Synthesis, characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety

Kallanagouda R. Alagawadi; Shankar G. Alegaon

doi:10.1016/j.arabjc.2010.07.012

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Original Article

4 (

); 465-472

doi:

10.1016/j.arabjc.2010.07.012

Synthesis, characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety

Kallanagouda R. Alagawadi, Shankar G. Alegaon^*

Department of Pharmaceutical Chemistry, KLE University’s College of Pharmacy, Belgaum 590 010, Karnataka, India

*Corresponding author. Tel.: +91 8312471399; fax: +91 8312472387 shankar_alegaon@yahoo.co.in (Shankar G. Alegaon)

Received: 2010-6-25, Accepted: 2010-7-12, Published: 2010-10-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer-review under responsibility of King Saud University.

Available online 17 July 2010

Abstract

The synthesis and antimicrobial activity of 2,4-thiazolidinedione derivatives 5a–g and 6a–g are described. The structures of the newly synthesized compounds were confirmed by IR, NMR, mass and elemental analyses. All compounds were evaluated for their preliminary in vitro antibacterial and antifungal activity. The results revealed that most of the compounds showed high or moderate biological activity against tested microorganisms.

Keywords

Antibacterial activity

Antifungal activity

Thiazolidinedione (TZD)

Thiadiazole

Arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide

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1 Introduction

The treatment of infectious diseases still remains an important and challenging problem because of a combination factors including emerging infectious diseases and increasing number of multi-drug resistant microbial pathogens with particular relevance for Gram-positive bacteria Tenover and McDonald, 2005; Pfeltz and Wilkinson, 2004; Roberts, 2004; Dessen et al., 2001; Muroi et al., 2004 ). In spite of the large number of antibiotics and chemotherapeutics available for medical use, the emergence of old and new antibiotic resistant bacterial strains in the last decades constitutes a substantial need for the new class of antibacterial agents (Chopra et al., 2008).

The varied biological activities of rhodanines (2-thioxothiazolidin-4-one) and their analogues have been known from the beginning of the 20th century. Rhodanines and 2,4-thiazolidinedione have become a pharmacologically important class of heterocyclic compounds since the introduction of various glitazones and epalrestat in to clinical use for the treatment of type II diabetes and diabetic complications, respectively (Terashima et al., 1984; Yoshioka et al., 1998). Chemical modification of these heterocycles has constantly resulted in compounds with broad spectrum of pharmacological activities. 2,4-Thiazolidinedione derivatives constitute an important class of heterocyclic compounds for which diverse biological properties such as antibacterial and antifungal (Ayhan-Kilcigil and Altanlar, 2000; Heerding et al., 2003; Tuncbilek and Altanlar, 2006; Bozdag-Dundar et al., 2007 ), antidiabetic (Cantello et al., 1994), cardiotonic (Andreani et al., 1993), anti-oedematus and analgesic (De-Lima et al., 1994), cyclooxygenase and lipoxygenase inhibitory (Boschelli et al., 1992) activities have been documented along past decades. On other hand a large number of imidazo[2,1-b][1,3,4]-thiadiazoles have been reported to possess various pharmacological properties such as anticancer (Terzioglu and Gursoy, 2003), antitubercular (Kolavi et al., 2006), antibacterial (Gadad et al., 2000), antifungal (Andotra et al., 1997), anticonvulsant, analgesic (Khazi et al., 1996) and antisecretory (Andreani et al., 2000).

In view of the facts mentioned above and as part of our initial efforts to discover potentially active new agents, we report herein the synthesis of 5-substituted-2,4-Thiazolidinedione derivatives and evaluation of their antibacterial and antifungal activities.

2 Materials and methods

2.1

2.1 Materials and reagents

Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. Melting point was determined by electro thermal melting point apparatus and is uncorrected. All reactions were monitored by thin-layer chromatography (TLC) on 0.25 mm silica gel (60GF-254) plates and visualized with UV light. Column chromatography was performed on silica gel (200–300 mesh). Infra red (IR) spectra were recorded on using KBr disk on a Nicolet MX-1 FTIR spectrophotometer, ¹H NMR spectra were recorded AMX-400 and Bruker-400 liquid-state NMR spectrometer using tetramethylsilane (TMS) as internal standard (chemical shift in δ ppm). Mass spectra were recorded on a JEOL MS-DX-303 spectrometer. Elemental analysis was carried out using a Perkin Elmer 2400-CHN Analyzer. Spectra facilities and elemental analysis were carried out by Sophisticated Analytical Instruments Facility (SAIF) division of Indian Institute of Science, Bangalore, India.

2.2

2.2 Synthesis

2.2.1

2.2.1 Synthesis of 2,4-thiazolidinedione (1)

Thiourea (0.48 mol) was added to a stirred solution of chloroacetic acid (0.5 mol) in concentrated hydrochloric acid (80 ml) and the reaction mixture was heated under reflux for 15 h. On cooling the product was precipitated, filtered, dried and recrystallized from water. Yield 78%; m.p; 123–124 °C.

¹H NMR (DMSO-d₆) δ in ppm: 12.00 (s, 1H, NH), 4.14 (s, 2H); ¹H NMR (DMSO-d₆) D₂O Exchange experiment δ in ppm: 4.16 (s, 2H); MS: m/z 116.4[M].

2.2.2

2.2.2 Synthesis of 2-amino-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole (2)

A mixture of equimolar quantities of 3,4,5-trimethoxy benzoic acid (0.1 mol), thiosemicarbazide (0.1 mol) and phosphorus oxychloride (30 ml) was refluxed gently for half an hour. After cooling, water was added (90 ml) and the mixture was refluxed for 4 h and filtered. The solution was neutralized by saturated solution of potassium hydroxide. The precipitate was filtered and recrystallized from ethanol. Yield 80%; m.p; 205–208 °C.

