decade, several papers were published on new general methods of synthesis oforganophosphates, including paraoxon. The key reactions are based on the interaction ofphenols with phosphates and phosphites. The methods differ in the reaction conditions:electrolysis [60], a LiI/TBHP-mediated oxidative cross-coupling reaction [61], or interactionin the presence Tf2O/Py [62] (Scheme 18).


HO

NO2PO

OEtOEtH+ i or ii O2N O

PEtO OEt

O

i: LiI, aq. TBHP, MeCN, r.t., 15 min, 95%ii: electrolysis (I= 20mA), MeCN, r.t., air, 87%

HO

NO2PO

OEtOEtEtO +Tf2O, Py

DCM, 10 min

paraoxon85%

Scheme 18. Methods for the synthesis of paraoxon.

In 2020, Jiang et al. published a simple, convenient, and cheap approach to the con-struction of sulfonamides of various natures. This method is based on the direct sul-fonamidation of the corresponding nitroarenes in the presence of boronic acids and so-dium metabisulphite (Scheme 19). It is noteworthy that this method allows the quick and easy synthesis of pharmacologically oriented sulfonamides of both natural and synthetic origins, such as sulfanitran—a sulfonamide antibiotic actively used in the poultry in-dustry to combat coccidioides [63].

Scheme 19. Jiang’s method for the synthesis of sulfanitran.

3. Nitro Heterocycles Along with the nitroarenes discussed above, nitroheterocyclic compounds constitute

another important class of nitrodrugs. Basically, the nitroheterocyclic moiety causes broad-spectrum antibacterial, antiprotozoal, and antiparasitic activities. The widely rec-ognized drugs nitrofural (5-nitro-2-furaldehyde semicarbazone) and metronidazole were initially developed in the 1940–1950s, and their numerous analogs possess an excellent balance between medicinal efficiency and chemical simplicity. However, further chemi-cal modification of approved efficient nitrodrugs may result in a significant decrease in IC50 and/or toxicity values. This section encompasses recent advances in the synthesis of known drugs containing a nitroaromatic heterocyclic skeleton. The main classes of het-erocycles considered are furans and imidazoles. In addition, some miscellaneous heter-ocyclic nitrodrugs of other classes will be discussed.

3.1. Nitrofurans Nitrofurans represent a family of widely used antibacterial and antiparasitic drugs

containing 5-nitro-2-hydrazonylfuran pharmacophore. However, they are usually asso-ciated with a variety of side effects such as hepatotoxicity or gastrointestinal disorders. The mechanisms that generate the cytotoxic effects of nitrofuran drugs are not yet clearly understood. The results obtained recently by Gallardo-Garrido and coworkers [64] sug-gest that the toxic effect of nitrofurans on mammalian cells is caused by the combined 2-hydrazonylfuran moiety, redox cycling of 5-nitrofuran, and inhibitory effects on anti-oxidant enzymes.

Nitrofurantoin (Furantin©) is an antibiotic generally used to treat urinary tract in-fections such as cystitis. Due to a poor solubility of nitrofurantoin in water, efforts have been made to prepare its cocrystals with a number of simple organic conformers: urea, nicotinamide, L-proline, 4-hydroxybenzoic, and citric and vanillic acids [65]. Among all synthesized cocrystals, only two of them were found to be stable in EtOH (urea and L-proline), and a cocrystal of nitrofurantoin with vanillic acid was stable in water. It was concluded that the significantly higher solubility of the conformers used provided co-crystals that were more soluble than the stable form of the drug in water.


In 2020, Jiang et al. published a simple, convenient, and cheap approach to theconstruction of sulfonamides of various natures. This method is based on the directsulfonamidation of the corresponding nitroarenes in the presence of boronic acids andsodium metabisulphite (Scheme 19). It is noteworthy that this method allows the quick andeasy synthesis of pharmacologically oriented sulfonamides of both natural and syntheticorigins, such as sulfanitran—a sulfonamide antibiotic actively used in the poultry industryto combat coccidioides [63].


HO

NO2PO

OEtOEtH+ i or ii O2N O

PEtO OEt

O

i: LiI, aq. TBHP, MeCN, r.t., 15 min, 95%ii: electrolysis (I= 20mA), MeCN, r.t., air, 87%

HO

NO2PO

OEtOEtEtO +Tf2O, Py

DCM, 10 min

paraoxon85%


In 2020, Jiang et al. published a simple, convenient, and cheap approach to the con-struction of sulfonamides of various natures. This method is based on the direct sul-fonamidation of the corresponding nitroarenes in the presence of boronic acids and so-dium metabisulphite (Scheme 19). It is noteworthy that this method allows the quick and easy synthesis of pharmacologically oriented sulfonamides of both natural and synthetic origins, such as sulfanitran—a sulfonamide antibiotic actively used in the poultry in-dustry to combat coccidioides [63].


3. Nitro Heterocycles Along with the nitroarenes discussed above, nitroheterocyclic compounds constitute

another important class of nitrodrugs. Basically, the nitroheterocyclic moiety causes broad-spectrum antibacterial, antiprotozoal, and antiparasitic activities. The widely rec-ognized drugs nitrofural (5-nitro-2-furaldehyde semicarbazone) and metronidazole were initially developed in the 1940–1950s, and their numerous analogs possess an excellent balance between medicinal efficiency and chemical simplicity. However, further chemi-cal modification of approved efficient nitrodrugs may result in a significant decrease in IC50 and/or toxicity values. This section encompasses recent advances in the synthesis of known drugs containing a nitroaromatic heterocyclic skeleton. The main classes of het-erocycles considered are furans and imidazoles. In addition, some miscellaneous heter-ocyclic nitrodrugs of other classes will be discussed.

3.1. Nitrofurans Nitrofurans represent a family of widely used antibacterial and antiparasitic drugs

containing 5-nitro-2-hydrazonylfuran pharmacophore. However, they are usually asso-ciated with a variety of side effects such as hepatotoxicity or gastrointestinal disorders. The mechanisms that generate the cytotoxic effects of nitrofuran drugs are not yet clearly understood. The results obtained recently by Gallardo-Garrido and coworkers [64] sug-gest that the toxic effect of nitrofurans on mammalian cells is caused by the combined 2-hydrazonylfuran moiety, redox cycling of 5-nitrofuran, and inhibitory effects on anti-oxidant enzymes.

Nitrofurantoin (Furantin©) is an antibiotic generally used to treat urinary tract in-fections such as cystitis. Due to a poor solubility of nitrofurantoin in water, efforts have been made to prepare its cocrystals with a number of simple organic conformers: urea, nicotinamide, L-proline, 4-hydroxybenzoic, and citric and vanillic acids [65]. Among all synthesized cocrystals, only two of them were found to be stable in EtOH (urea and L-proline), and a cocrystal of nitrofurantoin with vanillic acid was stable in water. It was concluded that the significantly higher solubility of the conformers used provided co-crystals that were more soluble than the stable form of the drug in water.



3. Nitro Heterocycles

Along with the nitroarenes discussed above, nitroheterocyclic compounds constituteanother important class of nitrodrugs. Basically, the nitroheterocyclic moiety causes broad-spectrum antibacterial, antiprotozoal, and antiparasitic activities. The widely recognizeddrugs nitrofural (5-nitro-2-furaldehyde semicarbazone) and metronidazole were initiallydeveloped in the 1940–1950s, and their numerous analogs possess an excellent balancebetween medicinal efficiency and chemical simplicity. However, further chemical modifica-tion of approved efficient nitrodrugs may result in a significant decrease in IC50 and/ortoxicity values. This section encompasses recent advances in the synthesis of known drugscontaining a nitroaromatic heterocyclic skeleton. The main classes of heterocycles consid-ered are furans and imidazoles. In addition, some miscellaneous heterocyclic nitrodrugs ofother classes will be discussed.

3.1. Nitrofurans

Nitrofurans represent a family of widely used antibacterial and antiparasitic drugs con-taining 5-nitro-2-hydrazonylfuran pharmacophore. However, they are usually associatedwith a variety of side effects such as hepatotoxicity or gastrointestinal disorders. The mech-anisms that generate the cytotoxic effects of nitrofuran drugs are not yet clearly understood.The results obtained recently by Gallardo-Garrido and coworkers [64] suggest that the toxiceffect of nitrofurans on mammalian cells is caused by the combined 2-hydrazonylfuranmoiety, redox cycling of 5-nitrofuran, and inhibitory effects on antioxidant enzymes.

Nitrofurantoin (Furantin©) is an antibiotic generally used to treat urinary tract in-fections such as cystitis. Due to a poor solubility of nitrofurantoin in water, efforts havebeen made to prepare its cocrystals with a number of simple organic conformers: urea,nicotinamide, L-proline, 4-hydroxybenzoic, and citric and vanillic acids [65]. Among all syn-thesized cocrystals, only two of them were found to be stable in EtOH (urea and L-proline),and a cocrystal of nitrofurantoin with vanillic acid was stable in water. It was concludedthat the significantly higher solubility of the conformers used provided cocrystals that weremore soluble than the stable form of the drug in water.

The environmentally benign gram-scale method for the preparation of nitrofurantoinand the myorelaxant dantrolene (Dantrium©), as well as their structural analogs, wasreported by Colacino and coworkers [66]. This novel mechanochemical procedure has anumber of indisputable advantages: solvent-, base-, and waste-free; and high yields withno further purification required. In addition, the elaborated method allows the cost of thesynthesis to be reduced considerably (Scheme 20).


The environmentally benign gram-scale method for the preparation of nitrofu-rantoin and the myorelaxant dantrolene (Dantrium©), as well as their structural analogs, was reported by Colacino and coworkers [66]. This novel mechanochemical procedure has a number of indisputable advantages: solvent-, base-, and waste-free; and high yields with no further purification required. In addition, the elaborated method allows the cost of the synthesis to be reduced considerably (Scheme 20).

NNH

O

OH2N

ArCHON

NH

O

ON

ArHCl

0.25-2 hno solvent

10 examples87-98% yield

NNH

O

ON

OO2N

NNH

O

ON

O

O2N

NNH

O

ON

O2N

90%90%95%Nitrofurantoin Dantrolene

Scheme 20. Gram-scale method for the preparation of nitrofurantoin and dantrolene.

A number of structural analogs of the antimicrobial nifuroxazide were synthesized and tested for antimicrobial activity against a panel of bacteria and the pathogenic fungus Candida albicans [67]. Chemical diversity was achieved by shuffling the substituents in the furan and benzene rings. Most compounds showed activity against Gram-negative bacteria, while only 5-nitrofuran derivatives were active against Candida albicans, thus indicating the crucial role of the nitro group (Scheme 21).

Scheme 21. Synthesis of nifuroxazide analogs.

A simple high-yield method for the synthesis of nitrofural (Furacilin) under the ac-tion of the supported catalyst CuO/CNTs has been patented [68]. An intermediate 5-nitrofurfural was synthesized from furfuryl alcohol used as a raw material through esterification, nitration, deprotection, and oxidation. Then, 5-nitrofurfural and semi-carbazide were subjected to a condensation to give nitrofural. The authors positioned this method as simple to operate and the adopted catalyst as nontoxic, easy to remove, and renewable.

Application of nitrofural as a source of novel semicarbazones with potential anti-bacterial and antifungal activity was recently reported by Fesenko et al. [69]. Reactions of nitrofural with aldehydes and p-toluene sulfinic acid gave N(4)-substituted semicarba-zones, which upon reduction with NaBH4 underwent tosyl group removal (Scheme 22).


