Synthesis, Characterization and In Vitro Antimicrobial Activity of Some New 2,3-Disubstituted-4-Thiazolidinone and 2,3-Disubstituted-5- Methyl-4-Thiazolidinone Derivatives As a Biologically Active Scaffold

In recent years, there has been a rising interest in researching and finding new antimicrobial agents from various sources to fight against microbial infectious pathogens. Therefore, a greater attention has been paid to synthesize new molecules. In this regarding a straightforward two-step protocol for the synthesis of 2,3-disubstituted-4-thiazolidinone (4a-f) and 2,3disubstituted-5-methyl-4-thiazolidinone (5a-f) libraries has been developed from Schiff base (3a-f) by conventional method and screened for their in vitro antimicrobial activity against Staphylococcus aureus [MTCC-96], Bacillus subtilis [MTCC441], Escherichia coli [MTCC-443] Salmonella paratyphi-A [MTCC-735] as bacterial pathogenic strains and Fusarium solani [MTCC-350] as fungal pathogenic strain. The newly synthesized compounds were characterized by IR, 1 H NMR and elemental analysis. Some derivatives exerted promising antimicrobial activity. Compounds 4d, 4e, 5c and 5d appeared as most proficient members of the series and may be used as the lead compound in a future study. Anjani Solankee Department of Chemistry, B. K. M. Science College, Valsad 396001, Gujarat. Veer Narmad South Gujarat University, Surat, Gujarat, India. Submission: 5 July 2016 Accepted: 10 July 2016 Published: 25 July 2016 www.ijppr.humanjournals.com Citation: Anjani Solankee et al. Ijppr.Human, 2016; Vol. 6 (4): 386-399. 387 INTRODUCTION The treatment of infectious diseases still remain essential and challenging problem due to a combination of factors including rising infectious diseases and the increasing number of multi-drug resistant microbial pathogens 1 . This imparts discovery of new antibiotics having improved potency and lesser toxicity is an exclusively important objective. There are various biologically active molecules with five membered rings containing two heteroatoms among which is the 4-thiazolidinone ring system is a core structure of various synthetic compounds and drugs molecules such as Darbufelon, Pioglitazone and Etozolin 2 . Thiazolidinone, a saturated form of thiazole with carbonyl group on fourth carbon has been considered as a wonder nucleus which shows almost all types of pharmacological properties. It belongs to an imperative cluster of heterocyclic compounds bearing sulfur and nitrogen in a five member ring 3 . They displaying a broad spectrum of biological activities such as, antimicrobial 4 , antimycobacterial 5 , anticancer 6 , antiviral 7 , antihistaminic 8 , anticonvulsant 9 etc. The presence thiazolidone or thiazole ring at different positions in arylazo 10 , sulfamoylphenylazo 11 or phenylhydrazono 12 moieties showed improved antimicrobial activity. Moreover, the combination of the 4-thiazolidinone ring with substituted pyran or fused azolopyrimidine moieties which are also known to having several biological activities 13 . Inspired by the above facts and in continuation of our ongoing research program 14 in the field of synthesis and potent antimicrobial 4-thiazolidinones, we aimed to synthesize some 4-thiazolidinones and investigate their antimicrobial potential against some selected antibacterial and antifungal pathogens. The synthesis of 4-thiazolidinones mentioned in this report can be done in simple steps with most of the compounds being produced in >50% overall yield. MATERIALS AND METHODS All reagents and chemicals for reaction were of analytical reagent (AR) grade. All the melting points were determined in open capillary method and are uncorrected. Analytical thin layer chromatography was performed with E. Merck silica gel 60F glass plates and detection of the components were made by exposure to UV light or keeping the plates in iodine chamber. IR spectra of the synthesized compounds were obtained by preparing KBr pellet, using Shimadzu 8400 FTIR spectrophotometer. 