Green Synthetic Approach: An Efficient Eco-Friendly Tool for ...

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Review

Green Synthetic Approach: An Efficient Eco-Friendly Tool forSynthesis of Biologically Active Oxadiazole Derivatives

Bimal Krishna Banik 1,*, Biswa Mohan Sahoo 2,*, Bera Venkata Varaha Ravi Kumar 2, Krishna Chandra Panda 2,Jasma Jena 2 , Manoj Kumar Mahapatra 3 and Preetismita Borah 4

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Citation: Banik, B.K.; Sahoo, B.M.;

Kumar, B.V.V.R.; Panda, K.C.; Jena, J.;

Mahapatra, M.K.; Borah, P. Green

Synthetic Approach: An Efficient

Eco-Friendly Tool for Synthesis of

Biologically Active Oxadiazole

Derivatives. Molecules 2021, 26, 1163.

https://doi.org/10.3390/

molecules26041163

Academic Editor: Magrioti Victoria

Received: 23 November 2020

Accepted: 7 January 2021

Published: 22 February 2021

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1 Department of Mathematics and Natural Sciences, College of Sciences and Human Studies, PrinceMohammad Bin Fahd University, Al Khobar 31952, Saudi Arabia

2 Roland Institute of Pharmaceutical Sciences, Biju Patnaik University of Technology Nodal Centre of Research,Berhampur 760010, India; [email protected] (B.V.V.R.K.);[email protected] (K.C.P.); [email protected] (J.J.)

3 Kanak Manjari Institute of Pharmaceutical Sciences, Rourkela 769015, India; [email protected] CSIR-Central Scientific Instruments Organization, Chandigarh 160030, India; [email protected]* Correspondence: [email protected] (B.K.B.); [email protected] (B.M.S.)

Abstract: Green synthetic protocol refers to the development of processes for the sustainable pro-duction of chemicals and materials. For the synthesis of various biologically active compounds,energy-efficient and environmentally benign processes are applied, such as microwave irradiationtechnology, ultrasound-mediated synthesis, photo-catalysis (ultraviolet, visible and infrared irra-diation), molecular sieving, grinding and milling techniques, etc. Thesemethods are consideredsustainable technology and become valuable green protocol to synthesize new drug molecules astheyprovidenumerous benefits over conventional synthetic methods.Based on this concept, oxadi-azole derivatives are synthesized under microwave irradiation technique to reduce the formationof byproduct so that the product yield can be increased quantitatively in less reaction time. Hence,the synthesis of drug molecules under microwave irradiation follows a green chemistry approachthat employs a set of principles to minimize or remove the utilization and production of hazardoustoxic materials during the design, manufacture and application of chemical substances.This approachplays a major role in controlling environmental pollution by utilizing safer solvents, catalysts, suitablereaction conditions and thereby increases the atom economy and energy efficiency. Oxadiazole isa five-membered heterocyclic compound that possesses one oxygen and two nitrogen atoms inthe ring system.Oxadiazole moiety is drawing considerable interest for the development of newdrug candidates with potential therapeutic activities including antibacterial, antifungal, antiviral,anticonvulsant, anticancer, antimalarial, antitubercular, anti-asthmatic, antidepressant, antidiabetic,antioxidant, antiparkinsonian, analgesic and antiinflammatory, etc. This review focuses on differentsynthetic approaches of oxadiazole derivatives under microwave heating method and study of theirvarious biological activities.

Keywords: drug; green chemistry; microwave; oxadiazole; synthesis; biological activities

1. Introduction

The green chemistry approach refers to the utilization of a set of principles that reducesthe generation of chemical hazardous during the design, manufacture and use of chemicalsubstances. This protocol plays a major role in controlling environmental pollution byusing safer solvents, catalysts, suitable reaction conditions and thereby increases theatom economy and energy efficiency of the synthetic process. Hence, microwave-assistedsynthesis followsthe green chemistry approach as it makes the synthetic process eco-friendly by reducing environmental pollution [1]. Microwave radiation energy offerssignificant benefits to carry out drug synthesis, including increased reaction rates, productyield enhancements, and cleaner reactions.The chemical transformations which take hours,

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or even days, to complete can now be completed in minutes with the help of microwaveheating [2].

Similarly, the ultrasonic irradiation method is applied to accelerate various chemicalreactions, including both homogeneous and heterogeneous systems. The use of ultra-sound in organic synthesis involves specific activation based on the physical phenomenon,i.e., acoustic cavitations.In contrast, photo-catalytic reactions involve the use of ultra-violet,visible light and infrared radiation to generate new medicinally active compounds withdiverse molecular structures. To carry out a photochemical reaction, the UV-visible spectraof the photoactive compounds are recorded. The photoactive compound is the moleculethat can be electronically excited and undergoes chemical reaction from its excited state [3].

The grinding technique is also considered a green synthetic method to perform chem-ical reactions under solvent-free conditions with high product yield. Grinding of therecanting substances for a chemical reaction can be carried out by using mortar and pes-tle or by using a high-speed vibrating mill. Due to the collision between the reactingmolecules, the chemical reaction is carried forward [4]. A milling technique like ball millingis considered to be one of the automated forms of mortar and pestle. In the case of theballmill, the reacting materials are placed in a reaction vessel equipped with grinding balls andcovered with a lid. The vessel is allowed to shake at high-speed to carry out the chemicalreactions [5].

Based on these above facts, oxadiazole derivatives are synthesized to reduce theformation of byproducts so that the product yield can be increased in less reaction time.Further, the structural motif like oxadiazole is drawing considerable attention for thedevelopment of new drug candidates with potential therapeutic activities including an-tibacterial, antifungal, antiviral, anticonvulsant, anticancer, antimalarial, antitubercular,anti-asthmatic, antidepressant, antidiabetic, antioxidant, antiparkinsonian, analgesic andantiinflammatory, etc.

Oxadiazole moiety is considered to be derived from furan ring by replacing twomethane groups (-CH=) with two pyridine-type nitrogen (-N=).The aromaticity of oxadia-zole is decreased due to the replacement of these groups in the furan ring so that it exhibitsthe property of conjugated diene. The oxadiazole ring is also recognized as furadiazole,furoxans, azoximes, oxybiazole, biozole and diazoxole. Oxadiazole derivatives are found tobe a very weak base due to the inductive effect of the additional heteroatoms.Hence, thereis the possibility of four isomers of oxadiazole, including 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,3,4-oxadiazole that depends on the position of nitrogen in the ring [6].

The therapeuticpotentials of oxadiazole derivatives mainly depend on the effectivebinding interactions of drug molecules with different receptors or enzymes in the biologicalsystems and thereby eliciting diverse bioactivities. This review provides new insightsinto the rational design to develop potential oxadiazole-based medicinal agents with lesstoxicity and improved pharmacokinetic properties.

2. Green Chemistry Approaches

There are various green chemistry approaches to carry out different chemical reactionsthat include microwave irradiation (MWI), ultrasonication, photo-catalysis, grinding andmilling methods (Figure 1). By applying these technologies, organic reactions become moreefficient and economic by enhancing the rate of reaction with reduced reaction time andhigh product yield. Synthetic approaches like grinding or milling techniques involve theapplication of mechanochemistry for the rapid, clean, efficient and solvent-free synthesisof various biologically active compounds [7].

Molecules 2021, 26, 1163 3 of 23Molecules 2021, 26, x FOR PEER REVIEW 3 of 24

Microwave irradiation technology

Milling technique

Ultrasound mediated reaction

Green chemistry approaches Grinding techniques

Figure 1. Green chemistry approaches.

During the year 1991, the Environmental Protection Agency (EPA) and the National Science Foundation (NSF) initiated the Green Chemistry Program. P.T. Anastas and J.C. Warner have formulated twelve major principles of green chemistry to reduce or elimi-nate the risk of chemical hazards and environmental pollution [8–11]. 1. Prevention of waste or byproducts: It is essential to carry out the synthesis in such a way

that the formation of waste or byproducts is less or absent. 2. Atom economy: It represents the design of synthetic methods to maximize the incorporation

of reactants (starting materials and reagents) to get the final products. 3. Use of less hazardous and toxic chemicals: Various synthetic methods should be designed

properly so that the use and generation of substances have less or no toxic effect on human health and the environment.

4. Designing of Safer chemicals: The design of the chemical product should preserve efficacy while reducing toxicity.

5. Selection of Safer solvents: Avoid the use of auxiliary materials (solvents, extractants) if possible, or otherwise, make them innocuous.

6. Energy efficiency: Energy requirements should be minimized and conduct synthesis at am-bient temperature and pressure.

7. Renewable feedstock: Raw materials should be renewable. 8. Reduce derivatives: Unnecessary derivatization should be avoided where possible. 9. Smart catalysis: Selectively catalyzed processes are superior to stoichiometric processes. 10. Biodegradable design: The design of chemical products should be in such a way that these

can be degradable to innocuous products when disposed of. 11. Real-time analysis for pollution prevention: Monitor the processes in real time to avoid

excursions leading to the formation of hazardous substances. 12. Prevention of hazards and accidents: Materials used in a chemical process should be se-

lected to minimize hazardsand risk for chemical accidents.

3. Chemistry of OxadiazoleMoiety Oxadiazoles are five-membered heterocyclic compounds that possess one oxygen

atom and two nitrogen atoms in the ring system [12]. Depending on the position of het-eroatoms (oxygen or nitrogen), there are different isomeric forms of oxadiazole moiety such as 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole (Figure 2).These chemical compounds are of the azole family with the molecular formula C2H2N2O.Among these isomers, 1,2,3-oxadiazole is unstable and ring-opens to form the diazoketone tautomer. However, 1,3,4-oxadiazole is a thermally stable aromatic molecule and plays a major role in developing new drug candidates with diverse biological activi-ties such as anticancer, antiparasitic, antifungal, antibacterial, antidepressant, antituber-cular and antiinflammatory, etc. [13].

Figure 1. Green chemistry approaches.

During the year 1991, the Environmental Protection Agency (EPA) and the NationalScience Foundation (NSF) initiated the Green Chemistry Program. P.T. Anastas and J.C.Warner have formulated twelve major principles of green chemistry to reduce or eliminatethe risk of chemical hazards and environmental pollution [8–11].

1. Prevention of waste or byproducts: It is essential to carry out the synthesis in such a waythat the formation of waste or byproducts is less or absent.

2. Atom economy: It represents the design of synthetic methods to maximize the incorporationof reactants (starting materials and reagents) to get the final products.

3. Use of less hazardous and toxic chemicals: Various synthetic methods should be designedproperly so that the use and generation of substances have less or no toxic effect on humanhealth and the environment.

4. Designing of Safer chemicals: The design of the chemical product should preserve efficacywhile reducing toxicity.

5. Selection of Safer solvents: Avoid the use of auxiliary materials (solvents, extractants) ifpossible, or otherwise, make them innocuous.

6. Energy efficiency: Energy requirements should be minimized and conduct synthesis atambient temperature and pressure.

7. Renewable feedstock: Raw materials should be renewable.8. Reduce derivatives: Unnecessary derivatization should be avoided where possible.9. Smart catalysis: Selectively catalyzed processes are superior to stoichiometric processes.10. Biodegradable design: The design of chemical products should be in such a way that these

can be degradable to innocuous products when disposed of.11. Real-time analysis for pollution prevention: Monitor the processes in real time to avoid

excursions leading to the formation of hazardous substances.12. Prevention of hazards and accidents: Materials used in a chemical process should be

selected to minimize hazardsand risk for chemical accidents.

3. Chemistry of OxadiazoleMoiety

Oxadiazoles are five-membered heterocyclic compounds that possess one oxygen atomand two nitrogen atoms in the ring system [12]. Depending on the position of heteroatoms(oxygen or nitrogen), there are different isomeric forms of oxadiazole moiety such as 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole (Figure 2).These chemicalcompounds are of the azole family with the molecular formula C2H2N2O. Among theseisomers, 1,2,3-oxadiazole is unstable and ring-opens to form the diazoketone tautomer.However, 1,3,4-oxadiazole is a thermally stable aromatic molecule and plays a major rolein developing new drug candidates with diverse biological activities such as anticancer,antiparasitic, antifungal, antibacterial, antidepressant, antitubercular and antiinflammatory,etc. [13].


Figure 2. Chemical structures of oxadiazole isomers.

The electrophilic-substitution reaction is very difficult at the carbon atom in the oxadiazole ring because of the relatively low electron density on the carbon atom. How-ever, the electrophilic attack occurs at nitrogen if the oxadiazole ring is substituted with electron releasing groups. Similarly, the oxadiazole ring is usually resistant to nucleophilic attack. However, the halogen-substituted oxadiazole undergoes nucleophilic substitution with the replacement of halogen atom by nucleophiles [14]. Although 1,3,4-oxadiazole ring system was known in 1880, significant studies were carried out regarding its chemis-try, structure, physical properties and application of its various derivatives from 1950 (Ta-ble 1).1,3,4-oxadiazole is a liquid with a boiling point of 150 °C. The percentage of C, H, N present in 1,3,4-oxadiazole is 34.29%, 2.88%, 40.00%, respectively [15].

Table 1. Bond angle and bond length of 1,3,4-oxadiazole moiety.

