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
2
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.
5
(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).
7
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].
9
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.
10
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
11
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
12
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].
13
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).
14
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].
15
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
17
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.
18
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).
19
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
20
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.
21
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
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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