A number of structural analogs of the antimicrobial nifuroxazide were synthesizedand tested for antimicrobial activity against a panel of bacteria and the pathogenic fungusCandida albicans [67]. Chemical diversity was achieved by shuffling the substituents inthe furan and benzene rings. Most compounds showed activity against Gram-negative


bacteria, while only 5-nitrofuran derivatives were active against Candida albicans, thusindicating the crucial role of the nitro group (Scheme 21).


The environmentally benign gram-scale method for the preparation of nitrofu-rantoin and the myorelaxant dantrolene (Dantrium©), as well as their structural analogs, was reported by Colacino and coworkers [66]. This novel mechanochemical procedure has a number of indisputable advantages: solvent-, base-, and waste-free; and high yields with no further purification required. In addition, the elaborated method allows the cost of the synthesis to be reduced considerably (Scheme 20).

NNH

O

OH2N

ArCHON

NH

O

ON

ArHCl

0.25-2 hno solvent

10 examples87-98% yield

NNH

O

ON

OO2N

NNH

O

ON

O

O2N

NNH

O

ON

O2N

90%90%95%Nitrofurantoin Dantrolene


A number of structural analogs of the antimicrobial nifuroxazide were synthesized and tested for antimicrobial activity against a panel of bacteria and the pathogenic fungus Candida albicans [67]. Chemical diversity was achieved by shuffling the substituents in the furan and benzene rings. Most compounds showed activity against Gram-negative bacteria, while only 5-nitrofuran derivatives were active against Candida albicans, thus indicating the crucial role of the nitro group (Scheme 21).


A simple high-yield method for the synthesis of nitrofural (Furacilin) under the ac-tion of the supported catalyst CuO/CNTs has been patented [68]. An intermediate 5-nitrofurfural was synthesized from furfuryl alcohol used as a raw material through esterification, nitration, deprotection, and oxidation. Then, 5-nitrofurfural and semi-carbazide were subjected to a condensation to give nitrofural. The authors positioned this method as simple to operate and the adopted catalyst as nontoxic, easy to remove, and renewable.

Application of nitrofural as a source of novel semicarbazones with potential anti-bacterial and antifungal activity was recently reported by Fesenko et al. [69]. Reactions of nitrofural with aldehydes and p-toluene sulfinic acid gave N(4)-substituted semicarba-zones, which upon reduction with NaBH4 underwent tosyl group removal (Scheme 22).


A simple high-yield method for the synthesis of nitrofural (Furacilin) under theaction of the supported catalyst CuO/CNTs has been patented [68]. An intermediate5-nitrofurfural was synthesized from furfuryl alcohol used as a raw material through ester-ification, nitration, deprotection, and oxidation. Then, 5-nitrofurfural and semicarbazidewere subjected to a condensation to give nitrofural. The authors positioned this method assimple to operate and the adopted catalyst as nontoxic, easy to remove, and renewable.

Application of nitrofural as a source of novel semicarbazones with potential antibac-terial and antifungal activity was recently reported by Fesenko et al. [69]. Reactions ofnitrofural with aldehydes and p-toluene sulfinic acid gave N(4)-substituted semicarbazones,which upon reduction with NaBH4 underwent tosyl group removal (Scheme 22).


Scheme 22. Synthesis of new bioactive molecules on the basis of nitrofural.

The obtained compounds showed potent antifungal activity against C. albicans and C. neoformans, with MIC values of 8–32 µg/mL. They also possessed high antibacterial activity against Gram-positive S. aureus (MIC 8–16 µg/mL), Gram-negative E. coli, and A. baumannii (MIC 8–16 µg/mL).

Arylsemicarbazones, including nitrofural and its (N2)-alkyl derivative, were identi-fied as valuable compounds for the development of novel anticancer agents [70]. The synthesis was accomplished starting with 5-nitrofurfural and semicarbazide, followed by alkylation with n-butyl bromide (Scheme 23).

Scheme 23. Synthesis of nitrofural derivative.

The N-butyl compound was found to be active against the K562, HL-60, MOLT-4, HEp-2, NCI-H292, HT-29, and MCF-7 cancer cell lines, and was more cytotoxic for the HL-60 cell line, with an IC50 value of 11.38 µM. It also strongly inhibited the CK1δ/ε ki-nase.

Nifuratel in its racemic form is used in gynecology as an antiprotozoal and anti-fungal agent. It has been reported to have a broad antibacterial spectrum of activity [71]. Several methods for its synthesis suitable for large-scale industrial production were elaborated and patented during the past decade [72–74]. Its general synthetic scheme is presented in Scheme 24.

OO2NN N O

O

S

OCl

H2NNH

SMeOH

(EtO)2CO N

O

H2N

O

SMe

rac-Nifuratel Scheme 24. Synthesis of rac-nifuratel.


The obtained compounds showed potent antifungal activity against C. albicans andC. neoformans, with MIC values of 8–32 µg/mL. They also possessed high antibacterialactivity against Gram-positive S. aureus (MIC 8–16 µg/mL), Gram-negative E. coli, andA. baumannii (MIC 8–16 µg/mL).

Arylsemicarbazones, including nitrofural and its (N2)-alkyl derivative, were identifiedas valuable compounds for the development of novel anticancer agents [70]. The synthesiswas accomplished starting with 5-nitrofurfural and semicarbazide, followed by alkylationwith n-butyl bromide (Scheme 23).








OO2NN N O

O

S

OCl

H2NNH

SMeOH

(EtO)2CO N

O

H2N

O

SMe

rac-Nifuratel Scheme 24. Synthesis of rac-nifuratel.



The N-butyl compound was found to be active against the K562, HL-60, MOLT-4,HEp-2, NCI-H292, HT-29, and MCF-7 cancer cell lines, and was more cytotoxic for theHL-60 cell line, with an IC50 value of 11.38 µM. It also strongly inhibited the CK1δ/ε kinase.

Nifuratel in its racemic form is used in gynecology as an antiprotozoal and antifungalagent. It has been reported to have a broad antibacterial spectrum of activity [71]. Severalmethods for its synthesis suitable for large-scale industrial production were elaboratedand patented during the past decade [72–74]. Its general synthetic scheme is presented inScheme 24.








OO2NN N O

O

S

OCl

H2NNH

SMeOH

(EtO)2CO N

O

H2N

O

SMe

rac-Nifuratel Scheme 24. Synthesis of rac-nifuratel. Scheme 24. Synthesis of rac-nifuratel.

The target compound was obtained at a high yield with excellent purity.Optically pure (R)-nifuratel was found to possess a better antimicrobial activity than

(S)-enantiomer or racemate [75]. The authors reported on the synthesis of both (R)- and(S)-nifuratel starting with the corresponding oxiranes. This method allows the resolutionof the racemic compound to be avoided (Scheme 25).


The target compound was obtained at a high yield with excellent purity. Optically pure (R)-nifuratel was found to possess a better antimicrobial activity than

(S)-enantiomer or racemate [75]. The authors reported on the synthesis of both (R)- and (S)-nifuratel starting with the corresponding oxiranes. This method allows the resolution of the racemic compound to be avoided (Scheme 25).

Scheme 25. Synthesis of enantiomerically pure (R)- and (S)-nifuratel.

3.2. 2-Nitroimidazoles Misonidazole was considered as a radiosensitizer used in radiotherapy to cause

normally resistant hypoxic tumor cells to become sensitive to the treatment [76]. It was also reported to possess potent inhibitory activity against glutathione peroxidase (GPX) from mouse liver [77]. The above-mentioned properties relate to racemic misonidazole, while two (R)- and (S)-enantiomers were synthesized independently and tested in vitro on bovine erythrocyte GPx-1 [78]. Synthesis was started with 2-aminoimidazole hemi-sulfate using enentiomerically pure epoxides in the second step (Scheme 26).

Scheme 26. Synthesis of (R)- and (S)-misonodazole.

However, the authors did not detect any significant inhibitory activity on the bovine enzyme for either isomer.

A fluorinated analog of misonidazole, namely fluoromisanidazole (FMISO) in its 18F-labeled form, is used as a radiopharmaceutical for PET imaging of hypoxia [79]. A number of synthetic approaches to 18F-fluoromisonidazole and its unlabeled derivative have been developed during the last decade. Several 1-alkyl-2-nitroimidazoles were used as starting materials, such as 1-(2,3-dihydroxypropyl)-2-nitroimidazole [80] (Scheme 27).


3.2. 2-Nitroimidazoles

Misonidazole was considered as a radiosensitizer used in radiotherapy to causenormally resistant hypoxic tumor cells to become sensitive to the treatment [76]. It wasalso reported to possess potent inhibitory activity against glutathione peroxidase (GPX)from mouse liver [77]. The above-mentioned properties relate to racemic misonidazole,while two (R)- and (S)-enantiomers were synthesized independently and tested in vitro onbovine erythrocyte GPx-1 [78]. Synthesis was started with 2-aminoimidazole hemisulfateusing enentiomerically pure epoxides in the second step (Scheme 26).



The target compound was obtained at a high yield with excellent purity. Optically pure (R)-nifuratel was found to possess a better antimicrobial activity than

(S)-enantiomer or racemate [75]. The authors reported on the synthesis of both (R)- and (S)-nifuratel starting with the corresponding oxiranes. This method allows the resolution of the racemic compound to be avoided (Scheme 25).


3.2. 2-Nitroimidazoles Misonidazole was considered as a radiosensitizer used in radiotherapy to cause

normally resistant hypoxic tumor cells to become sensitive to the treatment [76]. It was also reported to possess potent inhibitory activity against glutathione peroxidase (GPX) from mouse liver [77]. The above-mentioned properties relate to racemic misonidazole, while two (R)- and (S)-enantiomers were synthesized independently and tested in vitro on bovine erythrocyte GPx-1 [78]. Synthesis was started with 2-aminoimidazole hemi-sulfate using enentiomerically pure epoxides in the second step (Scheme 26).


However, the authors did not detect any significant inhibitory activity on the bovine enzyme for either isomer.

A fluorinated analog of misonidazole, namely fluoromisanidazole (FMISO) in its 18F-labeled form, is used as a radiopharmaceutical for PET imaging of hypoxia [79]. A number of synthetic approaches to 18F-fluoromisonidazole and its unlabeled derivative have been developed during the last decade. Several 1-alkyl-2-nitroimidazoles were used as starting materials, such as 1-(2,3-dihydroxypropyl)-2-nitroimidazole [80] (Scheme 27).


However, the authors did not detect any significant inhibitory activity on the bovineenzyme for either isomer.

A fluorinated analog of misonidazole, namely fluoromisanidazole (FMISO) in its18F-labeled form, is used as a radiopharmaceutical for PET imaging of hypoxia [79]. Anumber of synthetic approaches to 18F-fluoromisonidazole and its unlabeled derivativehave been developed during the last decade. Several 1-alkyl-2-nitroimidazoles were usedas starting materials, such as 1-(2,3-dihydroxypropyl)-2-nitroimidazole [80] (Scheme 27).


Scheme 27. Synthesis of FMISO.

A similar fluorination procedure was applied to the intermediates bearing other protective groups instead of THP, such as acetyl [81], TBDMS, and ethoxyethyl [82].

Preparation of enantiomerically enriched [18F]FMISO via transition-metal-mediated enantioselective radiofluorination of epoxides and further kinetic resolution was also reported [83,84].

A route excluding the deprotection step was reported by Doyle et al. [85]. An enan-tioselective ring opening of a nitroimidazole-substituted epoxide with benzoyl fluo-ride/HFIP as a fluorine source in the presence of a (salen)Co catalyst and DBN gave un-labeled FMISO at a 40% yield and 93% ee (Scheme 28).

Scheme 28. Synthesis of unlabeled FMISO.