N

O

Na

b

cd

e

1

2

34

5

A

BCD

E

Angles Bond Angle (°) Bonds Bond Length (Pm)

A 105.6 a 139.9

B 113.4 b 129.7

C 102.0 c 134.8

D 113.4 d 134.8

E 105.6 e 129.7

The first monosubstituted 1,3,4-oxadiazoles were reported in 1955 by two independ-ent laboratories. Since 1955, other research groups have performed the reactions of 1,3,4-oxadiazole and reported that it is a liquid that boils at 150°C. Ainsworth first prepared 1,3,4-oxadiazole (2) in 1965 by the thermolysis of ethylformate formyl hydrazone (1) at atmospheric pressure as depicted in Scheme 1 [16].

Scheme 1. Synthesis of 1,3,4-oxadiazole.

ON

N

ON

N

NO

NO

NN

12

34

5 5 5 5

4 4 43 3 3

2 2 2

1 1 1

1,2,3-oxadiazole 1,2,4-oxadiazole 1,2,5-oxadiazole 1,3,4-oxadiazole

O

HCHN N COOC2H5

Heat

O

NN

+ C2H5OH

(1) (2)


The electrophilic-substitution reaction is very difficult at the carbon atom in theoxadiazole ring because of the relatively low electron density on the carbon atom. However,the electrophilic attack occurs at nitrogen if the oxadiazole ring is substituted with electronreleasing groups. Similarly, the oxadiazole ring is usually resistant to nucleophilic attack.However, the halogen-substituted oxadiazole undergoes nucleophilic substitution withthe replacement of halogen atom by nucleophiles [14]. Although 1,3,4-oxadiazole ringsystem was known in 1880, significant studies were carried out regarding its chemistry,structure, physical properties and application of its various derivatives from 1950 (Table 1).1,3,4-oxadiazole is a liquid with a boiling point of 150 ◦C. The percentage of C, H, N presentin 1,3,4-oxadiazole is 34.29%, 2.88%, 40.00%, respectively [15].


Molecules 2021, 26, x FOR PEER REVIEW 4 of 24




N

O

Na

b

cd

e

1

2

34

5

A

BCD

E


A 105.6 a 139.9

B 113.4 b 129.7

C 102.0 c 134.8

D 113.4 d 134.8

E 105.6 e 129.7



ON

N

ON

N

NO

NO

NN

12

34

5 5 5 5

4 4 43 3 3

2 2 2

1 1 1


O

HCHN N COOC2H5

Heat

O

NN

+ C2H5OH

(1) (2)

Angles Bond Angle (◦) Bonds Bond Length (Pm)

A 105.6 a 139.9

B 113.4 b 129.7

C 102.0 c 134.8

D 113.4 d 134.8

E 105.6 e 129.7

The first monosubstituted 1,3,4-oxadiazoles were reported in 1955 by two independentlaboratories. Since 1955, other research groups have performed the reactions of 1,3,4-oxadiazole and reported that it is a liquid that boils at 150◦C. Ainsworth first prepared1,3,4-oxadiazole (2) in 1965 by the thermolysis of ethylformate formyl hydrazone (1) atatmospheric pressure as depicted in Scheme 1 [16].





N

O

Na

b

cd

e

1

2

34

5

A

BCD

E


A 105.6 a 139.9

B 113.4 b 129.7

C 102.0 c 134.8

D 113.4 d 134.8

E 105.6 e 129.7



ON

N

ON

N

NO

NO

NN

12

34

5 5 5 5

4 4 43 3 3

2 2 2

1 1 1


O

HCHN N COOC2H5

Heat

O

NN

+ C2H5OH

(1) (2)Scheme 1. Synthesis of 1,3,4-oxadiazole.

The 1,2,4-oxadiazole was synthesized first time in 1884 by Tiemann and Kruger. Mostof the oxadiazole synthesis is based on heterocyclization of amidoxime and carboxylic

Molecules 2021, 26, 1163 5 of 23

acid derivatives or 1,3-dipolar cycloaddition of nitrile and nitrile oxide [17]. Microwaveirradiation can also be applied in the heterocyclization of amidoximes and acyl chlo-rides/carboxylic acid esters in the presence of NH4F/Al2O3 or K2CO3 to produce corre-sponding oxadiazole derivatives [18]. Similarly, oxadiazole derivatives are produced bythe reaction of aryl-nitrile with hydroxylamine hydrochloride to aryl-amidoxime inthepresence of a catalyst (MgO or CH3COOH or KF) under a microwave-assisted method. Inthe year 2017, Baykov et al. reported a study on the first one-pot synthetic procedure forthe synthesis of 3,5-disubstituted-1,2,4-oxadiazoles (3) at room temperature from corre-sponding amidoximes (1) and carboxylic acids methyl or ethyl esters (2) in the presence ofsuperbase medium NaOH/DMSOas presented in the Scheme 2 [19,20].


The 1,2,4-oxadiazole was synthesized first time in 1884 by Tiemann and Kruger. Most of the oxadiazole synthesis is based on heterocyclization of amidoxime and carboxylic acid derivatives or 1,3-dipolar cycloaddition of nitrile and nitrile oxide [17]. Microwave irradiation can also be applied in the heterocyclization of amidoximes and acyl chlo-rides/carboxylic acid esters in the presence of NH4F/Al2O3 or K2CO3 to produce corre-sponding oxadiazole derivatives [18].Similarly, oxadiazole derivatives are produced by the reaction of aryl-nitrile with hydroxylamine hydrochloride to aryl-amidoxime inthe presence of a catalyst (MgO or CH3COOH or KF) under a microwave-assisted method.In the year 2017, Baykov et al. reported a study on the first one-pot synthetic procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles (3) at room temperature from corre-sponding amidoximes (1) and carboxylic acids methyl or ethyl esters (2) in the presence of superbase medium NaOH/DMSOas presented in the Scheme 2 [19,20].

Scheme 2. Synthesis of 1,2,4-oxadiazole analogs. R1 = 4-methylphenyl, R2 = methyl or phenyl, X = methoxy or ethoxy.

Gorjizadeh et al. reported the efficient synthesis of a series of 1,3,4-oxadiazoles (3) from the cyclization–oxidation reaction of acyl hydrazones (1) with substituted aldehydes (2) by using 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate (BTPPDS) as an ox-idant in a solvent-free medium under microwave irradiation (Scheme 3). The reaction was found to proceed smoothly under microwave irradiation within 25 min, whereas 12 h were required to complete the reaction under reflux conditions [21].

Scheme 3. Synthesis of a series of 1,3,4-oxadiazoles.

4. Therapeutic Potentials of Oxadiazole Derivatives Various medicinally active drug molecules containing oxadiazole moiety are used

clinically for the treatment of different disease states (Figure 3).Oxolamine possesses a 1,2,4-oxadiazole ring and is used as a cough suppressant.Similarly, prenoxdiazine is a cough suppressant. Its IUPAC name is 3-(2,2-diphenylethyl)-5-(2-piperidin-1-ylethyl)-1,2,4-oxadiazole. Proxazole is chemically N,N-diethyl-2-[3-(1-phenylpropyl)-1,2,4-oxadi-azol-5-yl]ethanamine. It is a drug used for functional gastrointestinal disorders. Butala-mine is a vasodilator and is chemically known as N′,N′-dibutyl-N-(3-phenyl-1,2,4-oxadi-azol-5-yl)ethane-1,2-diamine.

NOH

NH2R1

+O

XR2

NaOH/DMSO

RT

N

NO R2

R1

1 2 3

1 2 3

+OPh

H2NHNR-CHO

BTPPDS

MWI, SiO2, 25min

O

N N

R Ph

Scheme 2. Synthesis of 1,2,4-oxadiazole analogs. R1 = 4-methylphenyl, R2 = methyl or phenyl,X = methoxy or ethoxy.

Gorjizadeh et al. reported the efficient synthesis of a series of 1,3,4-oxadiazoles (3) fromthe cyclization–oxidation reaction of acyl hydrazones (1) with substituted aldehydes (2) byusing 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate (BTPPDS) as an oxidant ina solvent-free medium under microwave irradiation (Scheme 3). The reaction was found toproceed smoothly under microwave irradiation within 25 min, whereas 12 h were requiredto complete the reaction under reflux conditions [21].


The 1,2,4-oxadiazole was synthesized first time in 1884 by Tiemann and Kruger. Most of the oxadiazole synthesis is based on heterocyclization of amidoxime and carboxylic acid derivatives or 1,3-dipolar cycloaddition of nitrile and nitrile oxide [17]. Microwave irradiation can also be applied in the heterocyclization of amidoximes and acyl chlo-rides/carboxylic acid esters in the presence of NH4F/Al2O3 or K2CO3 to produce corre-sponding oxadiazole derivatives [18].Similarly, oxadiazole derivatives are produced by the reaction of aryl-nitrile with hydroxylamine hydrochloride to aryl-amidoxime inthe presence of a catalyst (MgO or CH3COOH or KF) under a microwave-assisted method.In the year 2017, Baykov et al. reported a study on the first one-pot synthetic procedure for the synthesis of 3,5-disubstituted-1,2,4-oxadiazoles (3) at room temperature from corre-sponding amidoximes (1) and carboxylic acids methyl or ethyl esters (2) in the presence of superbase medium NaOH/DMSOas presented in the Scheme 2 [19,20].

Scheme 2. Synthesis of 1,2,4-oxadiazole analogs. R1 = 4-methylphenyl, R2 = methyl or phenyl, X = methoxy or ethoxy.

Gorjizadeh et al. reported the efficient synthesis of a series of 1,3,4-oxadiazoles (3) from the cyclization–oxidation reaction of acyl hydrazones (1) with substituted aldehydes (2) by using 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfate (BTPPDS) as an ox-idant in a solvent-free medium under microwave irradiation (Scheme 3). The reaction was found to proceed smoothly under microwave irradiation within 25 min, whereas 12 h were required to complete the reaction under reflux conditions [21].


4. Therapeutic Potentials of Oxadiazole Derivatives Various medicinally active drug molecules containing oxadiazole moiety are used

clinically for the treatment of different disease states (Figure 3).Oxolamine possesses a 1,2,4-oxadiazole ring and is used as a cough suppressant.Similarly, prenoxdiazine is a cough suppressant. Its IUPAC name is 3-(2,2-diphenylethyl)-5-(2-piperidin-1-ylethyl)-1,2,4-oxadiazole. Proxazole is chemically N,N-diethyl-2-[3-(1-phenylpropyl)-1,2,4-oxadi-azol-5-yl]ethanamine. It is a drug used for functional gastrointestinal disorders. Butala-mine is a vasodilator and is chemically known as N′,N′-dibutyl-N-(3-phenyl-1,2,4-oxadi-azol-5-yl)ethane-1,2-diamine.

NOH

NH2R1

+O

XR2

NaOH/DMSO

RT

N

NO R2

R1

1 2 3

1 2 3

+OPh

H2NHNR-CHO

BTPPDS

MWI, SiO2, 25min

O

N N

R Ph


4. Therapeutic Potentials of Oxadiazole Derivatives

Various medicinally active drug molecules containing oxadiazole moiety are usedclinically for the treatment of different disease states (Figure 3).Oxolamine possesses a1,2,4-oxadiazole ring and is used as a cough suppressant.Similarly, prenoxdiazine is acough suppressant. Its IUPAC name is 3-(2,2-diphenylethyl)-5-(2-piperidin-1-ylethyl)-1,2,4-oxadiazole. Proxazole is chemically N,N-diethyl-2-[3-(1-phenylpropyl)-1,2,4-oxadiazol-5-yl]ethanamine. It is a drug used for functional gastrointestinal disorders. Butalamineis a vasodilator and is chemically known as N′,N′-dibutyl-N-(3-phenyl-1,2,4-oxadiazol-5-yl)ethane-1,2-diamine.


N O

N

N

O N

NN

ON

NN

Oxolamine Prenoxdiazine Proxazole

ON

N NH

N O N

N

COOH

F

O

NO

NO

NF3C

Butalamine Ataluren (PTC124) Pleconaril

Figure 3.Chemical structures of drugs based on a 1,2,4-oxadiazole moiety.

Ataluren (PTC124) is a drug for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union. Chemically, it is 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid. Pleconaril is an antiviral drug. It exhibits its action by inhibiting viral replication. It was developed by Schering-Plough for the prevention of asthma exacerbations and common cold symptoms in patients exposed to picornavirus respiratory infections. Chemically, it is 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole [22–24].

Carbone M. et al. isolated two indole alkaloids,phidianidine-A and phidianidine-B (Figure 4), from sea slug opisthobranch Phidiana militaris. Chemically, phidianidine-B is 2-[5-[[5-(1H-indol-3-ylmethyl)-1,2,4-oxadiazol-3-yl]amino]pentyl]guanidine. Both phidian-idines exhibit in vitro cytotoxic activity against tumor and non-tumor mammalian cell lines (rat glial-C6, human cervical-HeLa, colon adenocarcinoma-CaCo-2, mouse embryo-3T3-L1 and rat heart myoblast-H9c2) [25]. Similarly, quisqualic acid is a naturally occur-ring compound bearing 1,2,4-oxadiazole moiety. It is obtained from seeds of Quisqualis indica. It is usedfor the treatment of stroke, epilepsy and neurodegenerative disorders [26,27].