IR (KBr) cm⁻¹; 3590.6 (NH₂), 3117 (Ar—CH), 1620 (C⚌N). ¹H NMR (DMSO-d₆) δ in ppm: 8.85 (s, 2H, —NH₂), 6.95 (d, 2H, C2, C6), 3.80 (s, 6H, C3—OCH₃, C5—OCH₃), 3.83 (s, 3H, C4—OCH₃).

2.2.3

2.2.3 General procedure: synthesis of 2-(3,4,5-trimethoxyphenyl) 6-(4’substituted aryl)imidazo[2,1-b][1,3,4]-thiadiazoles 3a–g

A mixture of equimolar quantities of 2-amino-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole (0.01 mol) and an appropriate α-bromoketones (0.01 mol) was refluxed in dry ethanol (300 ml) for 10 h. Excess of solvent was removed under reduced pressure the solid hydrobromide salts suspended in water, and neutralized by aqueous sodium carbonate solution to get free base. It was filtered, washed with water, dried and recrystallized from suitable solvent.

2.2.3.1

2.2.3.1 2-(3,4,5-trimethoxyphenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (3a)

Yield 70%; m.p; 205–208 °C; IR (KBr) cm⁻¹; 3095, 3033, 2943, 1576, 1490, 1339, 1130, 843; ¹H NMR (DMSO-d₆) δ in ppm: 8.75 (s, 1H, H-5 imidazole), 7.40 (m, 5H, Ar—H), 7.41 (d, 2H, Ar—H), 3.89 (s, 6H, 2OCH₃), 3.70 (s, 3H, OCH₃).

2.2.3.2

2.2.3.2 2-(3,4,5-trimethoxyphenyl)-6-(4-methylphenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3b)

Yield 71 %; m.p; 136–137 °C; IR (KBr) cm⁻¹; 3090, 3025, 2947, 1586, 1489, 1329, 1130, 839; ¹H NMR (DMSO-d₆) δ in ppm: 8.64 (s, 1H, H-5 imidazole), 7.77 (d, 2H, Ar—H), 7.22 (d, 2H, Ar—H), 7.14 (d, 2H, Ar—H), 3.89 (s, 6H, 2OCH₃), 3.87 (s, 3H, OCH₃), 3.29 (s, 3H, CH₃).

2.2.3.3

2.2.3.3 2-(3,4,5-trimethoxyphenyl)-6-(4-methoxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3c)

Yield 70%; m.p; 205–208 °C; IR (KBr) cm⁻¹; 3085, 3043, 2973, 1596, 1481, 1343, 1150, 843; ¹H NMR (DMSO-d₆) δ in ppm: 8.46 (s, 1H, H-5 imidazole), 7.62 (d, 2H, Ar—H), 7.42 (d, 2H, Ar—H), 7.14 (d, 2H, Ar—H), 3.89 (s, 6H, 2OCH₃), 3.87 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃).

2.2.3.4

2.2.3.4 2-(3,4,5-trimethoxyphenyl)-6-(4-nitrophenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3d)

Yield 70%; m.p; 205–208 °C; IR (KBr) cm⁻¹; 3060, 3021, 2959, 1587, 1494, 1346, 1128, 853; ¹H NMR (DMSO-d₆) in ppm: 8.85 (s, 1H, H-5 imidazole), 8.40 (d, 2H, Ar—H), 8.16 (d, 2H, Ar—H), 8.04 (d, 2H, Ar—H), 3.89 (s, 6H, 2OCH₃), 3.70 (s, 3H, OCH₃).

2.2.3.5

2.2.3.5 2-(3,4,5-trimethoxyphenyl)-6-(4-bromophenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3e)

Yield 70%; m.p; 188–190 °C; IR (KBr) cm⁻¹; 3095, 3043, 2944, 1586, 1490, 1329, 1130, 833; ¹H NMR (DMSO-d₆) δ in ppm: 8.74 (s, 1H, H-5 imidazole), 8.30 (d, 2H, Ar—H), 8.15 (d, 2H, Ar—H), 8.07 (d, 2H, Ar—H), 3.90 (s, 6H, 2OCH₃), 3.75 (s, 3H, OCH₃).

2.2.3.6

2.2.3.6 2-(3,4,5-trimethoxyphenyl)-6-(4-chlorophenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3f)

Yield 70%; m.p; 205–208 °C; IR (KBr) cm⁻¹; 3075, 3053, 2933, 1566, 1490, 1359, 1128, 833; ¹H NMR (DMSO-d₆) δ in ppm: 8.76 (s, 1H, H-5 imidazole), 7.89 (d, 2H, Ar—H), 7.49 (d, 2H, Ar—H), 7.41 (d, 2H, Ar—H), 3.90 (s, 6H, 2OCH₃), 3.75 (s, 3H, OCH₃).

2.2.3.7

2.2.3.7 2-(3,4,5-trimethoxyphenyl)-6-(6-(2,5-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole (3g)

Yield 70%; m.p; 205–208 °C; IR (KBr) cm⁻¹; 3095, 3055, 2983, 1576, 1480, 1339, 1130, 843; ¹H NMR (DMSO-d₆) δ in ppm: 8.56 (s, 1H, H-5 imidazole), 7.65 (m, 3H, Ar—H), 7.24 (d, 2H, Ar—H), 3.89 (s, 6H, 2OCH₃), 3.87 (s, 3H, OCH₃), 3.85 (s, 3H, OCH₃), 3.8 (s, 3H, OCH₃).

