Taghreed Hashim Al-Noor

Abaas Obaid Hussein

Amer. Jabar. Jarad

Mixed Ligand Complexes of Saccharin and

Β-Lactams Antibiotics

Taghreed Hashim Al-Noor

Abaas Obaid Hussein

Amer. Jabar. Jarad

Mixed Ligand Complexes of Saccharin and

Β-Lactams Antibiotics

LAP LAMBERT Academic Publishing

1

Contents

Page Subject

3 General Introduction

3 Metal Complexes In The Body

5 Metal Complexes In Cancer Treatment

6 Metal Complexes In Neurological Disorders

6 Metal Complex In Diabetes

6 Metal Complexes In Therapy

7 Metal Complexes With Schiff Bases

10 Metal Complexes As Antimicrobial Agents

12 Metal Complexes With Antibiotics

13 Β-Lactam Antibiotics

15 Tetracycline

15 Chloramphenicol

16 Cephalosporins

19 Aminoglycoside

19 Sparfloxacin Metal Complex

21 Levofloxacin

23 Neurological

22 Metal Interacts With Quinolone Drug

22 Sulphonamide

42 Norfloxacin

25 Ciprofloxacin

25 Ligands And Starting Materials In This Study

25 Β-Lactams Antibiotics (Cephalexin, Ampicillin And

Amoxicillin)

26 Saccharin (Saccharine)

27 Chlorobenzaldehyde

28 4-Hydroxybenzaldehyde

28 4-Chlorobenzophenone

28 Mixed Ligand Metal Complexes

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29 Mixed Ligand Metal Complex of Saccharin

29 Saccharinates

31 Monodentate O-Coordinated Metal Complexes

32 Bidentate N, O- Coordinated Metal Complexes

32 Saccharinate Complexes of The Trivalent Lanthanides

33 Other Peculiar Coordination Behavior

36 Antimicrobial Activities Of Schiff Base Metal Complexes

54-48 References

3

1.1. General Introduction

Chelating ligands in the field of coordination chemistry and their metal

complexes are of great interest since many years. It is well known that N, S and O

atoms play a key role in the coordination of metals at the active sites of numerous

metallobiomolecules. Chelating ligands containing O, N and S donor atoms show

broad biological activity and are of special interest because of the variety of ways in

which they are bonded to metal ions[1].

Many biologically active compounds used as drugs possess modified

pharmacological and toxicological potentials when administered in the form of metal

based compounds. Various metal ions potentially and commonly used are Cobalt,

Copper, Nickel and Zinc because of forming low molecular weight complexes and

therefore, prove to be more beneficial against several diseases[2].

The treatment of infectious diseases still remains an important and challenging

problem because of a combination of factors including emerging infectious diseases

and the increasing number of multi-drug resistant microbial pathogens. In spite of a

large number of antibiotics and chemotherapeutics available for medical use, at the

same time the emergence of old and new antibiotic resistance created in the last

decades revealed a substantial medical need for new classes of antimicrobial agents.

Some metals have been used as drugs and diagnostic agents to treat a variety of

diseases and conditions. Platinum compounds, cisplatin (cis- [Pt(NH3)2Cl2]),

carboplatin and oxaloplatin are among the most widely used cancer therapeutic

agents[3].

1.1.1. Metal complexes in the body

The field of bioinorganic chemistry, which deals with the study of role of metal

complexes in biological systems, has opened a new horizon for scientific research in

coordination compounds. A large number of compounds are important from the

biological point of view. Some metals are essential for biological functions and are

found in enzymes and cofactors required for various processes. For example,

hemoglobin in red blood cells contains an Iron porphyrin complex Figure (1-1),

which is used for oxygen transport and storage in the body. Chlorophyll in green

plants, which is responsible for photosynthetic process, contains chlorophyll in green

plants complex. Cobalt is found in the coenzyme B12 Figure (1-2), which is essential

for the transfer of alkyl groups from one molecule to another in biological systems.

4

Metals such as Copper, Zinc, Iron and Manganese are incorporated into catalytic

proteins (the metalloenzymes), which facilitate a multitude of chemical reactions

needed for life.

Figure (1-1): Iron porphyrin ligand (The hemi complex )

Figure (1-2): Coenzyme B12

α-(5, 6-dimethylbenzimidazolyl) cobamidcyanide

Generally [2,3], drug combinations have proven to be an essential feature of

antimicrobial treatment due to a number of important considerations:

(1)They increase activity through the use of compounds with synergistic or

additive activity.

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(2) They thwart drug resistance.

(3) They decrease required doses, reducing both cost and the chances of toxic

side effects.

(4) They increase the spectrum of activity.

Various biological aspects of the metal based drugs/ligands entirely depend on

the ease of cleaving the bond between the metal ion and the ligand [3].

As a sequence, it is essential to understand the relationship between ligand and

the metal in biological systems. The pharmacyological activity of metal complexes is

highly dependent on the nature of the metal ions and the donor sequence of the

ligands because different ligands exhibit different biological properties. There is a

real perceived need for the discovery of new compounds endowed with antimicrobial

activities [4].

The newly prepared compounds should be more effective and possibly act

through a distinct mechanism from those of well-known classes of antimicrobial

agents to which many clinically relevant pathogens are now resistant[5,6].

Metal ions bound with ligands in some process, and to oxidize and reduce in

biological systems. The important metal present in the body is Iron which plays a

central role in all living cells. Generally Iron complexes are used in the transport of

Oxygen in the blood and tissues. The hemi group is metal complex, with Iron as

central metal atom, which bind or release molecular Oxygen [7].

1.1.2. Metal complexes in cancer treatment

Metal complexes have a higher position in medicinal chemistry. The therapeutic

use of metal complexes in cancer and leukemia are reported from the sixteenth

century. In 1960 an inorganic complex cis-platin Figure (1-3) was discovered, today

more than 50 years [8].

It is still one of the world’s best-selling anticancer drugs. Metal complexes

formed with other metals like Copper, Gold, Gallium, Germanium, Tin, Ruthenium,

and Iridium showed significant antitumor activity in animals. Formation of DNA

adducts with cancer cell and results in the inhibition of DNA replication. In the

treatment of ovarian cancer Ruthenium compounds containing aryl azopyridine

ligands show cytotoxic activity. Now a day’s metal complex in the form of nano

shells are used in the treatment of various types of cancer [9].

6

Figure (1-3): Cis-platin and transplatin

1.1.3. Metal complexes in neurological disorders

Metal complexes also play a vital role in the treatment of various neurological

disorders. Lithium on complex with drug molecules may cure many nerve disorders

like Huntington’s chorea, parkinsonism, organic brain disorder, epilepsy and in

paralysis etc. Other transition metals such as Copper and Zinc are involved as a

transmitter in the neuronal signaling pathway [9,10].

1.1.4. Metal complex in diabetes

In diabetes intake of Chromium metal complex, it showed considerable

reduction in the glucose level. Insulin mimetic Zinc complex with different

coordination structures and with a blood glucose lowering effect to treat type2

diabetes [11].

1.1.5. Metal complexes in therapy

1.1.5.1. Metal complexes with Schiff bases

The common structural feature of these compounds is the azomethine group

with a general formula RHC=N-R’, where R and R’ are alkyl, aryl, cycle alkyl or

heterocyclic groups which may be variously substituted. Ammonia or primary amines

were added to the carbonyl group of the aldehyde or ketone to give hemi aminals

(also called “aldehyde ammonias”) which decompose to the imines or Schiff bases as

shown below [12],as shown in Figure (1-4).