1 H NMR studies were carried out on the Bruker Avance 400 F (MHz) spectrometer. Multiplicities are recorded as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), br (broadened), m (multiplet). Elemental analysis was carried out by Perkin-Elmer 2400 series-II elemental analyzer www.ijppr.humanjournals.com Citation: Anjani Solankee et al. Ijppr.Human, 2016; Vol. 6 (4): 386-399. 388 (Perkin-Elmer, USA). Reference drugs used for antimicrobial evaluation were Chloramphenicol, Streptomycin and Griseofulvin of commercial grade. General procedure for the preparation of N-4-benzylidineamino-(phenyl/substituted phenyl)-N-methylacetamide (3a-f): N-4-benzylidineamino-(phenyl/substituted phenyl)-N-methylacetamide (3a-f) were achieved by reacting the 4-amino-N-methyl acetanilide (1) (0.01mol) with appropriate aromatic aldehyde (2a-f) (0.01mol) in toluene using Dean-Stark water separator as the reported procedure explained previously 15 . General procedure for the preparation of 2-(phenyl/substituted phenyl)-3-(4'-N-methylN-acetylamino) phenyl-4-thiazolidinone (4a-f): A mixture of Schiff base (3a-f) (0.01 mol) and mercaptoacetic acid (0.015 mol) dissolved in toluene were taken in 250 ml round bottom flask attached with Dean-Stark water separator and were refluxed for 12 hours. The progress of the reaction was monitored by TLC using toluene: methanol (12:8 V/V) eluent as mobile phase. After completion of the reaction, the mixtures were poured into evaporating disk and allow to evaporated excess toluene to remove. Then the fallout product was treated 5 to 6 times with saturated solution of sodium bicarbonate to remove excess mercaptoacetic acid. The product (4a-f) thus obtained was filtered, washed with water and recrystallized from methanol. The physical and analytical data are given in Table1 and their spectral data are given below. 2-Phenyl-3-(4'-N-methyl-N-acetylamino)phenyl-4-thiazolidinone (4a): IR (KBr, vmax, cm -1 ): 3024 (aromatic =CH str.), 2953 (C-H str.of alkane) 1674 (C=O str. of thiazolidinone), 1525 (aromatic C=C str.), 1390 (CH3 str.), 1380 (C-N str.), 1223 (asymmetric C-O-C str. of ether linkage), 814 (C-H bending 1,4 disubstituted benzene ring), 678 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 1.4 (s, 3H, C-CH3), 3.0 (s, 3H, NCH3), 4.2 (m, 2H, -CH2, thiazolidinone ring), 5.9 (s, 1H, -CH, thiazolidinone ring), 7.0-8.0 (m, 9H, Ar-H). www.ijppr.humanjournals.com Citation: Anjani Solankee et al. Ijppr.Human, 2016; Vol. 6 (4): 386-399. 389 2-(2'-Chlorophenyl)-3-(4'-N-methyl-N-acetylamino)phenyl-4-thiazolidinone (4b): IR (KBr, vmax, cm -1 ): 3053 (aromatic =CH str.), 2908 (C-H str.of alkane) 1671 (C=O str. of thiazolidinone), 1529 (aromatic C=C str.), 1345 (CH3 str.), 1338 (C-N str.), 1241 (asymmetric C-O-C str. of ether linkage), 720 (C-H bending 1,2 disubstituted benzene ring), 761 (C-Cl str.), 654 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 1.7 (s, 3H, CCH3), 3.2 (s, 3H, N-CH3), 4.1 (m, 2H, -CH2, thiazolidinone ring), 6.3 (s, 1H, -CH, thiazolidinone ring), 7.3-7.9 (m, 8H, Ar-H). 