2.2.4

2.2.4 General procedure for the synthesis of 6-Aryl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4a–g

Vilsmeier–Haak reagent was prepared by adding phosphoryl chloride (3 ml), in dimethylformamide (20 ml), at 0 °C with stirring. Then appropriately substituted 2-alkyl/aryl-6-arylimidazo[2,1-b][1,3,4]thiadiazole (3a–g 0.01 mol), was added to the reagent and stirred at 0 °C for 30 min. The mixture was further stirred for 2 h at room temperature and at 60 °C for additional 2 h. The reaction mixture was then poured in sodium carbonate solution and stirred at 90 °C for 2 h. After cooling, the mixture was diluted with water, extracted with chloroform, and collective extract was washed with water and dried over anhydrous sodium sulphate. The residue obtained after the removal of chloroform was recrystallized from suitable solvent to get the crystalline solid.

2.2.4.1

2.2.4.1 6-phenyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4a)

Yield 70%; Dark brown crystals m.p; 180–182 °C; IR (KBr) cm⁻¹; 3016, 2840, 2737, 1674, 1130, 732. ¹H NMR (DMSO-d₆) δ in ppm: 10.09 (s, 1H, CHO), 7.60 (m, 5H, Ar—H), 23 (d, 2H, Ar—H), 3.91 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃)

2.2.4.2

2.2.4.2 6-(4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4b)

Yield 70%; colourless crystals m.p; 145–148 °C; IR (KBr) cm⁻¹; 3089, 2892, 2765, 1677, 1130, 798. ¹H NMR (DMSO-d₆) δ in ppm: 10.05 (s, 1H, CHO), 7.88 (d, 2H, Ar—H), 8.33 (d, 2H, Ar—H), 7.22 (d, 2H, Ar—H), 3.89 (s, 6H, OCH₃), 3.76 (s, 3H, OCH₃), 3.29 (s, 3H, CH₃)

2.2.4.3

2.2.4.3 6-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4c)

Yield 70%; brownish product m.p; 155–157 °C; IR (KBr) cm⁻¹; 3087, 2940, 2860, 2798, 1680, 1201, 1167, 823. ¹H NMR (DMSO-d₆) δ in ppm: 10.08 (s, 1H, CHO), 7.67 (d, 2H, Ar—H), 8.43 (d, 2H, Ar—H), 7.24 (d, 2H, Ar—H), 3.90 (s, 6H, OCH₃), 3.74 (s, 3H, OCH₃), 3.70 (s, 3H, OCH₃)

2.2.4.4

2.2.4.4 6-(4-nitrophenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d)

Yield 70%; brownish-yellow crystals m.p; 175–176 °C; IR (KBr) cm⁻¹; 3056, 2976, 2835, 2787, 1674, 1204, 1354, 798. ¹H NMR (DMSO-d₆) δ in ppm: 9.55 (s, 1H, CHO), 7.86 (d, 2H, Ar—H), 8.43 (d, 2H, Ar—H), 7.21 (d, 2H, Ar—H), 3.88 (s, 6H, OCH₃), 3.87 (s, 3H, OCH₃)

2.2.4.5

2.2.4.5 6-(4-bromophenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4e)

Yield 70%; light brown crystals m.p; 195–196 °C; IR (KBr) cm⁻¹; 3050, 2945, 2854, 2789, 1680, 1167, 843, 788. ¹H NMR (DMSO-d₆) δ in ppm: 9.43 (s, 1H, CHO), 8.29 (d, 2H, Ar—H), 8.15 (d, 2H, Ar—H), 7.20 (d, 2H, Ar—H), 3.87 (s, 6H, OCH₃), 3.75 (s, 3H, OCH₃)

2.2.4.6

2.2.4.6 6-(4-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4f)

Yield 70%; dark brown crystals m.p; 176–178 °C; IR (KBr) cm⁻¹; 3056, 2894, 2793, 1673, 1203, 1156, 785. ¹H NMR (DMSO-d₆) δ in ppm: 10.09 (s, 1H, CHO), 8.06 (d, 2H, Ar—H), 7.60 (d, 2H, Ar—H), 7.24 (d, 2H, Ar—H), 3.91 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃)

2.2.4.7

2.2.4.7 6-(2,5-dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4g)

Yield 70%; brownish product m.p; 177–178 °C; IR (KBr) cm⁻¹; 3076, 2914, 2773, 1669, 1234, 1136, 775.¹H NMR (DMSO-d₆) δ in ppm: 10.06 (s, 1H, CHO), 7.57 (m, 3H, Ar—H), 7.24 (d, 2H, Ar—H), 3.90 (s, 6H, OCH₃), 3.74 (s, 3H, OCH₃), 3.50 (s, 3H, OCH₃), 3.47 (s, 3H, OCH₃)

2.2.5

2.2.5 General procedure for the synthesis of 5-[(2-(3,4,5-trimethoxyphenyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione 5a–g

A mixture of the 6-Aryl-2-(3,4,5-trimethoxyphenyl) imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4a–g (0.001 mol), 2,4-thiazolidinedione (0.001 mol), piperidine (0.001 mol) and acetic acid (0.001 mol) in toluene (50 ml) was heated under reflux with azeotropic removal of water for 16 h. The mixture was cooled to 5 °C; filtration gave crude 5-[(2-(3,4,5-trimethoxyphenyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione. The crude product was recrystallized from appropriate solvents.

2.2.5.1

2.2.5.1 5-[(2-(3,4,5-trimethoxyphenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione (5a)

Yield 77%; light yellow crystals; m.p; 198–200 °C; IR (KBr) cm⁻¹; 3395, 3077, 2976, 1730, 1700, 1610, 1330, 1176. ¹H NMR (DMSO-d₆) δ in ppm: 12.50 (s, 1H, NH), 8.10 (d, 2H, Ar—H), 7.77 (s, 1H, R—CH⚌C, TZD), 7.60 (m, 5H, Ar—H), 3.91 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃). Anal. Calcd for (C₂₃H₁₈N₄O₅S₂) (%): C, 50.56; H, 3.67; N, 13.33. Found; C, 50.76; H, 3.87; N, 11.37.