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Figure (1-4): Preparation of Schiff bases

Schiff’s base complexes continue to attract many researchers because of their

wide application in food industry, dye industry, analytical chemistry, catalysis

antimicrobial activity and pharmacological application like antitumoral, antifungal,

antibacterial and antimicrobial etc. Schiff bases are important intermediates for the

synthesis of some bioactive compounds such as ß-lactams (Anacona, 2006) [13], and

employed as ligands for the complexation of metal ions. Among these novel metal

complexes derivative which show considerable biological activity may represent an

interesting approach for designing new antibacterial drugs. This may be due to the

dual possibility of both ligands plus metal ion interacting with different steps of the

pathogen life cycle [14]. See Table (1-1)

Table (1-1): Some applications of Schiff’s base complexes

Metal complex Activity Schiff base-Arsenic

Complex Antifungal Schiff base-Antimony

Complex Antifungal Schiff base-Bismuth

Complex Antifungal Schiff base-Silver

Complex Antiviral Schiff base-Cobalt

Complex Dyes for giving color to leathers

In (2010), Suresh and Prakash [15],synthesized a novel bidentate Schiff base

Figure(1-5) from 1-phenyl-2,3-dimethyl-4-aminopyrazol-5-one (4-aminoantipyrene)

and vanillin forms stable complexes with transition metal ions such as Cr (III), Mn

(II), Co (II), Ni (II), Cu (II), Zn (II) and Cd (II). Their structures were investigated by

elemental analysis, infrared spectroscopy, electronic spectroscopy, NMR

spectroscopy; thermo gravimetric analysis and electron spin resonance spectroscopy.

8

On the basis of the studies, the coordination sites were proven to be through oxygen

of the ring C= O and Nitrogen of the azomethine CH = N group. The microbiological

studies revealed the anti-bacterial nature of the complexes; Figure (1-6).

Figure (1-5): Structure and preparation of Schiff base ligand

Figure (1-6): Structure of 1-phenyl 2, 3-dimethyl-4-aminopyrazol-5–one

(4-aminoantipyrene) and vanillin complexes

M(II)= Cr (III), Mn (II), Co (II), Ni (II), Cu (II), Zn (II) and Cd (II )

Sivagamasundari and Ramesh (2007)[16], reported that the reaction of the

chelating ligand with[RuHCl(CO)(EPh3)2(B)]. (where E=P;B=PPh3,py or pip) Figure

(1-7)in benzene afforded new stable Ruthenium(II)carbonyl complexes. The

luminescence efficiency of the Ruthenium (II) complexes was explained based on the

ligand environment around the metal ion. These compounds catalyze oxidation of the

primary and secondary alcohol into their corresponding carbonyl compounds in the

presence of N-methyl morpholine-N-oxide(NMO)as the source of oxygen [16].

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Figure (1-7): [RuHCl (CO)(EP h3)2( B )]complex.

Osowole and Akpan (2012)[17], reported the Schiff base, 3-{[(4,6-

dimethoxypyrimidin-2-yl)imino]methyl}naphthalen-2-ol,Figure (1-8)and its VO(II),

Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Pd(II) complexes were synthesized and

characterized by IR, electronic and 1H-NMR spectroscopies, elemental analysis and

conductance measurements. The ligand coordinated to the metal ions through the

azomethine N and phenol O atoms, resulting in a 5-coordinate, square-pyramidal

geometry for the VO(II) complex and a 4-coordinate square planar/ tetrahedral

geometry for the Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes. The complexes

were non-electrolytes in nitro methane and melted within the temperature range 240-

352°C. The in vitro anticancer studies reveal that the Pd(II) and Cu(II) complexes had

the best anticancer activity against MCF-7(Human breast adenocarcinoma) cells with

IC values of 3.89 μM and 504.90 μM, which were within the same order of activity

as cis-platin; and the Pd(II) complex activity against HT-29 (Colon carcinoma) cells

was the best being about the same order as cis-platin (7.0 μM) with an IC of 6.69

50μM. The antimicrobial studies showed that the ligand and the Zn (II) complex

exhibited broad-spectrum antibacterial activity against P. mirabilis, B. subtilis, B.

cereus and S. typhi with inhibitory zones range of (7.0-21.0) mm and (10.0-19.0) mm

respectively.

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Figure (1-8):3-{[(4, 6-dimethoxy pyrimidin-2-yl) imino].methyl}

naphthalen- 2-ol

Raj and She et al (2013) [18], reported Titanium(IV) complexes of composition

[TiCl2(SB)2], have been synthesized by reacting TiCl4 and Schiff bases (SBs) where

(SBs: A1(tetracycline hydrochloride Schiff’s base) ;B1(Streptomycin Schiff’s base

);C1( Ceffixime Schiff’s base);D1( ampicillin Schiff’s base) in fixed molar ratio 1:2.

Titanium and chlorine estimation were estimated by gravimetrical. These were

characterized by mass, FT- IR, UV- Visible and1H-NMR spectral techniques. The

synthesized complexes were screened, tested for their antimicrobial activity against

pathogenic bacterial strains.

1.1.5.2. Metal complexes as antimicrobial agents

Metal complexes have powerful antimicrobial such as, Zinc antiseptic creams,

Bismuth drugs for the treatment of ulcers and metal clusters as anti-HIV drugs

[1].Joseyphus and Nair(2008) [19].

A series of antibacterial and antifungal amino acid-derived compounds and their

Cobalt(II), Copper(II), Nickel(II), and Zinc(II) metal complexes have been

synthesized and characterized by their elemental analyses, molar conductance,

magnetic moments, IR, and electronic spectral measurements. Ligands

(L1−L5),Figure (1-9)were derived by condensation of β-diketones with glycine,

phenylalanine, valine, alanine and histidine and act as bidentate towards metal ions

(Cobalt, Copper, Nickel, and Zinc) via the azomethine-N and deprotonated-O of the

respective amino acid. The synthesized ligands, along with their metal(II) complexes,

Figures (1-10) were screened for their in vitro antibacterial activity against four

gram-negative (Escherichia coli, Shigellaflexeneri, Pseudomonas aeruginosa, and

Salmonella typhi) and two gram-positive (Bacillus subtilis and Staphylococcus

aureus) bacterial strains and for in vitro antifungal activity

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against Trichophytonlongifusus, Candida albicans, Aspergillusflavus,

Microsporumcanis, Fusariumsolani, and Candida glaberata. The results of these

studies show the metal(II) complexes to be more antibacterial/antifungal against one

or more species as compared to the uncomplexed ligands.

Figure (1-9): Ligands (L1−L5) were derived by condensation of

β-diketones with glycine, phenylalanine, valine, and histidine

Figures (1-10):Schiff basses (L1-L5) complexes

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Nair, et al(2012 )[20], reported the Co(II), Ni(II), Cu(II) and Zn(II) complexes

Figure (1-11)of the Schiff base derived from indole-3-carboxaldehyde and m-

aminobenzoic acid were synthesized and characterized by elemental analysis ,molar

conductance, IR, UV–Vis and magnetic moment. The antimicrobial activity of the

synthesized ligand and its complexes were screened by disc diffusion method. The

results show that the metal complexes were found to be more active than the ligand.

Figure (1-11): Complexes of the Schiff base derived from

indole-3-carboxaldehyde and m-aminobenzoic acid

1.1.5.3. Metal complexes with antibiotics

The most useful classification system, based on the chemical structures is as

follows of antibiotics:

• β-lactam antibiotics

• Sulfonamides.

• Macrolides.

• Penicillins.

• Aminoglycosides.

• Amphenicols.

• Quinolones.

• norfloxacin.

Each class is composed of many drugs having similar structures [21].