Another efficient approach to both enantiopure (R)- and (S)-fluoromesonidazole was described by Borzecka et al. [86]. The first step uses microwave-assisted alkylation of 2-nitroimidazole with 1-chloro-3-fluoropropan-2-one to give intermediate fluoroketone. The ketone was involved in the bioreduction catalyzed by two alcohol dehydrogenases: from Lactobacillus brevis (LBADH) and Escherichia coli (E. coli/ADH-A), respectively af-fording enantiopure (S)- and (R)-FMISO (Scheme 29).

Scheme 29. Borzecka’s synthesis of enantiopure (R)- and (S)-fluoromesonidazole.

Evofosfamide, one more 2-nitroimidazole derivative, is a hypoxia-activated pro-drug that is considered for cancer treatment. It was synthesized, and its cytotoxicity was evaluated in PC-3 and DU145 human prostate cancer cell lines [87]. Reaction of phos-


A similar fluorination procedure was applied to the intermediates bearing otherprotective groups instead of THP, such as acetyl [81], TBDMS, and ethoxyethyl [82].

Preparation of enantiomerically enriched [18F]FMISO via transition-metal-mediatedenantioselective radiofluorination of epoxides and further kinetic resolution was alsoreported [83,84].

A route excluding the deprotection step was reported by Doyle et al. [85]. An enantios-elective ring opening of a nitroimidazole-substituted epoxide with benzoyl fluoride/HFIPas a fluorine source in the presence of a (salen)Co catalyst and DBN gave unlabeled FMISOat a 40% yield and 93% ee (Scheme 28).












Another efficient approach to both enantiopure (R)- and (S)-fluoromesonidazole wasdescribed by Borzecka et al. [86]. The first step uses microwave-assisted alkylation of 2-nitroimidazole with 1-chloro-3-fluoropropan-2-one to give intermediate fluoroketone. Theketone was involved in the bioreduction catalyzed by two alcohol dehydrogenases: fromLactobacillus brevis (LBADH) and Escherichia coli (E. coli/ADH-A), respectively affordingenantiopure (S)- and (R)-FMISO (Scheme 29).











Evofosfamide, one more 2-nitroimidazole derivative, is a hypoxia-activated prodrugthat is considered for cancer treatment. It was synthesized, and its cytotoxicity was eval-uated in PC-3 and DU145 human prostate cancer cell lines [87]. Reaction of phosphorusoxychloride with 2-bromoethylamine resulted in intermediate dibromide, which uponreaction with 5-hydroxymethyl-1-methyl-2-nitroimidazole, gave evofosfamide at an 11.7%total yield (Scheme 30).


phorus oxychloride with 2-bromoethylamine resulted in intermediate dibromide, which upon reaction with 5-hydroxymethyl-1-methyl-2-nitroimidazole, gave evofosfamide at an 11.7% total yield (Scheme 30).

Scheme 30. Synthesis of evofosfamide.

The authors found that evofosfamide demonstrated an increased cytotoxicity in both cell lines under hypoxic conditions relative to normoxic conditions, while a lower hypoxia selectivity in PC-3 cells relative to DU145 cells was revealed. A related method for the synthesis of evofosfamide has been recently reported [88]. The difference lies in the use of N,N’-bis(2-bromoethyl)phosphorodiamidic acid as an intermediate in place of the above-mentioned chloride.

3.3. 4(5)-Nitroimidazoles Isomeric 4(5)-nitroimidazoles are frequently applied as efficient drugs. An example

is azathioprine (Imuran), an immunosuppressant used in rheumatoid arthritis and many other conditions, including in kidney transplants, to prevent rejection. It was first syn-thesized in 1957, and since that time some efforts have been made to improve the syn-thetic route. The most recent publication reported on the use of a Pd/PTABS (7-phospha-1,3,5-triaza-admantane butane sulfonate) system to link thiopurine to the ni-troimidazole moiety [89] (Scheme 31).

Scheme 31. Synthesis of azathioprine.

An efficient method for the synthesis of the antituberculosis drug delamanid and VL-2098, an antileishmanial lead candidate, was proposed by Sharma and coworkers [90]. These two related compounds incorporate a nitroimidazooxazole skeleton, which can be constructed via the nucleophilic ring opening of the chiral epoxide followed by intramolecular base-promoted cyclization (Scheme 32).


The authors found that evofosfamide demonstrated an increased cytotoxicity in bothcell lines under hypoxic conditions relative to normoxic conditions, while a lower hypoxiaselectivity in PC-3 cells relative to DU145 cells was revealed. A related method for thesynthesis of evofosfamide has been recently reported [88]. The difference lies in the use ofN,N′-bis(2-bromoethyl)phosphorodiamidic acid as an intermediate in place of the above-mentioned chloride.

3.3. 4(5)-Nitroimidazoles

Isomeric 4(5)-nitroimidazoles are frequently applied as efficient drugs. An exam-ple is azathioprine (Imuran), an immunosuppressant used in rheumatoid arthritis andmany other conditions, including in kidney transplants, to prevent rejection. It was firstsynthesized in 1957, and since that time some efforts have been made to improve the syn-thetic route. The most recent publication reported on the use of a Pd/PTABS (7-phospha-1,3,5-triaza-admantane butane sulfonate) system to link thiopurine to the nitroimidazolemoiety [89] (Scheme 31).

An efficient method for the synthesis of the antituberculosis drug delamanid andVL-2098, an antileishmanial lead candidate, was proposed by Sharma and coworkers [90].These two related compounds incorporate a nitroimidazooxazole skeleton, which can beconstructed via the nucleophilic ring opening of the chiral epoxide followed by intramolec-ular base-promoted cyclization (Scheme 32).



phorus oxychloride with 2-bromoethylamine resulted in intermediate dibromide, which upon reaction with 5-hydroxymethyl-1-methyl-2-nitroimidazole, gave evofosfamide at an 11.7% total yield (Scheme 30).


The authors found that evofosfamide demonstrated an increased cytotoxicity in both cell lines under hypoxic conditions relative to normoxic conditions, while a lower hypoxia selectivity in PC-3 cells relative to DU145 cells was revealed. A related method for the synthesis of evofosfamide has been recently reported [88]. The difference lies in the use of N,N’-bis(2-bromoethyl)phosphorodiamidic acid as an intermediate in place of the above-mentioned chloride.

3.3. 4(5)-Nitroimidazoles Isomeric 4(5)-nitroimidazoles are frequently applied as efficient drugs. An example

is azathioprine (Imuran), an immunosuppressant used in rheumatoid arthritis and many other conditions, including in kidney transplants, to prevent rejection. It was first syn-thesized in 1957, and since that time some efforts have been made to improve the syn-thetic route. The most recent publication reported on the use of a Pd/PTABS (7-phospha-1,3,5-triaza-admantane butane sulfonate) system to link thiopurine to the ni-troimidazole moiety [89] (Scheme 31).


An efficient method for the synthesis of the antituberculosis drug delamanid and VL-2098, an antileishmanial lead candidate, was proposed by Sharma and coworkers [90]. These two related compounds incorporate a nitroimidazooxazole skeleton, which can be constructed via the nucleophilic ring opening of the chiral epoxide followed by intramolecular base-promoted cyclization (Scheme 32).



N

N OO2N O

OCF3

VL-20986 steps, 36% overall yield

N

N OO2N O

N

Delamanid7steps, 26.5% overall yield

O

OCF3

O

OCF3

OHO

OCF3

NH

NO2N

BrDIPEA, 110oC, 2 h

NN HO

O2N O

OCF3

Br

Cs2CO3, DMF

50oC, 2 h

O

N

O

OCF3

O

Scheme 32. Sharma’s method for the synthesis of delamanid.

The elaborated strategy avoids the use of protecting groups and provides the op-portunity for the synthesis of opposite enantiomers. Several other routes to (R)- and (S)-delamanid and their analogs using chiral intermediates have been reported recently by the same authors [91] and others [92].

Another antibiotic medication used for the treatment of drug-resistant tuberculosis is known as pretomanid (PA-824). A new efficient and sustainable protocol for the syn-thesis of PA-824 was developed in 2020 [93]. The interaction of 2-chloro-4(5)-nitroimidazole with (S)-epichlorohydrin followed by hydrolysis and pri-mary alcohol protection gave the key intermediate. Further O-alkylation, deprotection, and base-mediated cyclization afforded the (S)-enantiomer of PA-824 at a high yield (Scheme 33).

Scheme 33. Synthetic scheme for pretomanid.

On the other hand, (R)-PA-824 was found to be inactive against M. tuberculosis, but showed potent activity against Leishmania donovani. The (R)-isomer was found to be 6-fold more active than (S)-PA-824 [94]. The synthesis was accomplished using a se-quence similar to the one indicated above: starting with chiral O-protected epoxide and 2-bromo-4(5)-nitroimidazole, the intermediate secondary alcohol was involved in alkyl-ation, deprotection, and base-promoted intramolecular cyclization to give the target compound at a 7% total yield (Scheme 34).


The elaborated strategy avoids the use of protecting groups and provides the op-portunity for the synthesis of opposite enantiomers. Several other routes to (R)- and(S)-delamanid and their analogs using chiral intermediates have been reported recently bythe same authors [91] and others [92].

Another antibiotic medication used for the treatment of drug-resistant tuberculosis isknown as pretomanid (PA-824). A new efficient and sustainable protocol for the synthesisof PA-824 was developed in 2020 [93]. The interaction of 2-chloro-4(5)-nitroimidazole with(S)-epichlorohydrin followed by hydrolysis and primary alcohol protection gave the keyintermediate. Further O-alkylation, deprotection, and base-mediated cyclization affordedthe (S)-enantiomer of PA-824 at a high yield (Scheme 33).


N

N OO2N O

OCF3

VL-20986 steps, 36% overall yield

N

N OO2N O

N

Delamanid7steps, 26.5% overall yield

O

OCF3

O

OCF3

OHO

OCF3

NH

NO2N

BrDIPEA, 110oC, 2 h

NN HO

O2N O

OCF3

Br

Cs2CO3, DMF

50oC, 2 h

O

N

O

OCF3

O


The elaborated strategy avoids the use of protecting groups and provides the op-portunity for the synthesis of opposite enantiomers. Several other routes to (R)- and (S)-delamanid and their analogs using chiral intermediates have been reported recently by the same authors [91] and others [92].

Another antibiotic medication used for the treatment of drug-resistant tuberculosis is known as pretomanid (PA-824). A new efficient and sustainable protocol for the syn-thesis of PA-824 was developed in 2020 [93]. The interaction of 2-chloro-4(5)-nitroimidazole with (S)-epichlorohydrin followed by hydrolysis and pri-mary alcohol protection gave the key intermediate. Further O-alkylation, deprotection, and base-mediated cyclization afforded the (S)-enantiomer of PA-824 at a high yield (Scheme 33).


On the other hand, (R)-PA-824 was found to be inactive against M. tuberculosis, but showed potent activity against Leishmania donovani. The (R)-isomer was found to be 6-fold more active than (S)-PA-824 [94]. The synthesis was accomplished using a se-quence similar to the one indicated above: starting with chiral O-protected epoxide and 2-bromo-4(5)-nitroimidazole, the intermediate secondary alcohol was involved in alkyl-ation, deprotection, and base-promoted intramolecular cyclization to give the target compound at a 7% total yield (Scheme 34).


On the other hand, (R)-PA-824 was found to be inactive against M. tuberculosis,but showed potent activity against Leishmania donovani. The (R)-isomer was foundto be 6-fold more active than (S)-PA-824 [94]. The synthesis was accomplished using a


sequence similar to the one indicated above: starting with chiral O-protected epoxide and 2-bromo-4(5)-nitroimidazole, the intermediate secondary alcohol was involved in alkylation,deprotection, and base-promoted intramolecular cyclization to give the target compoundat a 7% total yield (Scheme 34).