2.2.5.2

2.2.5.2 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5b)

Yield 75%; light yellow crystals; m.p; 189–191 °C; IR (KBr) cm⁻¹; 3380, 3060, 2965, 1725, 1696, 1615, 1330, 1166. ¹H NMR (DMSO-d₆) δ in ppm: 12.40 (s, 1H, NH), 8.12 (d, 2H, Ar—H), 7.74 (s, 1H, R—CH⚌C,TZD), 7.50 (m, 4H, Ar—H), 3.91 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃), 3.49 (s, 3H, CH₃). Anal. Calcd for (C₂₄H₂₀N₄O₅S₂) (%): C, 56.68; H, 3.96; N, 11.02. Found; C, 50.70; H, 3.99; N, 11.35.

2.2.5.3

2.2.5.3 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-methoxylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5c)

Yield 70%; yellow crystals; m.p; 205–206 °C; IR (KBr) cm⁻¹; 3340, 3080, 2956, 1735, 1698, 1620, 1320, 1156. ¹H NMR (DMSO-d₆) δ in ppm: 12.35 (s, 1H, NH), 8.14 (d, 2H, Ar—H), 7.74 (s, 1H, R—CH⚌C,TZD), 7.60 (d, 2H, Ar—H), 7.41 (d, 2H, Ar—H), 3.90 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃). Anal. Calcd for (C₂₄H₂₀N₄O₆S₂) (%): C, 54.95; H, 3.84; N, 10.68. Found; C, 54.99; H, 3.88; N, 10.86.

2.2.5.4

2.2.5.4 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-nitrolphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5d)

Yield 69%; yellow powder; m.p; 194–195 °C; IR (KBr) cm⁻¹; 3360, 3089, 2876, 1730, 1695, 1625, 1323, 1150. ¹H NMR (DMSO-d₆) δ in ppm: 12.25 (s, 1H, NH), 8.17 (d, 2H, Ar—H), 7.77 (s, 1H, R—CH⚌C, TZD), 7.59 (d, 2H, Ar—H), 7.49 (d, 2H, Ar—H), 3.91 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃), Anal. Calcd for (C₂₃H₁₇N₅O₇S₂) (%): C, 51.20; H, 3.18; N, 12.98. Found; C, 51.29; H, 3.19; N, 12.99.

2.2.5.5

2.2.5.5 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-bromophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5e)

Yield 78%; yellowish orange powder; m.p; 210–211 °C; IR (KBr) cm⁻¹; 3370, 3069, 2897, 1720, 1695, 1620, 1325, 1155. ¹H NMR (DMSO-d₆) δ in ppm: 12.20 (s, 1H, NH), 8.27 (d, 2H, Ar—H), 8.12 (d, 2H, Ar—H), 7.67 (s, 1H, R—CH⚌C, TZD), 7.40 (d, 2H, Ar—H), 3.99 (s, 6H, OCH₃), 3.87 (s, 3H, OCH₃), Anal. Calcd for (C₂₃H₁₈ BrN₄O₅S₂) (%): C, 48.17; H, 2.99; N, 9.77. Found; C, 48.29; H, 3.03; N, 8.03.

2.2.5.6

2.2.5.6 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5f)

Yield 78%; light orange solid; m.p; 215–216 °C; IR (KBr) cm⁻¹; 3382, 3063, 2957, 1729, 1698, 1627, 1329, 1145. ¹H NMR (DMSO-d₆) δ in ppm: 12.40 (s, 1H, NH), 8.26 (d, 2H, Ar—H), 8.15 (d, 2H, Ar—H), 7.77 (s, 1H, R—CH⚌C, TZD), 7.45 (d, 2H, Ar—H), 3.97 (s, 6H, OCH₃), 3.89 (s, 3H, OCH₃), Anal. Calcd for (C₂₃H₁₈ ClN₄O₅S₂) (%): C, 52.22; H, 3.24; N, 10.59. Found; C, 52.24; H, 3.26; N, 11.03.

2.2.5.7

2.2.5.7 5-{[2-(3,4,5-trimethoxyphenyl)-6-(2,5-dimethoxylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5g)

Yield 69%; light yellow solid; m.p; 213–215 °C; IR (KBr) cm⁻¹; 3362, 3054, 2966, 1733, 1698, 1637, 1339, 1148. ¹H NMR (DMSO-d₆) δ in ppm: 12.38 (s, 1H, NH), 8.26 (d, 2H, Ar—H), 7.77 (s, 1H, R—CH⚌C,TZD), 7.45 (m, 3H, Ar—H), 3.92 (s, 6H, OCH₃), 3.81 (s, 3H, OCH₃), 3.75 (s, 3H, OCH₃), 3.73 (s, 3H, OCH₃). Anal. Calcd for (C₂₅H₂₂N₄O₇S₂) (%): C, 54.14; H, 4.00; N, 10.10. Found; C, 54.16; H, 4.06; N, 10.13.

2.2.6

2.2.6 General procedure for the synthesis of N-[(dimethylamino)methylidene]-5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide 6a–g

A mixture of the N-(dimethylaminomethylidene)-5-formyl-6-arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (0.001 mol), 2,4-thiazolidinedione (0.001 mol), piperidine (0.001 mol) and acetic acid (0.001 mol) in toluene (50 ml) was heated under reflux with azeotropic removal of water for 16 h. The mixture was cooled to 5 °C; filtration gave crude N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide. The crude product was recrystallized from appropriate solvents.

