Schiff Bases : A Versatile Pharmacophore

Schiff bases are condensation products of primary amines with carbonyl compounds gaining importance day by day in present scenario. Schiff bases are the compounds carrying imine or azomethine (–C=N–) functional group and are found to be a versatile pharmacophore for design and development of various bioactive lead compounds. Schiff bases exhibit useful biological activities such anti-inflammatory, analgesic, antimicrobial, anticonvulsant, antitubercular, anticancer, antioxidant, anthelmintic, antiglycation, and antidepressant activities. Schiff bases are also used as catalysts, pigments and dyes, intermediates in organic synthesis, polymer stabilizers, and corrosion inhibitors. The present review summarizes information on the diverse biological activities and also highlights the recently synthesized numerous Schiff bases as potential bioactive core.


Introduction
Schiff bases are the compounds carrying imine or azomethine (-C=N-) functional group.These are the condensation products of primary amines with carbonyl compounds and were first reported by Hugo Schiff [1][2][3].Schiff bases form an important class of the most widely used organic compounds and have a wide variety of applications in many fields including analytical, biological, and inorganic chemistry.Schiff bases have gained importance in medicinal and pharmaceutical fields due to a broad spectrum of biological activities like anti-inflammatory [4][5][6][7], analgesic [5][6][7][8], antimicrobial [9,10], anticonvulsant [11], antitubercular [12], anticancer [13,14], antioxidant [15], anthelmintic [16], and so forth.The nitrogen atom of azomethine may be involved in the formation of a hydrogen bond with the active centers of cell constituents and interferes in normal cell processes [17,18].Apart from biological activities, Schiff bases are also used as catalysts, intermediates in organic synthesis, dyes, pigments, polymer stabilizers [3], and corrosion inhibitors [19].Studies enlightened that metal complexes show greater biological activity than free organic compounds [20].Augmentation of biological activity was reported by implementation of transition metals into Schiff bases [21].Schiff bases played an influencing role in development of coordination chemistry and were involved as key point in the development of inorganic biochemistry and optical materials [22].Schiff bases have been utilized as synthons in the preparation of a number of industrial and biologically active compounds like formazans, 4-thiazolidinines, benzoxazines, and so forth, via ring closure, cycloaddition, and replacement reactions [23].Schiff base derivatives in various processes promoted the researchers for designing of novel heterocyclic/aryl Schiff bases for development of new environmental-friendly technology [24].
Evaluation was carried out for the in vitro antimicrobial activity by cup plate method.For this, S. aureus, P. aeruginosa, B. subtilis, and C. albicans were employed.Penicillin G and amphotericin B were taken as standard drugs.Results revealed that all compounds have moderate to poor antifungal activity and good antibacterial activity [26].
Synthesis of new open (4-6) (Figures 4-6) and macrocyclic (7) (Figure 7) Schiff bases has been done and evaluated for the antimicrobial activity.Open Schiff bases were synthesized by the condensation of salicylaldehyde and o-vanillin with 4,4  -diaminodiphenylmethane, 4,4  -diamino diphenyl sulphide, and diethyl ester of terephthalic acid, respectively.Macrocyclic Schiff bases were reported as the condensation product of 1,6-bis(2-formylphenyl)hexane with thiocarbohydrazide.In order to test the biological activity of the synthesized compounds, four microorganisms (K.pneumoniae, E. coli, S. aureus, and S. typhimurium) were employed.All the synthesized compounds were found to be moderate to strongly active [28].
The compounds were evaluated in vitro for their antioxidant and in vivo for their antidyslipidemic activity.Triton WR-1339 was employed to induce hyperlipidemia.The results revealed that the compounds 13a, 13e, and 13i displayed significant lowering of total cholesterol, phospholipids, and triglycerides in the plasma.Gemfibrozil was used as a standard to compare the results [32].
Piperazine citrate was used as a reference standard while DMSO as a control for comparison.Results revealed that all the synthesized compounds were moderately active except compound 14c which was found to be the most potent anthelmintic agent due to presence of chloro group.Chloro group may improve the conductance of worm muscle membrane that causes reduction in hyperpolarization and excitability which leads to flaccid paralysis that results in expulsion of worm by peristaltic movement [33].
A series of twelve new N-substituted-2-hydroxyacetophenonimine derivatives, 15(a-l) (Figure 15) was synthesized by conventional as well as microwave method.Synthesized compounds were evaluated for their antinemic activity by calculating LC 50 values of different synthesized imines against J 2s of M. incognita.Carbofuran was employed as a standard.