Scheme 34. Synthesis of (R)-PA-824.

Gram-scale synthesis of pretomanid has been developed using a highly enantiose-lective addition of TMSBr to 3-alksoxyoxetan promoted by a chiral squaramide catalyst [95]. The resulting bromide was then reacted with 2-chloro-4-nitroimidazole to give an N-alkylation product, which was deprotected and cyclized in a one-pot procedure. The total yield of the recrystallized product was 34% over three steps (Scheme 35).

Scheme 35. Gram-scale enantioselective synthesis of pretomanid.

Other related examples of the synthesis of PA-824 and its analogs also have been reported [96,97].

A new class of membrane-associated carbonic anhydrase IX (CA IX) inhibitors con-taining a 2- and 5-nitroimidazole fragment along with a sulfonamide moiety was syn-thesized and tested in vitro by Rami and coworkers [98]. The target compounds were obtained via alkylation of 2-nitroimidazole followed by reactions with amines containing an aromatic sulfonamide group or reactions of 1-(2-aminoethyl)-2-methyl-5-nitroimidazole with rhodanobenzenes or chlorosulfonyl isocyanate (Scheme 36).

Scheme 36. Synthesis of new class of membrane-associated carbonic anhydrase IX (CA IX) inhibi-tors.

Most of the synthesized compounds were found to inhibit CA IX and XII isoforms in nanomolar concentrations.


Gram-scale synthesis of pretomanid has been developed using a highly enantioselec-tive addition of TMSBr to 3-alksoxyoxetan promoted by a chiral squaramide catalyst [95].The resulting bromide was then reacted with 2-chloro-4-nitroimidazole to give an N-alkylation product, which was deprotected and cyclized in a one-pot procedure. The totalyield of the recrystallized product was 34% over three steps (Scheme 35).










Other related examples of the synthesis of PA-824 and its analogs also have beenreported [96,97].

A new class of membrane-associated carbonic anhydrase IX (CA IX) inhibitors contain-ing a 2- and 5-nitroimidazole fragment along with a sulfonamide moiety was synthesizedand tested in vitro by Rami and coworkers [98]. The target compounds were obtainedvia alkylation of 2-nitroimidazole followed by reactions with amines containing an aro-matic sulfonamide group or reactions of 1-(2-aminoethyl)-2-methyl-5-nitroimidazole withrhodanobenzenes or chlorosulfonyl isocyanate (Scheme 36).









Scheme 36. Synthesis of new class of membrane-associated carbonic anhydrase IX (CA IX) inhibitors.

Most of the synthesized compounds were found to inhibit CA IX and XII isoforms innanomolar concentrations.


Fexinidazole and its structural analogs were synthesized on a basis of readily available4(5)-nitroimidazoles [99] (Scheme 37). The compounds were tested for their activity againsthuman African trypanosomiasis caused by Trypanosoma brucei. In vitro testing showedpotent activity of the pyridine analog of fexinidazole against T. brucei with a low cytotoxicity.


Fexinidazole and its structural analogs were synthesized on a basis of readily available 4(5)-nitroimidazoles [99] (Scheme 37). The compounds were tested for their ac-tivity against human African trypanosomiasis caused by Trypanosoma brucei. In vitro testing showed potent activity of the pyridine analog of fexinidazole against T. brucei with a low cytotoxicity.

Scheme 37. Synthesis of fexinidazole and its analogs.

A new and interesting synthesis of fexinidazole and nitazoxanide (a broad-spectrum antiparasitic and antiviral medication) was published in 2015 [100]. The key feature of this synthetic route deals with ipso-nitration of the imidazole- or thia-zole-5-carboxylic acid. An efficient novel reagent representing a mixture of nitronium tetrafluoroborate and silver carbonate was used by the authors in the synthesis of a wide range of aromatic nitro compounds, including some that were pharmaceutically oriented (Scheme 38).

Scheme 38. The key step in synthesis of fexinidazole and nitazoxanide.

Metronidazole is an antibiotic that is used for treatment of a wide range of bacterial infections, as well as trichomoniasis. Recently, Zeb et al. reported on the synthesis of metronidazole esters as a new class of antiglycation agents [101]. Reactions of metroni-dazole with substituted benzoic or hetarene carboxylic acids in the presence of DCC and DMAP gave corresponding esters in moderate to high yields (Scheme 39). Some of the synthesized compounds were found to be more potent as antiglycation agents than metronidazole itself.


A new and interesting synthesis of fexinidazole and nitazoxanide (a broad-spectrumantiparasitic and antiviral medication) was published in 2015 [100]. The key feature ofthis synthetic route deals with ipso-nitration of the imidazole- or thiazole-5-carboxylicacid. An efficient novel reagent representing a mixture of nitronium tetrafluoroborate andsilver carbonate was used by the authors in the synthesis of a wide range of aromatic nitrocompounds, including some that were pharmaceutically oriented (Scheme 38).


Fexinidazole and its structural analogs were synthesized on a basis of readily available 4(5)-nitroimidazoles [99] (Scheme 37). The compounds were tested for their ac-tivity against human African trypanosomiasis caused by Trypanosoma brucei. In vitro testing showed potent activity of the pyridine analog of fexinidazole against T. brucei with a low cytotoxicity.


A new and interesting synthesis of fexinidazole and nitazoxanide (a broad-spectrum antiparasitic and antiviral medication) was published in 2015 [100]. The key feature of this synthetic route deals with ipso-nitration of the imidazole- or thia-zole-5-carboxylic acid. An efficient novel reagent representing a mixture of nitronium tetrafluoroborate and silver carbonate was used by the authors in the synthesis of a wide range of aromatic nitro compounds, including some that were pharmaceutically oriented (Scheme 38).


Metronidazole is an antibiotic that is used for treatment of a wide range of bacterial infections, as well as trichomoniasis. Recently, Zeb et al. reported on the synthesis of metronidazole esters as a new class of antiglycation agents [101]. Reactions of metroni-dazole with substituted benzoic or hetarene carboxylic acids in the presence of DCC and DMAP gave corresponding esters in moderate to high yields (Scheme 39). Some of the synthesized compounds were found to be more potent as antiglycation agents than metronidazole itself.


Metronidazole is an antibiotic that is used for treatment of a wide range of bacterialinfections, as well as trichomoniasis. Recently, Zeb et al. reported on the synthesis ofmetronidazole esters as a new class of antiglycation agents [101]. Reactions of metron-idazole with substituted benzoic or hetarene carboxylic acids in the presence of DCCand DMAP gave corresponding esters in moderate to high yields (Scheme 39). Some ofthe synthesized compounds were found to be more potent as antiglycation agents thanmetronidazole itself.

Pharmaceuticals 2022, 15, 705 17 of 24Pharmaceuticals 2022, 15, x FOR PEER REVIEW 18 of 25

Scheme 39. Synthesis of metronidazole derivatives.

Development of environmentally friendly methods for the synthesis of the parent metronidazole also has been reported [102,103].

The increased resistance of T. vaginalis, which causes trichomoniasis, to metronida-zole encouraged the study of new, more efficient analogs. Mandalapu and coworkers [104] synthesized a library of 4(5)-nitroimidazole derivatives and evaluated their efficacy against T. vaginalis. The synthetic scheme comprised a reaction of 2-methyl-4(5)-nitroimidazole with epichlorohydrin, epoxide formation, and its succes-sive ring opening with a variety of substituted amines or carbamodithiolates (Scheme 40). Most of the target compounds showed higher activity as compared with metronidazole.

NH

NMeO2N

N

N Me

O2N O

1. Epichlorohydrin, AlCl3, 0oC2. NaOH, H2O/CH2Cl2

N

N Me

O2NOH

NR2

R1R1R2NH

N

N Me

O2NOH

S

S

NR2

R1

KS

S

NR2

R1

72%

68-91%

40-85%

Scheme 40. Synthesis of metronidazole analogs.

Secnidazole is a structural analog of metronidazole used to treat vaginal infections caused by bacteria and protozoa. A series of secnidazole esters were synthesized and screened for their activities as novel enzyme inhibitors [105]. The synthesis was carried out according to a CDI-mediated coupling procedure for a wide range of substituted benzoic acids and racemic secnidazole as a partner. This protocol provided high yields of the target compounds and had an easy work-up (Scheme 41). Many of obtained com-pounds showed potent inhibitory activity against hCA, AChE, BChE, and α-glucosidase.

Scheme 41. Synthesis of secnidazole esters.

Tinidazole is widely known as a treatment for a variety of anaerobic amoebic and bacterial infections. It is also a member of the nitroimidazole antibiotic class. Over the past decade, efforts have been made to improve the preparation of tinidazole salts in order to enhance their solubility and antibacterial activity [106,107]. In addition, Li and


Development of environmentally friendly methods for the synthesis of the parentmetronidazole also has been reported [102,103].

The increased resistance of T. vaginalis, which causes trichomoniasis, to metronidazoleencouraged the study of new, more efficient analogs. Mandalapu and coworkers [104]synthesized a library of 4(5)-nitroimidazole derivatives and evaluated their efficacy againstT. vaginalis. The synthetic scheme comprised a reaction of 2-methyl-4(5)-nitroimidazolewith epichlorohydrin, epoxide formation, and its successive ring opening with a varietyof substituted amines or carbamodithiolates (Scheme 40). Most of the target compoundsshowed higher activity as compared with metronidazole.





NH

NMeO2N

N

N Me

O2N O


N

N Me

O2NOH

NR2

R1R1R2NH

N

N Me

O2NOH

S

S

NR2

R1

KS

S

NR2

R1

72%

68-91%

40-85%






Secnidazole is a structural analog of metronidazole used to treat vaginal infectionscaused by bacteria and protozoa. A series of secnidazole esters were synthesized andscreened for their activities as novel enzyme inhibitors [105]. The synthesis was carried outaccording to a CDI-mediated coupling procedure for a wide range of substituted benzoicacids and racemic secnidazole as a partner. This protocol provided high yields of the targetcompounds and had an easy work-up (Scheme 41). Many of obtained compounds showedpotent inhibitory activity against hCA, AChE, BChE, and α-glucosidase.





NH

NMeO2N

N

N Me

O2N O


N

N Me

O2NOH

NR2

R1R1R2NH

N

N Me

O2NOH

S

S

NR2

R1

KS

S

NR2

R1

72%

68-91%

40-85%






Tinidazole is widely known as a treatment for a variety of anaerobic amoebic andbacterial infections. It is also a member of the nitroimidazole antibiotic class. Over the pastdecade, efforts have been made to improve the preparation of tinidazole salts in order toenhance their solubility and antibacterial activity [106,107]. In addition, Li and coworkersreported on tinidazole synthesis using selective late-stage oxygenation of the correspondingsulfide with ground-state oxygen under ambient conditions [108] (Scheme 42).



coworkers reported on tinidazole synthesis using selective late-stage oxygenation of the corresponding sulfide with ground-state oxygen under ambient conditions [108] (Scheme 42).

Scheme 42. Li’s improved method for the synthesis of tinidazole.

The above-mentioned procedure was also applied in the synthesis of other sulfox-ide- and sulfone-containing pharmaceuticals, such as omeprazole, fulvestrant, sulindac, and others.

3.4. Miscelanous nitroheterocycles The nitrofurans and nitroimidazoles discussed in this chapter form the basis of het-

eroarene nitrodrugs. However, representatives of some other heterocyclic classes should be considered. For example, Shin et al. reported on the synthesis and structure–activity relationship study of 5-nitrothiophene derivatives [109]. A recently identified nonpor-phyrin synthetic ligand for Rev-erbα, GSK4112/SR6452, was taken as the lead, and a number of its analogs were synthesized via reductive amination of 5-nitrothiophene-2-carbaldehyde with 4-chlorobenzylamine in the presence of sodium triacetoxyborohydride, followed by alkylation and protective group exchange. As a re-sult, the authors were able to greatly improve the efficacy and potency of compounds in this series when compared to GSK4112/SR6452 (Scheme 43).

