Synthesis and evaluation of antimicrobial activity of some 5-[(5-substituted furan-2-yl) methylene]-(3H)-3-substituted benzyl-4-thioxo thiazolidine-2-one derivatives

Dahikar G.D.*, Ramteke A.N., Gadwe A.A., Yeole P.G.

Institute of Pharmaceutical Education and Research, Borgaon (Meghe), Wardha (M.S.) India. 442001

*Corresponding Author E-mail: girishdd1@rediffmail.com

ABSTRACT:

A series of thiazolidine-2, 4-dione was prepared as potential antimicrobial agents by conventional method. All the synthesised compounds have been screened for their antibacterial activity against S. aureus, E.coli and antifungal activity against C.albicans. The identification and characterization of the synthesised compounds were carried out by melting point, thin layer chromatography, ¹H NMR, IR, and MASS spectra. Among the synthesised compounds, compound (IIIb and IIIf) showed better antimicrobial activity as compared to other analogues (IIIa, IIIc, IIId and IIIe) against S.aureus, and E.coli and C.abicans.The antibacterial and antifungal activities of the compounds were compared with the standard drugs like Ciprofloxacin and Miconazole respectively.

KEYWORDS: Thiazolidine - 2, 4-dione; In vitro MIC assay; antimicrobial activity; S.aureus, E.coli, C.abicans.

INTRODUCTION:

The primary objective of medicinal chemistry is the design and discovery of new compounds that are suitable for use as drugs. The search to find less toxic medicines than those based on natural sources resulted in the introduction of synthetic substances as a drug in late nineteenth century and their widespread use in the twentieth century. Initially this development was centred around the natural products isolated from plant and animal material but as knowledge increased a wide range of synthetic compounds were evolved as drugs. The original pharmacological active compound from which these synthetic analogues are developed is known as the lead compound. The work of the medicinal compound is centred around the discovery of the new lead compounds with the specific medicinal properties. It includes the development of more effective and safer analogues of these new and existing lead compounds. This usually involves synthesizing and testing many hundreds of compounds before a suitable compound is produced. It is estimated that for every 100000 compounds synthesized, only one is suitable for medicinal use¹_.

The thiazolidine 2, 4-dione derivative possessed potent antimicrobial activity. In the view of these facts and in order to study the influence of substituted aldehyde on antimicrobial activity, we have now prepared a series of thiazolidine 2, 4-dione coupled with substituted furaldehyde moieties in the hope of discovering more active compounds. The presence of thiazolidine ring in the penicillin and related derivatives was the first recognition of its occurrence in nature.Thiazolidine derivatives are reported to show a variety of biological activities such as antimicrobial, cytotoxic activity, antidibetic and anti inflammatory².Thiazolidine 2, 4‑ diones are the derivatives of thiazolidine which belongs to an important group of heterocyclic compounds containing sulphur and nitrogen in a five member ring. A lot of research works on thiazolidine 2, 4 ‑dione has been done in the past. The nucleus is also known as wonder nucleus because it gives out different types of biological activities^{3, 4}. A convenient synthetic method was developed for synthesis of thiazolidine‑2,4‑ diones analogues.The analogues were prepared by the reaction between thiourea and chloracetic acid which was reflux for 8 hours to form the thiazolidine 2,4-dione which was treated with substituted benzyl chloride and reflux for 18 hours to give intermediate I then this intermediate was reflux with dioxane and lawenssons’s reagent for 24 hours to give intermediate II and then the title compounds.

EXPERIMENTAL AND RESULTS:

2,4‑thiazolidinedione was synthesized by refluxing a mixture of thiourea and chloroacetic acid for 8hours, then it was reflux for 18 hours with 3‑substituted benzyl chloride gave intermediate I. The resultant intermediate I upon refluxing with dioxane and Lawesson’s reagent for 24 hours gave intermediate II⁴. Finally intermediate II treated with 5‑ substituted furfural gave the title compounds. The progress of the reaction was monitored by TLC. The synthesized compounds were purified by recrystallization.

Synthesis of compound IIIa:

In the solution of intermediate II (1.34g, 0.01mol) and anhydrous sodium acetate (0.8203g, 0.01mol) in glacial acetic acid (1.41g, 0.01mol) of furaldehyde was added. The mixture was stirred under reflux for 8 hrs and then poured into ice-cold water. Then the precipitate was filtered, washed with water and n-hexane, dried and recrystallize from methanol⁵. Similarly the compound nos. IIIb to IIIf were prepared by taking the 0.01mol of intermediate II and 0.01mol of 5- substituted furfuraldehyde respectively.

Analytical data of compounds IIIa to IIIf:

IIIa:C₁₅H₁₁NO₂S₂; Rf 0.53(methanol);yield 82.16%; mp270‑273°C^*; UV 669.40 λmax; IR(KBr)1225. 43(C=S), 1683.74(C=O),707.83(C‑S‑C),1635.81(C=C),1090.53(C‑O‑C)3018.39(Aromatic C‑H)cm^‑1; ¹H NMR (300Mhz,CDCl₃) δ 4.299Methylene(CH2)H,7.074,7.094,7,201(Ar H),6.746 (Ethylene H); FAB-MS 301(M+H)⁺

IIIb:C₁₅H₁₀N₂O₄S ₂;Rf 0.43(methanol);yield 67.14%; mp210‑213°C^*; UV 685.40 λmax; IR(KBr) 1221.64(C=S), 1701.10(C=O),705.90(C‑S‑C),1627.88(C=C),1104.49(C‑O‑C), 3012.60(Aromatic