Figure 4. Structures of naturally occurring compounds containing 1,2,4-oxadiazole ring.

Tiodazosin is a new antihypertensive drug, structurally resembles prazosin. It pos-sesses alpha-adrenergic-blocking activity and exerts a direct vasodilation effect. Chemi-cally, it is (4-(4-amino-6,7-dimethoxyquinolin-2-yl)piperazin-1-yl)(5-(methylthio)-1,3,4-oxadiazol-2-yl)-methanone [28].Furamizole is a nitrofuran derivative and possesses anti-bacterial activity. Chemically, it is (E)-5-(1-(furan-2-yl)-2-(5-nitrofuran-2-yl)vinyl)-1,3,4-oxadiazol-2-amine.Raltegravir (MK-0518) is an antiretroviral drug produced by Merck and Co., Kenilworth, NJ, USA. It was approved by the U.S. Food and Drug Administration

NH2

H2N N

NH

ON

N

HNBr

O

NNH

O

OHOOC

H2N

Phidianidine-A Phidianidine-BQuisqualic acid

NH2

H2N N

NH

ON

N

HN

Figure 3. Chemical structures of drugs based on a 1,2,4-oxadiazole moiety.

Ataluren (PTC124) is a drug for the treatment of Duchenne muscular dystrophy. Itwas designed by PTC Therapeutics and is sold under the trade name Translarna in theEuropean Union. Chemically, it is 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid.Pleconaril is an antiviral drug. It exhibits its action by inhibiting viral replication. It wasdeveloped by Schering-Plough for the prevention of asthma exacerbations and commoncold symptoms in patients exposed to picornavirus respiratory infections. Chemically, itis 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole [22–24].

Carbone M. et al. isolated two indole alkaloids, phidianidine-A and phidianidine-B(Figure 4), from sea slug opisthobranch Phidiana militaris. Chemically, phidianidine-B is2-[5-[[5-(1H-indol-3-ylmethyl)-1,2,4-oxadiazol-3-yl]amino]pentyl]guanidine. Both phidi-anidines exhibit in vitro cytotoxic activity against tumor and non-tumor mammalian celllines (rat glial-C6, human cervical-HeLa, colon adenocarcinoma-CaCo-2, mouse embryo-3T3-L1 and rat heart myoblast-H9c2) [25]. Similarly, quisqualic acid is a naturally occurringcompound bearing 1,2,4-oxadiazole moiety. It is obtained from seeds of Quisqualis indica. Itis usedfor the treatment of stroke, epilepsy and neurodegenerative disorders [26,27].


N O

N

N

O N

NN

ON

NN

Oxolamine Prenoxdiazine Proxazole

ON

N NH

N O N

N

COOH

F

O

NO

NO

NF3C

Butalamine Ataluren (PTC124) Pleconaril

Figure 3.Chemical structures of drugs based on a 1,2,4-oxadiazole moiety.

Ataluren (PTC124) is a drug for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union. Chemically, it is 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid. Pleconaril is an antiviral drug. It exhibits its action by inhibiting viral replication. It was developed by Schering-Plough for the prevention of asthma exacerbations and common cold symptoms in patients exposed to picornavirus respiratory infections. Chemically, it is 3-[3,5-dimethyl-4-[3-(3-methyl-1,2-oxazol-5-yl)propoxy]phenyl]-5-(trifluoromethyl)-1,2,4-oxadiazole [22–24].

Carbone M. et al. isolated two indole alkaloids,phidianidine-A and phidianidine-B (Figure 4), from sea slug opisthobranch Phidiana militaris. Chemically, phidianidine-B is 2-[5-[[5-(1H-indol-3-ylmethyl)-1,2,4-oxadiazol-3-yl]amino]pentyl]guanidine. Both phidian-idines exhibit in vitro cytotoxic activity against tumor and non-tumor mammalian cell lines (rat glial-C6, human cervical-HeLa, colon adenocarcinoma-CaCo-2, mouse embryo-3T3-L1 and rat heart myoblast-H9c2) [25]. Similarly, quisqualic acid is a naturally occur-ring compound bearing 1,2,4-oxadiazole moiety. It is obtained from seeds of Quisqualis indica. It is usedfor the treatment of stroke, epilepsy and neurodegenerative disorders [26,27].


Tiodazosin is a new antihypertensive drug, structurally resembles prazosin. It pos-sesses alpha-adrenergic-blocking activity and exerts a direct vasodilation effect. Chemi-cally, it is (4-(4-amino-6,7-dimethoxyquinolin-2-yl)piperazin-1-yl)(5-(methylthio)-1,3,4-oxadiazol-2-yl)-methanone [28].Furamizole is a nitrofuran derivative and possesses anti-bacterial activity. Chemically, it is (E)-5-(1-(furan-2-yl)-2-(5-nitrofuran-2-yl)vinyl)-1,3,4-oxadiazol-2-amine.Raltegravir (MK-0518) is an antiretroviral drug produced by Merck and Co., Kenilworth, NJ, USA. It was approved by the U.S. Food and Drug Administration

NH2

H2N N

NH

ON

N

HNBr

O

NNH

O

OHOOC

H2N

Phidianidine-A Phidianidine-BQuisqualic acid

NH2

H2N N

NH

ON

N

HN


Tiodazosin is a new antihypertensive drug, structurally resembles prazosin. It pos-sesses alpha-adrenergic-blocking activity and exerts a direct vasodilation effect. Chemically,it is (4-(4-amino-6,7-dimethoxyquinolin-2-yl)piperazin-1-yl)(5-(methylthio)-1,3,4-oxadiazol-2-yl)-methanone [28]. Furamizole is a nitrofuran derivative and possesses antibacterialactivity. Chemically, it is (E)-5-(1-(furan-2-yl)-2-(5-nitrofuran-2-yl)vinyl)-1,3,4-oxadiazol-2-amine.Raltegravir (MK-0518) is an antiretroviral drug produced by Merck and Co.,Kenilworth, NJ, USA. It was approved by the U.S. Food and Drug Administration (USFDA)in October 2007. It is the new class of anti-HIV drug and acts as an integrase inhibitor.

Molecules 2021, 26, 1163 7 of 23

Chemically, it is N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-(2-methyl-1,3,4-oxadiazole-5-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide. Nesapidilisacal-cium channel blocker and exerts vasodilation effect. Its IUPAC name is1-(3-(1,3,4-oxadiazol-2-yl)phenoxy)-3-(4-(3-methoxyphenyl)piperazin-1-yl)propan-2-ol (Figure 5, Table 2) [29,30].


(USFDA) in October 2007. It is the new class of anti-HIV drug and acts as an integrase inhibitor. Chemically, it is N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(2-(2-methyl-1,3,4-oxadiazole-5-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidine-4-carboxamide. Nesapidilisacalcium channel blocker and exerts vasodilation effect. Its IUPAC name is1-(3-(1,3,4-oxadiazol-2-yl)phenoxy)-3-(4-(3-methoxyphenyl)piperazin-1-yl)propan-2-ol (Figure 5, Table 2) [29,30].

.

Figure 5. Structure of clinically useful drugs containing 1,3,4-oxadiazole scaffold.

Table 2. Therapeutic potentials oxadiazole derivatives.

Type Oxadiazole Derivatives Name of Compounds Therapeutic Uses

1,2,4-oxadiazole

Phidianidine-A, B Antitumor Quisqualic acid Antiepileptic

Oxolamine Cough suppressant Prenoxdiazine Cough suppressant

Butalamine Vasodilator Fasiplon Anxiolytic

Pleconaril Antiviral Ataluren Treatment of muscular dystrophy Proxazole Treatment of GI disorders

1,3,4-oxadiazole

Tiodazosin Antihypertensive Furamizole Antibacterial Raltegravir Antiretroviral Nesapidil Vasodilator

Zibotentan Anticancer

5. Microwave-Assisted Synthesis of Biologically Active Oxadiazoles Microwave-assisted drug synthesis is a Green technology that utilizes microwave ra-

diation as a heating source to perform various synthetic reactions. The microwave radia-tion is used as an alternative energy source to complete various organic transformations in minutes instead of hours or even days. Microwaves are electromagnetic radiation with wavelengths ranging from one meter to one millimeter with frequencies between 300 MHz and 300 GHz [31]. These high-frequency electric fields of the microwave are applied

N

NH2

H3CO

H3CO N

N

O

NN

OSCH3

Tiodazosin Furamizole

N N

OH2NO

O

N

O

O

N

N

O

OHH3C

O

HN

F

HN

O

NN

OH3C

H3C CH3

Raltegravir (MK-0518)

NN

OOH

ONN

O

Nesapidil

Figure 5. Structure of clinically useful drugs containing 1,3,4-oxadiazole scaffold.

Table 2. Therapeutic potentials oxadiazole derivatives.

Type Oxadiazole Derivatives Name of Compounds Therapeutic Uses

1,2,4-oxadiazole

Phidianidine-A, B Antitumor

Quisqualic acid Antiepileptic

Oxolamine Cough suppressant

Prenoxdiazine Cough suppressant

Butalamine Vasodilator

Fasiplon Anxiolytic

Pleconaril Antiviral

Ataluren Treatment of musculardystrophy

Proxazole Treatment of GI disorders

1,3,4-oxadiazole

Tiodazosin Antihypertensive

Furamizole Antibacterial

Raltegravir Antiretroviral

Nesapidil Vasodilator

Zibotentan Anticancer

5. Microwave-Assisted Synthesis of Biologically Active Oxadiazoles

Microwave-assisted drug synthesis is a Green technology that utilizes microwaveradiation as a heating source to perform various synthetic reactions. The microwave radia-tion is used as an alternative energy source to complete various organic transformationsin minutes instead of hours or even days. Microwaves are electromagnetic radiation withwavelengths ranging from one meter to one millimeter with frequencies between 300 MHzand 300 GHz [31]. These high-frequency electric fields of the microwave are applied to heat

Molecules 2021, 26, 1163 8 of 23

the reacting substances of an organic reaction with electric charges. In the case of the polarreaction medium, these are heated due to their dipolar rotation with the electric field andloose energy during collisions between reacting molecules. With the help of microwaveheating technology, the rate of organic synthesis can be improved, and the drug productscan be manufactured selectively by utilizing suitable microwave parameters. Thus, mi-crowave technology provides several advantages such as instantaneous, rapid heating,homogeneity and selective heating as compared to conventional heating techniques likewater bath, oil bath or sand batch, etc. [32].

The synthesis of drug substances under microwave irradiation is primarily dependenton the ability of the reaction medium to absorb microwave energy efficiently and alsodepends on the selection of the solvent system to perform the synthetic reaction [33]. Dueto the diverse polar and ionic properties of different solvents, they interact differentlywith microwave radiation. Hence, the ability of suitable solvents or reaction mediumto convert microwave energy to heat is called as loss tangent (δ). Based on the value oftan δ, solvents can be categorized into high (tanδ > 0.5), medium (tanδ 0.1–0.5), and lowmicrowave absorbing (tanδ < 0.1) type. Higher the value of tan δ represents that the solventis suitable for absorption of microwave radiation so as to causes efficient heating [34].

Polar solvents such as DMA, DMF, DMSO, NMP, methanol, ethanol, and acetic acidare selected for carrying out organic synthesis under microwaves due to their polarity.The solvents with low boiling points (e.g., methanol, dichloromethane and acetone) havelower reaction temperatures due to the pressure developed inside the reaction vessel. Ifa higher temperature is desirable to achieve a faster reaction, it is suggested to changethe closely related solvent with a higher boiling point (e.g., dichloroethane instead ofdichloromethane). Solvents can behave differently at elevated temperatures, and most ofthe solvents become less polar with an increase in temperature. For example, the bondangle in water widens at elevated temperatures, and its dielectric properties approachthe organic solvents. Similarly, water at 250 ◦C possesses similar dielectric properties likeacetonitrile at room temperature. Hence, water can be used as a pseudo-organic solvent atelevated temperatures where organic compounds will dissolve, not only because of thetemperature but also because of the change in dielectric properties. Nonpolar solvents(e.g., toluene, dioxane, THF) can only be heated if other components in the reaction mixturerespond to microwave energy [35,36].

However, ionic liquids (ILs) are reported as new, environmentally friendly, recyclablealternatives to dipolar aprotic solvents for organic synthesis. ILs are salts consisting of ions,which exist in the liquid state at ambient temperatures (<100 ◦C or 212 ◦F). [EtNH3][NO3]was the first example of a protic ionic liquid with a melting point of 12 ◦C. The ionicliquids possess unique physicochemical properties, such as negligible vapor pressure, highionic conductivity, excellent solubility with many substances, high thermal and chemicalstabilities. The dielectric properties of ionic liquids make them most suitable to utilize assolvents in microwave accelerated organic synthesis. As ionic liquids possess ions withlow vapor pressure, they absorb microwave irradiation more efficiently [37,38].

Various oxadiazole derivatives are subjected to synthesis under microwave irradi-ation, and their biological activities are reported that include antibacterial, antifungal,antiviral, anticonvulsant, antitumor, antimalarial, antitubercular, anti-asthmatic, antide-pressant, antidiabetic, antioxidant, antiparkinsonian, analgesic and antiinflammatory, etc.(Figure 6) [39–44].