Scheme 43. Synthesis of 5-nitrothiophene derivatives.

Halicin, a 5-nitrothiazole derivative, was originally tested as an enzyme c-Jun N-terminal kinase (JNK) inhibitor [110], and was considered for treatment of diabetes; however, later it showed rather poor results. It was synthesized at a 68% yield through a nucleophilic substitution of bromine in 2-bromo5-nitrothiazole with thiol (Scheme 44).


The above-mentioned procedure was also applied in the synthesis of other sulfoxide-and sulfone-containing pharmaceuticals, such as omeprazole, fulvestrant, sulindac, and others.

3.4. Miscelanous Nitroheterocycles

The nitrofurans and nitroimidazoles discussed in this chapter form the basis of het-eroarene nitrodrugs. However, representatives of some other heterocyclic classes should beconsidered. For example, Shin et al. reported on the synthesis and structure–activity rela-tionship study of 5-nitrothiophene derivatives [109]. A recently identified nonporphyrinsynthetic ligand for Rev-erbα, GSK4112/SR6452, was taken as the lead, and a number of itsanalogs were synthesized via reductive amination of 5-nitrothiophene-2-carbaldehyde with4-chlorobenzylamine in the presence of sodium triacetoxyborohydride, followed by alkyla-tion and protective group exchange. As a result, the authors were able to greatly improvethe efficacy and potency of compounds in this series when compared to GSK4112/SR6452(Scheme 43).


coworkers reported on tinidazole synthesis using selective late-stage oxygenation of the corresponding sulfide with ground-state oxygen under ambient conditions [108] (Scheme 42).


The above-mentioned procedure was also applied in the synthesis of other sulfox-ide- and sulfone-containing pharmaceuticals, such as omeprazole, fulvestrant, sulindac, and others.

3.4. Miscelanous nitroheterocycles The nitrofurans and nitroimidazoles discussed in this chapter form the basis of het-

eroarene nitrodrugs. However, representatives of some other heterocyclic classes should be considered. For example, Shin et al. reported on the synthesis and structure–activity relationship study of 5-nitrothiophene derivatives [109]. A recently identified nonpor-phyrin synthetic ligand for Rev-erbα, GSK4112/SR6452, was taken as the lead, and a number of its analogs were synthesized via reductive amination of 5-nitrothiophene-2-carbaldehyde with 4-chlorobenzylamine in the presence of sodium triacetoxyborohydride, followed by alkylation and protective group exchange. As a re-sult, the authors were able to greatly improve the efficacy and potency of compounds in this series when compared to GSK4112/SR6452 (Scheme 43).


Halicin, a 5-nitrothiazole derivative, was originally tested as an enzyme c-Jun N-terminal kinase (JNK) inhibitor [110], and was considered for treatment of diabetes; however, later it showed rather poor results. It was synthesized at a 68% yield through a nucleophilic substitution of bromine in 2-bromo5-nitrothiazole with thiol (Scheme 44).


Halicin, a 5-nitrothiazole derivative, was originally tested as an enzyme c-Jun N-terminal kinase (JNK) inhibitor [110], and was considered for treatment of diabetes; how-ever, later it showed rather poor results. It was synthesized at a 68% yield through anucleophilic substitution of bromine in 2-bromo5-nitrothiazole with thiol (Scheme 44).


N N

SH2N SHS

NBr

NO2

MeONaMeOH, rt N N

SH2N SS

N

NO2Halicin, 68% yield

Scheme 44. Synthesis of halicin.

Later, halicin was predicted as an antibacterial molecule, and showed broad-spectrum antibiotic activities in mice [111].

The non-nucleoside broad-spectrum antiviral drug triazavirin was originally de-veloped as a potential treatment for influenza [112]. Later, it was investigated for other potential applications against virus infections. During the COVID-19 pandemic, it was tested against SARS-CoV-2 [113]. A synthesis of triazavirin was carried out at the multi-gram scale by Voinkov and coworkers [114] using an in situ formation of 1,2,4-triazolyl diazonium salt and its azo-coupling with ethyl nitroacetate in basic media (Scheme 45).

Scheme 45. Multigram synthesis of triazavirin.

The introduction of stable isotopes such as 2H or 15N into the structures of drug candidates is an important and efficient approach to their detection by spectroscopic methods during the study of pharmacokinetics and metabolism. For this purpose, a number of labeled triazavirin molecules were synthesized recently using labeled simple starting compounds [115,116] (Scheme 46).

Scheme 46. Synthesis of labeled triazavirin derivatives.

4. Conclusions One of the goals of this review was to show the continuing interest in nitro com-

pounds and their uses as biologically active compounds (drugs). The opinion that the nitro group negatively affects potential beneficial biological activity, and that the only possible area of application for nitro-containing molecules is compounds with special properties (explosives, energetic materials), was quite common among researchers. However, this is not the case. Many drugs that have been actively used for several dec-ades have been created on the basis of compounds containing a nitro group. An analysis of the literature for only the last 10 years showed that the chemistry of nitro compounds is actively developing: syntheses of already-known compounds are being improved and optimized, new syntheses are being published, and new nitro-containing drugs are being



Later, halicin was predicted as an antibacterial molecule, and showed broad-spectrumantibiotic activities in mice [111].

The non-nucleoside broad-spectrum antiviral drug triazavirin was originally devel-oped as a potential treatment for influenza [112]. Later, it was investigated for otherpotential applications against virus infections. During the COVID-19 pandemic, it wastested against SARS-CoV-2 [113]. A synthesis of triazavirin was carried out at the multi-gram scale by Voinkov and coworkers [114] using an in situ formation of 1,2,4-triazolyldiazonium salt and its azo-coupling with ethyl nitroacetate in basic media (Scheme 45).


N N

SH2N SHS

NBr

NO2

MeONaMeOH, rt N N

SH2N SS

N











The introduction of stable isotopes such as 2H or 15N into the structures of drugcandidates is an important and efficient approach to their detection by spectroscopicmethods during the study of pharmacokinetics and metabolism. For this purpose, anumber of labeled triazavirin molecules were synthesized recently using labeled simplestarting compounds [115,116] (Scheme 46).


N N

SH2N SHS

NBr

NO2

MeONaMeOH, rt N N

SH2N SS

N











4. Conclusions

One of the goals of this review was to show the continuing interest in nitro compoundsand their uses as biologically active compounds (drugs). The opinion that the nitro groupnegatively affects potential beneficial biological activity, and that the only possible area ofapplication for nitro-containing molecules is compounds with special properties (explosives,energetic materials), was quite common among researchers. However, this is not the case.Many drugs that have been actively used for several decades have been created on thebasis of compounds containing a nitro group. An analysis of the literature for only the last10 years showed that the chemistry of nitro compounds is actively developing: synthesesof already-known compounds are being improved and optimized, new syntheses arebeing published, and new nitro-containing drugs are being created. Thus, the field ofchemistry associated with the synthesis of pharmaceutically oriented molecules based onnitro compounds continues to be in demand and relevant.

Author Contributions: Both authors discussed, commented on, and wrote the manuscript. Allauthors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.


Data Availability Statement: Data sharing not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

References1. Nepali, K.; Lee, H.-Y.; Liou, J.-P. Nitro-Group-Containing Drugs. J. Med. Chem. 2019, 62, 2851–2893. [CrossRef] [PubMed]2. Parry, R.; Nishino, S.; Spain, J. Naturally-occurring nitro compounds. Nat. Prod. Rep. 2011, 28, 152–167. [CrossRef] [PubMed]3. Natarajan, P.; Chaudhary, R.; Rani, N.; Sakshi; Venugopalan, P. 3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium

cation: A green alternative to tert-butyl nitrite for synthesis of nitrogroup-containing arenes and drugs at room temperature.Tetrahedron Lett. 2020, 61, 151529. [CrossRef]

4. Patterson, S.; Wyllie, S. Nitro drugs for the treatment of trypanosomatid diseases: Past, present, and future prospects. TrendsParasitol. 2014, 30, 289–298. [CrossRef] [PubMed]

5. Patterson, S.; Fairlam, A.H. Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis.Curr. Med. Chem. 2019, 26, 4454–4475. [CrossRef]

6. Chung, M.C.; Bosquesi, P.L.; dos Santos, J.L. Prodrug Approach to Improve the Physico-Chemical Properties and Decrease theGenotoxicity of Nitro Compounds. Curr. Pharm. Des. 2011, 17, 3515–3526. [CrossRef]

7. Dong, J.; Du, D.-M. Highly enantioselective synthesis of Warfarin and its analogs catalysed by primary amine–phosphinamidebifunctional catalysts. Org. Biomol. Chem. 2012, 10, 8125–8131. [CrossRef]

8. Isık, M.; Akkoca, H.U.; Akhmedov, I.M.; Tanyeli, C. A bis-Lewis basic 2-aminoDMAP/prolinamide organocatalyst for applicationto the enantioselective synthesis of Warfarin and derivatives. Tetrahedron Asymm. 2016, 27, 384–388. [CrossRef]

9. Ueda, A.; Umeno, T.; Doi, M.; Akagawa, K.; Kudo, K.; Tanaka, M. Helical-Peptide-Catalyzed Enantioselective Michael AdditionReactions and Their Mechanistic Insights. J. Org. Chem. 2016, 81, 6343–6356. [CrossRef]

10. Rogozin’ska-Szymczak, M.; Mlynarski, J. Asymmetric synthesis of warfarin and its analogues on water. Tetrahedron Asymm. 2014,25, 813–820. [CrossRef]

11. Lim, J.Y.; Kim, D.Y. Enantioselective Conjugate Addition of 4-Hydroxycoumarin to Enones Catalyzed by Binaphthyl-ModifiedPrimary Amine Organocatalyst. Bull. Korean Chem. Soc. 2012, 33, 1825–1826. [CrossRef]

12. Alonzi, M.; Bracciale, M.P.; Broggi, A.; Lanari, D.; Marrocchi, A.; Santarelli, M.L.; Vaccaro, L. Synthesis and characterization ofnovel polystyrene-supported TBD catalysts and their use in the Michael addition for the synthesis of Warfarin and its analogues.J. Catal. 2014, 309, 260–267. [CrossRef]

13. Liu, J.; Li, Y.; Ke, M.; Liu, M.; Zhan, P.; Xiao, Y.-C.; Chen, F. Unified Strategy to Amphenicol Antibiotics: Asymmetric Synthesis of(−)-Chloramphenicol, (−)-Azidamphenicol, and (+)-Thiamphenicol and Its (+)-3-Floride. J. Org. Chem. 2020, 85, 15360–15367.[CrossRef]

14. Xia, Y.; Jiang, M.; Liu, M.; Zhang, Y.; Qu, H.; Xiong, T.; Huang, H.; Cheng, D.; Chen, F. Catalytic Syn-Selective Nitroaldol Approachto Amphenicol Antibiotics: Evolution of a Unified Asymmetric Synthesis of (−)-Chloramphenicol, (−)-Azidamphenicol, (+)-Thiamphenicol, and (+)-Florfenicol. J. Org. Chem. 2021, 86, 11557–11570. [CrossRef]

15. Lu, H.; Chanco, E.; Zhao, H. CmlI is an N-oxygenase in the biosynthesis of chloramphenicol. Tetrahedron 2012, 68, 7651–7654.[CrossRef]