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a-β- lactam antibiotics:

The β -lactams are a family of antibiotics that are characterized by the presence

ofβ-lactam ring Figure (1-12). They are a diverse and varied family which include the

penicillins, cephalosporins and carbapenems, and are the most commonly prescribed

antibiotics in Europe Molstad et al(2002)[22]. Collectively β-lactams show activity

against gram-negative and gram-positives organisms, including anaerobes. The

penicillins, despite being one of the first discovered antibiotics, remain one of the

most commonly prescribed antibiotics, particularly for urinary tract infections (UTIs),

largely due to their high absorption rates Holten and Onsuko(2000)[23].For more

complicated or resistant infections, the cephalosporins are often prescribed due to

their broader spectrum of activity.

Figure (1-12): Primary structure of ampicillin.

In (2000), Zahid et al[24], reported some Co(II),Cu(II), Ni(II) and Zn(II)

complexes of antibacterial drug cephradine have been prepared and characterized by

their physical, spectral and analytical data. Cephradine acts as bidentate and the

complexes have compositions,[M(L)2X2], where,[M=Co(II), Ni(II) and Zn(II),

L=cephradine and X=CI2],showing octahedral geometry, and , [M(L)2], where,

[M=Cu(II), L=cephradine], showing square planar geometry. In order to evaluate the

effect of metal ions upon chelation, cephradine and its complexes have been screened

for their antibacterial activity against bacterial strains, Escherichia coli,

Staphylococcusaureus, and Pseudomonas aeruginosa, Figure (1-13).

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Figure(1-13): Structure of antibacterial drug cephardine

Metallo-β-lactamases (mbl) Figure (1-14)and phosphotriesterase (PTE) are

Zinc(II)enzymes, which hydrolyze the β-lactam antibiotics and toxic organo-

phosphotriesters, respectively. These Zinc(II) complexes were studied for their mbl

and PTE activities. β –lactam antibiotics are the most widely used class of antibiotics,

and the bacterial enzymes that hydrolyze these antibiotics are known as β-lactamases.

β-lactamases are classified into serine- β-lactamases (sbl) and metallo- β- lactamases

(mbl). The serine β-lactamases possess an active site serine residue which is essential

for its hydrolytic activity. Currently, the inhibitors namely clavulanic acid, sulbactam

and tazobactam are known for sbl. However, bacteria have evolved the Zinc(II)

containing metallo-β -lactamases that are capable of hydrolyzing a variety of β-

lactam antibiotics including the latest generation of cephalosporins and carbapenems

(e.g.imipenem)[25,26].

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Figure (1-14) : [ Zn(lactamase) ]complex

b. Tetracycline

Chartone-Souza, et al. (2005)[27], reported the synthesis of Platinum (II)

complex with tetracycline. A tetracycline Pt(II) complex Figure (1-15)turned out to

be as efficient as the ligand alone against Escherichia coli bacterial strains.

Moreover, this complex is six times more potent against Escherichia coli than free

tetracycline[27].

Figure (1-15) : [Pt(tetracycline)]complex.

c. Chloramphenicol

Pranay(2009)[28],carried out the synthesis on the metal Vanadate with organic

ligand, the synthesis scheme describes Nickel(II) with chloramphenicol

(C11H12Cl2N2O5) in the presence of Vandate. The complex Figure (1-16) has been

synthesized and characterized using analytical and spectral methods like infrared,

TGA, XRD, [28].

16

,

Figure (1-16):[M(Chloramphenicol)]complex

d. Cephalosporins

Cephalosporins are classed as β-lactam antibiotics, and they are widely used in

clinical therapy for the treatment of severe infections, because of their antibacterial

activity [29,30]. Most common among several mechanisms by which bacteria

develop resistance to β-lactam antibiotics is by elaboration of the enzyme β-

lactamase, which hydrolyzes the β-lactam ring. A second mechanism is through

alteration of penicillin-binding proteins(PBPs), which are found as both membrane-

bound and cytoplasmic enzymes that catalyze cross-linking reactions in bacterial cell

wall synthesis [31,32].

PBPs are targets of β-lactam antibiotics, which interfere with cell wall synthesis

by binding covalently to the catalytic site. Most bacterial species produce several

PBPs, differing in molecular weight, affinity for binding β-lactam antibiotics, and

enzymatic function (e.g., trans-peptidase, carboxy- peptidase, or endo-peptidase).The

PBPs are usually broadly classified into high-molecular-weight and low-molecular-

weight categories [31,32].

Anacona and Rodriguez (2004)[33],reported the synthesis and antibacterial

activity of cefatoxime. Different metal bind with cefatoxime and shows antibiotic

activity which is shown in Figure(1-17).Metals like Mn(II),Fe(II),Co(II),

Ni(II),Cu(II), and Cd(II).The anti-bacterial study of Cu(II) Cefatoxime and Zn(II)

Cefatoxime complexes demonstrated that the complexation of Cefatoxime with these

metals enhances its activity significantly compared to Cefatoxime alone. The

complex, [Cu(Cefatoxime) Cl] was found to have higher activity than that of

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Cefatoxime against the bacterial strains studied under the test conditions, showing

that it has a good activity as bactericide.

Figure (1-17):[M(Cefatoxime)] complexes

Anacona, et al [34–39], mentioned the interaction of antibiotics with main and

transition metal ions has attracted attention and compelled to combine their chemistry

in order to establish whether complexation affects the pharmacological properties of

the ligand and to derive additional fundamental knowledge about antibiotic action ,

Anacona and Maried(2012)[40],reported the synthesis reacts Nickel(II) with

cephalosporins plus sulfathiazole (Hstz) to form the following mixed-ligand

complexes of general formula ,[Ni(L)(stz)(H2O)x].n(L=1,4, x = 1; L2,3,x = 0; L

=monoanion of cefazolin HL1, cephalothin HL2, cefatoxime HL3, ceftriaxone HL4)

Figure (1-18) and ,[Ni(L5)(stz)].Cl (cefepime L5),which were characterized by

physicochemical and spectroscopic methods.

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Figure(1-18):The structure of the ligands(cephalosporins plus sulfathiazole)

Their spectra indicated that cephalosporins are acting as multidentate chelating

agents, via the lactam carbonyl , carboxylate and N azo moieties. The complexes are

insoluble in water and common organic solvents but soluble in DMSO, where the

[Ni(L5)(stz)]Cl complex is 1 : 1 electrolyte. They probably have polymeric structures.

They have been screened for antibacterial activity, and the results are compared with

the activity of commercial cephalosporins, as shown in Figure (1-19).

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Figure (1-19): Suggested structure of [Ni(L5)(stz)].+cation complex.

e. Aminoglycoside

Aminoglycoside have been determined to bind Cu+2

,including lincomycin,

Kanamycin,Genticin and Tobramycin.These complexes exhibit oxidative activity

[41,42].

f. Sparfloxacin metal complex

Nadia(2011)[43], reported that Sparfloxacin forms metal complex with

Cu(II),Co(II),Ni(II),Mn(II),Cr(III) and Fe(III),Figure (1-20) .All complexes were of

the high spin type and found to have six-coordinate octahedral geometry except the

Cu(II) complexes which were four coordinate, square planner, U-and La-atoms in

the Uranyl and Lanthanide have a pentagonal bipyramidal coordination sphere.

Figure (1-20): [M(Sparfloxacin)2]complexes

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Efthimiadou et al(2008)[44], reported Copper(II) complexes, Figure (1-21) of

the third generation quinolone antibacterial drug sparfloxacin in the presence of a

Nitrogen donor heterocyclic ligand 2,2'-bipyridine, 1,10-phenanthroline or 2,2'-

dipyridylamine have been prepared and characterized physico chemically and

spectroscopically [44].

Figure (1-21):[Cu(Sparfloxacin)(1,10-phenanthroline)]complex.