Microwave-assisted synthesis permitresearcher to synthesize drug molecules withhigh purity and to scale up the experiments reliably from milligrams to larger quantitieswithout altering the reaction conditions. It provides precise control over conditions oftemperature and pressure as compared to conventional heating methods. In the case ofa solvent-less or solvent-free reaction, the microwave energy is directly absorbed by thereactant molecules [45–48].


Oxadiazole Derivatives Anti-inflammatory

AnticonvulsantAntitumor

Anti-malarial

Antiviral

Anti-tubercular

Antifungal

Antibacterial

Figure 6. Biological activities of oxadiazole derivatives.

Microwave-assisted synthesis permitresearcher to synthesize drug molecules with high purity and to scale up the experiments reliably from milligrams to larger quantities without altering the reaction conditions. It provides precise control over conditions of temperature and pressure as compared to conventional heating methods. In the case of a solvent-less or solvent-free reaction, the microwave energy is directly absorbed by the re-actant molecules[45–48].

5.1. Oxadiazole Derivatives as Analgesic and AntiinflammatoryAgents Hyperalgesia refers to the enhancement in sensitivity to pain caused by nociceptors

or peripheral nerves. Analgesics are the agents that relieve the pain by acting selectively on the CNS and peripheral pain mediators without changing consciousness. Analgesics may be narcotic or non-narcotic. Inflammation is a complex biological response that oc-curs when the body is exposed to infective agents or to physical or chemical injury. In-flammation may be three types such as acute (inflammation lasts for few days), subacute (inflammation lasts for 2–6 weeks) and chronic inflammation (inflammation lasts for months or years). The inflammatory mediators are the messenger that acts on blood ves-sels or cells to promote the inflammatory responses. Various inflammatory mediators in-clude prostaglandins (PGs), inflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-15 and chemokines such as IL-8 and GRO-alpha. The treatment of inflammation depends on the cause and severity. Due to the presence of common side effects of NSAIDs (gas, bloat-ing, heartburn, ulcer, stomach pain), it is required to develop new drugs for the treatment of pain and inflammation without any side effects. Hence, theoxadiazole derivatives play a major role in the treatment of pain and inflammation as compared to NSAIDs [49,50].

Bijuet al. reported the design and microwave-assisted synthesis of 1,3,4-oxadiazole derivatives for analgesic and antiinflammatoryactivity.In step-I, a mixture of isoniazid, aromatic aldehyde and DMF (5 drops) was subjected to microwave irradiation at 300 w for 3 min to get the solid product (1a).In step-II, chloramine-T was added to the solution of compound 1a in ethanol. The reaction mixture was subjected to microwave irradiation at 300W for 4 min to yield 2-aryl-5-(4-pyridyl)-1,3,4-oxadiazole (2a–i) (Scheme 4).Among the newly synthesized 1,3,4-oxadiazole analogs,compounds 2a, 2c and 2i displayed good analgesic and antiinflammatory activity as compared to the standard drug,indomethacin.

Figure 6. Biological activities of oxadiazole derivatives.

5.1. Oxadiazole Derivatives as Analgesic and Antiinflammatory Agents

Hyperalgesia refers to the enhancement in sensitivity to pain caused by nociceptors orperipheral nerves. Analgesics are the agents that relieve the pain by acting selectively on theCNS and peripheral pain mediators without changing consciousness. Analgesics may benarcotic or non-narcotic. Inflammation is a complex biological response that occurs whenthe body is exposed to infective agents or to physical or chemical injury. Inflammation maybe three types such as acute (inflammation lasts for few days), subacute (inflammation lastsfor 2–6 weeks) and chronic inflammation (inflammation lasts for months or years). Theinflammatory mediators are the messenger that acts on blood vessels or cells to promotethe inflammatory responses. Various inflammatory mediators include prostaglandins(PGs), inflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-15 and chemokinessuch as IL-8 and GRO-alpha. The treatment of inflammation depends on the cause andseverity. Due to the presence of common side effects of NSAIDs (gas, bloating, heartburn,ulcer, stomach pain), it is required to develop new drugs for the treatment of pain andinflammation without any side effects. Hence, theoxadiazole derivatives play a major rolein the treatment of pain and inflammation as compared to NSAIDs [49,50].

Biju et al. reported the design and microwave-assisted synthesis of 1,3,4-oxadiazolederivatives for analgesic and antiinflammatoryactivity. In step-I, a mixture of isoniazid,aromatic aldehyde and DMF (5 drops) was subjected to microwave irradiation at 300 wfor 3 min to get the solid product (1a). In step-II, chloramine-T was added to the solutionof compound 1a in ethanol. The reaction mixture was subjected to microwave irradiationat 300W for 4 min to yield 2-aryl-5-(4-pyridyl)-1,3,4-oxadiazole (2a–i) (Scheme 4). Amongthe newly synthesized 1,3,4-oxadiazole analogs, compounds 2a, 2c and 2i displayed goodanalgesic and antiinflammatory activity as compared to the standard drug, indomethacin.From the acute toxicity study, it is revealed that the oxadiazole analogs are safe with lowtoxicity [51].

Molecules 2021, 26, 1163 10 of 23


From the acute toxicity study, it is revealed that the oxadiazole analogs are safe with low toxicity [51].

N

O NHNH2

+

CHO

R

N

OHN

N

HC

R

N

N N

O RChloramine-T

(2a - i)MWI

1a

DMF

MWI, Ethanol

Scheme 4.Microwave-assisted synthesis of 1,3,4-oxadiazole derivatives (2a–i).

Frank et al. reported the microwave-assisted as well as the conventional synthesis of 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles containing the ni-troimidazole moiety (Scheme 5).These compounds are evaluated forantiinflammatory ac-tivity based on the method of Winter et al. Formalin-induced edema test was employed. All the tested compounds exhibitantiinflammatory activity at a dose of 50 mg/kg. The antiinflammatory activity of 7b, 7c and 7d is compared with that of a standard drug (in-domethacin) at a dose of 1⋅5 mg/kg [52].

NH

N CH3O2N+ ClCH2COOC2H5

Dry Acetone

K2CO3,

N

N CH3O2N

CH2COOC2H5

NH2.NH2.H2O

N

N CH3O2N

CH2CONHNH2

(1) (2) (3)

(4)

EtOH

RCOOH (5/6)

POCl3Conventional/MWI

N

N CH3O2N

(7a - l)

N N

O R

Scheme 5.Synthesis of 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles (7a–l).

Sahoo et al. reported a series of various Schiff bases of 1,3,4-oxadiazole analogs (Scheme 6). These compounds are synthesized by utilizing the principles involved in green chemistry that significantly reduce the chemical waste and reaction time. To demon-strate these advantages in the synthesis of bioactive oxadiazole derivatives, various envi-ronmentally benign protocols that involve greener alternatives are studied. The efficiency of microwave heating technology has resulted in remarkable reductions of reaction times from hours to minutes with better product yield. The antiinflammatoryactivity of the se-lected compounds is evaluated. This result indicates that some of the compounds exhibit significant activity as compared to standard Indomethacin [53].

Scheme 4. Microwave-assisted synthesis of 1,3,4-oxadiazole derivatives (2a–i).

Frank et al. reported the microwave-assisted as well as the conventional synthesisof 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles containing thenitroimidazole moiety (Scheme 5).These compounds are evaluated forantiinflammatoryactivity based on the method of Winter et al. Formalin-induced edema test was employed.All the tested compounds exhibitantiinflammatory activity at a dose of 50 mg/kg. Theantiinflammatory activity of 7b, 7c and 7d is compared with that of a standard drug(indomethacin) at a dose of 1·5 mg/kg [52].


From the acute toxicity study, it is revealed that the oxadiazole analogs are safe with low toxicity [51].

N

O NHNH2

+

CHO

R

N

OHN

N

HC

R

N

N N

O RChloramine-T

(2a - i)MWI

1a

DMF

MWI, Ethanol

Scheme 4.Microwave-assisted synthesis of 1,3,4-oxadiazole derivatives (2a–i).

Frank et al. reported the microwave-assisted as well as the conventional synthesis of 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles containing the ni-troimidazole moiety (Scheme 5).These compounds are evaluated forantiinflammatory ac-tivity based on the method of Winter et al. Formalin-induced edema test was employed. All the tested compounds exhibitantiinflammatory activity at a dose of 50 mg/kg. The antiinflammatory activity of 7b, 7c and 7d is compared with that of a standard drug (in-domethacin) at a dose of 1⋅5 mg/kg [52].

NH

N CH3O2N+ ClCH2COOC2H5

Dry Acetone

K2CO3,

N

N CH3O2N

CH2COOC2H5

NH2.NH2.H2O

N

N CH3O2N

CH2CONHNH2

(1) (2) (3)

(4)

EtOH

RCOOH (5/6)

POCl3Conventional/MWI

N

N CH3O2N

(7a - l)

N N

O R

Scheme 5.Synthesis of 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles (7a–l).

Sahoo et al. reported a series of various Schiff bases of 1,3,4-oxadiazole analogs (Scheme 6). These compounds are synthesized by utilizing the principles involved in green chemistry that significantly reduce the chemical waste and reaction time. To demon-strate these advantages in the synthesis of bioactive oxadiazole derivatives, various envi-ronmentally benign protocols that involve greener alternatives are studied. The efficiency of microwave heating technology has resulted in remarkable reductions of reaction times from hours to minutes with better product yield. The antiinflammatoryactivity of the se-lected compounds is evaluated. This result indicates that some of the compounds exhibit significant activity as compared to standard Indomethacin [53].

Scheme 5. Synthesis of 5-substituted-2-(2-methyl-4-nitro-1-imidazomethyl)-1,3,4-oxadiazoles (7a–l).

Sahoo et al. reported a series of various Schiff bases of 1,3,4-oxadiazole analogs(Scheme 6). These compounds are synthesized by utilizing the principles involved in greenchemistry that significantly reduce the chemical waste and reaction time. To demonstratethese advantages in the synthesis of bioactive oxadiazole derivatives, various environ-mentally benign protocols that involve greener alternatives are studied. The efficiency ofmicrowave heating technology has resulted in remarkable reductions of reaction timesfrom hours to minutes with better product yield. The antiinflammatoryactivity of theselected compounds is evaluated. This result indicates that some of the compounds exhibitsignificant activity as compared to standard Indomethacin [53].


NH2

COOH(1)

C2H5OH

Conc.H2SO4

NH2

COOC2H5(2)

NH2.NH2.H2ONH2

CONHNH2

CS2/KOHN NH

O S

NH2

N NH

O S

N CH

R

CHO

R

Microwave ( 10-20 min, 210W)

or Conventional ( Reflux 5-6h)

(3)(4)

(4a - j) Scheme 6. Synthetic route of Schiff base of 1,3,4-oxadiazole analogs (4a–j).

Both conventional and microwave-assisted methods are applied to synthesize vari-ous 2-(4′-methylbiphenyl-2-yl)-5-aryl-1,3,4-oxadiazole analogs (4a–n) (Scheme 7). These compounds are further evaluated for analgesic and antiinflammatory activity by invi-vomodels. The tested compounds exhibited significant analgesic and antiinflammatory activities as compared to standard drugs. Docking studies are performed to determine the binding mode of designed compounds with the COX-2 enzyme. The pharmacokinetic pa-rameters are calculated for the synthesized compounds and are found to be within the acceptable range defined for human use revealing their potential as possible drug-like compounds. Hence, the results obtained indicate that these compounds can serve as good leads for further modification and optimization [54].

H3C

HOOC

H2SO4

C2H5OHH3C

C2H5OOC

NH2.NH2.H2OH3C

C

H3C

ON

N

R

R-COOHPOCl3

3

MWI

21

4(a - n)

O

H2N-HN

Scheme 7. Synthesis of various 2-(4′-methylbiphenyl-2-yl)-5-aryl-1,3,4-oxadiazole analogs (4a–n).

5.2. Oxadiazole Derivatives as Antioxidant and Antimicrobial Agents Farshori et al. reported the facile one-pot synthesis of novel 2,5-disubstituted-1,3,4-

oxadiazoles under conventional and microwave conditions(Scheme 8) and evaluation of their in vitro antimicrobial activities. The newly synthesized compounds are screened for

Scheme 6. Synthetic route of Schiff base of 1,3,4-oxadiazole analogs (4a–j).

Both conventional and microwave-assisted methods are applied to synthesize various2-(4′-methylbiphenyl-2-yl)-5-aryl-1,3,4-oxadiazole analogs (4a–n) (Scheme 7). These com-pounds are further evaluated for analgesic and antiinflammatory activity by invivomodels.The tested compounds exhibited significant analgesic and antiinflammatory activities ascompared to standard drugs. Docking studies are performed to determine the bindingmode of designed compounds with the COX-2 enzyme. The pharmacokinetic parametersare calculated for the synthesized compounds and are found to be within the acceptablerange defined for human use revealing their potential as possible drug-like compounds.Hence, the results obtained indicate that these compounds can serve as good leads forfurther modification and optimization [54].


NH2

COOH(1)

C2H5OH

Conc.H2SO4

NH2

COOC2H5(2)

NH2.NH2.H2ONH2

CONHNH2

CS2/KOHN NH

O S

NH2

N NH

O S

N CH

R

CHO

R

Microwave ( 10-20 min, 210W)

or Conventional ( Reflux 5-6h)

(3)(4)

(4a - j) Scheme 6. Synthetic route of Schiff base of 1,3,4-oxadiazole analogs (4a–j).