16. Makris, T.M.; Vu, V.V.; Meier, K.K.; Komor, A.J.; Rivard, B.S.; Münck, E.; Que, L.; Lipscomb, J.D. An Unusual Peroxo Intermediateof the Arylamine Oxygenase of the Chloramphenicol Biosynthetic Pathway. J. Am. Chem. Soc. 2015, 137, 1608–1617. [CrossRef]

17. Franchino, A.; Jakubec, P.; Dixon, D.J. Enantioselective synthesis of (−)-chloramphenicol via silver-catalysed asymmetricisocyanoacetate aldol reaction. Org. Biomol. Chem. 2016, 14, 93–96. [CrossRef]

18. Ellis, K.O.; Castellion, A.W.; Honkomp, L.J.; Wessels, F.L.; Carpenter, J.E.; Halliday, R.P. Dantrolene, a direct acting skeletal musclerelaxant. J. Pharm. Sci. 1973, 62, 948–951. [CrossRef]

19. Snyder, H.R.; Davis, C.S.; Bickerton, R.K.; Halliday, R.P. 1-[5-Arylfurfurylidene)amino]hydantoins. A New Class of MuscleRelaxants. J. Med. Chem. 1967, 10, 807–810. [CrossRef]

20. Ahmed, J.; Sau, S.C.; Sreejyothi, P.; Hota, P.K.; Vardhanapu, P.K.; Vijaykumar, G.; Mandal, S.K. Direct C-H Arylation ofHeteroarenes with Aryl Chlorides using Abnormal NHC Coordinated Palladium Catalyst. Eur. J. Org. Chem. 2017, 5, 1004–1011.[CrossRef]

21. Song, A.-X.; Zeng, X.-X.; Ma, B.-B.; Xu, C.; Liu, F.-S. Direct (Hetero)arylation of Heteroarenes Catalyzed by UnsymmetricalPd-PEPPSI-NHC Complexes under Mild Conditions. Organometallics 2021, 39, 3524–3534. [CrossRef]

22. Crisostomo, F.P.; Martin, T.; Carrillo, R. Ascorbic Acid as an Initiator for the Direct C-H Arylation of (Hetero)arenes with AnilinesNitrosated in situ. Angew. Chem. Int. Ed. 2014, 53, 2181–2185. [CrossRef] [PubMed]

23. Harisha, A.S.; Nayak, S.P.; Pavan, M.S.; Shridhara, K.; Rao, S.K.; Rajendra, K.; Pari, K.D.; Sivaramkrishnan, H.; Row, T.N.G.;Nagarajan, K. A new synthesis of Entacapone and report on related studies. J. Chem. Sci. 2015, 127, 1977–1991. [CrossRef]

24. Harisha, A.S.; Nayak, S.P.; Nagarajan, K.; Row, T.N.G.; Hosamani, A.A. Novel triethylamine mediated thermal reactions of3-aryl-2-cyanoprop-2-enoic acid derivatives—Demethylation, reduction and vinylogation. Tetrahedron Lett. 2015, 56, 1427–1431.[CrossRef]

25. Guo, M.; Mao, S. Entacapone Preparation Method. CN Patent 108440340 A, 24 August 2017.

http://doi.org/10.1021/acs.jmedchem.8b00147

http://www.ncbi.nlm.nih.gov/pubmed/30295477

http://doi.org/10.1039/C0NP00024H


http://doi.org/10.1016/j.tetlet.2019.151529

http://doi.org/10.1016/j.pt.2014.04.003


http://doi.org/10.2174/0929867325666180426164352

http://doi.org/10.2174/138161211798194512

http://doi.org/10.1039/c2ob26334c

http://doi.org/10.1016/j.tetasy.2016.04.001

http://doi.org/10.1021/acs.joc.6b00982

http://doi.org/10.1016/j.tetasy.2014.04.008

http://doi.org/10.5012/bkcs.2012.33.6.1825

http://doi.org/10.1016/j.jcat.2013.10.009

http://doi.org/10.1021/acs.joc.0c02181

http://doi.org/10.1021/acs.joc.1c01124

http://doi.org/10.1016/j.tet.2012.06.036

http://doi.org/10.1021/ja511649n

http://doi.org/10.1039/C5OB02141C

http://doi.org/10.1002/jps.2600620619

http://doi.org/10.1021/jm00317a011

http://doi.org/10.1002/ejoc.201601218

http://doi.org/10.1021/acs.organomet.0c00494

http://doi.org/10.1002/anie.201309761


http://doi.org/10.1007/s12039-015-0961-4

http://doi.org/10.1016/j.tetlet.2015.01.148


26. Fu, Y.; Zhong, H.; Lin, F.; Xiao, H.; Zheng, Y.; Lin, X.; Tang, X. Method for Producing Entacapone. CN Patent 112624941 A,9 April 2021.

27. Srikanth, G.; Ray, U.K.; Rao, D.V.N.S.; Gupta, P.B.; Lavanya, P.; Islam, A. Efficient approach to pure entacapone and relatedcompounds. Synth. Commun. 2012, 42, 1359–1366. [CrossRef]

28. Veerareddy, A.; Reddy, G.S. Synthesis of entacapone by Pd-catalyzed Heck coupling reaction. Synth. Commun. 2014, 44, 1274–1278.[CrossRef]

29. Baker, J.W.; Bachman, G.L.; Schumacher, I.; Roman, D.P.; Tharp, A.L. Synthesis and bacteriostatic activity of some nitrofluoromethylanilides. J. Med. Chem. 1967, 10, 93–95. [CrossRef]

30. Neri, R.O.; Topliss, J.G. Substituted Anilides as Anti-Androgens. US Patent 4144270 A, 13 March 1979.31. Peer, L.; Maye, J. Process for Nitrating Anilides. US Patent 4302599 A, 24 November 1981.32. Bandgar, B.P.; Sawant, S.S. Novel and Gram-Scale Green Synthesis of Flutamide. Synth. Commun. 2006, 36, 859–864. [CrossRef]33. Ghaffarzadeh, M.; Rahbar, S. A novel method for synthesis of flutamide on the bench-scale. J. Chem. Res. 2014, 38, 200–201.

[CrossRef]34. McPherson, C.G.; Livingstone, K.; Jamieson, C.; Simpson, I. Palladium-Catalyzed Synthesis of Aryl Amides through Silanoate-

Mediated Hydrolysis of Nitriles. Synlett 2016, 27, 88–92. [CrossRef]35. Tan, B.Y.-H.; Teo, Y.-C. Mild and Efficient Cobalt-Catalyzed Cross-Coupling of Aliphatic Amides and Aryl Iodides in Water.

Synlett 2015, 26, 1697–1701. [CrossRef]36. Wang, J.; Zhang, X.; Wan, Z.; Ren, F. TCDA: Practical synthesis and application in trifluoromethylation of arenes and heteroarenes.

Org. Proc. Res. Dev. 2016, 20, 836–839. [CrossRef]37. Divi, M.; Krishna, P.; Rao, M.A.N.; Rajuri, V. Process for the Preparation of 4-iodo-3-nitrobenzamide. US Patent 2013172618 A1,

4 July 2013.38. Zhang, L.; Zhao, X.; Cui, Z.; Ma, T. Method of Preparing 4-iodo-3-nitrobenzamide. CN Patent 106366012 A, 1 February 2016.39. Cant, A.A.; Bhalla, R.; Pimlott, S.L.; Sutherland, A. Nickel-catalysed aromatic Finkelstein reaction of aryl and heteroarylbromides.

Chem. Commun. 2012, 48, 3993–3995. [CrossRef]40. Prasanthi, G.; Prasad, K.V.S.R.G.; Bharathi, K. Synthesis, anticonvulsant activity and molecular properties prediction of dialkyl

1-(di(ethoxycarbonyl)methyl)-2,6-dimethyl-4-substituted-1,4-dihydropyridine-3,5-dicarboxylates. Eur. J. Med. Chem. 2014, 73,97–104. [CrossRef]

41. Subudhi, B.B.; Sahoo, S.P. Synthesis and Evaluation of Antioxidant, Anti-inflammatory and Antiulcer Activity of Conjugates ofAmino Acids with Nifedipine. Chem. Pharm. Bull. 2011, 59, 1153–1156. [CrossRef]

42. Sliskovic, D.R. Cardiovascular Drugs. In Drug Discovery: Practices, Processes, and Perspectives; Li, J.J., Corey, E.J., Eds.; John Wiley &Sons: Hoboken, NJ, USA, 2013; pp. 141–204.

43. Siddaiah, V.; Basha, G.M.; Rao, G.P.; Prasad, U.V.; Rao, R.S. PEG-mediated catalyst-free synthesis of Hantzsch 1,4-dihydropyridinesand polyhydroquinoline derivatives. Synth. Commun. 2012, 42, 627–634. [CrossRef]

44. Affeldt, R.F.; Benvenutti, E.V.; Russowsky, D. A new In–SiO2 composite catalyst in the solvent-free multicomponent synthesis ofCa2+ channel blockers nifedipine and nemadipine B. New J. Chem. 2012, 36, 1502–1511. [CrossRef]

45. Wu, X.Y. Facile and green synthesis of 1,4-dihydropyridine derivatives in n-butyl pyridinium tetraflouroborate. Synth. Commun.2012, 42, 454–459. [CrossRef]

46. Katakami, T.; Yokoyama, T.; Miyamoto, M.; Mori, H.; Kawauchi, N.; Nobori, T.; Sannohe, K.; Kamiya, J.; Ishii, M.;Yoshihara, K. Pyrimidinedione Compounds, Method of Producing the Same and Antiarrythmic Agents Containing the Same.US Patent 5008267 A, 16 April 1991.

47. Zhu, Y.; Wang, Y.; Xiao, J.; Li, H. Preparation Method of High-Purity Nifekalant Hydrochloride. CN Patent 103288751 A,11 September 2013.

48. Elks, J.; Ganellin, C.R. The Dictionary of Drugs: Chemical Data, Structures and Bibliographies; Springer: Boston, MA, USA, 2014;pp. 845–891.

49. Kreipl, A.; Boege, N.; Thiel, W.R.; Zylum, B.P. Method for Coupling Halgen-Substituted Aromatic Compounds with OrganicCompounds Comprising Trialkylsilyl-Sustituted Heteroatoms. US Patent 2012142937 A1, 7 June 2012.

50. Yamamoto, Y.; Hisa, T.; Arai, J.; Saito, Y.; Yamamoto, F.; Mukai, T.; Ohshima, T.; Maeda, M.; Ohkubo, Y. Isomeric methoxy analogof nimesulide for development of brain cyclooxygenase-2 (COX-2)-targeted imaging agents: Synthesis, in vitro COX-2 inhibitorypotency, and cellular transport properties. Bioorg. Med. Chem. 2015, 23, 6807–6814. [CrossRef]

51. Attolono, E. Crystalline Inhibitor of 4-hydroxyphenylpyruvate dioxygenase, and a Process of Synthesis and CrystallizationThereof. US Patent 9783485 B1, 10 October 2017.

