Synthesis and In Vitro Anti-inflammatory Activity of Some 1- [(2-(Methylsulphonyl amino) thiazole-4-yl) methyl]-3- aryl thioureas

Headnote

ABSTRACT:

New thioureas (4a-f) bearing 2-methylsulhonyl amino thiazol-4-methyl moiety have been synthesized by multistep synthesis depicted in Scheme.1. Intermediate 2-Amino-4-(isothiocynatomethyl) thiazole (2) has been synthesized from 2-amino-4-chloromethyl thiazole hydrochloride (1) by nucleophilic displacement of chlorine by isothiocynate. The compound (2) on subsequent condensation with methyl sulphonyl chloride carried in the presence of triethyl amine in DCM yielded 2-methylsulphonyl amino-4-(isothiocynatomethyl) thiazole (3) which on addition with aryl amines in refluxed pyridine gave the titled thioueras. Synthesized intermediates and final compounds were characterized by I.R, ¹H NMR, MASS spectroscopic techniques and C, H, N and S analysis. Synthesized final compounds were evaluated for in vitro anti-inflammatory activity by HRBC membrane stabilization method. Most of the synthesized compound exhibited good anti-inflammatory activity as compared to standard Diclofenac sodium.

KEYWORDS: Amino-4-(isothiocynatomethyl) thiazole, aryl amine, pyridine, in vitro anti -inflammatory activity.

INTRODUCTION:

Thiourea derivatives exhibit diverse biological and pharmacological activities. Derivatives of N-aryl- or Nheteroarylthioureas are known as potential inhibitors of HIV-1,1 antihyperthyroid2 acaricidal3 wide spectrum of anthelmintic4 anti-inflammatory and analgetic agents.5 Various symmetrical and unsymmetrical thioureas, N, N'-disubstituted thioureas have shown remarkable antiinflammatory activitiy. Derivatives of N-aroyl- or Nheteroaryl thioureas are known for their better antiinflammatory activity and low toxicity.

Disubstituted thioureas possessing N-substituent like pyrimidine, quinazoline, acridinyl thiophene etc have displayed appreciable anti-inflammatory activity. Literature survey reveals N-substituted thioueras 1(para-nitrobenzoyl)-3-(2, 3-dimethyl-oxo-1phenylpyrazolin-4-yl)-thiourea,6 N-(4-alkoxyphenyl)-N'(2-alkylthio-6-methyl-4pyrimidinyl) thiocarbamides,7 1- (2-phenyl quinazolin-3 -yl-4(3 H) -one)-3 -substituted thioureas,8 have displayed considerable antiinflammatory activities. Literature survey revealed that 2-amino 4-substitued thiazoles9 and their various derivatives such as 2-(2, 4-disubstituted-thiazole-5-yl) -3 - aryl-3Hquinazoline- 4-ones,10 3-[4'(p-chlorophenyl) thiazol-2'-yl] -2-[(substituted azetidinone/thiazolidinone) - aminomethy]-6-bromoquinazolin-4-ones,11 4oxothiazolidine and its 5-arylidenes,12 (Z)-4-((2,4dioxothiazolidin-5-ylidene) methyl) -N-(4-substitute d phenylthiazol-2-yl) benzene sulfonamides and 2-substituted-N-(4-Substituted-phenylthiazol-2yl) acetamides,13 thiazolyl-N-Ph piperazines,14 2-(4arylthiazol-2-yl-amino)-n-aryl acetamides15 have displayed considerable anti-inflammatory activity. When methane sulphonamido moiety was incorporated in the heteocycles the modified products are found to have appreciable anti-inflammatory activity with COX-2 selectivity.16 Literature revealed that there is no attention on the synthesis of thioureas having 2-sulphonyl amino thiazol-4-yl methyl moiety. Considering the pharmacological importance of thioureas and disbstituted thiazoles, here we decided to synthesize new thioureas like 1- [(2- (methylsulphonyl amino) thiazole4-yl) methyl]-3- arylthioureas so as to obtain the compounds/ leads with better anti-inflammatory activity with reduced side effects.

MATERIAL AND METHODS:

Chemicals and reagents:

Reactions were monitored by thin layer chromatography....