Both conventional and microwave-assisted methods are applied to synthesize vari-ous 2-(4′-methylbiphenyl-2-yl)-5-aryl-1,3,4-oxadiazole analogs (4a–n) (Scheme 7). These compounds are further evaluated for analgesic and antiinflammatory activity by invi-vomodels. The tested compounds exhibited significant analgesic and antiinflammatory activities as compared to standard drugs. Docking studies are performed to determine the binding mode of designed compounds with the COX-2 enzyme. The pharmacokinetic pa-rameters are calculated for the synthesized compounds and are found to be within the acceptable range defined for human use revealing their potential as possible drug-like compounds. Hence, the results obtained indicate that these compounds can serve as good leads for further modification and optimization [54].

H3C

HOOC

H2SO4

C2H5OHH3C

C2H5OOC

NH2.NH2.H2OH3C

C

H3C

ON

N

R

R-COOHPOCl3

3

MWI

21

4(a - n)

O

H2N-HN


5.2. Oxadiazole Derivatives as Antioxidant and Antimicrobial Agents Farshori et al. reported the facile one-pot synthesis of novel 2,5-disubstituted-1,3,4-

oxadiazoles under conventional and microwave conditions(Scheme 8) and evaluation of their in vitro antimicrobial activities. The newly synthesized compounds are screened for


5.2. Oxadiazole Derivatives as Antioxidant and Antimicrobial Agents

Farshori et al. reported the facile one-pot synthesis of novel 2,5-disubstituted-1,3,4-oxadiazoles under conventional and microwave conditions (Scheme 8) and evaluationof their in vitro antimicrobial activities. The newly synthesized compounds are screened

Molecules 2021, 26, 1163 12 of 23

for their antibacterial activity against Escherichia coli (ATCC-25922), methicillin-resistantStaphylococcus aureus (MRSA +Ve), Pseudomonas aeruginosa (ATCC-27853), Streptococcuspyogenes and Klebsiella pneumoniae (clinical isolate) bacterial strains by disc diffusion method.Ciprofloxacin (30 µg) is used as a positive control.


their antibacterial activity against Escherichia coli (ATCC-25922), methicillin-resistant Staphylococcus aureus (MRSA +Ve), Pseudomonas aeruginosa (ATCC-27853), Streptococcus py-ogenes and Klebsiella pneumoniae (clinical isolate) bacterial strains by disc diffusion method. Ciprofloxacin (30 µg) is used as a positive control.

Similarly, antifungal activity is determined by the disk diffusion method against Can-dida albicans,Aspergillus fumigatus, Penicillium marneffei and Trichophytonmentagrophytes (recultured) in DMSO. The fungal activity of each compound is compared with greseoful-vin as a standard drug. The compounds 3f, 3j and 3l, are found to be the most potent antimicrobial agents. The lowest concentration (highest dilution) required to arrest the growth of the fungus is regarded as a minimum inhibitory concentration (MIC). Similarly, MFC is defined as the lowest drug concentration at which 99.9% of the inocula are killed [55].

R

OH2N-HN R1

O

OH

+O

NN

R R1

1 (a - f) 2 (a - b) 3 (a - l)

POCl3

Reflux

POCl3,Al2O3

MWI

Scheme 8. Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles under conventional and microwave irradiation (3a–l).

A new series of novel chromene-based oxadiazole derivatives are synthesized from a variety of Chromene-based amidoximes with readily available carboxylic acids under both conventional heating and microwave irradiation method (Scheme 9). The coupling reagents such as EDCI and HOBt in DMF are subjected to microwave heating that results in high yields and purities of the product, 1,2,4-oxadiazoles in an expeditious manner. The results were obtained for both conventional and microwave irradiation methods. It indi-cates that microwave irradiation led to an enhancement in the rate as well as the yield of the products (80–92%) over the conventional method (65–78%). All the synthesized com-pounds are evaluated for their invitro antibacterial activity against two different patho-genic bacterial strains, such as Escherichia coli (MTCC614) and Klebsiella pneumoniae (MTCC4031). The obtained results reveal that 6g and 6h exhibited good antibacterial ac-tivity as compared to the standard drug (Gentamicin) [56].

O

R2

R1

NOH

NH2

4 (a - i)

R6

R5

R4

R3

O

HO

5 (a - h)

O

R2

R1

N

ON

R6

R5

R4

R3

6 (a - r)

+Conventional

MWI

DMF,80oC,2-6h

DMF,30W,10-20min

R1= H, OMe, OEt, Cl, Br; R2= H, Cl, BrR3= H, OMe,Cl; R4= H, MeR5= H, OMe, Cl, Br; R6= H, OMe

Scheme 9.Synthesis of chromene-fused oxadiazole derivatives 6(a–r).

Bodke et al. reported the conventional and microwave-assisted synthesis of 5-phenyl-2-substituted-1,3,4-oxadiazole derivatives (Scheme 10). The title compounds are screened for their antimicrobial and antioxidant activity. The antimicrobial activity of the synthe-sized compounds is performed against four bacterial strains and two fungal strains (Chrysosporium keratinophilum and Candida albicans) by using the agar well diffusion

Scheme 8. Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles under conventional and microwaveirradiation (3a–l).

Similarly, antifungal activity is determined by the disk diffusion method againstCandida albicans, Aspergillus fumigatus, Penicillium marneffei and Trichophytonmentagrophytes(recultured) in DMSO. The fungal activity of each compound is compared with greseofulvinas a standard drug. The compounds 3f, 3j and 3l, are found to be the most potent antimi-crobial agents. The lowest concentration (highest dilution) required to arrest the growth ofthe fungus is regarded as a minimum inhibitory concentration (MIC). Similarly, MFC isdefined as the lowest drug concentration at which 99.9% of the inocula are killed [55].

A new series of novel chromene-based oxadiazole derivatives are synthesized from avariety of Chromene-based amidoximes with readily available carboxylic acids under bothconventional heating and microwave irradiation method (Scheme 9). The coupling reagentssuch as EDCI and HOBt in DMF are subjected to microwave heating that results in highyields and purities of the product, 1,2,4-oxadiazoles in an expeditious manner. The resultswere obtained for both conventional and microwave irradiation methods. It indicates thatmicrowave irradiation led to an enhancement in the rate as well as the yield of the products(80–92%) over the conventional method (65–78%). All the synthesized compounds areevaluated for their invitro antibacterial activity against two different pathogenic bacterialstrains, such as Escherichia coli (MTCC614) and Klebsiella pneumoniae (MTCC4031). Theobtained results reveal that 6g and 6h exhibited good antibacterial activity as compared tothe standard drug (Gentamicin) [56].


their antibacterial activity against Escherichia coli (ATCC-25922), methicillin-resistant Staphylococcus aureus (MRSA +Ve), Pseudomonas aeruginosa (ATCC-27853), Streptococcus py-ogenes and Klebsiella pneumoniae (clinical isolate) bacterial strains by disc diffusion method. Ciprofloxacin (30 µg) is used as a positive control.

Similarly, antifungal activity is determined by the disk diffusion method against Can-dida albicans,Aspergillus fumigatus, Penicillium marneffei and Trichophytonmentagrophytes (recultured) in DMSO. The fungal activity of each compound is compared with greseoful-vin as a standard drug. The compounds 3f, 3j and 3l, are found to be the most potent antimicrobial agents. The lowest concentration (highest dilution) required to arrest the growth of the fungus is regarded as a minimum inhibitory concentration (MIC). Similarly, MFC is defined as the lowest drug concentration at which 99.9% of the inocula are killed [55].

R

OH2N-HN R1

O

OH

+O

NN

R R1

1 (a - f) 2 (a - b) 3 (a - l)

POCl3

Reflux

POCl3,Al2O3

MWI

Scheme 8. Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles under conventional and microwave irradiation (3a–l).

A new series of novel chromene-based oxadiazole derivatives are synthesized from a variety of Chromene-based amidoximes with readily available carboxylic acids under both conventional heating and microwave irradiation method (Scheme 9). The coupling reagents such as EDCI and HOBt in DMF are subjected to microwave heating that results in high yields and purities of the product, 1,2,4-oxadiazoles in an expeditious manner. The results were obtained for both conventional and microwave irradiation methods. It indi-cates that microwave irradiation led to an enhancement in the rate as well as the yield of the products (80–92%) over the conventional method (65–78%). All the synthesized com-pounds are evaluated for their invitro antibacterial activity against two different patho-genic bacterial strains, such as Escherichia coli (MTCC614) and Klebsiella pneumoniae (MTCC4031). The obtained results reveal that 6g and 6h exhibited good antibacterial ac-tivity as compared to the standard drug (Gentamicin) [56].

O

R2

R1

NOH

NH2

4 (a - i)

R6

R5

R4

R3

O

HO

5 (a - h)

O

R2

R1

N

ON

R6

R5

R4

R3

6 (a - r)

+Conventional

MWI

DMF,80oC,2-6h

DMF,30W,10-20min

R1= H, OMe, OEt, Cl, Br; R2= H, Cl, BrR3= H, OMe,Cl; R4= H, MeR5= H, OMe, Cl, Br; R6= H, OMe

Scheme 9.Synthesis of chromene-fused oxadiazole derivatives 6(a–r).

Bodke et al. reported the conventional and microwave-assisted synthesis of 5-phenyl-2-substituted-1,3,4-oxadiazole derivatives (Scheme 10). The title compounds are screened for their antimicrobial and antioxidant activity. The antimicrobial activity of the synthe-sized compounds is performed against four bacterial strains and two fungal strains (Chrysosporium keratinophilum and Candida albicans) by using the agar well diffusion

Scheme 9. Synthesis of chromene-fused oxadiazole derivatives 6(a–r).

Bodke et al. reported the conventional and microwave-assisted synthesis of 5-phenyl-2-substituted-1,3,4-oxadiazole derivatives (Scheme 10). The title compounds are screenedfor their antimicrobial and antioxidant activity. The antimicrobial activity of the syn-thesized compounds is performed against four bacterial strains and two fungal strains(Chrysosporium keratinophilum and Candida albicans) by using the agar well diffusion method.The compounds 3e and 3g are endowed with high antibacterial activity when compared

Molecules 2021, 26, 1163 13 of 23

with standard antibacterial drugs. Among all tested compounds, 3d and 3n displayedsignificant activity against both fungal pathogens with MIC values 750 µg/mL. Similarly,all the synthesized compounds are screened for free radical scavenging activity by theDPPH method. Among the tested compounds, 3a, 3b, 3c, 3e, and 3f have potential radi-cal scavengingactivity, while compounds 3a, 3b, 3c, 3h, and 3j have the potential metalchelating ability as compared to the standard drug. The antioxidant results revealed thatthe compounds exhibit antioxidant activity in a dose-dependent manner [57].


method. The compounds 3e and 3g are endowed with high antibacterial activity when compared with standard antibacterial drugs. Among all tested compounds, 3d and 3n displayed significant activity against both fungal pathogens with MIC values 750 µg/mL. Similarly, all the synthesized compounds are screened for free radical scavenging activity by the DPPH method. Among the tested compounds, 3a, 3b, 3c, 3e, and 3f have potential radical scavengingactivity,while compounds 3a, 3b, 3c, 3h, and 3j have the potential metal chelating ability as compared to the standard drug. The antioxidant results revealed that the compounds exhibit antioxidant activity in a dose-dependent manner [57].

O

O

1

NH2NH2.H2O

C2H5OH, Reflux, 4h

O

NH

NH2

2

O

NNR

3 (a - n)

R-COOHPOCl3C/M

Comp. R Compd. R Compd. R

3a N

NHN

3f

N NN

CH3

3k -C16H34

3b SBr

3g N

N

3l

ClCl

Cl

3c N

O

3h -C11H25 3m F

FF

3d N

N

3i -C13H27 3n

FF

F

3e

F

O 3j -C14H29 - -

Scheme 10. Synthesis of 5-phenyl-2-substituted-1,3,4-oxadiazole derivatives 3(a–n).

5.3. Oxadiazole Derivatives as Antimycobacterial Agents A series of newer analogs of 5-(pyridine-4-yl)-1,3,4-oxadiazole-2(3H)-thione is de-

signed and synthesized by incorporating 1,3,4-oxadiazole and bezo[d]thiazole by Man-nich base reaction using conventional as well as microwave irradiation method (Scheme 11). This process has considerable advantages such as milder reaction conditions, an ac-celerated rate of reaction, less time-consuming and higher product yields as compared to conventional heating methods.

Scheme 10. Synthesis of 5-phenyl-2-substituted-1,3,4-oxadiazole derivatives 3(a–n).

5.3. Oxadiazole Derivatives as Antimycobacterial Agents

A series of newer analogs of 5-(pyridine-4-yl)-1,3,4-oxadiazole-2(3H)-thione is de-signed and synthesized by incorporating 1,3,4-oxadiazole and bezo[d]thiazole by Mannichbase reaction using conventional as well as microwave irradiation method (Scheme 11).This process has considerable advantages such as milder reaction conditions, an accel-erated rate of reaction, less time-consuming and higher product yields as compared toconventional heating methods.