Somia Gul, et al(2013) [45],reported four new metal complexes (S12–S15) of

SPFX (third-generation quinolones) via heavy metals, Figure (1-22) have been

synthesized in good yield and characterized by physicochemical and spectroscopic

methods including TLC, IR, NMR, and elemental analyses. Sparfloxacinato ligand

binds with metals through pyridone and oxygen atom of carboxylic group. The

biological actives of complexes have been tested against four gram-positive and

seven gram-negative bacteria and six different fungi. Statistical analysis of

antimicrobial data was done by one-way ANOVA, Dunnett’s test; it was observed

that S13, S14, and S15 were found to be most active complexes. Antifungal data

confirm that all four synthesized complexes are most active and show significant

activity against F. solani with respect to parent drug and none of complexes show

activity against A. parasiticus, A. effuris, and S. cervicis. To study inhibitory effects

of newly formed complexes, enzyme inhibition studies have been conducted against

urease, �-chymotrypsin, and carbonic anhydrase. Enzymatic activity results of these

complexes indicated them to be good inhibitors of urease enzyme while all

complexes show mild activities against carbonic anhydrase enzyme.

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Figure (1-22): Graphical representation of enzymatic inhibition

S12 to S15.

g. Levofloxacin

Patel et al [46], studied the drug based Copper (II) complexes, Figure (1-23)

with levofloxacin inpresence of 2,2’-bipyridylamine(bpd).It shows antibacterial

activity [46].

Figure (1-23):[Cu(Levo)(bpd)] complex.

22

H. Metal interacts with quinolone drug

Norfloxacin and Ciprofloxacin with Mg(II),Ca(II), and Ba(II)increase

antibacterial activity and decrease toxicity. Upadhyay et al [47],reported the

complexation of Zn(II) ions with quinolone in aqueous solution depending mainly

upon pH. To investigate the pH dependence of the complexation between Zn(II) and

the quinolone derivative ciprofloxacin (cfH),UV-Vis spectroscopy was used. The

crystal structure of the compound, [C17H19N2O3F]2,[ZnCl4].2H2O, see Figure (1-

24)was determined by X-ray diffraction. These complexes were characterized by

elemental analysis, mass spectrometry, TG analysis and IR spectroscopy [48].

Figure(1-24):[Zn(Ciprofloxacin)2]2H2O complex.

i. Sulphonamide

Microbial nucleic acids synthesis was inhibited along with microbial folic acid

synthesis. Sulphon amide possess free or substituted amino group, binding site for

metal complexes. Subudhi, et al(2007)[49],reported the synthesis of Cu(II),

Zn(II),Co(II),Ni(II)and Pb(II)complexes of 4-(2'-hydroxy phenyl imino) phenyl

sulphonamide ,see Figure (1-25).The complexes were evaluated for their antibacterial

activity using two gram positive bacteria (S.aureus, E. faecalis) and two gram

negative bacteria (E. coli, P. aeruginosa) by disc diffusion method. The results show

that metal complexes were found to enhance the antimicrobial potential of the ligand.

Quinolinyl sulfonamides, such as N-(quinolin-8-yl) methane sulfonamide and N-(5-

23

chloroquinolin-8-yl) methane sulfonamide,[potent methionine aminopeptidase

(MetAP)],inhibitors showed different inhibitory potencies on Co(II), Ni(II),

Fe(II),Mn(II),and Zn(II)forms of Ecoli.(MetAP), and their inhibition was dependent

on metal concentration and form metal complex with residue at the enzyme active

site [50].

Figure (1-25):4-(2'-hydroxy phenylimino) phenyl sulphonamide.

M(II) = Cu(II), Zn(II), Co(II), Ni(II) and Pb(II)

Raheem et al(2014) [51],reported the synthesis and identification of the mixed

ligands complexes of M(II)ions in general composition ,[M(Leu)2(SMX)]where L-

leucine(C6H13NO2)symbolized (LeuH) as primary ligand and Sulfamethoxazole

(C10H11N3O3S)symbolized(SMX)as secondary ligand, Figure (1-26).The ligands and

the metal chlorides were brought into reaction at room temperature in(v/v) ethanol

/water as solvent containing NaOH. The reaction required the following ,[(metal:

2(Na+Leu

-):(SMX)], molar ratios with M(II) ions, where

M(II)=Mn(II),Co(II),Ni(II),Cu(II),Zn(II),Cd(II),and Hg(II).

The UV–Vis and magnetic moment data revealed an octahedral geometry

around M(II).The conductivity data show a non-electrolytic nature of the complexes.

24

The antimicrobial activities of ligands and their mixed ligand complexes were

screened by disc diffusion method.

Figure (1-26): Preparation of[M(Leu)2(SMX)] complexes

j. Norfloxacin

Sadeek [52], reported the synthesis of Mn(II),Co(II) and Fe(III) norfloxacin

complexes Figure (1-27).The complexes were characterized by elemental analysis,

infrared, electronic, mass spectra and thermal analysis. It was found that the

norfloxacin act as bidentate ligands through one of the oxygen atoms of the

carboxylic group and the ring carbonyl oxygen atom.

25

Figure (1-27): [M(Norfloxacin)2] complex;

where M(II)= Mn(II) or Co(II).

K. Ciprofloxacin

Jezowska [53], prepared from aqueous solutions the Iron (III) complex with

ciprofloxacin and nitriloacetate(Nta) as a ligand additional,

[Fe(Cf)(Nta)]3.5H2O.The complexes have been characterized by elemental

analysis, reflectance spectra, IR and mass spectroscopy.

1.2. Ligands and starting materials in this study

A) Ligands

1.2.1. β-lactams antibiotics (Cephalexin, Ampicillin and Amoxicillin), [54-56].

β-lactams Antibiotics (Cephalexin , Ampicillin and Amoxicillin) are multi-

dentate ligands, Figure (1-28).

26

Figure (1-28): Structural formulas of β-lactams antibiotics (Cephalexin,

Ampicillin and Amoxicillin)

1.2.2. Saccharin (Saccharine)

The structure of saccharin (sacH), 1,2-benzisothiazoline-3-(2H)one 1,l -dioxide

or o- sulphobenzoimide is shown in Figure (1-29).

IUPAC name

2-benzothiazol-1,1,3-trione

Other names

Benzoic sulfimide ortho-

sulphobenzamide

Figure (1-29): Structural formula of saccharin

Cephalexin Ampicillin Amoxicillin

Systematic

(IUPAC)

name

6R,7R)-7-{[(2R)-2-amino-2-

phenylacetyl]amino}-3-

methyl-8-oxo-5-thia-1-

azabicyclo[4.2.0] oct-2-ene- 2-

carboxylic acid

Trade names: Keflex

(2S,5R,6R)-6-([(2R)-2-amino-

2-phenylacetyl].amino)-3,3-

dimethyl-7-oxo-4-thia-1-

azabicyclo[3.2.0] heptane-2-

carboxylic Acid

2S,5R,6R)- 6-{,[(2R)-2-amino-2-

(4-hydroxyphenyl)- acetyl].amino}-

3,3-dimethyl- 7-oxo- 4-thia- 1-

azabicyclo[3.2.0]heptane-2-

carboxylic acid

27

Saccharin can be produced in various ways. The original route by Remsen &

Fahlberg starts with toluene; another route begins with o-chlorotoluene [57].

Sulfonation by chlorosulfonic acid gives the ortho and para substituted sulfonyl

chlorides. The ortho isomer is separated and converted to the sulfonamide with

ammonia. Oxidation of the methyl substituent gives the carboxylic acid, which

cyclizes to give saccharin free acid, which is shown in Figure (1-30),[58].

Figure(1-30):Synthesis of saccharin

1.2.3.4-Chlorobenzaldehyde

Chlorobenzaldehyd as shown in Figure (1-31),[59].

