276 Letters in Drug Design & Discovery, 2012, 9, 276-281 1875-628X/12 $58.00+.00 © 2012 Bentham Science Publishers Synthesis of New S-alkylated-3-mercapto-1,2,4-triazole Derivatives Bearing Cyclic Amine Moiety as Potent Anticancer Agents M.S.R. Murty* ,a , Kesur R. Ram a , Rayudu Venkateswara Rao a , J.S. Yadav a , Janapala Venkateswara Rao b , R. Pamanji b and L.R. Velatooru b a Organic Chemistry Division-I; b Toxicology Unit, Biology Division, Indian Institute of Chemical Technology, Hyderabad-500607, India Received August 01, 2011: Revised November 04, 2011: Accepted November 28, 2011 Abstract: A series of 3-[3-[4-(Substituted)-1-cyclicamine]propyl]thio-5-substituted[1,2,4]triazoles (8a-j) were synthesized with good yields starting from corresponding carboxylic acids. The cytotoxicity studies of these derivatives were studied against five different human cancer cell lines. Three compounds had shown good anticancer activity. The triazole derivatives, 8i and 8j were most potent particularly against U937 and HL-60 cells. The cytotoxic potency of the compounds varied between the cell lines suggesting that a structural property of these compounds as possible determinants of their biological activity. Keywords: 1,2,4-Triazoles, Acid hydrazides, Piperazines, Anticancer. INTRODUCTION Cancer drug discovery has traditionally focused on targeting DNA synthesis, angiogenesis and cell division [1]. Although existing drugs show efficacy, their lack of selectivity for tumor cells over normal cells can lead to severe side effects [2]. Design and synthesis of novel small molecules which can specifically block some targets in tumor cells are in perspective direction in modern medicinal chemistry. Hence, there is an urgent need for the discovery and development of new anticancer agents. From different groups of heterocycles, many synthetic small molecules with cytotoxic activity have been reported and several of them have undergone the clinical trials [3]. The chemistry of 1,2,4-triazoles and their fused heterocyclic derivatives has received considerable attention in the last few decades, owing to their synthetic and effective biological importance [4]. The 1H-1,2,4-triazole compounds possess an important pharmacological activities such as, anti-inflammatory, CNS stimulants sedatives, antianxiety, antimicrobial [5,6], and antimycotic agents such as fluconazole, intraconazole and voriconazole [7]. Also, there are known drugs containing the 1,2,4-triazole group e.g. Triazolam [8], Alprazolam [9], Etizolam, and Furacylin. Moreover, sulphur containing heterocycles represent an important group of compounds and these heterocycles i.e., the mercapto- and thione-substituted 1,2,4-triazole ring systems exhibit biological activities, such as anticancer [10,11], antitubercular [12], diuretic [13], antibacterial [14], antifungal [15], antimycobacterial [16], and hypoglycemic [17]. Several piperazine derivatives were synthesized in the last decade, as useful chemotherapeutic agents for various diseases, such as crivixan (indinavir sulphate) and *Address correspondence to this author at the Organic Chemistry Division- I, Indian Institute of Chemical Technology, Hyderabad-500607, India; Fax: 91-40-27193189; E-mail: msrmurty@ymail.com delaviridine (rescriptor), powerful inhibitors for the protease and reverse transcriptase inhibitor of HIV enzymes, respectively [18]. Some piperizinyl [1,2,4]triazole deriva- tives were reported as 5-HT 1A serotonin receptor ligands [19]. In view of these facts, the aim of the present study was to synthesize new compounds containing 1,2,4-triazole and piperazine moieties in a single molecular framework as possible anticancer agents. In the present work we have described synthesis of 3-[3-[4-(substituted)-1-cyclicamine] propyl]thio-5-substituted[1,2,4]triazoles (8). The cytotoxic activity of these derivatives was studied against five different types of human cancer cell lines i.e. U937, THP-1, Colo205, MCF7 and HL-60. RESULTS AND DISCUSSION Chemistry 5-Substituted [1,2,4]triazole-3-thiones (5) were synthesized by following reported sequence of the reactions from corresponding aryl carboxylic acids (1) (Scheme 1). The aryl carboxylic acids (1) were converted to corresponding methyl esters (2) with catalytic amount of sulfuric acid in methanol. This was confirmed by disappearance of broad carboxylic acid peak in 1 H NMR spectra and disappearance of broad ‘OH’ stretching of carboxylic acid in IR spectra of the product. It was also supported by appearance of OCH 3 peak in 1 H NMR spectra of methyl esters (2). The methyl esters (2) were converted to corresponding acid hydrazides (3) using hydrazine hydrate in methanol [20]. This was confirmed by disappearance of - OCH 3 peak and appearance of NH and NH 2 peaks in 1 H NMR spectra of the product. It was also supported by the appearance of NH stretching and C=O stretching of acid hydrazide in IR spectra of the product. The acid hydrazides (3) were reacted with potassium thiocyanate and concentrated hydrochloric acid to produce corresponding thiosemicarbazides (4) [21]. Appearance of additional NH