Antitubercular Activity.
A novel series of forty-four, 17(i-xxxxiv), (Figure 17) Schiff bases of isonicotinic acid hydrazide (INH) was synthesized by structural modification of 16 (Figure 16) in which hydrazine unit was chemically blocked at N 2 position by deactivating acetylation by Narylaminoacetyl transferase (NATs) enzyme.The deactivation phenomenon seems to be associated with rise of resistance.Synthesized Schiff bases were blocked toward the enzymatic deactivation process.The results revealed that compound 17(xv) was found to be the most potent antitubercular agent with MIC 0.05 g/mL and logP 4.04 [35].
A series of Schiff bases of indoline-2,3-dione derivatives and nalidixic acid carbohydrazides, 18(a-n) (Figure 18) was synthesized and screened for antitubercular activity against four Mycobacterium strains (M.xenopi, M. cheleneo, M. intraccllulave, and M. smegmatis) using isonicotinic acid hydrazide as a standard drug.Agar dilution method was opted for screening the activity.From the results, compound 18f was found to be the most potent antitubercular agent with MIC 0.625 g/mL which is 20 times higher than the MIC of standard drug (12.5 g/mL) [36].
From the results, it was concluded that all the compounds were found to be active and less toxic than phenytoin which was employed as a standard drug.Compound 21l substituted with nitro group at ortho position of distal aryl ring was reported as the most potent anticonvulsant agent [39].
Synthesis of novel Schiff base analogues of 4-amino-1,5dimethyl-2-phenylpyrazol-3-one, 25(a-m), (Figure 25) was carried out.Synthesized compounds were screened for  the anti-inflammatory and antioxidant activities.Compound 25f was found to be the most potent anti-inflammatory agent and antioxidant.The anti-inflammatory activity of 25f was evaluated in terms of its potential of nitric oxide (NO) production inhibition in LPS-pretreated RAW 264.7 cells using the Griess method.Lipopolysaccharide (LPS), an endotoxin which is derived from the cell wall of Gram-negative bacteria, can induce multiple signaling pathways to stimulate the production of inflammatory modulators involving NO, PGE 2 , TNF-, and interleukins.The results indicated that 50 g/mL of 25f inhibited the LPS-stimulated COX-2 mRNA levels [43].