N

NH

O

NH2 N

O

NN

SH

N

O

NHN

S

N

O

NN

S

iii

NH

SN

R2

R1

(1a - j)

Scheme 11. Synthesis of 3-((substituted-benzo[d]thiazol-2-ylamino)methyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole-2(3h)-thi-one. Reaction condition:(i) potassium-o-ethyldithicarbonate, IPA: MeOH, 80 °C, 4 h. (ii) Conventional: 37% HCHO, sub-stituted-2-amino-benzo[d]thiazole, DMF: EtOH, 80 °C, 8–9 h and microwave: 37% HCHO, substituted-2-amino-benzo[d]thiazole, DMF: EtOH, 400 W, 10–12 min.

The synthesized compounds are evaluated for their antimycobacterial activity against M. tuberculosis. Among the tested compounds, compound 1c containing methyl group at ortho position on an aromatic ring exhibited better activity against M. tuberculosis H37Ra using the MABA method. Hence, the modification of substituents on bezo[d]thia-zole ring with various electron releasing and electron-withdrawing groups affect the ac-tivity [58].

5.4. Oxadiazole Derivatives with Antitumor Activity Oliveira et al. focused on microwave irradiation-assisted synthesis of N-cyclohexyl-

1,2,4-oxadiazole derivatives with antitumor activity. Arylamidoximes (1a–i) and dicyclo-hexyl-carbodiimide (DCC) in DMF is subjected to focused microwave irradiation (FMWI) to obtain 1,2,4-oxadiazoles (2a–i) with 61–81% yields (Scheme 12). All these compounds exhibit antiproliferative activity invitro against three human cancer cell lines, HCT-116, PC-3, and SNB-19. The cytotoxicity of the compounds is evaluated by using the MTT assay method.Compounds such as 2b (m-CH3) and 2c (m-Br) are found to have antitumor ac-tivity againstSNB-19 (13.62 mM) and PC-3 (21.74 mM), respectively [59].

N

NH2

OH

R+ N C N

MWI,150W, 10min

DMF

N O

N HNR

(1a - i) (2a - i) Scheme 12.Previously reported synthetic methods vs. this work (FMWI).

Modi et al. reported the synthesis of novel achiral and chiral amides incorporating the 1,3,4-oxadiazole ring by applying both conventional and microwave methods (Scheme 13). The synthesis of these compounds by microwave method produces comparatively more yield and requires less time to complete the reaction.The synthesized compounds are screened for microbial and cytotoxic activities. The synthesized compounds are tested for their antibacterial activity invitro against two microorganisms viz. Escherichia coli and

Scheme 11. Synthesis of 3-((substituted-benzo[d]thiazol-2-ylamino)methyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole-2(3h)-thione.Reaction condition:(i) potassium-o-ethyldithicarbonate, IPA: MeOH, 80 ◦C, 4 h. (ii) Conventional: 37% HCHO, substituted-2-amino-benzo[d]thiazole, DMF: EtOH, 80 ◦C, 8–9 h and microwave: 37% HCHO, substituted-2-amino-benzo[d]thiazole,DMF: EtOH, 400 W, 10–12 min.

The synthesized compounds are evaluated for their antimycobacterial activity againstM. tuberculosis. Among the tested compounds, compound 1c containing methyl group atortho position on an aromatic ring exhibited better activity against M. tuberculosis H37Rausing the MABA method. Hence, the modification of substituents on bezo[d]thiazole ringwith various electron releasing and electron-withdrawing groups affect the activity [58].

5.4. Oxadiazole Derivatives with Antitumor Activity

Oliveira et al. focused on microwave irradiation-assisted synthesis of N-cyclohexyl-1,2,4-oxadiazole derivatives with antitumor activity. Arylamidoximes (1a–i) and dicyclohexyl-carbodiimide (DCC) in DMF is subjected to focused microwave irradiation (FMWI) toobtain 1,2,4-oxadiazoles (2a–i) with 61–81% yields (Scheme 12). All these compoundsexhibit antiproliferative activity invitro against three human cancer cell lines, HCT-116,PC-3, and SNB-19. The cytotoxicity of the compounds is evaluated by using the MTTassay method.Compounds such as 2b (m-CH3) and 2c (m-Br) are found to have antitumoractivity againstSNB-19 (13.62 mM) and PC-3 (21.74 mM), respectively [59].


N

NH

O

NH2 N

O

NN

SH

N

O

NHN

S

N

O

NN

S

iii

NH

SN

R2

R1

(1a - j)

Scheme 11. Synthesis of 3-((substituted-benzo[d]thiazol-2-ylamino)methyl)-5-(pyridin-4-yl)-1,3,4-oxadiazole-2(3h)-thi-one. Reaction condition:(i) potassium-o-ethyldithicarbonate, IPA: MeOH, 80 °C, 4 h. (ii) Conventional: 37% HCHO, sub-stituted-2-amino-benzo[d]thiazole, DMF: EtOH, 80 °C, 8–9 h and microwave: 37% HCHO, substituted-2-amino-benzo[d]thiazole, DMF: EtOH, 400 W, 10–12 min.

The synthesized compounds are evaluated for their antimycobacterial activity against M. tuberculosis. Among the tested compounds, compound 1c containing methyl group at ortho position on an aromatic ring exhibited better activity against M. tuberculosis H37Ra using the MABA method. Hence, the modification of substituents on bezo[d]thia-zole ring with various electron releasing and electron-withdrawing groups affect the ac-tivity [58].

5.4. Oxadiazole Derivatives with Antitumor Activity Oliveira et al. focused on microwave irradiation-assisted synthesis of N-cyclohexyl-

1,2,4-oxadiazole derivatives with antitumor activity. Arylamidoximes (1a–i) and dicyclo-hexyl-carbodiimide (DCC) in DMF is subjected to focused microwave irradiation (FMWI) to obtain 1,2,4-oxadiazoles (2a–i) with 61–81% yields (Scheme 12). All these compounds exhibit antiproliferative activity invitro against three human cancer cell lines, HCT-116, PC-3, and SNB-19. The cytotoxicity of the compounds is evaluated by using the MTT assay method.Compounds such as 2b (m-CH3) and 2c (m-Br) are found to have antitumor ac-tivity againstSNB-19 (13.62 mM) and PC-3 (21.74 mM), respectively [59].

N

NH2

OH

R+ N C N

MWI,150W, 10min

DMF

N O

N HNR

(1a - i) (2a - i) Scheme 12.Previously reported synthetic methods vs. this work (FMWI).

Modi et al. reported the synthesis of novel achiral and chiral amides incorporating the 1,3,4-oxadiazole ring by applying both conventional and microwave methods (Scheme 13). The synthesis of these compounds by microwave method produces comparatively more yield and requires less time to complete the reaction.The synthesized compounds are screened for microbial and cytotoxic activities. The synthesized compounds are tested for their antibacterial activity invitro against two microorganisms viz. Escherichia coli and

Scheme 12. Previously reported synthetic methods vs. this work (FMWI).

Modi et al. reported the synthesis of novel achiral and chiral amides incorporating the1,3,4-oxadiazole ring by applying both conventional and microwave methods (Scheme 13).The synthesis of these compounds by microwave method produces comparatively moreyield and requires less time to complete the reaction.The synthesized compounds arescreened for microbial and cytotoxic activities. The synthesized compounds are testedfor their antibacterial activity invitro against two microorganisms viz. Escherichia coli and

Molecules 2021, 26, 1163 15 of 23

Staphylococcus aureus, which are pathogenic in human beings by cup plate agar diffusionmethod. The tested compounds showed moderate to good microbial activities.


Staphylococcus aureus, which are pathogenic in human beings by cup plate agar diffusion method. The tested compounds showed moderate to good microbial activities.

Scheme 13. Synthetic route for series I compounds. Reagents and conditions: (a) hydrazine hydrate, ethanol, reflux; (b) carbon disulfide, KOH (c) 1-bromo tetradecane, triethyl amine; (d) stannous chloride; (e) substituted alkoxy acid chloride. R= -CnH2n+1, where n = 4, 5, 6, 7, 8, 10 (Ia–f) and n = chiral alkoxyacid chloride (Ig, h).

Similarly, these compounds are tested for their antifungal activity invitro against As-pergillus oryzae and Aspergillus niger by cup-plate agar diffusion method. Further, all the synthesized compounds (Ia–h) are tested for cytotoxic activity by the BSLT bioassay method. Among them, compounds Ia, Ic, Ih exhibited cytotoxic activity in a dose-depend-ent manner at concentrations of 24.27 µg/mL, 37.05 µg/mL, 39.26 µg/mL, respectively. Podophyllotoxin is used as a standard drug for the BSLT assay method [60].

5.5. Miscellaneous Saravanan et al. reported the facile synthesis of N-1,2,4-oxadiazole substituted sul-

foximines from N-cyano sulfoximines (Scheme 14).This method involves the utilization ofa wide range of substrate thatincludes alkyl, fluoroalkyl, aryl, heteroaryl and saturated heterocyclic compounds. The major advantage of this method is metal-free and the utility of environmentally friendly solvents such as 2-methyl THF and ionic liquids [61].

Scheme 14. Synthesis of N-1,2,4-oxadiazole sulfoximine (6y) from 3a and 4y on a gram scale.

Bharatiya et al. reported the green and efficient microwave one-pot synthetic ap-proachto N-phenyl piperazinyl-1,3,4-oxadiazole derivatives (Scheme 15) and evaluation of their antioxidant and antiinflammatory activity. Microwave-assisted synthesis has proved to be a green and efficient synthetic protocol to enhance reaction rates, higher se-lectivity, efficiency and higher yield. The one-pot synthetic strategy includes successive

O2NO

OC2H5a

O2NO

NHNH2

O2NO

NHN

S

O2NO

NHN

SC14H29

H2NO

NHN

SC14H29

HNO

NHN

SC14H29O

RO

(I) (II)

b

(III)

(IV)

c

(V)

d

e

(VI)

S

N

O

NH2

OH

+

Cl

OH

O

S

N

O

N

ON

CH3

Cl

T3P, DIPEA

2-methyl THF, 80°C

(6y) (3a) (4y)

Scheme 13. Synthetic route for series I compounds. Reagents and conditions: (a) hydrazine hydrate, ethanol, reflux; (b)carbon disulfide, KOH (c) 1-bromo tetradecane, triethyl amine; (d) stannous chloride; (e) substituted alkoxy acid chloride.R = -CnH2n+1, where n = 4, 5, 6, 7, 8, 10 (Ia–f) and n = chiral alkoxyacid chloride (Ig, h).

Similarly, these compounds are tested for their antifungal activity invitro against As-pergillus oryzae and Aspergillus niger by cup-plate agar diffusion method. Further, all the syn-thesized compounds (Ia–h) are tested for cytotoxic activity by the BSLT bioassay method.Among them, compounds Ia, Ic, Ih exhibited cytotoxic activity in a dose-dependent mannerat concentrations of 24.27 µg/mL, 37.05 µg/mL, 39.26 µg/mL, respectively. Podophyllo-toxin is used as a standard drug for the BSLT assay method [60].

5.5. Miscellaneous

Saravanan et al. reported the facile synthesis of N-1,2,4-oxadiazole substituted sul-foximines from N-cyano sulfoximines (Scheme 14). This method involves the utilizationofa wide range of substrate thatincludes alkyl, fluoroalkyl, aryl, heteroaryl and saturatedheterocyclic compounds. The major advantage of this method is metal-free and the utilityof environmentally friendly solvents such as 2-methyl THF and ionic liquids [61].


Staphylococcus aureus, which are pathogenic in human beings by cup plate agar diffusion method. The tested compounds showed moderate to good microbial activities.

Scheme 13. Synthetic route for series I compounds. Reagents and conditions: (a) hydrazine hydrate, ethanol, reflux; (b) carbon disulfide, KOH (c) 1-bromo tetradecane, triethyl amine; (d) stannous chloride; (e) substituted alkoxy acid chloride. R= -CnH2n+1, where n = 4, 5, 6, 7, 8, 10 (Ia–f) and n = chiral alkoxyacid chloride (Ig, h).

Similarly, these compounds are tested for their antifungal activity invitro against As-pergillus oryzae and Aspergillus niger by cup-plate agar diffusion method. Further, all the synthesized compounds (Ia–h) are tested for cytotoxic activity by the BSLT bioassay method. Among them, compounds Ia, Ic, Ih exhibited cytotoxic activity in a dose-depend-ent manner at concentrations of 24.27 µg/mL, 37.05 µg/mL, 39.26 µg/mL, respectively. Podophyllotoxin is used as a standard drug for the BSLT assay method [60].

5.5. Miscellaneous Saravanan et al. reported the facile synthesis of N-1,2,4-oxadiazole substituted sul-

foximines from N-cyano sulfoximines (Scheme 14).This method involves the utilization ofa wide range of substrate thatincludes alkyl, fluoroalkyl, aryl, heteroaryl and saturated heterocyclic compounds. The major advantage of this method is metal-free and the utility of environmentally friendly solvents such as 2-methyl THF and ionic liquids [61].