2.2.6.1

2.2.6.1 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6a)

Condensation of 5-formyl-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione furnished bright yellow crystals of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 79%; light yellow solid; m.p; 236–238 °C; IR (KBr) cm⁻¹; 3407, 3090, 1735, 1699, 1610. ¹H NMR (DMSO-d₆) δ in ppm: 12.56 (s, 1H, NH), 8.40 (s, 1H, —N⚌CH—), 7.77 (s, 1H, R—CH⚌C, TZD), 7.63–7.51 (m, 5H, Ar—H), 3.24 (s, 3H of —N(CH₃)₂), 3.07 (s, 3H of —N(CH₃)₂). MS: m/z 463.53[M+H]. Anal. Calcd for (C₁₇H₁₄N₆O₄S₃) (%): C, 44.15; H, 3.06; N, 18.17. Found; C, 44.00; H, 3.00; N, 18.37.

2.2.6.2

2.2.6.2 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide(6b)

Condensation of 5-formyl-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione furnished yellow crystals of N-[(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 80%; light yellow solid; m.p; 260–261 °C; IR (KBr) cm⁻¹; 3433, 3080, 1730, 1707, 1612. ¹H NMR (DMSO-d₆) δ in ppm: 12.56 (s, 1H, NH), 8.38 (s, 1H, —N⚌CH—), 8.25–8.00 (m, 4H, Ar—H), 7.77 (s, 1H, R—CH⚌C,TZD), 3.28 (s, 3H, CH₃), 3.24 (s, 3H of —N(CH₃)₂), 3.03 (s, 3H of —N(CH₃)₂), 2.30(s, 3H, Ar—CH₃). MS: m/z 477.36[M+H]. Anal. Calcd for (C₁₈H₁₆N₆O₄S₃) (%): C, 45.37; H, 3.88; N, 17.63. Found; C, 45.30; H, 3.44; N, 18.66.

2.2.6.3

2.2.6.3 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6c)

Condensation of 5-formyl-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione yielded yellow solid N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 81%; light yellow solid; m.p; 262–264 °C; IR (KBr) cm⁻¹; 3427, 3085, 2960, 1730, 1707, 1610. ¹H NMR (DMSO-d₆) δ in ppm: 12.56 (s, 1H, NH), 8.40 (s, 1H, —N⚌CH—), 7.77 (s, 1H, R—CH⚌C,TZD), 7.63 (d, 2H, C3, C5, Ar—H), 7.54 (d, 2H, C2, C6, Ar—H), 3.32 (s, 3H, OCH₃), 3.24 (s, 3H of —N(CH₃)₂), 3.07 (s, 3H of —N(CH₃)₂). MS: m/z 493.36[M+H]. Anal. Calcd for (C₁₈H₁₆N₆O₅S₃) (%): C, 43.89; H, 3.27; N, 17.06. Found; C, 43.85; H, 3.25; N, 17.14.

2.2.6.4

2.2.6.4 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6d)

Condensation of 5-formyl-6-(4-nitroyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione yielded light yellow solid of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 83%; light yellow solid; m.p; 258–260 °C; IR (KBr) cm⁻¹; 3443, 3080, 1730, 1699, 1615. ¹H NMR (DMSO-d₆) δ in ppm: 12.56 (s, 1H, NH), 8.40 (s, 1H, —N⚌CH—), 8.29 (d, 2H, C2, C6–H phenyl), 8.14 (d, 2H, C3, C5 Ar—H), 7.77 (s, 1H, R—CH⚌C, TZD), 3.28 (s, 3H, OH₃), 3.32 (s, 3H of —N (CH₃)₂), 3.02 (s, 3H of —N(CH₃)₂). MS: m/z 509[M]. Anal. Calcd for (C₁₇H₁₅N₇O₆S₃) (%): C, 40.07; H, 2.97; N, 19.24. Found; C, 44.10; H, 2.97; N, 19.28.

2.2.6.5

2.2.6.5 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-bromophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6e)

Condensation of 6-(4-bromophenyl)-5-formylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione furnished light yellow solid of 6-(4-bromophenyl)-N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 82%; light yellow solid; m.p; 264–266 °C; IR (KBr) cm⁻¹; 3426, 3085, 1733, 1710, 1610. ¹H NMR (DMSO-d₆) δ in ppm: 12.59 (s, 1H, NH), 8.40 (s, 1H, —N⚌CH—), 7.76 (s, 1H, R—CH⚌C,TZD), 7.75 (d, 2H, C2, C6, Ar—H), 7.60 (d, 2H, C3, C5–H, Phenyl), 3.28 (s, 3H of —N(CH₃)₂), 3.06 (s, 3H of —N(CH₃)₂). MS: m/z 542.8[M+H]. Anal. Calcd for (C₁₇H₁₃BrN₆O₄S₃) (%): C, 37.71; H, 2.42; N, 15.52. Found; C, 37.69; H, 2.40; N, 15.50.

2.2.6.6

2.2.6.6 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6f)

Condensation of 6-(4-chlorophenyl)-5-formylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione furnished yellow crystals of 6-(4-chlorophenyl)-N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 80%; light yellow solid; m.p; 272–274 °C; IR (KBr) cm⁻¹; 3434, 3085, 1730, 1698, 1610. ¹H NMR (DMSO-d₆) δ in ppm: 12.60 (s, 1H, NH), 8.46 (s, 1H, —N⚌CH—), 7.75 (s, 1H, R—CH⚌C,TZD), 7.68 (d, 2H, C2, C, Ar—H), 7.66 (d, 2H, C3, C5, Ar—H), 3.28 (s, 3H of —N(CH₃)₂), 3.06 (s, 3H of —N(CH₃)₂). MS: m/z 496.9[M+H]. Anal. Calcd for (C₁₇H₁₃ClN₆O₄S₃) (%): C, 41.09; H, 2.64; N, 16.91. Found; C, 41.00; H, 2.60; N, 16.94.