IUPAC name

4-Chlorobenzaldehyde

Molecular formula: C7H5ClO

Other names

p-Chlorobenzenecarboxaldehyde

P-Chlorobenzaldehyde;

4-Chlorobenzoic aldehyde;

Figure (1-31): Structural formula of 4-Chlorobenzaldehyde

28

1.2.4. 4-Hydroxybenzaldehyde [59].

4-Hydroxybenzaldehyde is one of the three isomers of hydroxy-benzaldehyde.

as shown in Figure(1-32),

IUPAC name

4-hydroxybenzaldehyde

Molecular formula

C7H6O2

Other names

p-hydroxybenzaldehyde,

p-formylphenol, 4-formylphenol,

Figure (1-32): Structural formula of 4-hydroxybenzaldehyde

1.2.5. 4-Chlorobenzophenone [59].

IUPAC name

Molecular formula

C13H9ClO

Other names

p-Chlorobenzophenone

Benzophenone,4-Chloro-methanone,

(4-Chlorophenyl)phenyl-p-CBP

Figure (1-33): Structural formula of 4-chlorobenzophenone

1.3. Mixed ligand metal complexes

Mixed ligand complexes play an important role in numerous chemical and

biological systems like water softening, ion exchange resin, electroplating, dying,

antioxidant, photosynthesis in plants, and removal of undesirable and harmful metals

from living organisms. Many of these metal complexes showed good biological

activity against pathogenic microorganisms [50, 51].

29

Mixed ligand metal complex of saccharin

Since the compounds of saccharin1 with various metals were suspected to be

potentially carcinogenic, a notable interest has been shown to study their structural

properties. The saccharinato salts and complexes are thus, both structurally and

spectroscopically, well investigated. Saccharin is a weak acid [60], which can easily

donate its imido proton nitrogen to form a saccharinate anion.

Bart [61] and Okaya [62], initially reported the X-ray structure of the saccharin

molecule and have shown that saccharin has the lactam structure (1).Metal complexes

of saccharin have gained a significant role in coordination chemistry. The studies of

metal complexes that have been reported are neither systematic nor exhaustive.

Replacement of the acidic hydrogen from a saccharin molecule produces a negative

center on the nitrogen atom, which could then coordinate with a suitable metal(II)

atom. In this brief overview, we would like to give an insight into the fascinating

chemistry derived from this simple molecule, on the basis of some selected

examples[63].

Ionic saccharinates

Studying the coordination nature of saccharin and determining the binding sites

to metal ions are perhaps a key to understand the bioinorganic chemistry of saccharin

[63].A lot of saccharin ,see Figure (1-34) was discovered by Remsen and of Fahlberg

in 1879 in chemical abstracts, besides the conventional name, saccharin appears as

1,2-benzisothiazole-3(2H)-one 1,1-dioxide. Saccharin is about 500 times sweeter than

sugar [64,65].

Figure (1-34): Saccharin(I) and saccharinato anion (II)

30

The data obtained indicate that saccharin acts either as a mono-dentate anion,

coordinating via the nitrogen or carbonyl oxygen atoms, or as a bidentate ligand

using both donor atoms. A different mode of coordination has also been reported for

saccharin[66], in the complexes ,[M(sac)2L2]xH2O (M = Cu(II)or Co(II), L = H2O or

pyridine, X = 1, 2 or 4). The octahedral coordination sphere associated with these

complexes contains two carbonyl groups of two saccharin molecules and two

sulphonyl groups of two other saccharin molecules.

Zaki et al (2007)[67], reported the structure of the mercury saccharinate

complex with pyridine by IR and single crystal X-ray diffraction methods, see Figure

(1-35). The Hg atom has slightly distorted tetrahedral configuration with four

nitrogen (N) atoms from two pyridine and two saccharinate anions in the complex.

Figure (1-35): Structure of saccharin and its Mercury complex with

pyridine [Hg(sac)2(py)2].

The structures of Co(II) [68], Ni(II) [69], Cu(II) [70] and Cd(II) [71],imidazole

saccharinates were reported. The binuclear Copper(II) and Cadmium(II) compounds,

however, having the general formula [M2(HIm)4(sac)4]2, are rather special.

Four novel mixed ligand complexes of Cu(II), Co(II), Ni(II) and Zn(II) with

saccharin and nicotinamide were synthesized and characterized on the basis of

elemental analysis, FT-IR spectroscopic study, UV–Vis spectrometric and magnetic

susceptibility data. The structure of the Cu (II) complex is completely different from

those of the Co(II), Ni(II) and Zn(II) complexes. From the frequencies of the

31

saccharinato CO and SO2 modes, it has been proven that the saccharinato ligands in

the structure of the Cu complex are coordinated to the metal ion

[Cu(NA)2(Sac)2(H2O)], where, ( NA:nicotinamide, Sac :saccharinato ligand or ion),

whilst in the Co(II), Ni(II) and Zn(II) complexes are uncoordinated and exist as ions

([M(NA)2(H2O)4].(Sac)2) [72].

The electrochemical behavior and thermal decomposition of a ternary complex

of Cu(II) with saccharin and nicotinamide,[73]have been investigated by means of

voltammetric (square-wave and cyclic voltammetry), spectroscopic and thermo

analysis (TG,DTA,DTG) measurements. ESR and magnetic susceptibility data

suggest that the structure of the complex is square–pyramidal in the solid state. The

thermal behavior of the complex from ambient temperature up to 1000 °C in a static

air atmosphere was studied. The decomposition pathway of the complex is

interpreted in terms of the structural data. A possible mechanism for the

decomposition of the complex is proposed [73].

The saccharinato complexes of Au(III), ZrO(II), VO(II) and UO2(II) metal ions

have been prepared by Teleb, (2004) [74], and the coordination of saccharin in these

complexes has been investigated through their 1H-NMR and IR spectra as well as by

thermal analysis. It was found that saccharin interacts with all of these metal ions in

the anionic form and coordinates in a monodentate fashion through its nitrogen to

Au(III), ZrO(II) and VO(II) ions, where as it coordinates to UO2(II) ion as a bidentate

ligand using its carbonyl and sulphonyl groups. A square structure has been proposed

for Au(III) complexes, polymeric chain structures for ZrO(II) and VO(II) complexes

and an octahedral structure for UO2 saccharin complex. The thermal properties of

these complexes were shown to be consistent with the proposed structures and

indicate that metallic Gold, ZrO2, V2O5 and UO2SO4 are obtained as final thermal

decomposition products of these complexes[75,76].Also in some Pd(II) and Pt(II)

complexes of the type ,[MCl(sac)L2]. (L = different phosphine ligands) coordination

of saccharinate also involves Pd-N and Pt-N bonds [77].

Monodentate O-coordinated metal complexes.

The carbonyl O-atom often participates in bonding, when Saccharinate acts as a

bidentate ligand, as shall be discussed but, monodentate coordination by this O-atom

is rather unusual. The first example of this form of interaction was reported for a

V(IV)complex, namely,[V(sac)2(py)4].2p,[78]. Similar M-O bonds were found latter

32

in the cases of , [Ni(sac)2(py)4] , [79], and bis(saccharinate) tetra (isoquinoline)

Copper(II),[80].Taking into account that, as mentioned above, the lighter divalent

transition metal cations prefer M-N interactions, the appearance of M-O bonds in the

mentioned complexes may probably be originated by steric effects.

This last supposition is additionally confirmed by the structure of the Copper (I)

complex of composition ,[Cu(sac)(PPh3)3], containing the bulky triphenyl phosphine

ligands (PPh3), in which saccharinate also coordinates through the carbonyl O-

atom,[80],where is, interestingly, in a similar compound with one PPh3 group less,

[Cu(sac)(PPh3)2], the coordination occurs through the N-atom[81].