C‑H),1627.88,1388.65(NO₂assym ,sym)cm^‑1; ¹H NMR (300Mhz,CDCl₃) δ 4,270(Methylene CH₂), 7,087, 7.098, 7.127(Ar H),6.887(Ethylene H); FAB-MS 346 (M+H)+

IIIc:C₁₆H₁₃NO ₂S ₂;Rf 0.48(methanol);yield 70.25%; mp 255‑258°C^*; UV 673.70 λmax; IR(KBr) 1217.72(C=S), 1693.38(C=O),701.56(C‑S‑C),1630.66(C=S),1089.50(C‑O‑C),3023.67 (Aromatic C‑H)2916.17(CH₃) cm^‑1 ;¹H NMR (300Mhz,CDCl₃) δ 4.227(Methylene CH₂), 7.074, 7.156,7.196(ArH), 6.734(EthyleneH),2.987(Methyl); FAB MS 315(M+H)⁺

Table-1. Antimicrobial activity data of compounds:

Compound	Bacteria and fungi along with zone of inhibition(mm)
	S. aureus			E. coli			C. albicans
	50 µg/ml	100 µg/ml	150 µg/ml	50 µg/ml	100 µg/ml	150 µg/ml	50 µg/ml	100 µg/ml	150 µg/ml
IIIa	12	14	16	14	16	21	12	14	18
IIIb	15	17	20	15	18	22	15	17	20
IIIc	10	14	15	10	14	16	10	13	17
IIId	11	15	17	12	15	19	12	14	16
IIIe	13	17	21	14	17	20	12	15	19
IIIf	16	21	26	17	21	24	15	17	22
Std-1 Ciprofloxacin	18	24	29	17	22	26	-	-	-
Std-2 Miconazole	-	-	-	-	-	-	16	20	24

IIId: C₁₆H₁₀F₃NO₂S ₂;Rf 0.63(methanol);yield 87.81%; mp 227‑ 228°C ^*; UV 665.80 λmax; IR(KBr) 1224.71(C=S), 1681.81(C=O),703.97(C‑S‑C),1631.32(C=S),1074.28(C‑O‑C),3033.82(Aromatic C‑H),1338.51,1379.01(CF₃)cm^‑1; ¹H NMR (300Mhz,CDCl₃δ 4.277(Methylene CH₂),7.067, 7.071,7.097(Ar H),6.790(Ethylene H); FAB-MS 369 (M+H)⁺

IIIe:C₁₇H₁₂F₃NO₂S ₂;Rf 0.56(methanol);yield 85.79%; mp 240‑242°C ^*;UV 689.80 λmax; IR(KBr) 1216.71(C=S), 1690.95(C=O), 702.58(C‑S‑C), 1625.18(C=C), 1091.78 (C‑O‑C), 3018.39 (Aromatic C‑H), 1334.79, 1382.72(CF₃), 2916.17 (CH₃) cm^‑1; ¹H NMR (300Mhz,CDCl₃) δ 4.277 (Methylene CH₂),7.007,7.071,7.097(Ar H),6.763(Ethylene H )2.187(Methyl).FAB-MS 383(M+H)⁺

IIIf:C₁₆H ₉F₃N₂O₄S₂;Rf 0.42(methanol);yield 76.93%; mp 233‑238°C ^*; UV 681.20 λmax; IR(KBr)1224.71 (C=S),1700.74(C=O),706.65(C‑S‑C),1626.10(C=C),1105.68(C‑O‑C), 3012.60 (Aromatic C‑H),1332.29, 1382.01(CF₃), 1615.81,1338.51(NO₂ assym, sym)cm^‑1; ¹H NMR (300Mhz,CDCl₃) δ 4.225(Methylene CH₂),7.084,7.104, 7.104,7.116(Ar H)6.704 (Ethylene H);FAB-MS 414(M+H)⁺* Uncorrected

Antimicrobial activity screening:

The preliminary antibacterial activity of synthesised compounds was studied against E.coli, S.aureus, and antifungal activity of compounds was studied against C.albicans. Ciprofloxacine and Miconazole were used as standard for antibacterial and antifungal activity respectively. The agar dilution method was performed using Mueller-Hinton agar (Hi-Media) for antibacterial activity and Saburoud’s dextrose agar (Hi-Media) medium for antifungal activity. This method depends on the diffusion of drug from bore through the solidified agar layer of petridish to an extent such that growth of the inoculated microorganism is prevented entirely in an circular area” zone” around the cup containing the solution of the compound under test. The medium was sterilised by autoclaving at 15lb pressure for 30 minutes. The test compounds (5mg) were dissolved in DMSO (5mL) and volume was made up to 10 ml to produce a concentration of 500microgram/ ml. Further dilutions were made with DMSO to produce 50,100 and150 micrograms/ ml. Similarly the dilutions were made for standard drugs in concentration of 50,100 and micrograms/ ml respectively. All the operations were carried out under aseptic conditions inhibition produced by test compounds were measured and activity index was calculated against the standard⁶(table-1).

CONCLUSION:

We have successfully prepared new derivatives of thiazolidine-2,4-dione under the above specified conditions. All the above compounds were evaluated for their antimicrobial activity. Among the six synthesized compounds IIIb and IIIf were found to be more active as compare to the other derivatives.

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