Biological Activities of Schiff Bases and Their Complexes: A Review of Recent Works

Schiff base compounds and their metal complexes have been extensively investigated due to their wide range of applications including catalysts [1,2], medicine [3,4] crystal engineering [5], anti-corrosion agent [6,7]. Schiff bases are studied widely due to their synthetic flexibility, selectivity and sensitivity towards the central metal atom; structural similarities with natural biological compounds and also due to presence of azomethine group(-N=CH-) which imports in elucidating the mechanism of transformation and racemization reaction biologically [8,9]. Schiff bases having chelation with oxygen, nitrogen etc. donors and their complexes have been used as drugs and reported to possess a wide variety of biological activities against bacteria, fungi, and certain type of tumors and also, they have many biochemical, clinical and pharmacological properties [10-14]. Imine or azomethine groups are present in various natural, naturally derived and nonnatural compounds (Figure 1). The imine group present in such compounds has been shown to be critical to their biological activities [15-17]. This review concentrates on the synthesis and biologi-


Introduction
Schiff base compounds and their metal complexes have been extensively investigated due to their wide range of applications including catalysts [1,2], medicine [3,4] crystal engineering [5], anti-corrosion agent [6,7]. Schiff bases are studied widely due to their synthetic flexibility, selectivity and sensitivity towards the central metal atom; structural similarities with natural biological compounds and also due to presence of azomethine group(-N=CH-) which imports in elucidating the mechanism of transformation and racemization reaction biologically [8,9]. Schiff bases having chelation with oxygen, nitrogen etc. donors and their complexes have been used as drugs and reported to possess a wide variety of biological activities against bacteria, fungi, and certain type of tumors and also, they have many biochemical, clinical and pharmacological properties [10][11][12][13][14]. Imine or azomethine groups are present in various natural, naturally derived and nonnatural compounds (Figure 1). The imine group present in such compounds has been shown to be critical to their biological activities [15][16][17].
This review concentrates on the synthesis and biologi- cal activity of Schiff bases and their complexes.

Biological Activities of Schiff Bases
Schiff bases are generally bi-or tridentate ligands capable of forming very stable complexes with transition metals. In organic synthesis, Schiff base reactions are useful in making carbon-nitrogen bonds.
Complexes of Co(II) and Ni(II) with new Schiff bases (Scheme 1) derived from 4-amino-5-sulfanyl-1.2.4-triazoles and glyoxal, biacetyl or benzil have been prepared. All have the stoichiometry ML(H 2 O) 2 , with L coordination via the two imine nitrogens and two thiolato sulfurs in an overall octahedral geometry. Some of the complexes were screened for their antibacterial and antifungal activity, and one representative Co(II) complex was evaluated for oxytocic. Furthermore, complex(c) (R; Me, R 1 ; H) was found to inhibit the oxytocic activity of oxytocin on isolated rat uterus ( Table 1) [18]. Tumer    w free ligands and their complexes were found to be highly active against both the Bacillus megaterium and Candida tropicalis. However, the metal complexes were active compared with corresponding ligands as regards to antimicrobial activity of the molecule [19].
Paola et al have reported the synthesis, n and evaluation as antibacterial and antifungal agents of a series of hydrazones (Scheme 4) of 1.2-benzisothiazole hydrazides as well as their cyclic and acyclic 1.2benzisothiazole parent hydrazides. All of the 2-amino-1.2-benzisothiazol-3(2H)-one derivatives, belonging to series I and IV, showed a good antibacterial activity against Gram positive bacteria. Most of them were active against yeasts too. Compounds 1 and 4, together with II, proved to be the most effective compounds [21]. Sevim and coworkers have reported the synthe aluation a series of hydrazide hydrazones and 1.3.4oxadiazolines of 4-fluorobenzoic and hydrazide (Scheme 5) as potential antimicrobial agents and have tested for their antibacterial and antifungal activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans. From these compounds, 4-fluorobenzoic acid [(5-nitro-2-furanyl) methylene] hydrazide(1a) showed equal activity with ceftriaxone against S. aureus [22].
Natarajan a utral tetradentate chelate complexes of Cu(II), Ni(II), Co(II), Mn(II), Zn(II) and VO(II) in EtOH using Schiff bases (Scheme 7) derived from acetoacetanilido-4-aminoantipyrine and 2-aminophenol/2-aminothiophenol. Microanalytical data, magnetic susceptibility, IR., UV-vis., 1 H-NMR. and ESR spectral techniques were used to confirm the structures of the chelates. The in vitro antimicrobial activity of the investigated compounds was tested against the microorganisms such as Salmonella typhi, Staphylococcus aureus, Klebsiella pneumoniae, Bacillus subtilis, Shigella flexneri, Pseudomonas aeruginosa, Aspergillus niger and Rhizoctonia bataicola. Most of the metal chelates have higher antimicrobial activity than the free ligands [24].