Bharatiya et al. reported the green and efficient microwave one-pot synthetic ap-proachto N-phenyl piperazinyl-1,3,4-oxadiazole derivatives (Scheme 15) and evaluation of their antioxidant and antiinflammatory activity. Microwave-assisted synthesis has proved to be a green and efficient synthetic protocol to enhance reaction rates, higher se-lectivity, efficiency and higher yield. The one-pot synthetic strategy includes successive

O2NO

OC2H5a

O2NO

NHNH2

O2NO

NHN

S

O2NO

NHN

SC14H29

H2NO

NHN

SC14H29

HNO

NHN

SC14H29O

RO

(I) (II)

b

(III)

(IV)

c

(V)

d

e

(VI)

S

N

O

NH2

OH

+

Cl

OH

O

S

N

O

N

ON

CH3

Cl

T3P, DIPEA

2-methyl THF, 80°C

(6y) (3a) (4y)


Bharatiya et al. reported the green and efficient microwave one-pot synthetic ap-proachto N-phenyl piperazinyl-1,3,4-oxadiazole derivatives (Scheme 15) and evaluation oftheir antioxidant and antiinflammatory activity. Microwave-assisted synthesis has provedto be a green and efficient synthetic protocol to enhance reaction rates, higher selectivity,efficiency and higher yield. The one-pot synthetic strategy includes successive reactions

Molecules 2021, 26, 1163 16 of 23

in just one reaction vessel to improve the efficiency of a chemical reaction. This syntheticprotocol avoids the lengthy separation process and purification of the intermediates andhence increases the product yield.The synthesized compounds were screened for invit-roantiinflammatory activity. The antioxidant activity of the synthesized compounds wasdetermined by reducing power assay and hydrogen peroxide scavenging activity at 700 nmand 250 nm, respectively.The tested compounds exhibited significant antiinflammatoryand antioxidant activity [62].


reactions in just one reaction vessel to improve the efficiency of a chemical reaction. This synthetic protocol avoids the lengthy separation process and purification of the interme-diates and hence increases the product yield.The synthesized compounds were screened for invitroantiinflammatory activity. The antioxidant activity of the synthesized com-pounds was determined by reducing power assay and hydrogen peroxide scavenging ac-tivity at 700 nm and 250 nm, respectively.The tested compounds exhibited significant anti-inflammatory and antioxidant activity [62].

Scheme 15. Synthesis of N-phenyl-piperazinyl-1,3,4-oxadiazole derivatives. Ar-Cl= Cl-C6H4NO2(p), Cl-C6H3NO2(o,p), Cl-C6H4NO2(p), Cl-C6H3NO2(m), NH2(p), Cl- C6H4NO2(p), Cl-C6H3NH2(p), Cl-C6H4CHO(p), Cl-C6H3COOH(p).

Sondhi et al. performed the microwave-assisted synthesis of oxadiazole derivatives (Scheme 16) with antiinflammatory and anticancer activities. N’-hydroxypicolinamidine and 2,5-dimethoxybenzaldehyde were mixed together to furnish a homogeneous mixture, and then this reaction mixture was subjected to microwave irradiation for 3 min at a power level of 450 W.Antiinflammatory activity (Winter et al.) evaluation of IIa-c and IVa–f was carried out by using carrageenan-induced paw edema assay.The result indicates that compounds IIj, IIk, and IVb exhibited 35%, 34%, and 35% antiinflammatory activity, respectively, whereas standard drug ibuprofen exhibited 39%antiinflammatory activity at 50 mg/kg p.o. Similarly, compound IVd exhibited good anticancer activity against various cancer cell lines, i.e., lung (NCIH-522), breast (T47D), liver (HepG2) [63].

ZY

X NOH

NH2 R-CHOMWI, 450W, 7min

ZY

X N O

N R

IIIa - c IVa - f

N

(I)

CH3COCH3

Cl-CH2COOC2H5

Anhyd. K2CO3

N

(II)

N CH2COOC2H5

N

(III)

N CH2CONHNH2

NH2NH2

N

(IV)

N CH2

CS2KOH

O

NHN

SDMFAnhyd. K2CO3

Ar-ClN

(Va-Vf)

N CH2O

NN

S

Ar

NH2

H

C2H5OH

Scheme 15. Synthesis of N-phenyl-piperazinyl-1,3,4-oxadiazole derivatives. Ar-Cl = Cl-C6H4NO2 (p), Cl-C6H3NO2 (o,p),Cl-C6H4NO2 (p), Cl-C6H3NO2(m), NH2 (p), Cl- C6H4NO2 (p), Cl-C6H3NH2 (p), Cl-C6H4CHO (p), Cl-C6H3COOH (p).

Sondhi et al. performed the microwave-assisted synthesis of oxadiazole derivatives(Scheme 16) with antiinflammatory and anticancer activities. N’-hydroxypicolinamidineand 2,5-dimethoxybenzaldehyde were mixed together to furnish a homogeneous mixture,and then this reaction mixture was subjected to microwave irradiation for 3 min at apower level of 450 W.Antiinflammatory activity (Winter et al.) evaluation of IIa-c andIVa–f was carried out by using carrageenan-induced paw edema assay.The result indicatesthat compounds IIj, IIk, and IVb exhibited 35%, 34%, and 35% antiinflammatory activity,respectively, whereas standard drug ibuprofen exhibited 39%antiinflammatory activity at50 mg/kg p.o. Similarly, compound IVd exhibited good anticancer activity against variouscancer cell lines, i.e., lung (NCIH-522), breast (T47D), liver (HepG2) [63].

A rational approach was adopted by Desai et al.for the synthesisof novel series of 1-(2-(1H-benzo[d]imidazol-2-yl)-2-methyl-5-aryl-1,3,4-oxadiazol-3(2H)-yl)-3-(4-chlorophenyl)prop-2-en-1-ones (5a–n) under microwave irradiation technique (Scheme 17). The synthesizedcompounds were screened for their in vitro antimicrobial activity against Gram-positive,Gram-negative strains of bacteria as well as fungal strains, and in vitro cytotoxicity study(HeLa cell lines) by using MTT colorimetric assay. Among the tested compounds, 5b, 5c, 5d,5g, and 5h exhibited the most potent antibacterial activity, while compounds 5c, 5d, 5g, and5h emerged as the most effective antifungal agents. Further, the results of a preliminaryMTT cytotoxicity study on HeLa cells revealed that potent antimicrobial activity of 5b, 5c,5d, 5g, and 5h is accompanied by low cytotoxicity. The structure–activity relationships(SAR) study suggested that the presence of inductively electron-withdrawing groups (flu-oro, chloro, bromo, nitro, methoxy, hydroxy) remarkably enhances the activity of newlysynthesized oxadiazole derivatives [64].

Molecules 2021, 26, 1163 17 of 23


reactions in just one reaction vessel to improve the efficiency of a chemical reaction. This synthetic protocol avoids the lengthy separation process and purification of the interme-diates and hence increases the product yield.The synthesized compounds were screened for invitroantiinflammatory activity. The antioxidant activity of the synthesized com-pounds was determined by reducing power assay and hydrogen peroxide scavenging ac-tivity at 700 nm and 250 nm, respectively.The tested compounds exhibited significant anti-inflammatory and antioxidant activity [62].

Scheme 15. Synthesis of N-phenyl-piperazinyl-1,3,4-oxadiazole derivatives. Ar-Cl= Cl-C6H4NO2(p), Cl-C6H3NO2(o,p), Cl-C6H4NO2(p), Cl-C6H3NO2(m), NH2(p), Cl- C6H4NO2(p), Cl-C6H3NH2(p), Cl-C6H4CHO(p), Cl-C6H3COOH(p).

Sondhi et al. performed the microwave-assisted synthesis of oxadiazole derivatives (Scheme 16) with antiinflammatory and anticancer activities. N’-hydroxypicolinamidine and 2,5-dimethoxybenzaldehyde were mixed together to furnish a homogeneous mixture, and then this reaction mixture was subjected to microwave irradiation for 3 min at a power level of 450 W.Antiinflammatory activity (Winter et al.) evaluation of IIa-c and IVa–f was carried out by using carrageenan-induced paw edema assay.The result indicates that compounds IIj, IIk, and IVb exhibited 35%, 34%, and 35% antiinflammatory activity, respectively, whereas standard drug ibuprofen exhibited 39%antiinflammatory activity at 50 mg/kg p.o. Similarly, compound IVd exhibited good anticancer activity against various cancer cell lines, i.e., lung (NCIH-522), breast (T47D), liver (HepG2) [63].

ZY

X NOH

NH2 R-CHOMWI, 450W, 7min

ZY

X N O

N R

IIIa - c IVa - f

N

(I)

CH3COCH3

Cl-CH2COOC2H5

Anhyd. K2CO3

N

(II)

N CH2COOC2H5

N

(III)

N CH2CONHNH2

NH2NH2

N

(IV)

N CH2

CS2KOH

O

NHN

SDMFAnhyd. K2CO3

Ar-ClN

(Va-Vf)

N CH2O

NN

S

Ar

NH2

H

C2H5OH


Comp. X Y Z Comp. X Y Z R

IIIa N CH CH IVa N CH CH

OCH3

H3CO

IIIb CH N CH IVb CH N CH

OCH3

H3CO

IIIc N CH N IVc N CH N

OCH3

H3CO

- - - - IVd N CH CH OCH3

OH

- - - - IVe CH N CH OCH3

OH

- - - - IVf N CH N OCH3

OH

Scheme 16. Microwave-assisted synthesis of oxadiazole derivatives (IVa–f).

A rational approach was adopted by Desai et al.for the synthesisof novel series of 1-(2-(1H-benzo[d]imidazol-2-yl)-2-methyl-5-aryl-1,3,4-oxadiazol-3(2H)-yl)-3-(4-chloro-phenyl)prop-2-en-1-ones (5a–n) under microwave irradiation technique (Scheme 17). The synthesized compounds were screened for their in vitro antimicrobial activity against Gram-positive, Gram-negative strains of bacteria as well as fungal strains, and in vitro cytotoxicity study (HeLa cell lines) by using MTT colorimetric assay. Among the tested compounds, 5b, 5c, 5d, 5g, and 5h exhibited the most potent antibacterial activity, while compounds 5c, 5d, 5g, and 5h emerged as the most effective antifungal agents. Further, the results of a preliminary MTT cytotoxicity study on HeLa cells revealed that potent antimicrobial activity of 5b, 5c, 5d, 5g, and 5h is accompanied by low cytotoxicity. The structure–activity relationships (SAR) study suggested that the presence of inductively electron-withdrawing groups (fluoro, chloro, bromo, nitro, methoxy, hydroxy) remarka-bly enhances the activity of newly synthesized oxadiazole derivatives [64].

Scheme 16. Microwave-assisted synthesis of oxadiazole derivatives (IVa–f).Molecules 2021, 26, x FOR PEER REVIEW 18 of 24

NH

NC

O

CH3

CONHNH2

R

1

+

2a - n

1,4-dioxane

MWI, 3-5min NH

N

3a - n

N

CH3

NH

O

R

NH

N

MWI, 4-6min(CH3CO)2O

O

NNH3C

CH3

O

R

4a - nNH

NO

NNH3C

HC

O

R

CH

Cl

5a - n

Cl CHO

MWI, 6-9minEthanol, KOH

Comp. R Comp. R Comp. R 5a -H 5f -4-CH3 5k -3-OCH3

5b -3-Cl 5g -3-NO2 5l -4-OCH3

5c -4-Cl 5h -4-NO2 5m -3-Br

5d -4-F 5i -3-OH 5n -4-Br

5e -3-CH3 5j -4-OH - -

Scheme 17. Synthetic route for the preparation of title compounds (5a–n).

A series of 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their radical scavenging and antiinflammatory activity (Scheme 18). Molecular dock-ing simulation studies were performed on the proteins cyclooxygenase-1 (PDB: 1CQE) and cyclooxygenase-2 (PDB: 3LN1) to visualize the probable binding affinity.This insilico study was used to predictthe appreciable ADME and probable toxicity property of the compounds. The best-ranked 1,3,4-derivatives (5a–5j) were synthesized from 2-(benzo[d]thiazol-2-ylamino)acetohydrazide (4) on reaction with aryl/heteroaryl/aliphatic carboxylic acid derivatives via acid-catalyzed dehydrative cyclization. N-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl)benzo[d]thiazol-2-amine (5k) was synthesized by base-cata-lyzed condensation of hydrazide derivative 4 and with carbon disulfide. The 1,3,4-oxadi-azoles were evaluated for in vitro antioxidant activity by 2,2′-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging assay method and in vivo antiinflammatory activity by carra-geenan-induced paw edema method. The results of radical scavenging activity indicate that the 1,3,4-oxadiazoles at 25 µM test concentration exhibited significant radical scav-enging property ranging from 32.0 to 87.3% in comparison to 76.0% radical scavenging activity obtained for the reference drug (ascorbic acid). The results of the in vivo anti-inflammatory activity suggested that the 1,3,4-oxadiazoles at 25 mg kg−1 test dose exhib-ited significant edema inhibition with a mean value ranging from 23.6 to 82.3% in com-parison to 48.3% edema inhibition obtained for the reference drug (Indomethacin) [65].

Scheme 17. Synthetic route for the preparation of title compounds (5a–n).