2.2.6.7

2.2.6.7 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(2,5-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6g)

Condensation of 5-formyl-6-(2,5-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide and 2,4-thiazolidinedione yielded light yellow solid N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide.

Yield 78%; light yellow solid; m.p; 261–262 °C; IR (KBr) cm⁻¹; 3430, 3080, 2955, 1725, 1706, 1610. ¹H NMR (DMSO-d₆) δ in ppm: 12.60 (s, 1H, NH), 8.64 (s, 1H, —N⚌CH—), 7.67 (s, 1H, R—CH⚌C, TZD), 7.50 (m, 3H, Ar—H), 3.38 (s, 3H, OCH₃), 3.32 (s, 3H, OCH₃), 3.24 (s, 3H of —N(CH₃)₂), 3.07 (s, 3H of —N(CH₃)₂). MS: m/z 553.46[M+H]. Anal. Calcd for (C₁₉H₁₈N₆O₆S₃) (%): C, 43.67; H, 3.47; N, 16.08. Found; C, 43.85; H, 3.48; N, 16.01.

3 Antimicrobial activity

3.1

3.1 Microbiology

For the antibacterial and antifungal activity, the compounds were dissolved in dimethylsulfoxide (DMSO). Further dilutions of the compounds and standard drugs in the test medium were prepared at the required quantities of 256, 128, 64, 32, 16, 8, 4, 2, 1 μg/ml concentrations with Mueller–Hinton broth and Sabouraud dextrose broth. The minimum inhibitory concentrations (MIC) were determined using the twofold serial dilution technique (National Committee for Clinical Laboratory Standards, 2000). A control test was also performed containing inoculated broth supplemented with only DMSO at the same dilutions used in our experiments and found inactive in the culture medium. All the compounds were tested for their in vitro growth inhibitory activity against different bacteria and fungi.

3.2

3.2 Antibacterial and antifungal activity

The cultures were obtained from Mueller–Hinton broth for all the bacterial strains after 24 h of incubation at 37 ± 1 °C. Fungi were maintained in Sabouraud dextrose broth after incubation for 24 h at 25 ± 1 °C. Testing was carried out in Mueller–Hinton broth and Sabouraud dextrose broth at pH 7.4 and the twofold serial dilution technique was applied. The final inoculum size was 10⁵ CFU/ml for the antibacterial assay and 10⁴ CFU/ml for the antifungal assay. A set of tubes containing only inoculated broth was used as controls. For the antibacterial assay after incubation for 24 h at 37 ± 1 °C and after incubation for 48 h at 25 ± 1 °C for antifungal assay, the tube with no growth of microorganism was recorded to represent the MIC expressed in μg/ml. Every experiment in the antibacterial and antifungal assay was replicated twice.

4 Results and discussion

4.1

4.1 Chemistry

The synthetic route of the compounds (5a–g and 6a–g) is outlined in Schemes 1 and 2, respectively. The 2,4-thiazolidinedione 1 was prepared by cyclisation of equimolar quantities of chloroacetic acid and thiourea by published procedures (Andreani et al., 1993). 2-Amino-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole 2 was obtained by direct cyclisation of a 3,4,5-trimethoxy benzoic acid and thiosemicarbazide in the presence of phosphorus oxychloride, the latter refluxed with substituted α-haloaryl ketones in dry ethanol yielded the imidazothiadiazoles (3a–g) in good yield. It is well established that this reaction proceeds via the intermediate iminothiadiazole antibacterial (Gadad et al., 2000), which undergoes dehydrocyclisation to form the desired fused heterocycle under reflux temperature spontaneously. The electronic and steric factors at 5th position of 2-Amino-5-substituted-1,3,4-thiadiazole are crucial in determining the course of its reaction with substituted α-haloaryl ketones. The strongly electronegative groups impart less nucleophilic character to the nitrogen at 4th position of the 1,3,4-thiadiazole. Various α-haloaryl ketones were prepared by the bromination of the corresponding ketones.

Reagents: (a) HCl (b) phosphorus oxychloride, 5 h, 80%; (c) dry ethanol, 10 h, 80–85%; (d) Vilsmeiere–Haack reagent, 8 h, 78–86%; (e) 1, piperidine, acetic acid, toluene, 10 h, 85–90%.

Reagents: (a) dry ethanol, 10 h, 80–85%; (b) Vilsmeiere–Haack reagent, 8 h, 78–86%; (c) 1, piperidine, acetic acid, toluene, 10 h, 85–92%.

Vilsmeier–Haack reaction of imidazothiadiazoles (3a–g) in dimethylformamide and phosphorus oxychloride provided 6-Aryl-2-(3,4,5-trimethoxyphenyl) imidazo[2,1-b][1,3,4]thiadiazole–5-carbaldehyde derivatives (4a–g). The compounds (7a–g) were prepared by the multi-step reaction protocol as previously reported antibacterial (Gadad et al., 2000),

Thus, obtained imidazo[2,1-b][1,3,4]thiadiazoles-5-carbaldehydes (4a–g) and (7a–g) were subjected to Knoevenagel condensation with 2,4-thiazolidinedione in the presence of catalytic amount of piperidine and acetic acid to afford 5-substituted-2,4-Thiazolidinediones (5a–g) and (6a–g), respectively.