52. El-Moselhy, T.F.; Sidhom, P.A.; Esmat, E.A.; El-Mahdy, N.A. Synthesis, Docking Simulation, Biological Evaluations and 3D-QSARStudy of 1,4-Dihydropyridines as Calcium Channel Blockers. Chem. Pharm. Bull. 2017, 65, 893–903. [CrossRef]

53. Zhou, K.; Wang, X.; Zhao, Y.; Cao, Y.; Fu, Q.; Zhang, S. Synthesis and antihypertensive activity evaluation in spontaneouslyhypertensive rats of nitrendipine analogues. Med. Chem. Res. 2011, 20, 1325–1330. [CrossRef]

54. Palermo, V.; Sathicq, A.G.; Constantieux, T.; Rodrıguez, J.; Vazquez, P.G.; Romanelli, G.P. First Report About the Use of MicellarKeggin Heteropolyacids as Catalysts in the Green Multicomponent Synthesis of Nifedipine Derivatives. Catal. Lett. 2016, 146,1634–1647. [CrossRef]

http://doi.org/10.1080/00397911.2010.539894

http://doi.org/10.1080/00397911.2013.853190

http://doi.org/10.1021/jm00313a020

http://doi.org/10.1080/00397910500464848

http://doi.org/10.3184/174751914X13929219796481

http://doi.org/10.1002/chin.201623095

http://doi.org/10.1002/chin.201550041

http://doi.org/10.1021/acs.oprd.6b00079

http://doi.org/10.1039/c2cc30956d

http://doi.org/10.1016/j.ejmech.2013.12.001

http://doi.org/10.1248/cpb.59.1153

http://doi.org/10.1080/00397911.2010.528289

http://doi.org/10.1039/c2nj40060j

http://doi.org/10.1080/00397911.2010.525773

http://doi.org/10.1016/j.bmc.2015.10.007

http://doi.org/10.1248/cpb.c17-00186

http://doi.org/10.1007/s00044-010-9477-0

http://doi.org/10.1007/s10562-016-1784-8


55. Fedorova, O.V.; Koryakova, O.V.; Valova, M.S.; Ovchinnikova, I.G.; Titova, Y.A.; Rusinov, G.L.; Charushin, V.N. Catalytic Effect ofNanosized Metal Oxides on the Hantzsch Reaction. Kinet. Catal. 2010, 51, 566–572. [CrossRef]

56. Wang, B.; Zhu, G.; Wei, Q.; Qu, J.; Dai, Q. Nitrocefin Synthesis Method. CN Patent 106083894 A, 9 November 2016.57. Nabold, C.F.; Aebersold, C.; Grieko, P.G.; Aeschbacher, R.G. Route of Synthesis for Opicapone. US Patent 2018370958 A1,

27 December 2018.58. Sathe, D.G.; Das, A.; Gawas, D.V.; Chowkekar, S.B.; Jagtap, R.S. Process for the Preparation of Opicapone and Intermediates

Thereof. WO Patent 2019123066 A1, 27 June 2019.59. Kiss, L.E.; Ferreira, H.S.; Torrao, L.; Bonifacio, M.J.; Palma, P.N.; Soares-da-Silva, P.; Learmonth, D.A. Discovery of a Long-Acting,

Peripherally Selective Inhibitor of Catechol-O-methyltransferase. J. Med. Chem. 2010, 53, 3396–3411. [CrossRef]60. Zhong, Z.; Xu, P.; Zhou, A. Electrochemical phosphorylation of arenols and anilines leading to organophosphates and phospho-

ramidates. Org. Biomol. Chem. 2021, 19, 5342–5347. [CrossRef]61. Anitha, T.; Ashalu, K.C.; Sandeep, M.; Mohd, A.; Wencel-Delord, J.; Colobert, F.; Reddy, K.R. LiI/TBHP Mediated Oxidative Cross-

Coupling of P(O)–H Compounds with Phenols and Various Nucleophiles: Direct Access to the Synthesis of Organophosphates.Eur. J. Org. Chem. 2019, 45, 7463–7474. [CrossRef]

62. Huang, H.; Ash, J.; Kang, J.Y. Tf2O-Promoted Activating Strategy of Phosphate Analogues: Synthesis of Mixed Phosphates andPhosphinate. Org. Lett. 2018, 20, 4938–4941. [CrossRef]

63. Li, Y.; Wang, M.; Jiang, X. Straightforward Sulfonamidation via Metabisulfite-Mediated Cross Coupling of Nitroarenes andBoronic Acids under Transition-Metal-Free Conditions. Chin. J. Chem. 2020, 38, 1521–1525. [CrossRef]

64. Gallardo-Garrido, C.; Cho, Y.; Cortes-Rios, J.; Vasquez, D.; Pessoa-Mahana, C.D.; Araya-Maturana, R.; Pessoa-Mahana, H.;Faundez, M. Nitrofuran Drugs Beyond Redox Cycling: Evidence of Nitroreduction-independent Cytotoxicity Mechanism. Toxicol.Appl. Pharmacol. 2020, 401, 115104. [CrossRef]

65. Alhalaweh, A.; George, S.; Basavoju, S.; Childs, S.L.; Rizvi, S.A.A.; Velaga, S.P. Pharmaceutical Cocrystals of Nitrofurantoin:Screening, Characterization and Crystal Structure Analysis. CrystEngComm 2012, 14, 5078–5088. [CrossRef]

66. Colacino, E.; Porcheddu, A.; Halasz, I.; Charnay, C.; Delogu, F.; Guerra, R.; Fullenwarth, J. Mechanochemistry for “no solvent, nobase” preparation of hydantoin-based active pharmaceutical ingredients: Nitrofurantoin and dantrolene. Green Chem. 2018, 20,2973–2977. [CrossRef]

67. Alsaeedi, H.S.; Aljaber, N.A.; Ara, I. Synthesis and Investigation of Antimicrobal Activity of Some Nifuroxazide Analogs. Asian J.Chem. 2015, 27, 3639–3646. [CrossRef]

68. Shuai, F.; Wang, X.; Zhang, J. Method for synthesizing furacilin under catalysis of supported catalyst. CN Patent 108101874 A,1 June 2018.

69. Fesenko, A.A.; Yankov, A.N.; Shutalev, A.D. A General and Convenient Synthesis of 4-(Tosylmethyl)semicarbazones and TheirUse in Amidoalkylation of Hydrogen, Heteroatom and Carbon Nucleophiles. Tetrahedron 2019, 75, 130527. [CrossRef]

70. da Cruz, A.C.N.; Brondani, D.J.; de Santana, T.I.; da Silva, L.O.; Borba, E.F.D.; de Faria, A.R.; de Albuquerque, J.F.C.; Piessard, S.;Ximenes, R.M.; Baratte, B.; et al. Biological Evaluation of Arylsemicarbazone Derivatives as Potential Anticancer Agents.Pharmaceuticals 2019, 12, 169. [CrossRef]

71. Grueneberg, R.N.; Leakey, A. Treatment of Candidal Urinary Tract Infection with Nifuratel. Br. Med. J. 1976, 2, 908–910. [CrossRef]72. Cai, Z.; An, F.; He, Z. Preparation Method of Compound Nifuratel as Shown in Formula E. CN Patent 104402874 A, 11 March 2015.73. Hu, Z.; Li, F.; Jing, R. Industrial Preparation Method of Nifuratel. CN Patent 112745307 A, 4 May 2021.74. Yi, M.; Sun, B.; Xu, L.; Ma, Q.; Zhang, X.; Wang, X.; Zhang, N. Preparation Process of Anti-Infective Drug Nifuratel.

CN Patent 107987069 A, 4 May 2018.75. Gagliardi, S.; Consonni, A.; Mailland, F.; Bulgheroni, A. (R)-Nifuratel and synthesis of (R)- and (S)-Nifuratel. EP Patent 2662371 A1,

13 November 2013.76. Coleman, C.N. Modulating the Radiation Response. Oncologist 1996, 1, 227–231. [CrossRef]77. Sree Kumar, K.; Weiss, J.F. Inhibition of Glutathione Peroxidase and Glutathione Transferase in Mouse Liver by Misonidazole.

Biochem. Pharmacol. 1986, 35, 3143–3146. [CrossRef]78. Wilde, F.; Chamseddin, C.; Lemmerhirt, H.; Bednarski, P.J.; Jira, T.; Link, A. Evaluation of (S)- and (R)-Misonidazole as GPX

Inhibitors: Synthesis, Characterization Including Circular Dichroism and In Vitro Testing on Bovine GPx-1. Arch. Pharm. Chem.Life Sci. 2014, 347, 153–160. [CrossRef]

79. Rajendran, J.G.; Mankoff, D.A.; O’Sullivan, F.; Peterson, L.M.; Schwartz, D.L.; Conrad, E.U.; Spence, A.M.; Muzi, M.; Farwell, D.G.;Krohn, K.A. Hypoxia and Glucose Metabolism in Malignant Tumors: Evaluation by [18F]Fluoromisonidazole and[18F]Fluorodeoxyglucose Positron Emission Tomography Imaging. Clin. Cancer Res. 2004, 10, 2245–2252. [CrossRef]

80. Nieto, E.; Alajarin, R.; Alvarez-Builla, J.; Larranaga, I.; Gorospe, E.; Pozo, M.A. A New and Improved Synthesis of the HypoxiaMarker [18F]-FMISO. Synthesis 2010, 21, 3700–3704.

81. Kwon, Y.-D.; Seol, E.; Lim, S.-T.; Sohn, M.-H.; Kim, H.-K.; Jung, Y.; Lee, S.J. Practical Synthesis of 1-(2-nitro-1H-imidazol-1-yl)-3-(tosyloxy)propan-2-yl acetate for the Radiosynthesis of [18F]-FMISO. Bull. Korean Chem. Soc. 2015, 36, 559–563.

82. Kwon, Y.-D.; Jung, Y.; Lim, S.T.; Sohn, M.-H.; Kim, H.-K. Facile and Efficient Synthesis of [18F]Flouromisonidazole Using Novel2-Nitroimidazole Derivatives. J. Braz. Chem. Soc. 2016, 27, 1150–1156.

83. Revunov, E.; Zhuravlev, F. Co(salen)-mediated Enantioselective Radiofluorination of Epoxides. Radiosynthesis of Enantiomeri-cally Enriched [18F]F-MISO via Kinetic Resolution. J. Fluor. Chem. 2013, 156, 130–135. [CrossRef]

http://doi.org/10.1134/S0023158410040166

http://doi.org/10.1021/jm1001524

http://doi.org/10.1039/D1OB00779C

http://doi.org/10.1002/ejoc.201901362

http://doi.org/10.1021/acs.orglett.8b02073

http://doi.org/10.1002/cjoc.202000198

http://doi.org/10.1016/j.taap.2020.115104

http://doi.org/10.1039/c2ce06602e

http://doi.org/10.1039/C8GC01345D

http://doi.org/10.14233/ajchem.2015.18896

http://doi.org/10.1016/j.tet.2019.130527

http://doi.org/10.3390/ph12040169

http://doi.org/10.1136/bmj.2.6041.908

http://doi.org/10.1634/theoncologist.1-4-227

http://doi.org/10.1016/0006-2952(86)90399-0

http://doi.org/10.1002/ardp.201300285

http://doi.org/10.1158/1078-0432.CCR-0688-3

http://doi.org/10.1016/j.jfluchem.2013.09.006


84. Graham, T.J.A.; Lambert, R.F.; Ploessl, K.; Kung, H.F.; Doyle, A.G. Enantioselective Radiosynthesis of Positron EmissionTomography (PET) Tracers Containing [18F]Fluorohydrins. J. Am. Chem. Soc. 2014, 136, 5291–5294. [CrossRef]

85. Kalow, J.A.; Doyle, A.G. Mechanistic Investigations of Cooperative Catalysis in the Enantioselective Fluorination of Epoxides. J.Am. Chem. Soc. 2011, 133, 16001–16012. [CrossRef]

86. Borzecka, W.; Lavandera, I.; Gotor, V. Biocatalyzed Synthesisof Both Enantiopure Fluoromisonidazole Antipodes. Tetrahedron Lett.2013, 54, 5022–5025. [CrossRef]

87. Zhang, W.; Fan, W.; Zhou, Z.; Garrison, J. Synthesis and Evaluation of a Radiolabeled Phosphoramide Mustard with Selectivityfor Hypoxic Cancer Cells. ACS Med. Chem. Lett. 2017, 8, 1269–1274. [CrossRef]

88. Duan, J.-X.; Matteucci, M.; Davar, N.; Andersen, D. TH-302 Solid Forms and Method Related Thereto. WO Patent 2016011195 A1,21 January 2016.

