REV.CHIM.(Bucharest)♦68♦No. 4 ♦2017 http://www.revistadechimie.ro 745 Synthesis, Characterization and Antiproliferative Activity Assessment of a Novel 1 H-5-mercapto-1,2,4 Triazole Derivative MARIUS MIOC 1,2 , SORIN AVRAM 2 , VASILE BERCEAN 3 , MIHAELA BALAN PORCARASU 4 , CODRUTA SOICA 1 , RAZVAN SUSAN 1 , LUDOVIC KURUNCZI 1,2 * 1 University of Medicine and Pharmacy Victor Babes Timisoara, Faculty of Pharmacy, 2 Eftimie Murgu Sq., 300041, Timisoara, Romania 2 Institute of Chemistry Timisoara of Romanian Academy, Department of Computational Chemistry, 24 Mihai Viteazu Av., 300223, Timisoara, Romania 3 S.C. SINOFIN S.R.L., 41 Tigrului Str., Timisoara, 300544, Romania 4 Petru Poni Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, Iasi, 700487, Romania Angiogenesis plays an important function in tumor proliferation, one of the main angiogenic promoters being the vascular endothelial growth factor (VEGF) which activates specific receptors, particularly VEGFR- 2. Thus, VEGFR-2 has become an essential therapeutic target in the development of new antitumor drugs. 1,2,4-triazoles show a wide range of biological activities, including antitumor effect, which was documented by numerous reports. In the current study the selection of 5-mercapto-1,2,4-triazole structure (1H-3-styryl- 5-benzylidenehydrazino-carbonyl-methylsulfanil-1,2,4-triazole, Tz3a.7) was conducted based on molecular docking that emphasized it as suitable ligand for VEGFR-2 and EGFR1 receptors. Compound Tz3a.7 was synthesized and physicochemically and biologically evaluated thus revealing a moderate antiproliferative activity against breast cancer cell line MDA-MB-231. Keywords: 1,2,4-triazole, antiproliferative, angiogenesis, breast cancer, VEGFR-2, EGFR1 Cancer is a life threatening pathology that has the ability to spread to near or distant organs; angiogenesis represents an important process that contributes in tumor growth and proliferation [1]. One of the main angiogenic promoters is the vascular endothelial growth factor (VEGF) which activates the vascular endothelial growth factor receptors (VEGFR), in particular VEGFR-2 [2]. VEGFR-2 represents an intensely studied target in the field of drug discovery for the development of new anticancer treatment [3,4] with the aid of computational chemistry. Numerous triazole derivatives were documented as anticancer agents revealing strong antoproliferative activity through various mechanisms. 5-mercapto-1,2,4-triazole derivatives identified by in silico (protein-ligand docking) as DNA topoisomerase II inhibitors and were synthesized [5]; all compounds were in vitro assessed against EAC (Ehrlich ascites carcinoma) cells exhibiting good antiproliferative effect while five compounds also revealed significant anti- inflammatory activity. 4-Amino-4,5-disubstituted-[1,2,4] triazole-3-thiols were designed, synthesized and in vitro tested revealing a strong bonding to VEGF [6]. Dual VEGFR- 2 and tubulin inhibitors were developed in the effort to inhibit simultaneously tumor cells and vasculature [7] leading to the discovery of lead compounds with triazole/oxadiazole moieties with excellent anticancer properties. In our recent work we built a compound library, containing 1,2,4-triazole derivatives, that was subjected to molecular docking against two targets: VEGFR-2 and epidermal growth factor receptor 1 (EGFR1). As a result of extensive docking simulations, a candidate molecule, 1H- 3-styryl-5-benzylidenehydrazino-carbonyl-methylsulfanil- 1,2,4-triazole (Tz3a.7) emerged as a suitable ligand for both receptors. Some papers were previously published in the field of functionalization of mercapto-triazoles and their complexing abilities, as well their instrumental characterisation and stability [8], by well-known methods, including kinetic studies [9, 10]. The aim of the current study was the synthesis, physicochemical characterization and assessment of the antiproliferative activity of compound Tz3a.7. Materials and methods Chemistry Materials and methods Thiosemicarbazide, cinnamic acid, and solvents ( ethanol, N,N-dimethylformamide, pyridine) were purchased (Acros, Aldrich) and used as received. Cinnamoyl chloride was synthsized by treating cynnamic acid with thionyl chloride, and used without further purification. Synthesis of N-(benzylideneamino)-2-chloro- acetamide was carried out by a previously published procedure [11]. Synthesis route of compound Tz3a.7 is depicted in figure 1. Fig. 1. Synthesis route of 1H-3- styryl-5-benzylidenehydrazino- carbonyl-methylsulfanil-1,2,4- triazole (Tz3a.7) * Phone: (+40)256204476 / 483