The formation of 2-Aminothiadiazole (2) by the reaction between 3,4,5-trimethoxy benzoic acid and thiosemicarbazide was confirmed by IR spectra, which showed the presence of amine (—NH₂) band and the absence of carbonyl stretching of carboxylic acid. Structures of imidazothiadiazole derivatives (3a–g) were established by the absence of amine (—NH₂) band in IR spectra and appearance of imidazole proton (H-5) around δ 8.6 in the ¹H NMR spectra. IR spectra of aldehydes (4a–g) displayed a sharp band for carbonyl stretching frequency (v_c_⚌_o) around 1675 cm⁻¹ and the signal for imidazole proton (H-5) in ¹H NMR spectrum was absent. A new signal for aldehydic proton was observed around δ 10.00 in the ¹H NMR spectra, thus substantiating the formation of imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehydes. The absence of aldehydic protons and presence of the methylidene proton around δ 7.7 in ¹H NMR spectra of the product supported the formation of the title compounds (5a–g) and (6a–g). The mass spectra and elemental analysis of these compounds further confirmed the assigned structures. The physical data and the yield of the synthesized compounds are given in Table 1.

Table 1 Physical Constants of the compounds 5a–g and 6a–g.

Compounds	Ar	Yield (%)	m.p. (°C)	Molecular Formula
5a	C₆H₅	77	198–200	C₂₃H₁₈N₄O₅S₂
5b	4-CH₃·C₆H₄	75	189–191	C₂₄H₂₀N₄O₅S₂
5c	4-OCH₃·C₆H₄	70	205–206	C₂₄H₂₀N₄O₆S₂
5d	4-NO₂·C₆H₄	69	194–195	C₂₃H₁₇N₅O₇S₂
5e	4-Br·C₆H₄	78	210–211	C₂₃H₁₈ BrN₄O₅S₂
5f	4-Cl·C₆H₄	78	215–216	C₂₃H₁₈ ClN₄O₅S₂
5g	2,5-(OCH₃)C₆H₃	69	213–215	C₂₅H₂₂N₄O₇S₂
6a	C₆H₅	79	236–238	C₁₇H₁₄N₆O₄S₃
6b	4-CH₃·C₆H₄	80	260–261	C₁₈H₁₆N₆O₄S₃
6c	4-OCH₃·C₆H₄	81	262–264	C₁₈H₁₆N₆O₅S₃
6d	4-NO₂·C₆H₄	83	258–260	C₁₇H₁₅N₇O₆S₃
6e	4-Br·C₆H₄	82	264–266	C₁₇H₁₃BrN₆O₄S₃
6f	4-Cl·C₆H₄	80	272–274	C₁₇H₁₃ClN₆O₄S₃
6g	2,5-(OCH₃)C₆H₃	78	261–262	C₁₉H₁₈N₆O₆S₃

4.2

4.2 Antimicrobial activity

The synthesized compounds were tested for their in vitro antibacterial activity against the Gram-positive Staphylococcus aureus (ATCC25923), Enterococcus faecalis (ATCC35550), Gram-negative Escherichia coli (ATCC35218), Pseudomonas aeruginosa (ATCC25619) bacteria and Candida albicans (ATCC2091), Aspergillus flavus (NCIM No. 524), Aspergillus niger (ATCC6275), and Cryptococcus neoformans (Clinical isolate) fungi. The MIC values were determined by using the twofold serial dilution technique (National Committee for Clinical Laboratory Standards, 2000) in Mueller–Hinton broth and Sabouraud dextrose agar for the antibacterial and antifungal assays, respectively. Ampicillin was used as the reference antibacterial agents; ketoconazole was used as the reference antifungal agents. All the biological results of the tested compounds are given in Table 2. The combined data were reported that the synthesized compounds 5a–g and 6a–g showing MIC values between 4–256 μg/ml and 4–64 μg/ml, respectively.

Table 2 Inhibitory activity of compounds 5a–g and 6a–g expressed as minimum inhibitory concentration (MIC) in μg/mL.

Compounds	Ar	E.c	P.a	S.a	E.f	C.a	C.n	A.f	A.n
5a	C₆H₅	128	64	64	64	64	32	32	64
5b	4-CH₃·C₆H₄	256	256	64	64	64	32	32	64
5c	4-OCH₃·C₆H₄	256	256	64	64	64	64	64	32
5d	4-NO₂·C₆H₄	256	256	64	64	16	64	08	64
5e	4-Br·C₆H₄	256	256	32	32	4	8	4	4
5f	4-Cl·C₆H₄	128	64	32	32	4	8	32	32
5g	2,5-(OCH₃)C₆H₃	128	128	64	128	32	64	64	64
6a	C₆H₅	128	32	8	4	1	2	4	4
6b	4-CH₃·C₆H₄	64	64	32	32	64	64	32	64
6c	4-OCH₃·C₆H₄	64	64	32	32	64	32	64	32
6d	4-NO₂·C₆H₄	64	64	32	64	32	64	64	32
6e	4-Br·C₆H₄	64	64	8	8	4	8	4	4
6f	4-Cl·C₆H₄	64	64	8	4	32	64	32	4
6g	2,5-(OCH₃)C₆H₃	128	128	64	64	32	8	32	64
Ampicillin		2	2	1	2	NT	NT	NT	NT
Ketoconazole		NT	NT	NT	NT	2	1	2	1

NT, not tested; E.c, Escherichia coli; P.a, Pseudomonas aeruginosa; S.a, Staphylococcus aureus; E.f, Enterococcus faecalis; C.a, Candida albicans; C.n, Cryptococcus neoformans; A.f, Aspergillus flavus; A.n, Aspergillus niger.