89. Murthy, S.S.M.; Bhilare, S.; Cardozo, J.; Chrysochos, N.; Schulzke, C.; Sanghvi, Y.S.; Gunturu, K.C.; Kapdi, A.R. Pd/PTABS:Low-Temperature Thioetherification of Chloro(hetero)arenes. J. Org. Chem. 2019, 84, 8921–8940.

90. Sharma, S.; Anand, R.; Cham, P.S.; Raina, S.; Vishwakarma, R.A.; Singh, P.P. A Concise and Sequential Synthesis of theNitroimidazooxazole Based Drug, Delamanid and Related Compounds. RSC Adv. 2020, 10, 17085–17093. [CrossRef] [PubMed]

91. Sharma, S.; Ahmed, R.; Raina, S.; Vishwakarama, R.A.; Singh, P.P. Process for the Preparation of Derivatives of 1,1-dialkylethane-1,2-diols as Useful Intermediates. WO Patent 2020202205 A1, 8 October 2020.

92. Fairlamb, A.; Patterson, S.; Wylie, S.; Read, K. Treatment of Parasitic Disease. WO Patent 2017072523 A1, 4 May 2017.93. Chen, G.J.; Zhu, M.L.; Chen, Y.X.; Miao, X.Q.; Guo, M.; Jiang, N.; Zhai, X. An Efficient and Practical Protocol for the Production of

Pretomanid (PA-824) via a Novel Synthetic Strategy. Chem. Pap. 2020, 74, 3937–3945. [CrossRef]94. Patterson, S.; Wyllie, S.; Stoyanovski, L.; Perry, M.R.; Simeons, F.R.C.; Norval, S.; Osuna-Cabello, M.; De Rycker, M.; Read, K.D.;

Fairlamb, A.H. The R Enantiomer of the Antitubercular Drud PA-824 as a Potential Oral Treatment for Visceral Leishmaniasis.Antimicrob. Agents Chemother. 2013, 57, 4699–4706. [CrossRef]

95. Strassfeld, D.A.; Wickens, Z.K.; Picazo, E.; Jacobsen, E.N. Highly Enantioselective, Hydrogen-Bond-Donor Catalyzed Additionsto Oxetanes. J. Am. Chem. Soc. 2020, 142, 9175–9180. [CrossRef]

96. Marsini, M.A.; Reider, P.J.; Sorensen, E.J. A Concise and Convergent Synthesis of PA-824. J. Org. Chem. 2010, 75, 7479–7482.[CrossRef]

97. Thompson, A.M.; O’Connor, P.D.; Marshall, A.J.; Blaser, A.; Yardley, V.; Maes, L.; Gupta, S.; Launay, D.; Braillard, S.; Chatelain, E.;et al. Development of (6R)-2-Nitro-6-[4-(trifluoromethoxy)phenoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (DNDI-8219): ANew Lead for Visceral Leishmaniasis. J. Med. Chem. 2018, 61, 2329–2352. [CrossRef]

98. Rami, M.; Dubois, L.; Parvathaneni, N.-K.; Alterio, V.; van Kujik, S.J.A.; Monti, S.M.; Lambin, P.; De Simone, G.;Supuran, C.T.; Winum, J.-Y. Hypoxia-Targeting Carbonic Anhydrase IX Inhibitors by a New Series of Nitroimidazole-Sulfonamides/Sulfamides/Sulfamates. J. Med. Chem. 2013, 56, 8512–8520. [CrossRef]

99. Samant, B.S.; Sukhthankar, M.G. Compounds Containing 2-Substituted Imidazole Ring for Treatment Against Human AfricanTrypanosomiasis. Bioorg. Med. Chem. Lett. 2011, 21, 1015–1018. [CrossRef]

100. Natarajan, P.; Chaudhary, R.; Venugopalan, P. Silver(I)-Promoted ipso-Nitrtion of Carboxylic Acids by Nitronium Tetrafluorobo-rate. J. Org. Chem. 2015, 80, 10498–10504. [CrossRef]

101. Zeb, A.; Malik, I.; Rasheed, S.; Choudhary, I.M.; Basha, F.Z. Metronidazole Esters: A New Class of Antiglycation Agents. Med.Chem. 2012, 8, 846–852. [CrossRef]

102. Pi, J.; Zhao, T.; Yang, S.; Dong, J.; Rao, K.; Li, B.; Deng, J.; Zhang, Q. Environment-friendly Method for Metronidazole Synthesis.CN Patent 105348200, 24 February 2016.

103. Zhao, T.; Li, B.; Zhang, W.; Ai, J.; Pi, J.; Zhang, Q.; Xie, G.; Wu, M. Method for Synthesizing Metronidazole Under Catalysis ofSolid Acids. CN Patent 110172039, 27 August 2019.

104. Mandalapu, D.; Kushwaha, B.; Gupta, S.; Singh, N.; Shukla, M.; Kumar, J.; Tanpula, D.K.; Sankhwar, S.N.; Maikhuri, J.P.;Siddiqi, M.I.; et al. 2-Methyl-4/5-nitroimidazole Derivatives Potentiated Against Sexually Transmitted Trichomonas: Design,Synthesis, Biology and 3D-QSAR Study. Eur. J. Med. Chem. 2016, 124, 820–839. [CrossRef]

105. Ansari, M.A.; Saad, S.M.; Khan, K.M.; Salar, U.; Taslimi, P.; Taskin-Tok, T.; Saleem, F.; Jahangir, A. Biology-Oriented DrugSynthesis and Evaluation of Secnidazole Esters as Novel Enzyme Inhibitors. Arch. Pharm. 2021, 355, e2100376. [CrossRef]

106. Pantala, R.C.M.; Khagga, M.; Bhavani, R.; Bhavani, V. Novel Salt of Tinidazole with Improved Solubility and AntibacterialActivity. Orient. J. Chem. 2017, 33, 490–499.

107. Pantala, R.C.M.; Khagga, M.; Bhavani, R.; Bhavani, V. Synthesis, Characterization and Biological Activity of Novel Salt/MolecularSalts of Tinidazole. Orient. J. Chem. 2017, 33, 859–872.

108. Li, Y.M.; Rizvi, S.; Hu, D.Q.; Sun, D.W.; Gao, A.H.; Zhou, Y.B.; Li, J.; Jiang, X.F. Selective Late-Stage Oxygenation of Sulfides withGround-State Oxygen by Uranyl Photocatalysis. Angew. Chem. Int. Ed. 2019, 58, 13499–13506. [CrossRef]

109. Shin, Y.; Noel, R.; Banerjee, S.; Kojetin, D.; Song, X.; He, Y.; Lin, L.; Cameron, M.D.; Burris, T.P.; Kamenecka, T.M. Small MoleculeTertiary Amines as Agonists of the Nuclear Hormone Receptor Rev-erbα. Bioorg. Med. Chem. Lett. 2012, 22, 4413–4417. [CrossRef]

110. De, S.K.; Stebbins, J.L.; Chen, L.-H.; Riel-Mehan, M.; Machleidt, T.; Dahl, R.; Yuan, H.; Emdadi, A.; Barile, E.; Chen, V.; et al.Design, Synthesis, and Structure−Activity Relationship of Substrate Competitive, Selective, and in Vivo Active Triazole andThiadiazole Inhibitors of the c-Jun N-Terminal Kinase. J. Med. Chem. 2009, 52, 1943–1952. [CrossRef]

http://doi.org/10.1021/ja5025645

http://doi.org/10.1021/ja207256s

http://doi.org/10.1016/j.tetlet.2013.07.013

http://doi.org/10.1021/acsmedchemlett.7b00355

http://doi.org/10.1039/D0RA01662D


http://doi.org/10.1007/s11696-020-01211-4

http://doi.org/10.1128/AAC.00722-13

http://doi.org/10.1021/jacs.0c03991

http://doi.org/10.1021/jo1015807

http://doi.org/10.1021/acs.jmedchem.7b01581

http://doi.org/10.1021/jm4009532

http://doi.org/10.1016/j.bmcl.2010.12.040

http://doi.org/10.1021/acs.joc.5b02133

http://doi.org/10.2174/157340612802084360

http://doi.org/10.1016/j.ejmech.2016.09.006

http://doi.org/10.1002/ardp.202100376

http://doi.org/10.1002/anie.201906080

http://doi.org/10.1016/j.bmcl.2012.04.126

http://doi.org/10.1021/jm801503n


111. Stokes, J.M.; Yang, K.; Swanson, K.; Jin, W.; Cubillos-Ruiz, A.; Donghia, N.M.; MacNair, C.R.; French, S.; Carfrae, L.A.;Bloom-Ackermann, Z.; et al. A Deep Learning Approach to Antibiotic Discovery. Cell 2020, 180, 688–702. [CrossRef]

112. Karpenko, I.; Deev, S.; Kiselev, O.; Charushin, V.; Rusinov, V.; Ulomsky, E.; Deeva, E.; Yanvarev, D.; Ivanov, A.; Smirnova, O.; et al.Antiviral Properties, Metabolism, and Pharmacokinetics of a Novel Azolo-1,2,4-Triazine-Derived Inhibitor of Influenza A and BVirus Replication. Antimicrob. Agents Chemother. 2010, 54, 2017–2022. [CrossRef]

113. Sabitov, A.U.; Belousov, V.V.; Edin, A.S.; Oleinichenko, E.V.; Gladunova, E.P.; Tikhonova, E.P.; Kuzmina, T.Y.; Kalinina, Y.S.;Sorokin, P.V. Practical Experience of Using Riamilovir in Treatment of Patients with Moderate COVID-19. Antibiot. Chemother.2020, 65, 27–30. [CrossRef]

114. Voinkov, E.K.; Drokin, R.A.; Ulomskiy, E.N.; Slepukhin, P.A.; Rusinov, V.L.; Chupakhin, O.N. Crystal Structure of MedicinalProduct Triazavirin. J. Chem. Crystallogr. 2019, 49, 213. [CrossRef]

115. Shestakova, T.S.; Khalymbadzha, I.A.; Deev, S.L.; Eltsov, O.S.; Rusinov, V.L.; Shenkarev, Z.O.; Arseniev, A.S.; Chupakhin, O.N.Synthesis of the [2H,15N]-labeled Antiviral Drug “Triazavirine”. Russ. Chem. Bull. Int. Ed. 2011, 60, 729–732. [CrossRef]

116. Shestakova, T.S.; Deev, S.L.; Khalymbadzha, I.A.; Rusinov, V.L.; Paramonov, A.S.; Arseniev, A.S.; Shenkarev, Z.O.; Charushin, V.N.;Chupakhin, O.N. Antiviral Drug Triazavirin, Selectively Labeled with 2H, 13C and 15N Stable Isotopes. Synthesis and Properties.Chem. Heterocycl. Compd. 2021, 57, 479–482. [CrossRef] [PubMed]

http://doi.org/10.1016/j.cell.2020.01.021

http://doi.org/10.1128/AAC.01186-09

http://doi.org/10.37489/0235-2990-2020-65-7-8-27-30

http://doi.org/10.1007/s10870-018-0750-2

http://doi.org/10.1007/s11172-011-0113-z

http://doi.org/10.1007/s10593-021-02927-1


Recent Progress in the Synthesis of Drugs and ... - MDPI

Documents

Transcript of Recent Progress in the Synthesis of Drugs and ... - MDPI