SYNTHESIS, CHARACTERIZATION AND CYTOTOXIC EVALUATION OF NOVEL SCHIFF BASE DERIVATIVES OF 5-[2-(4-FLUOROPHENYL) PYRIDIN-3-YL]-1, 3, 4-THIADIAZOL-2-AMINE

Adimule Vinayak, Medapa Sudha, Raoprakash Kumar, Lalita Kumar, Sanjeev
2014 Indo American Journal of Pharmaceutical Research   unpublished
This research has focused on the incorporation of the thiadiazole moiety into versatile pyridine ring because of their diversified biological properties. In order to explore the possibilities of some altered biological action author envisaged that by synthesizing the Schiff base derivatives of 1, 3, 4-thiadiazole moiety and screening for their anticancer properties. The novel 1,3,4-thiadiazole Schiff base compounds have been synthesized by microwave-assisted synthesis and screened for their
more » ... toxicity on HeLa, HepG2 and MCF7 cancer cell lines. The key intermediate 2-(4-fluorophenyl) pyridine-3-carboxylic acid was obtained by hydrolyzing the ester (3) in presence of KOH and methanol. The obtained compound (4) was treated with thiosemicarbazide and phosphorous oxychloride and cyclized in microwave in order to get the intermediate compound 5-[2-(4-fluorophenyl) pyridin-3-yl]-1, 3, 4-thiadiazol-2-amine. The amine 5 was reacted with various aldehydes (a-h) in presence of catalytic amount of acetic acid and obtained series of novel Schiff base derivatives 6a-6h.The column purified (silica gel 100-200mesh) compounds 6a-6hwere screened for their cytotoxicity on three different human carcinoma cell lines (HeLa, Hep-G2 and MCF7). The synthesized compounds were characterized by MS, 1 H-NMR, IR and elemental analysis. Most of the compounds in this series have exhibited moderate cytotoxicity against all the three cancer cell lines at different concentrations, but two compounds 6f and 6h showed good inhibition towards liver carcinoma cell lines with IC 50 of 23.8µMand 13.4µM respectively. Please cite this article in press as Adimule Vinayak et al. INTRODUCTION The 1, 3, 4-thiadiazoles form a biologically important group of compounds having diversified biological activities such as anti-inflammatory [1],anti-microbial [2],anticancer [3], anticonvulsants[4] etc. The modification in the structure of the pyridine ring by introducing 4-fluorophenylgroup at C2 position enhances the potency of the 1,3,4-thiadiazoles.Different Schiff base derivatives containing pyridine moiety(Figure 1, B)attract much interest due to its synthetic as well as various biological activities[5]. In view of the above properties of 1, 3, 4-thiadiazoles we have synthesized various novel Schiff base molecules [6] that might possess anticancer properties. These compounds were obtained by the cyclization of 2-(4-fluorophenyl) pyridine-3-carboxylic acid 4 in presence of thiosemicarbazide and phosphorous oxytrichloride under microwave irradiation and obtained the reactive amine(Figure 1, A).The amine 5 was further converted into stable Schiff base derivatives by treating with various aldehydes(a-h) in presence of acetic acid and obtained the final compounds6a-6h.These types of novel pyridine ring systems have not been studied yet.The Schiff base compounds having 1, 3, 4-thiadiazole ring at C3 position of the pyridine system containing 4-fluoro phenyl group at the C2 position showed good anti-proliferative activity[7].In view of the above facts author envisaged that by modifying the structure of the 1, 3, 4-thiadiazole and substituting with different aromatic groups and thus substituted groups enhances the bio availability may possess good anticancer properties. Author substituted 4-fluoro phenyl group at C2 position and synthesized novel Schiff base derivatives of 5-[2-(4-fluorophenyl) pyridin-3-yl]-1, 3, 4-thiadiazol-2-amine. The Schiff base derivatives 6a-6h showed cytotoxicityagainst cancer cell lines. According to the SAR studies of these 1, 3, 4-thiadiazole ring, by introducing more water soluble groups in the ring systems enhances the bio availability and increases considerably TPSA (total polar surface area) of the molecules. The 1, 3, 4-thiadiazole ring system enhances the biological activity. As a contribution to the development of new anticancer drugs we have synthesized novel Schiff base derivatives 6a-6hand screened their cytotoxicity against HeLa, Hep-G2 and MCF7cell lines.
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