Synthesis, cytotoxicity assessment and molecular docking of N-(5-(substituted-benzylthio)-1,3,4thiadiazole-2-yl)-2-p-fluorophenylacetamide derivatives as tyrosine kinase inhibitors

Abstract

Compounds containing 1,3,4-thiadiazole nucleus appear to be potential tyrosine kinase inhibitors. Previous reports showed that some 1,3,4-thiadiazole derivatives were designed as probable tyrosine kinase inhibitors. Thiol derivative (2) was obtained from the reaction of 5-amino-1,3,4-thiadiazole-2-thiol with 4-fluorophenylacetic acid, ethyldimethyaminopropylcarbodiimide and hydroxybenzotriazole. Subsequent reaction of the obtained thiol derivative with diverse benzyl chlorides afforded the final compounds 3a-3l in a click reaction surprisingly. Derivatives with electron withdrawing moieties (F, Cl) exerted higher yield compared to methoxylated derivatives as electron donating group. Besides, docking studies using ArgusLab 4.0 was done for exploring the probable binding mode and interactions. Investigation of cytotoxicity of target compounds (3a-3l) by MTT assay revealed that these derivatives are more active against the breast cancer cell line MCF-7 and most of these were found to be more effective than imatinib as reference drug. Chlorine containing derivatives at ortho and meta positions were the most cytotoxic in these series.