Bidentate N,O- coordinated metal complexes

In this case the saccharinate moiety can act either as a single bidentate ligand for

only one metal center or, more frequently, as abidentate bridging ligand. A recent

example for the first situation is the complex [Pb(sac)2(phen)(H2O)2],(phen =1,10-

phenanthroline) in which Pb(II) presents the unusual coordination number eight, with

the two saccharinate anions acting as bidentate and the coordination sphere

completed by the two N atoms of ophen and the two water O-atoms[82].

In the case of the simpler ,[Pb(sac)2].H2O complex, the bidentate ligand

originates a dimeric structure[83].Nevertheless, probably the most interesting dimeric

species of this type is the ,[Cr2(sac)4py2].2py complex[84], in which the four

saccharinate moieties act as bidentate bridges between the two Cr(III)actions and

which therefore resembles the well-known Cr(III) carboxylate species[85].

Saccharinate complexes of the trivalent Lanthanides

The saccharinate complexes of the trivalent Lanthanides and Yttrium, constitute

an especially interesting series of compounds. They belong to three different

structural types. In the first family, of composition ,[Ln(sac)(H2O)8].(sac)2.H2O, with

Ln = La, Ce, Pr, Nd, Sm and Eu, the Ln(III) cation is in a tricapped trigonal prismatic

environment with nine-fold oxygen coordination, involving one Saccharinate

carbonylic O-atom and eight water O-atoms [76,86].

The second group of composition ,[Ln(sac)2(H2O)6].(sac)(sacH).4H2O with

Ln = Gd, Dy, Ho, Er, Yb, Lu and Y constitutes an interesting example of complexes

that contain simultaneously saccharin and its anion in the crystal lattice,[86].In the

third group, the Tm(III) and Tb(III)compounds, present two closely related structures

conformed by three and two ,[Ln(sac)(H2O)7] crystallographically independent

33

complexes, respectively, with the [Tm(sac)(H2O)7].3(sac)6.9H2O and,

[Tb(sac)(H2O)7].2(sac)3.6H2O composition. For all the heavier lanthanides (Gd-Lu)

and Yttrium the cation presents eight-fold oxygen coordination, with the ligands

arranged at the corners of a slightly distorted square Archimedean antiprism[76].

Other peculiar coordination behavior

Some saccharinate complexes present a very particular coordination

characteristic, which exemplify another fascinating aspect of this ligand. This

peculiarity, that was first found in two Copper(II) complexes, namely

,[Cu(sac)2(py)3][87],and[Cu(sac)2(dipyr)(H2O](dipyr:dipyridylamine),[88,89],is the

fact that they are simple mononuclear complexes in which one of the saccharinate

ligands is bonded through the N-atom and the other one through the O-atom. A

similar behavior was also observed with some mixed ligand complexes containing 2-

pyridylmethanol(mpy),i.e.,[Cd(sac)2(mpy)2],

[Zn(sac)2(mpy)2][90],[Co(sac)2(mpy)2][91],[Ni(sac)2(mpy)2][91].

Presence of bonded and not bonded saccharinate anions and of free saccharin in

complex species. Another interesting aspect, recently documented in a variety of

compounds, is the fact that in some species the saccharinate anion can be present both

in the complex cation and as a counter-ion, outside the coordination sphere. Some

examples have been presented above, in relation to the stoichiometry’s of the

complexes of the heavier Lanthanides [76].Other examples are found in the

complexes:

[Cu(sac)(bipy)2].(sac).2H2O[92],[Mn(sac)(bipy)2(H2O)].(sac)[93],

[Co(sac)(bipy)2(H2O)].(sac)[94] and [Mn(sac)(ophen)2(H2O)](sac)[94].

Obviously, an important number of compounds in which the saccharinate anion

is only present as a counter anion from a complex cation are also known. Some

recently reported examples are the following:

[Cu2(μ-oxal)(bipy)2(H2O)2].(sac)2with oxal = oxalate[95],

[Cd(tea)2].(sac)2 and [Hg(tea)2].(sac)2],with tea=triethanolamine

[96],[Co(H2O)4(py)2].(sac)2[97],[Ni(H2O)4(py)2].(sac)2[97],[Co(dmpy)2].(sac)2 and

[Ni(dmpy)2].(sac)2withdmpy = pyridine-2,6-dimethanol[98], [Fe(4,4’-

bipy)(HO)].(sac)2 with 4,4’-bipy = 4,4’-bipyridine,[99]

,[M(Nic)(H2O)].(sac)2 with M =Co(II),Ni(II),Zn(II),Nic =nicotinamide[100].

An especially interesting example of systems of this type is the material of

composition. [Cu(4,4’-bipy)2(H2O)2](sac)2.DMF , which is a square grid polymer

34

with the saccharinate anions sandwiched between the complex layers and the

dimethyl formamide (DMF) molecules filling the square holes[101].Besides, the

presence of free saccharin in the crystal lattices of certain complexes have been

established, as mentioned above in the case of the[Ln(sac)2(H2O)6] (sac)(sacH).4H2O

complexes[76]. Notwithstanding, the first case in which this situation was found is,

apparently, the VO(II) complex of composition ,[VO(OH)(sac)(H2O)2(Hsac)][102].

Shihab, et al(2012) [103],reported tetrahedral mercury(II) complexes containing

mixed ligands of mono or diphosphines and Saccharinate complexes of the types

,[HgCl(sac)(PPh3)2HgCl(sac)(diphos)],[Hg(sac)2(PPh3)2]

or[Hg(sac)2(diphos)]and octahedral complexes of the type ,[Hg(sac)2(dppe)2]or

[Hg(sac)2(dppp)2].{diphos = Ph2P(CH2)nPPh2; n=1,dppm; n=2,dppe;n=3,dppp;

n=4,dppb}were prepared and characterized Figure (1-36).

Figure (1-36): The suggested structures for the prepared Mercury(II)

complexes

35

Fayad et al (2012) [104],reported new six mixed ligand complexes of some

transition metal ions Manganese (II),Cobalt(II), Iron (II), Nickel (II) , and non-

transition metal ion Zinc (II) and Cadmium(II) with L-valine (Val H ) as a primary

ligand and Saccharin (HSac) as a secondary ligands have been prepared. All the

prepared complexes have been characterized by molar conductance, magnetic

susceptibility infrared, electronic spectral and A.A .The complexes with the formulas

[M(Val)2(HSac)2]

M(II) = Mn (II) , Fe (II) , Co(II) ,Ni(II), Cu (II),Zn(II) and Cd(II)

L- Val H= (C5H11NO2),SacH =C7H5NO3S

The study shows that these complexes have octahedral geometry; the metal

complexes have been screened for their in microbiological activities against bacteria.

Based on the reported results, it may be concluded that the deprotonated ligand (L-

valine) to (valinate ion (Val ) by using (NaOH) coordinated to metal ions as

bidentate ligand through the oxygen atom of the carboxylate group(COO ), and the

nitrogen atom of the amine group (NH2), where the saccharin (SacH)coordinated as a

monodentate through the nitrogen atom. See Figure (1-37).

Figure (1-37): Suggested structures and 3D-geometrical structure of the

complexes

36

The antibacterial activity of mixed ligand complexes 1-6 against Staphylococcus

aureus(+ve), and Escherichia coli , Salmonella typhi and Aeruginosa(-ve) were

carried out by measuring the inhibition diameter .

