Original article Synthesis and biological activity of 4-thiazolidinones, thiosemicarbazides derived from diflunisal hydrazide Güniz Küçükgüzel a, * , Ayla Kocatepe a , Erik De Clercq b , Fikrettin Şahin c,d , Medine Güllüce d a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Marmara University, Istanbul 34668, Turkey b Rega Institute for Medical Research, Katholieke Universiteit Leuven, 10 Minderbroedersstraat, B-3000 Leuven, Belgium c Department of Genetic and Bioengineering, Faculty of Engineering and Architecture, Yeditepe University, İstanbul 34755, Turkey d Biotechnology Application and Research Center, Ataturk University, Erzurum 25240, Turkey Received 11 June 2005; received in revised form 28 October 2005; accepted 3 November 2005 Available online 18 January 2006 Abstract Two novel series of 4-thiazolidinone derivatives, namely 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid [2-(5-nitro-2-furyl/substituted phenyl)-4-thiazolidinone-3-yl]amides (5a–g) and 2-(2′,4′-difluoro-4-hydroxybiphenyl-3-carbonylhydrazono)-3-alkyl/aryl-4-thiazolidinones (6a– e) together with 5-(2′,4′-difluoro-4-hydroxybiphenyl-5-yl)-2-cyclohexylamino-1,3,4-oxadiazole (7a) have been synthesized as title compounds. 1-(2′,4′-Difluoro-4-hydroxybiphenyl-3-carbonyl)-4-alkyl/arylthiosemicarbazides (4a–g) were also obtained and used as intermediate to give the title compounds. All synthesized compounds were screened for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, antiviral and antimicrobial activities against various virus, bacteria and fungi strains. © 2006 Elsevier SAS. All rights reserved. Keywords: 4-Thiazolidinone; Anti-HIV activity; Diflunisal; Thiosemicarbazide 1. Introduction 4-Thiazolidinone derivatives are known to possess antibac- terial [1–5], antifungal [6–8], antiviral [9–13] and antitubercu- losis [4,14–16] properties (Fig. 1). Peptidoglycan is an essen- tial component of the cell wall of both Gram-positive and Gram-negative bacteria. 4-Thiazolidinones have been reported as novel inhibitors of the bacterial enzyme Mur B which is a precursor acting during the biosynthesis of peptidoglycan [17]. Human immunodeficiency virus type 1 (HIV-1) was identified in the development of acquired immune deficiency syndrome (AIDS). Reverse transcriptase is a key enzyme, packaged with- in HIV virion capsid, which plays an essential role in the re- plication of virus. Combinations of reverse transcriptase nu- cleoside inhibitors, reverse transcriptase non-nucleoside inhibitors and protease inhibitors have been clinically used for the treatment of HIV infections. The result of observations culminated in the discovery of 4-thiazolidinone as a new class of highly potent non-nucleoside inhibitors [9–12]. Tuberculosis is a chronic infection disease caused by several species of my- cobacteria. The incidence of tuberculosis is increasing world wide, partly due to poverty and inequity and partly to the HIV/AIDS pandemic, which greatly increase the risk of infec- tious proceeding to overt disease. During recent years, Myco- bacterium tuberculosis and microorganisms increased resis- tance against drugs. Therefore, there is need to develop the new, potent, fast-acting antimicrobial, antiviral and antimyco- bacterial drugs with low toxicity. 4-Thiazolidinone derivatives of diflunisal, prepared from di- flunisal hydrazide-hydrazones can give corresponding 2′,4′-di- fluoro-4-hydroxybiphenyl-3-carboxylic acid (Diflunisal) as a metabolite via hydrolytic route. 4-Thiazolidinones of diflunisal were also designed as possible dual acting antimicrobial/anti- tuberculosis agents possessing anti-inflammatory properties via http://france.elsevier.com/direct/ejmech European Journal of Medicinal Chemistry 41 (2006) 353–359 * Corresponding author. Tel.: +90 216 349 12 16; fax: +90 216 345 29 52. E-mail address: gkucukguzel@marmara.edu.tr (G. Küçükgüzel). 0223-5234/$ - see front matter © 2006 Elsevier SAS. All rights reserved. doi:10.1016/j.ejmech.2005.11.005