Design, Synthesis, Characterization and Cancer Cell Growth-Inhibitory Properties of Novel Derivatives of 2-(4-Fluoro-phenyl)-5-(5-Aryl Substituted-1, 3, 4-Oxadiazol-2-yl) Pyridine

Aims: A series of novel 2-(4-Fluoro-phenyl)-5-(5-aryl substituted-1, 3, 4-oxadiazol-2-yl) pyridine derivatives 7a-7e were synthesized and evaluated for their cancer cell growth inhibitory properties.
Study Design: Designed and synthesized the novel derivatives of pyridine containing 1, 3, 4-oxadiazole ring based on the initial SAR studies of pyridine and their diversified biological properties.
Place and Duration of the Study: Synthesis, purification was performed at centre for scientific research and advanced learning, Mount Carmel College, Autonomous, Bangalore, India (between June 2013 to March 2014), characterization using 1H-NMR and 13C NMR was done at Indian Institute of Science (IISc), Bangalore, India. Cytotoxic evaluation was performed at Genelon Institute of Life Sciences, Yalahanka, Bangalore, India.
Methodology: A mixture of 6-Bromo-nicotinic acid ethyl ester with 4-Fluoro-phenyl boronic acid in ethyl alcohol afforded the 6-(4-Fluoro-phenyl)-nicotinic acid ethyl ester (4). Subsequent reaction of (4) with hydrazine hydrate in ethanol afforded 6-(4-Fluoro-phenyl)-nicotinic acid hydrazide. Reaction with compound (5) and various aldehydes furnished the novel Schiff base derivatives (6a-6e). Schiff base derivatives were cyclized using Chloramine-T under microwave irradiation and obtained novel derivatives 7a-7e. All the reagents, chemicals and solvents were purchased from S-d fine and spectro chem Ltd. Bengaluru. India. 1H-NMR and 13CNMR were recorded by Brucker 400 MHz spectrophotometer. Melting points were determined using Buchi melting point 545. Mass spectra were recorded by Agilent 1200 series. TLC was done on F254 grade silica 60 from Merck. IR spectra were recorded by using FTIR (1800S) series. Microwave used was whirlpool semi-automated specially designed. The human cancer cell lines were purchased from NCCS (National Centre for Cell Science), Pune, India.
Results: Compounds 7b and 7d showed better activity than 5-Fluorouracil against MCF7 cell line. Title compounds 7a-7e is prepared by the oxidative cyclization reaction of the corresponding Schiff base compounds 6a-6e using chloramine-T as promoter. Cytotoxicity of the 1, 3, 4-oxadiazole compounds were obtained by screening the compounds against human cancer cell lines using MTT assay. Among the various derivatives (7a-7e), compounds bearing 5-bromo-2-fluoro-phenyl ring and 3-methyl thiophene ring demonstrated potent antiproliferative activity. In this research work compounds 7b and 7d showed good cytotoxicity against MCF7 cell line.
Conclusion: Novel derivatives of 1, 3, 4-oxadiazole compounds namely, 5-[5-(5-Bromo-2-fluoro phenyl)-[1, 3, 4] oxadiazol-2-yl]-2-(4-fluoro-phenyl)-pyridine (7b) and 2-(4-Fluoro-phenyl)-5-[5-(3-methyl-thiophen-2-yl)-[1, 3, 4] oxadiazol-2-yl]-pyridine (7d) showed better anticancer properties against MCF7 cell line with IC50 of 6.9 µM and 3.8 µM respectively. Cytotoxicity of the compounds (7c), (7d) against Caco-2 cell line with IC50 of 23.6 µM and 56.5 µM respectively. Rest all the compounds showed more resistance against all the cell lines.