1.4. Antimicrobial activities of Schiff base metal complexes

Azza et al. [105] , synthesized mono and bi-nuclear acyclic and macro cyclic

complexes with hard-soft Schiff base, HL2, see Figure (1-38),ligand derived from the

reaction of 4,6-diacetylresorcinol and thiocarbohydrazide. The Schiff base ligand

HL2 and its metal complexes were evaluated for their antimicrobial activity against

one strain gram-positive bacteria S. aureus and P. fluorescens as gram-negative

bacteria as well as one pathogenic fungus, as F. Oxysporum. The data were compared

with standard antibiotics, chloramphenicolas gram-negative and Cephalothin as

standard reference for gram–positive bacteria. Cycloheximide was used as antifungal

standard reference. The in vitro antibacterial and antifungal activities demonstrated

that the complexes have higher antimicrobial activity in comparison with that of the

ligand.

Figure (1-38): Bi-nuclear acyclic and macrocyclic

complexes with Schiff base

Sobha et al[106],prepared series of Cu(II), Ni(II) and Zn(II) complexes of the

type ML(matel:ligand) have been synthesized with Schiff bases derived from o-

acetoacetotoluidide, 2-hydroxyl benzaldehyde and o-phenylene diamine see Figure

(1-39),1,4- diaminobutane explore the activity of the Schiff base ligands and there

metal(II)complexes against bacteria, while ampicillin is used as a standard drug for

37

comparison. The microorganisms used in the present investigations included S.

aureus, P. aeruginosa, E. coli, S. epidermidisand K. pneumoniae. The diffusion agar

technique was used to evaluate the antibacterial activity of the synthesized metal

complexes. The complexes were more potent bactericides than the free Schiff bases.

This higher antimicrobial activity of the metal complexes compared to Schiff bases

may be due to the change in structure due to coordination and chelating tends to make

metal complexes act as more powerful and potent bacteriostatic agents, thus

inhibiting the growth of the microorganisms.

Figure (1-39): Complexes Schiff base derived from o-acetoaceto -

toluidide,2-hydroxybenzaldehyde and o-phenylene diamine

Co(II), Ni(II), Cu(II) and Zn(II) complexes of the Schiff base derived from

indole-3- carboxaldehyde and m-aminobenzoic acid[107], see Figure(1-40), were

synthesized. The in vitro antifungal and antibacterial screening of the complexes

were checked. In some cases, ligand and its complexes have similar activity against

bacterial and fungal species. The in vitro fungal activity results revealed that

complexes are more microbial toxic than the ligand. The in vitro antibacterial activity

results revealed that the ligand was bacteriostatic against bacterial strains except P.

vulgaris and K. Pneumonia. The activity order of the synthesized compounds is as

follows:

Cu(II) > Co(II) >Ni(II) > Zn(II)> Ligand.

38

Figure (1-40): Complexes of the Schiff base derived fromindole-3-

carboxaldehyde and m-aminobenzoic acid

Metal complexes was synthesized with Schiff bases derived from

O-phthalaldehyde (opa) and amino acids viz., glycine (gly) l-alanine (ala), l-

phenyl alanine (pal)by Neelakantan et al[108].The antimicrobial activities of the title

Schiff base metal complexes (50μg per test) in vitro were tested against eleven

microbes by the modified disc diffusion method. Cu(II)and Ni(II) complexes exhibit

inhibition towards all the studied microorganisms.

However, Co(II) and Mn(II) complexes exhibit less inhibition and VO(II)

complexes have no activity towards the micro-organisms. Four new N2O2 type

tetradentate [108], Schiff base complexes of Co(III), derived from the condensation

of meso-1, 2diphenyl-1, 2-ethylenediamine (meso-stilbenediamine) with

salicylaldehyde derivatives see Figure (1-41),were synthesized. The in vitro

antimicrobial activity of the Schiff base complexes was tested against human

pathogenic bacteria such as Salmonella typhi, Pseudomonas aeruginosa, Klebsiella

pneumonia, Staphylococcus aureus and Listeria monocytogenes.

39

Figure (1-41): N2O2 type tetra dentate Schiff base complexes of Co(III).

The antibacterial activity studies for the complexes and standard compounds

(Gentamicin and Ciprofloxacin), evaluated by Kirby- Bauer disc diffusion method

and serial dilution sensitivity test against both gram-positive and gram-negative

bacteria. DMSO solvent was also used as positive control. As it could be seen from

these results, both gram positive and gram negative bacteria were affected by these

antibacterial agents and S.typhiwas the most sensitive microorganism to the studied

complexes. On the other hand, P. aeruginosa and S. aureus were, to some extent,

more resistant to these compounds [109].

Govindaraj Saravanan et al (2011) [110], developed a series of 1-

(substitutedbenzylidene)-4,4,2-(methyl/phenyl)-4-oxoquinazolin-3(4H)-yl)

phenyl)semi carbazide derivatives were synthesized with the aim of developing

potential antimicrobials. The in vitro antibacterial and antifungal properties were

tested against some human pathogenic microorganisms by employing the disc

diffusion technique and agar streak dilution method. All compounds showed activity

against the entire strain of microorganisms. The relationship between the functional

group variation and the biological activity of the evaluated compounds were well

discussed. Based on the results obtained, compounds were found to be very active

which were subjected to antimicrobial assay.

Noor-ul et al(2009)[111], prepared the complexes were screened in vitro for

their microbial activity against five gram (+), five gram (−) and three fungal

40

pathogens using agar cup method. The complexes were found to exhibit considerable

activity against gram (+) bacteria used in the present study and the results are

comparable with standard antibiotics streptomycin.

Salicylaldehyde- 2-phenylquinoline-4-carboylhydrazone (HL2), and its novel

tetra nuclear Co(II), Ni(II) and Ru (III) complexes, see Figure (1-42),have been

synthesized by Zhi-hong Xu. et al. (2011)[112].

The in vitro antibacterial activity of complexes against Escherichia coli,

Staphylococcus aureus, Bacillussubtilis was screened and compared to the activity of

the free ligand.

Figure (1-42): Salicylaldehyde 2-phenylquinoline-4-carboylhydrazone-Ru-

complex.

Thirteen optically active 1-naphthyl keto-oxiranes (1-naphthyl-4-yl-3-

(substituted phenyl) oxiran-2-ylmethanones) ,see Figure(1-43),have been synthesized

by phase transfer catalysed epoxidation of 1-naphthyl chaconnes. The yields of

oxiranes are more than 95%. These multipronged activities present in different keto

epoxides are intended to examine their activities against respective microbes-

bacteria’s, fungi and insect antifeedant activities against castor semi looper.

Figure (1-43): Schiff base 1-naphthyl keto-oxiranes[1-naphthyl-4-yl-3

(substituted phenyl) oxiran-2-yl] methanones

41

The antibacterial activities of all prepared epoxides have been evaluated against

two gram positive pathogenic strains Staphylococcus aureus, Enterococcus faecalis

while Escherichia coli, Klebsiella species, Pseudomonas and Proteus vulgaris were

gram negative strains. The disc diffusion technique was followed using the Kirby–

Bauer method, at a concentration of 250 μg/mL with Ampicillin and streptomycin

taken as the standard drugs. Measurement of antifungal activities of all epoxides have

been done using Candidaalbicans as the fungal strain and the disc diffusion

technique was followed for the antifungal activity while for the two other stains

Penicillium species and Aspergillusniger, dilution method was adopted. The drugs

dilution was50 μg/mL.Griseofulvin has been taken as the standard drug. All the

synthesized compounds showed good activity [113].

The clinically active functionalized b-diketones1-(20,40dihydroxyphenyl)-3-

(200-substitutedphenyl)- propane-1,3-dione (L1–L2) have been synthesized by Javed

Sheikh, et al(2011) [114],from Baker–Venkataraman transformation of 2,4-

diaroyloxy- acetophenones. Two gram-positive (S. aureus ATCC 25923 and B.