The synthesis and vitro antifungal act hiff bases (Scheme 9) and their Sn(IV) complexes has been tested against plant pathogenic fungi and it is found that they possess excellent fungicidal activity [30].
The vitro antibacterial antifungal activities of fiv rent amino acid Schiff bases (Scheme 10) derived from the reaction of 2-hydroxy-1-naphthaldehyde with glycine, L-alanine L-phenylalanine, L-histidine, L-tryptophane and the manganese(III) complexes of these bases were studied. In vitro activities against some Gram-positive (Staphylococcus aureus and Bacillus polymyxa) and Gram-negative (Escherichia coli) bacteria and the fungus Candida albicans were determined. The antimicrobial activities tended to decrease with the increasing size of the amino acid residues [31]. Two small sets of aromatic Schiff bases and 2,3-diia and coworkers have reported the synthesis two ne ryl-1,3-thiazolidin-4-one (Scheme 11) derivatives have been prepared and tested for anti-inflammatory and antinociceptive activities. The thiazolidinone derivatives have been obtained from the azomethines through the addition of α-mercaptoacetic acid. Both types of compounds displayed good level of activity against carrageenan induced edema in rat hind paw, while only moderate activity was observed in the writhing test in mice [32].    Raman and ur copper (II) complexes (Scheme 13) using macrocyclic ligands. The macrocyclic ligands have been synthesized by the condensation reaction of diethyl phthalate with Schiff bases derived from o-phenylene diamine and condensation of acetoacetanilide and substituted benzaldehydes). The in vitro antifungal activities of the compounds were tested against fungi such as Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola and Candida albicans. All the synthesized copper complexes showed stronger antifungal activities than free ligands [36].
Hitesh et al have reported the synthesis mixed-ligand complexes (Scheme 14 (II), and Cd(II) with biologically active Schiff bases, viz. potassium salt of o-hydroxyacetophenoneglycine [KHL] and bis(benzylidene) ethylenediamine [A 1 ] or thiophene-o-carboxaldene-p-toluidine [A 2 ]. The mixedligand complexes show higher antifungal activity as compared to the free ligands, metal salts, and the control (dimethylsulfoxide) but moderate activity as compared to the standard fungicides (bavistin and emcarb) [37].
A relationship between antimicrobial activities and the formation constants of amino acid-Schiff bases (Sch ) and their Cu(II) and Ni(II) complexes was studied. For this purpose, a series of Schiff bases were prepared from DL-amino acids (DL-glycine, DL-alanine) and haloaldehydes (5-chloro-2-hydroxybenzaldehyde, 5-  [38]. Dharmarajan and coworkers have reported the synthesis and evaluation various d and amides (Scheme 16) for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis [39].
Schiff base tetraazamacrocyclic ligand (Scheme 17), L (C H 40 28 4 2 uL]X 2 (M = Co(II), Ni(II), Zn(II); X=Cl − , 3 NO  ) were synthesized and characterized by elemental analyses, mass, 1 H-NMR, IR, UV-vis, magnetic susceptibility and molar conductance data. The ligand (L) and its complexes have also been screened against different fungi and bacteria in vitro. The complexes exhibited potential activity at the concentration dose of 5 mg/ml which is comparable to that of tetradentate 12-membered macrocyclic compounds, shown to have antimicrobial activity against various pathogens by disc diffusion technique [40,41].
Lei and coworkers have reported the synthesis of a series of Schiff bases ( ) by reacting 5-chlorolicylaldehyde and primary amines. The compounds were assayed for antibacterial (Bacillus subtilis, Esherichia coli, Pseudomonas fluorescence and Staphylococcus aureus) and antifungal (Aspergillus niger, Candida albicans and Trichophyton rubrum) activities. Among the compounds tested, (E)-4-chloro-2-((4-flurobenylimino)-methyl)phenol showed the most favorable antimicrobial activity with MIC s of 45.2, 1.6, 2.8, 3.4, and 47.7 μg/mL against B. Subtilis, E. coli, P. flurescence, S. aureus and A. niger, respectively. It is also reported that Salicylaldehyde derivatives, with one or more halo-atoms in the aromatic ring, showed variety of biological activities like antibacterial and antifungal activities [42,43].