2-(3'-Bromophenyl)-3-(4'-N-methyl-N-acetylamino)phenyl-4-thiazolidinone (4c): IR (KBr, vmax, cm -1 ): 3097 (aromatic =CH str.), 2902 (C-H str.of alkane) 1690 (C=O str. of thiazolidinone), 1536 (aromatic C=C str.), 1337 (CH3 str.), 1331 (C-N str.), 1238 (asymmetric C-O-C str. of ether linkage), 689 (C-H bending 1,3 disubstituted benzene ring), 590 (C-Br str.), 675 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 1.5 (s, 3H, CCH3), 2.9 (s, 3H, N-CH3), 4.7 (m, 2H, -CH2, thiazolidinone ring), 7.1 (s, 1H, -CH, thiazolidinone ring), 7.2-7.8 (m, 8H, Ar-H). 2-(3'-Phenoxyphenyl)-3-(4'-N-methyl-N-acetylamino)phenyl-4-thiazolidinone (4d): IR (KBr, vmax, cm -1 ): 3036 (aromatic =CH str.), 2952 (C-H str.of alkane) 1659 (C=O str. of thiazolidinone), 1534 (aromatic C=C str.), 1392 (CH3 str.), 1364 (C-N str.), 1212 (asymmetric C-O-C str. of ether linkage), 710 (C-H bending 1,3 disubstituted benzene ring), 703 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 2.0 (s, 3H, C-CH3), 3.3 (s, 3H, NCH3), 4.5 (m, 2H, -CH2, thiazolidinone ring), 6.1 (s, 1H, -CH, thiazolidinone ring), 6.8-8.1 (m, 13H, Ar-H). 2-(4'-Fluorophenyl)-3-(4'-N-methyl-N-acetylamino)phenyl-4-thiazolidinone (4e): IR (KBr, vmax, cm -1 ): 3112 (aromatic =CH str.), 2901 (C-H str.of alkane) 1702 (C=O str. of thiazolidinone), 1582 (aromatic C=C str.), 1359 (CH3 str.), 1323 (C-N str.), 1220 (asymmetric C-O-C str. of ether linkage), 1045 (C-F str.), 821 (C-H bending 1,4 disubstituted benzene ring), 664 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 1.4 (s, 3H, C-CH3), 2.2 (s, 3H, N-CH3), 2.9 (m, 2H, -CH2, thiazolidinone ring), 6.4 (s, 1H, -CH, thiazolidinone ring), 6.7-7.4 (m, 8H, Ar-H). www.ijppr.humanjournals.com Citation: Anjani Solankee et al. Ijppr.Human, 2016; Vol. 6 (4): 386-399. 390 2-(2,3'-Dichlorophenyl)-3-(4'-N-methyl-N-acetylamino)phenyl-4-thiazolidinone (4f): IR (KBr, vmax, cm -1 ): 3053 (aromatic =CH str.), 2937 (C-H str.of alkane) 1690 (C=O str. of thiazolidinone), 1525 (aromatic C=C str.), 1378 (CH3 str.), 1362 (C-N str.) 1250 (asymmetric C-O-C str. of ether linkage), 753 (C-Cl str.), 729 and 813 (C-H bending 1,2 and 1,4 disubstituted benzene ring), 680 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 1.6 (s, 3H, C-CH3), 3.5 (s, 3H, N-CH3), 4.2 (m, 2H, -CH2, thiazolidinone ring), 6.6 (s, 1H, -CH, thiazolidinone ring), 7.3-8.0 (m, 7H, Ar-H). General procedure for the preparation of 2-(phenyl/substituted phenyl)-3-(4'-N-methylN-acetylamino) phenyl-5-methyl-4-thiazolidinone (5a-f): A mixture of Schiff base (3a-f) (0.01 mol) and 2-mercaptopropionic acid (0.01 mol) dissolved in toluene were taken in 250 ml round bottom flask attached with Dean-Stark water separator and were refluxed for 12 hours. The progress of the reaction was monitored by TLC using toluene: methanol (12:6 V/V) eluent as mobile phase. After completion of the reaction, the mixtures were poured into evaporating disk and allow to evaporated excess toluene to remove. Then the fallout product was treated 5 to 6 times with saturated solution of sodium bicarbonate to remove excess 2-mercaptopropionic acid. The product (5a-f) thus obtained was filtered, washed with water and recrystallized from methanol. The physical and analytical data are given in Table1 and their spectral data are given below. 2-Phenyl-3-(4'-N-methyl-N-acetylamino)phenyl-5-methyl-4-thiazolidinone (5a): IR (KBr, vmax, cm -1 ): 3050 (aromatic =CH str.), 2920 (C-H str.of alkane) 1665 (C=O str. of thiazolidinone), 1515 (aromatic C=C str.), 1398 (CH3 str.), 1331 (C-N str.), 1235 (asymmetric C-O-C str. of ether linkage), 810 (C-H bending 1,4 disubstituted benzene ring), 675 (C-S-C linkage); 1 H NMR (400 MHz, CDCl3, δ ppm): 1.6 (d, 3H, CH-CH3), 1.8 (s, 3H, C-CH3), 3.2 (s, 3H, N-CH3) 4.2 (q, 1H, -CH-CH3, thiazolidinone ring), 6.0 (s, 1H, -CH-Ar, thiazolidinone ring), 7.2-8.0 (m, 9H, Ar-H). 2-(2'-Chlorophenyl)-3-(4'-N-methyl-N-acetylamino)phenyl-5-methyl-4-thiazolidinone