Subtilis ATCC 6633) and two gram-negative (E. coli ATCC 25922 and P. aeruginosa

ATCC 27853) bacteria were used as quality control strains. For determining anti-

yeast activities of the compounds, the following reference strains were tested: C.

Albicans ATCC 10231 and C. glabrata ATCC 36583. Ampicillin trihydrate were

used as standard antibacterial and antifungal agents, respectively.

A new series of oxovanadium(I1) complexes Figure (1-44), have been designed

and synthesized with a new class of triazole Schiff bases derived from the reaction of

3,5-diamino-1,2,4-triazole with 2-hydroxy-1-naphthaldehyde, pyrrole-2-

carboxaldehyde, pyridine-2-carboxaldehyde and acetyl pyridine-2-carboxaldehyde,

respectively. In order to evaluate the biological activity of Schiff bases and to assess

the role of Vanadium(IV) metal on biological activity, the triazole Schiff bases and

their oxovanadium(II) complexes have been studied for in vitro antibacterial activity

against four gram-negative (Escherichia coli, Shigellaflexenari, Pseudomonas

aeruginosa,Salmonellatyphi) and two gram-positive (Staphylococcus aureus,

Bacillus subtilis) bacterial strains, in vitro antifungal activity against

Trichophytonlongifucus, Candida albican, Aspergillusflavus, Microscopumcanis,

Fusariumsolani and Candida glaberata. The simple Schiff bases showed weaker to

significant activity against one or more bacterial and fungal strains. In most of the

42

cases, higher activity was exhibited upon coordination with Vanadium(IV) metal

[115].

Figure (1-44): Oxovanadium(II)-triazole Schiff bas complex

Patel, et al(2010)[116],designed novel homodinuclearZn(II) complexes with the

quinolone antibacterial drugs Ciprofloxacine, see Figure (1-45), and neutral bidentate

ligands have been synthesized. The efficiencies of the ligands and the complexes

have been tested against three gram(-ve), E. coli, S. merscences, P. aeruginosa, and

two gram(+ve),S. aureus, B. subtilis, microorganisms. From the experiment ,they

found that all the metal complexes were more active than the metal salts and ligands.

Figure(1-45): Homodinuclear Zinc(II) +quinolone antibacterial drug

Ciprofloxacine

43

Ajaykumar et al(2009)[117].A series of first complexes of Co(II), Ni(II), Cu(II),

Mn(II) and Fe(III) have been synthesized with Schiff base derived from isatin

monohydrazone and fluvastatin, see Figure (1-46).The Schiff bases and their complexes ,

see Figures (1-47) and (1-48) have been screened for their in vitro antibacterial

(Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus

subtilis) and antifungal (Aspergillusniger and Pencillium Chrysogenum) activities by

minimum inhibitory concentration (MIC) method.

Figure (1-46): Synthesis of Schiff base

44

Figure (1-47): Structure of metal complexes

Figure (1-48): Structure of Fe(III) complex

45

Taghreed et al. (2012)[118],reported the synthesis and characterization of the

tridentate Schiff base (HL) containing (N and O) as donor atoms type (ONO). The ligand

is: (HL) phenyl (HL) phenyl 2-(2-hydroxybenzylidenamino) benzoate Figure (1-49) .

This ligand was prepared by the reaction of (phenyl- 2-aminobenzoate) with

salicylaldehyde under reflux in ethanol and few drops of glacial acetic acid which gave

the ligand (HL). The prepared ligand was characterized by (FT- IR,UV–

Vis)spectroscopy, elemental analysis of carbon, hydrogen and nitrogen (C.H.N.) and

melting point. The ligand was reacted with some metal ions under reflux in ethanol with

(1 metal :2 ligand )mole ratio which gave complexes of the general formula:

[M(L)2]Cl , M = Cr (III ) ,La ((III)) and Pr(III) products were found to be solid

crystalline complexes, which have been characterized through the following techniques:

molar conductivity ,spectroscopic method ,[FT-IR and UV-Vis], additional measurement

magnetic susceptibility, chloride content and program,[Chem. office–CS. Chem.–3D pro

2006],was used. Research also includes studying the bio–activity of the ligand and,[La

(L)2]Cl, some compounds prepared against a kind of bacteria three of which were

negative to gram dye (Proteus mirabilis, Klebsiella pneumonia, Escherichia coli), and

one was positive to gram dye (Staphylococcus aureus). The[La(L)2]Cl, showed

inhibitive activity against some of bacteria under consideration. The magnetic moment

coupled with the electronic spectra suggested an octahedral geometry for all the

complexes .

Figure (1-49): Chemical structure of phenyl

2-(2-hydroxybenzylidenamino) benzoate (HL)

46

Taghreed et al. (2013) [119], reported new Schiff base ligand (Z)-7-(2-(4-

(dimethylamino)benzylideneamino)-2-phenylacetamido)-3-ethyl-8-oxo-5-thia-1-

azabicyclo,[4.2.0].oct-2-ene-2-carboxylic acid = (HL)was prepared via condensation of

Cephalexin and 4-dimethylamino) benzaldehyde in methanol . Polydentate mixed ligand

complexes were obtained from 1:1:2 molar ratio reactions with metal ions and HL, 2NA

on reaction with MCl2 .nH2O salt yields complexes corresponding to the

formulas[M(L)(NA)2Cl] ,where M(II) =Fe(II),Co(II),Ni(II),Cu(II)and Zn(II) and

NA=Nicotinamide .

The 1H-NMR, FT-IR, UV-Vis and elemental analysis were used for the

characterization of the ligand. The complexes were structurally studied through

A.A.S,FT-IR,UV-Vis, chloride contents, conductance, and magnetic susceptibility

measurements. All complexes are non-electrolytes in DMSO solution. Octahedral

geometries have been suggested for each of the complexes. See Figure (1-50).

CH

N

H3C

H3C

NH2

O

NH

H

N

SH

CH3

O

OOH

. H2O

N

NH

H

N

S

H

CH3

O

O

OH

(Z)-7-(2-(4-(dimethylamino)benzylideneamino)-2-phenylacetamido)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Cephalexin

O

+

MeOH Reflux 5 hours

C

O

H

N

H3C CH3

4-(dimethylamino)benzaldehyde

( HL )

Figure (1-50): Schematic representation of synthesis(Z)-7-

(2-(4-(dimethylamino) benzylideneamino)-2-phenylacetamido)-3-methyl-8-oxo-

5-thia-1-azabicyclo,[4.2.0].oct-2-ene-2-carboxylic acid ligand

47

Taghreed et al (2013)[120],reported new mixed ligand complexes of bivalent

metal ions, viz; M(II) = Co(II), Ni(II), Cu(II) and Zn(II) of the composition

,[M(Ceph)(NA)3] Cl in 1:1:3 molar ratio, (where Ceph = Cephalexin and

NA = Nicotinamide have been synthesized and characterized by repeated

melting point determination, solubility, molar conductivity, determination of the

percentage of the metal in the complexes by flame(A.A.S), FT-IR, magnetic

susceptibility measurements and electronic spectral data. The ligands and their

metal complexes were screened for their antimicrobial activity against six bacteria

gram (+ve) and gram (-ve). See Figure (1-51).

Figure (1-51): Schematic representation of synthesis

[M(Ceph)(NA)3]Cl

N

NH

H

N

SH

CH3

O

O

O

N

C

OH2N

M

N

CO

NH2

N

CO

NH2

NH2

O

NH

H

N

SH

CH3

O

OOH

. H2O +N

C

O

NH2

31 +

Cephalexin Nicotinamide

MeOH

Stirring 5 hours

KOH

O

H

H

MCl2

Cl

M=Fe(II), Co(II), Ni(II), Cu(II), and Zn(II)

48

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