Sammanta and coworkers have reported herein the synthesis thre Scheme 11. Aromatic Schiff Bases and 2,3-diaryl-1,3-thiazolidin-4-one.   On the basis of these studies, a five coordinate square pyramidal geometry has been proposed for all these complexes. The biological activities of the metal complexes have been tested in vitro against a number of pathogenic to assess their inhibiting potential. Some of these complexes have been found to exhibit remarkable antibacterial [45].
Complexes Rehman et al have reported the synthesis and characterization of a Schiff base (Scheme 22) derived from aniline and salicylaldehyde and its Co(II), Mn(II), and Zn(II) complexes; several p ental analysis, infrared and NMR techniques were used to investigate the chemical structure of the complexes. Biological screening of the complexes reveals that the Schiff base transition metal complexes show significant against all microorganisms [48].
A series of new Schiff base hydrazones (Scheme 21) were synthesized by condensation reaction of 4-amino-3-(4-pyridine)-5-mercapto-1,2,4-triazole with various aldehydes and/or dialdehydes. The ere assayed for antibacterial (Escherichia coli and Staphylococcus aureus) and antifungal (Candida albicans) activities by disc diffusion method. The results indicate that all tested compounds did not show any antibacterial activity against E. coli, as gram negative bacteria, and antifungal activity against C. albicans. But the compounds containing 4-Cl, 4-Me, 4-MeO, 2,4-di-Cl and 2-OH substituted phenyl moiety, respectively, showed good inhibition against S. aureus as compare to standard drugs [49].
Plech et al have proved that chemical character of the C-5 substituent significantly determines the antibacterial activity of the Mannich bases (Scheme 34) derived from 4,5-disubstituted 1,2,4-triazole-3-thiones. This activity was considerably increased by an introduction of a bromine atom to the phenyl ring. The obtained compounds were particularly active against opportunistic bacteria (Bacillus subtilis and Bacillus cereus). The antibacterial activity of some Mannich bases was similar or higher than the activity of commonly used antibiotics such as ampicillin and cefuroxime [62].
Schiff base ligand (H 3 L) was prepared from the condensation reaction of protochatechualdehyde (3,4-dihydroxybenzaldhyde)with 2-amino phenol. From the direct reaction of the ligand (H 3 L) with Co(II), Ni(II) and Cu(II) chlorides, and Fe(III)and Zn(II)nitrates in 2:1 L molar ratio, the five new neutral complexes were prepared. The characterization of the newly formed compounds was done by 1 H-NMR, UV-Vis, and IR spectroscopy and elemental analysis. The in vitro antibacterial activity of the metal complexes was studied and compared with that of free ligand [63]. Kalanithi  The anti-microbial activity of the ligands and metal(II) complexes against the species Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Candida albigans and Aspergillus niger has been carried out and compared [64].
Ugras et al have reported the synthesis, complexation, antifungal and antibacterial activity studied of a new macro cyclic Schiff base (Scheme 36) [65].
Preparation, physical characterization and antibacterial activity of Ni(II) Schiff base complex was reported by Morad et al. [65].
The biological evaluation of the simple uncomplexed  ligand in comparison to their comp rmined to their complexes have been determined against bacterial strains namely Escherichia coli, Staphylococcus aureous and Pseudomonas aeruginosa [65].
Baluja et al have studied the biological activities of the following Schiff base (Scheme 41) and metal complexes [65] Raman et al have reported the synthesis of the following Schiff ligands (Scheme 42). These authors have also bial activity of [65]. Synthesis of Schiff bases (Scheme 43) of the naptha [1,2-d] thiazol-amine and metal complexes of 2-(2'-hydroxy)benzylideneaminonaphthathiazole as potential antimicrobial agent was reported by Faizul and co-workers [65].
Raman et al have reported the synthesis of a novel 14-membered macrocyclic Schiff base (Scheme 45) derived from 3-cinnamalideneacetanalide and o-phenylenediamine which acts as a tetradentate and strongly conjugated ligand to form a cationic solid complex with Cu(II)/ Ni(II)/Co(II) and/Zn(II). The ligand complexes were characterized by the usual spectral and an lytical techbial tests were also recorded and gave good results in the presence of metal ions in the ligands system [65].

Conclusions
The Chemistry of Schiff bases is a field that is being noticed. Schiff base ligands are considered privileged ligands because they are easily prepared by a simple one pot condensation of an aldehyde and primary amines. In this review, the biological activities of Schiff base and their complexes are summarized from 1996-2012.