The investigation of antimicrobial screening revealed that some of the tested compounds showed moderate to good bacterial and fungal inhibition. Particularly compounds 5e, 5f, 6a, 6b, 6c, 6e and 6f have shown good activity against S. aureus and E. faecalis with MIC values between 4 and 32 μg/ml. All compounds were active against tested fungal strains at 1–64 μg/ml concentration. Some of the compounds 5e, 5f, 6a and 6e showed good antifungal activity against C. albicans at 1–4 μg/ml and 5e, 6a and 6e against C. neoformans. A. flavus. A. niger at 2–8 μg/ml concentration. Compound 5f is active against C. neoformans at 8 μg/ml and 6f against A. niger at 4 μg/ml concentration. From the results, it is evident that the presence of 6-p-chlorophenyl and 6-p-bromophenyl derivatives showed increased activity in series of 5-[(2-(3,4,5-trimethoxyphenyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene]-1,3-thiazolidine-2, 4-dione 5a–g in case N-[(dimethylamino)methylidene]-5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide 6a–g series 6-phenyl, 6-p-chlorophenyl and 6-p-bromophenyl derivatives showed very good biological activity.

5 Conclusion

We have synthesized series of novel 5-substituted-2,4-Thiazolidinedione derivatives. The results of antimicrobial screening revealed the discovery of new compounds series of antibacterial and antifungal agents. The mode of action of these compounds was unknown. This observation may promote a further development of this group of 2,4-Thiazolidinediones may lead to compounds with better pharmacological profile than standard antibacterial and antifungal drugs.

Acknowledgements

Authors are grateful to Dr. F.V. Manvi, Principal, Professor A.D. Taranalli, Vice-Principal, for providing necessary facilities. Author are also grateful to NMR Research center. IISC, Bangalore, India, for providing the Spectral data.

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Terzioglu N., Gursoy A., . Eur. J. Med. Chem.. 2003;38:781-786.
Tuncbilek M., Altanlar N., . Arch. Pharm. Chem. Life Sci.. 2006;339:213-216.
Yoshioka T., Fujita T., Kanai T., Aizawa Y., Kurumada T., Hasegawa K., Horikoshi H., . J. Med. Chem.. 1998;32:421-428.

Introduction

Materials and methods

Materials and reagents
Synthesis

Antimicrobial activity

Microbiology
Antibacterial and antifungal activity

Results and discussion

Chemistry
Antimicrobial activity

Conclusion

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Synthesis, characterization and antimicrobial activity evaluation of new 2,4-Thiazolidinediones bearing imidazo[2,1-b][1,3,4]thiadiazole moiety

Abstract

Keywords

Antibacterial activity

Antifungal activity

Thiazolidinedione (TZD)

Thiadiazole

Arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide

1 Introduction

2 Materials and methods

2.1 Materials and reagents

2.2 Synthesis

2.2.1 Synthesis of 2,4-thiazolidinedione (1)

2.2.2 Synthesis of 2-amino-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole (2)

2.2.3 General procedure: synthesis of 2-(3,4,5-trimethoxyphenyl) 6-(4’substituted aryl)imidazo[2,1-b][1,3,4]-thiadiazoles 3a–g

2.2.3.1 2-(3,4,5-trimethoxyphenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazole (3a)

2.2.3.2 2-(3,4,5-trimethoxyphenyl)-6-(4-methylphenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3b)

2.2.3.3 2-(3,4,5-trimethoxyphenyl)-6-(4-methoxyphenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3c)

2.2.3.4 2-(3,4,5-trimethoxyphenyl)-6-(4-nitrophenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3d)

2.2.3.5 2-(3,4,5-trimethoxyphenyl)-6-(4-bromophenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3e)

2.2.3.6 2-(3,4,5-trimethoxyphenyl)-6-(4-chlorophenyl)-imidazo[2,1-b][1,3,4]thiadiazole (3f)

2.2.3.7 2-(3,4,5-trimethoxyphenyl)-6-(6-(2,5-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole (3g)

2.2.4 General procedure for the synthesis of 6-Aryl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde 4a–g

2.2.4.1 6-phenyl-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4a)

2.2.4.2 6-(4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4b)

2.2.4.3 6-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4c)

2.2.4.4 6-(4-nitrophenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4d)

2.2.4.5 6-(4-bromophenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4e)

2.2.4.6 6-(4-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4f)

2.2.4.7 6-(2,5-dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde (4g)

2.2.5 General procedure for the synthesis of 5-[(2-(3,4,5-trimethoxyphenyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione 5a–g

2.2.5.1 5-[(2-(3,4,5-trimethoxyphenyl)-6-phenylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione (5a)

2.2.5.2 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5b)

2.2.5.3 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-methoxylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5c)

2.2.5.4 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-nitrolphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5d)

2.2.5.5 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-bromophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5e)

2.2.5.6 5-{[2-(3,4,5-trimethoxyphenyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5f)

2.2.5.7 5-{[2-(3,4,5-trimethoxyphenyl)-6-(2,5-dimethoxylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methylidene}-1,3-thiazolidine-2,4-dione (5g)

2.2.6 General procedure for the synthesis of N-[(dimethylamino)methylidene]-5-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-arylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide 6a–g

2.2.6.1 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-phenylimidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6a)

2.2.6.2 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide(6b)

2.2.6.3 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6c)

2.2.6.4 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-nitrophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6d)

2.2.6.5 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-bromophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6e)

2.2.6.6 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6f)

2.2.6.7 Synthesis of N-[-(dimethylamino)methylidene]-5-[-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-6-(2,5-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole-2-sulfonamide (6g)

3 Antimicrobial activity

3.1 Microbiology

3.2 Antibacterial and antifungal activity

4 Results and discussion

4.1 Chemistry

4.2 Antimicrobial activity

5 Conclusion

Acknowledgements

References

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