Antitumor Activity.
A novel series of fluoroquinolone C-3 heterocycles (IV), that is, s-triazole Schiff 27(a-k) (Figure 27) and mannich bases derivatives of ofloxacin was synthesized and evaluated for in vitro antitumor activity against a murine leukemia cell line (L1210), a human leukocytoma cell line (HL60), and a Chinese hamster ovary cell line (CHO) using the MTT assay.From the observed results it was concluded that a free phenol group containing compounds 27c, 27g, and 27h exhibited more potent activity than the other test compounds [45].
A series of thirteen quinolin-2(1H)-one-derived Schiff bases 28(a-m) (Figure 28) and their Cu(II) 29(a-m) (Figure 28) complexes was synthesized.Selected compounds were screened for their in vitro anticancer and antifungal activities.Human hepatic carcinoma cell line, Hep-G 2 was employed for screening of the anticancer potential.Cisplatin was used as a standard drug for the comparison.Screened compounds were found to be active antifungal agents and compound (7E)-7-(3-ethoxy-2-hydroxybenzylideneamino)-4-methylquinolin-2(1H)-one was reported as a potent cytotoxic agent which enlightened the good potential of Cu(II) complexes of Schiff base ligands as therapeutic agents [46].
2.9.Antioxidant Activity.A series of substituted-N  -[(1E)substituted phenylmethylidene]benzohydrazide analogs, 31(a-n) (Figure 30) was synthesized and evaluated for their in vitro antioxidant, anti-inflammatory, and antimicrobial activities.The antioxidant activity of all the synthesized compounds was evaluated by the phosphomolybdenum method.Compounds 31c, 31d, and 31f were reported to show good antioxidant activity due to presence of 4-nitro, 4methyl, and 3-nitro groups, respectively, whereas 31a having 4-hydroxy group did not possess such activity.From the results, it can be concluded that substitutions like nitro and alkyl lead to enhancement in antioxidant activity through one-electron transfer mechanism [48].
A new Schiff base ligand N-(2-hydroxylacetophenone)-3-oxapentane-1,5-diamine (HL), 32, and its Ni complex, [Ni 2 (L) 2 (NO 3 ) 2 ], 33, were synthesized and evaluated for antioxidation and DNA-binding properties.The complex showed inhibitory activity and the suppression ratio of OH radical increases with increase in the concentration of the complex.Mannitol and vitamin C were employed as the standard antioxidants for comparison.According to the results the 50% inhibitory concentration (IC 50 ) value of 33 was found to be 8.1 ± 0.078 M whereas IC 50 for mannitol was 9.6 M and 32 was devoid of antioxidant activity.Both 32 and 33 bind to DNA in intercalation mode but the binding strength of 33 was found to be better than 32 [49].
A series of thiazolines and azetidinones was synthesized by reaction of Schiff bases, 35(a-i), (Figure 32) (intermediate reaction) with thioglycolic acid and chloral acetyl chloride, respectively.Schiff bases were evaluated for antibacterial and antiviral (against HIV-I) potential.All the compounds were found to be good HIV-I inhibitors except 35f and 35g [51].antihyperlipidemic activity.Hyperlipidemia was induced in rats by atherogenic diet.After 45 days, levels of serum total cholesterol (TC) and LDL cholesterol were recorded to be 231.6 ± 1.435 mg/dL and 164.53 ± 1.26 mg/dL which were comparatively higher than normal rat serum TC (71.36 ± 1.195 mg/dL) and LDL-C (100.66 ± 0.88 mg/dL) levels whereas serum HDL-C level was found to be lower (19.012± 0.66 mg/dL) as compared to the normal level (50.66 ± 0.88 mg/dL).
Results revealed that 36a reduced TC and LDL-C levels to 172.41 ± 41 mg/dL and 91.10 ± 0.97 mg/dL and raised serum HDL-C level to 60.07 ± 0.67 mg/dL whereas 36b reduced serum TC and LDL-C levels to 93.63 ± 1.292 and 81.35 ± 0.81 mg/dL and raised serum HDL-C level to 59.40 ± 0.45 mg/dL at the dose of 200 mg/kg, p.o., once daily [52].

Antidiabetic and Antiglycation Activities.
A series of oxovanadium complexes with mixed ligands, a bidentate NN ligand, 37, and a tetradentate ONO-donor Schiff base ligand, 38 (Figure 34) was synthesized and evaluated for protein tyrosine phosphate (PTP) inhibition.PTP1B has been identified as key enzyme related to insulin resistance.Thus the inhibition of PTP1B has emerged out as an important approach to enhance insulin sensitivity.The kinetic analysis results revealed that oxovanadium complexes displayed potent reversible competitive inhibition PTP1B with IC 50 values in low nanomolar range [53].
A series of twenty-seven bis-Schiff base of isatin, 39(ixxvii) (Figure 35) was synthesized and evaluated for their in vitro antiglycation activity.Compounds 39(xx) and 39(xxi) substituted with nitro groups at para and ortho positions,

Conclusion
Schiff bases are one of the most important chemical classes of compounds having a common integral feature of a variety of medicinal agents.This review reflects the contribution of Schiff bases to the design and development of novel lead having potential biological activities with fewer side effects.This bioactive core has maintained the interest of researchers in gaining the most suggestive and conclusive access in the field of various Schiff bases of medicinal importance from last decades.The present paper is an attempt to review all the biological activities reported for Schiff bases in the current literature with an update of recent research findings.

M
Figure 3