Molecules 2021, 26, 1163 18 of 23

A series of 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated fortheir radical scavenging and antiinflammatory activity (Scheme 18). Molecular dockingsimulation studies were performed on the proteins cyclooxygenase-1 (PDB: 1CQE) andcyclooxygenase-2 (PDB: 3LN1) to visualize the probable binding affinity.This insilico studywas used to predictthe appreciable ADME and probable toxicity property of the compounds.The best-ranked 1,3,4-derivatives (5a–5j) were synthesized from 2-(benzo[d]thiazol-2-ylamino)acetohydrazide (4) on reaction with aryl/heteroaryl/aliphatic carboxylic acidderivatives via acid-catalyzed dehydrative cyclization. N-((5-mercapto-1,3,4-oxadiazol-2-yl)methyl)benzo[d]thiazol-2-amine (5k) was synthesized by base-catalyzed condensation ofhydrazide derivative 4 and with carbon disulfide. The 1,3,4-oxadiazoles were evaluated forin vitro antioxidant activity by 2,2′-diphenyl-1-picryl hydrazyl (DPPH) radical scavengingassay method and in vivo antiinflammatory activity by carrageenan-induced paw edemamethod. The results of radical scavenging activity indicate that the 1,3,4-oxadiazoles at25 µM test concentration exhibited significant radical scavenging property ranging from32.0 to 87.3% in comparison to 76.0% radical scavenging activity obtained for the referencedrug (ascorbic acid). The results of the in vivo antiinflammatory activity suggested thatthe 1,3,4-oxadiazoles at 25 mg kg−1 test dose exhibited significant edema inhibition with amean value ranging from 23.6 to 82.3% in comparison to 48.3% edema inhibition obtainedfor the reference drug (Indomethacin) [65].


N

SNH2

2

i

N

SNH

3

N

SNH

H2CO

NN

R

ii

iii/iv

5a - k

CH2 C

O

OC2H5

N

SNH

4

CH2 C

O

NHNH2

Scheme 18. Schematic representation for the synthesis of oxadiazole derivatives (5a–k). Reagents and reaction condition: (i) ClCH2COOC2H5, K2CO3, CH3COCH3, reflux 9h, (ii) NH2NH2.H2O, C2H5OH, reflux 16h, (iii) POCl3, RCOOH (15a–j), C2H5OH, reflux 14 h, (iv) CS2, KOH (15k), reflux 7h, R=C6H5 (15a), 2-NO2C6H4 (15b), 3,5-(NO2)2C6H3 (15c), 2-NH2C6H4 (15d), 4-NH2C6H4 (15e) 2-OHC6H4 (15f), 4-OHC6H4 (15g), 3-C5H4N (15h), H (15i), CH3 (15j), SH (15k).

6. Ultrasound-Mediated Synthesis of Oxadiazole Derivatives Ultrasound-mediated organic synthesis is a green synthetic approach and applied as

a powerful technique to enhance the rate of reaction and product yield. The ultrasonic irradiation is enhanced due to the formation of high energy intermediates.This synthetic method can be considered as an eco-friendly process for the conservation of energy and minimization of waste as compared to the conventional techniques. Similarly, molecular sieves assisted synthesis has attracted considerable attention due to their potential use in catalysis [66].

Nikalje et al. reported the ultrasound and molecular sieves assisted synthesis, molec-ular docking and antifungal evaluation of 5-(4-(benzyloxy)-substituted-phenyl)-3-((phe-nylamino)methyl)-1,3,4-oxadiazole-2(3H)-thiones. These oxadiazole derivatives were synthesized successfully by using molecular sieves under ultrasound irradiation with bet-ter product yields of 78–90% in shorter reaction times as compared to conventional heat-ing methods, which require 15–20 h for refluxing. The titled compounds exhibited prom-ising antifungal activity, and the developed scaffold provides a suitable template for gen-erating antifungal agents [67].

7. Structure–Activity Relationship (SAR) Study The presence of oxadiazole moiety is required for producing biological activities like

antibacterial, antifungal, anticancer, antitubercular, antioxidant, analgesic and antiinflam-matory, etc [68].

Position C2 and C5are essential for substitutions to generate different oxadiazole de-rivatives.

The presence of electron-withdrawing substituents (fluoro, chloro, bromo, nitro, methoxy and hydroxyl) potentiates the activity by imparting high-affinity and selectivity towards the target binding site of the receptor [69].

The intense biological activity of the compounds is also greatly influenced by the amount of activation or deactivation and the position of the groups or substituents on the ring.

The presence of aryl or hetero aryl group in the side chain of the oxadiazole nucleus is required for the lipophilic property of drug molecules.

Structural modification of the oxadiazole scaffold can generate different therapeuti-cally active compounds (Figure 7) [70].

Scheme 18. Schematic representation for the synthesis of oxadiazole derivatives (5a–k). Reagents and reaction condition: (i)ClCH2COOC2H5, K2CO3, CH3COCH3, reflux 9h, (ii) NH2NH2.H2O, C2H5OH, reflux 16h, (iii) POCl3, RCOOH (15a–j),C2H5OH, reflux 14 h, (iv) CS2, KOH (15k), reflux 7h, R=C6H5 (15a), 2-NO2C6H4 (15b), 3,5-(NO2)2C6H3 (15c), 2-NH2C6H4

(15d), 4-NH2C6H4 (15e) 2-OHC6H4 (15f), 4-OHC6H4 (15g), 3-C5H4N (15h), H (15i), CH3 (15j), SH (15k).

6. Ultrasound-Mediated Synthesis of Oxadiazole Derivatives

Ultrasound-mediated organic synthesis is a green synthetic approach and applied asa powerful technique to enhance the rate of reaction and product yield. The ultrasonicirradiation is enhanced due to the formation of high energy intermediates.This syntheticmethod can be considered as an eco-friendly process for the conservation of energy andminimization of waste as compared to the conventional techniques. Similarly, molecularsieves assisted synthesis has attracted considerable attention due to their potential use incatalysis [66].

Nikalje et al. reported the ultrasound and molecular sieves assisted synthesis, moleculardocking and antifungal evaluation of 5-(4-(benzyloxy)-substituted-phenyl)-3-((phenylamino)methyl)-1,3,4-oxadiazole-2(3H)-thiones. These oxadiazole derivatives were synthesizedsuccessfully by using molecular sieves under ultrasound irradiation with better productyields of 78–90% in shorter reaction times as compared to conventional heating methods,which require 15–20 h for refluxing. The titled compounds exhibited promising antifungal

Molecules 2021, 26, 1163 19 of 23

activity, and the developed scaffold provides a suitable template for generating antifungalagents [67].

7. Structure–Activity Relationship (SAR) Study

The presence of oxadiazole moiety is required for producing biological activities likeantibacterial, antifungal, anticancer, antitubercular, antioxidant, analgesic and antiinflam-matory, etc. [68].

Position C2 and C5 are essential for substitutions to generate differentoxadiazole derivatives.

The presence of electron-withdrawing substituents (fluoro, chloro, bromo, nitro,methoxy and hydroxyl) potentiates the activity by imparting high-affinity and selectivitytowards the target binding site of the receptor [69].

The intense biological activity of the compounds is also greatly influenced by the amountof activation or deactivation and the position of the groups or substituents on the ring.

The presence of aryl or hetero aryl group in the side chain of the oxadiazole nucleus isrequired for the lipophilic property of drug molecules.

Structural modification of the oxadiazole scaffold can generate different therapeuti-cally active compounds (Figure 7) [70].


Figure 7. SAR study ofoxadiazole derivatives.

8. Future Development Microwave radiation acts as a nonconventional energy source that can be used to

perform a wide range of drug synthesis within a short period of time with high yields as compared to conventional heating methods.The chemical reactions which are not possible under conventional techniques can sometimes be carried out by utilizing the high energy of MWI. By applying microwave technology, different oxadiazole derivatives can be syn-thesized and also screened to find out new therapeutic molecules with diverse biological activities such as antibacterial, antifungal, antidepressant, antitubercular and antiinflam-matory, etc. [71–74]. Hence, oxadiazole is considered a significant heterocyclic core and becomes a major scaffold for the development of new drug candidates because of its po-tential to be involved in the binding interactions with different targets or receptors with suitable metabolic profile [75–78].

9. Conclusions The synthesis of various heterocyclic compounds like oxadiazole derivatives under mi-

crowave irradiation demonstrates several advantages in terms of remarkably short reaction time, high product yields and a simple purification process in comparison with the classical synthetic strategies.Moreover, also, the volume of solvents used during a chemical reaction is reduced, which makes MWI an environmentally friendly synthetic approach. Further, oxadiazole derivatives have attracted medicinal chemists in search of new therapeutic agents due to the presence of diverse molecular structures. The therapeutic potentials of oxadiazole rings have been extensively studied to develop selective drug molecules inwhich the presence of different substituents or groups in the molecule is responsible for display-ingdifferent pharmacologicalactivities. In this review, the synthesisof oxadiazole derivatives by the conventional method and themicrowave method is reported to compare their effec-tive synthetic strategies followed by a study of theirdifferent therapeutic activities. From various results, it reveals that the structural modification or functionalization of oxadiazole scaffoldsto generate a compound library with diverse biological activities.

Author Contributions: B.K.B., B.M.S., B.V.V.R.K., K.C.P., J.J., M.K.M. and P.B. have contributed their ideas related to concept design, data collection, data analysis or interpretation, manuscript preparation, language editing and revision. All authors have read and agreed to the published ver-sion of the manuscript.

Funding: This research was unded by College of Sciences and Human Studies, Prince Mohammad Bin Fahd University, Saudi Arabia.

Institutional Review Board Statement:Not applicable.

Informed Consent Statement: Not applicable.

N O

N HNR

Oxadiazole ring(Play key role for optimum

biological activity)

Activity enhancing group

Boost up lipophilic property

N

N N

O R

Oxadiazole moiety(Crucial for optimum biological activity)

Electron withdrawing

groups to poentiate acticity

Aryl or hetero aryl ring for lipophilic property

Figure 7. SAR study ofoxadiazole derivatives.

8. Future Development

Microwave radiation acts as a nonconventional energy source that can be used toperform a wide range of drug synthesis within a short period of time with high yieldsas compared to conventional heating methods.The chemical reactions which are not pos-sible under conventional techniques can sometimes be carried out by utilizing the highenergy of MWI. By applying microwave technology, different oxadiazole derivatives canbe synthesized and also screened to find out new therapeutic molecules with diversebiological activities such as antibacterial, antifungal, antidepressant, antitubercular andantiinflammatory, etc. [71–74]. Hence, oxadiazole is considered a significant heterocycliccore and becomes a major scaffold for the development of new drug candidates because ofits potential to be involved in the binding interactions with different targets or receptorswith suitable metabolic profile [75–78].

9. Conclusions

The synthesis of various heterocyclic compounds like oxadiazole derivatives under mi-crowave irradiation demonstrates several advantages in terms of remarkably short reactiontime, high product yields and a simple purification process in comparison with the classicalsynthetic strategies.Moreover, also, the volume of solvents used during a chemical reactionis reduced, which makes MWI an environmentally friendly synthetic approach. Further,oxadiazole derivatives have attracted medicinal chemists in search of new therapeutic

Molecules 2021, 26, 1163 20 of 23

agents due to the presence of diverse molecular structures. The therapeutic potentialsof oxadiazole rings have been extensively studied to develop selective drug moleculesinwhich the presence of different substituents or groups in the molecule is responsible fordisplayingdifferent pharmacologicalactivities. In this review, the synthesisof oxadiazolederivatives by the conventional method and themicrowave method is reported to comparetheir effective synthetic strategies followed by a study of theirdifferent therapeutic activi-ties. From various results, it reveals that the structural modification or functionalization ofoxadiazole scaffoldsto generate a compound library with diverse biological activities.

Author Contributions: B.K.B., B.M.S., B.V.V.R.K., K.C.P., J.J., M.K.M. and P.B. have contributedtheir ideas related to concept design, data collection, data analysis or interpretation, manuscriptpreparation, language editing and revision. All authors have read and agreed to the publishedversion of the manuscript.

Funding: This research was unded by College of Sciences and Human Studies, Prince MohammadBin Fahd University, Saudi Arabia.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

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

AbbreviationsThe following abbreviations are used in this manuscript:BSLT Brine shrimp lethalityBTPPDS 1,4-bis(triphenylphosphonium)-2-butene peroxodisulfateCOX CyclooxygenaseDCC Dicyclohexyl-carbodiimideDMA DimethylacetamideDMF DimethylformamideDMSO Dimethyl sulfoxideDPPH 2,2-diphenyl-1-picrylhydrazylED50 Median effective doseEDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimideEPA Environmental Protection AgencyFDA Food and Drug AdministrationFMWI Focused microwave irradiationGHz GigahertzHOBt HydroxybenzotriazoleIC50 Half-maximal inhibitory concentrationILs Ionic liquidsIPA Isopropyl alcoholIUPAC International Union of Pure and Applied ChemistryMABA Microplate alamarBlueassayMFC Minimum fungicidal concentrationMHz MegahertzMIC Minimum inhibitory concentrationmM MillimeterMRSA Methicillin-resistant StaphylococcusaureusMTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromideMWI Microwave irradiationNMP N-Methyl-2-pyrrolidoneNSF National Science FoundationTHF Tetrahydrofuranµg Microgramµg/mL Microgram per microliter

Molecules 2021, 26, 1163 21 of 23

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