Design, Synthesis, and Preliminary Antiproliferative Evaluation of 1,2,4-Thiadiazole Derivatives as Possible Histone Deacetylase Inhibitors

Abstract

Histone deacetylase (HDAC) enzymes are involved in a wide range of clinical situations, encompassing cancer. Most o the current clinically used HDAC inhibitors are containing hydroxamate moiety as a zinc-binding group (ZBG). The poor selectivity and undesired pharmacokinetic characteristics of hydroxamate inhibitors prompted the exploration of new HDAC inhibitors. Therefore, the objective of this work is to design new HDAC inhibitors incorporating thiadiazole moiety as a ZBG. This study involved the design and virtual analysis of a series of thiadiazole derivatives using Maestro software. Compounds with accepted docking score which include compound 6a [4- (benzyloxy)-N-(1,2,4-thiadiazol-5-yl)benzamide] -8.953 kcal/mol, compound 6b [4-(naphthalen-1-ylmethoxy)-N-(1,2,4-thiadiazol-5- yl)benzamide] -9.290 kcal/mol, and compound 6c [ 4-((4-methoxybenzyl)oxy)benzoic acid] -8.57 kcal/mol while the FDA approved vorinostat has a docking score -5.613 kcal/mol against HDAC 2 (4LXZ). Compounds 6a-c were subjected to the organic synthesis applying traditional chemical reactions. The synthesis was commenced with 3a-c formation using Williamson reaction by reacting benzylic halogen derivatives 2a-c with methyl 4-hydroxybenzoate, then the intermediates underwent ester hydrolysis to produce 4-(benzyloxy)benzoic acid derivatives 4a-c and then reacted with 1,2,4-thiadiazol-5- amine to produce 6a-c using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as coupling reagent. The intermediates and final products were characterized by FT-IR, MS and NMR spectroscopy. The cytotoxic effect was assessed using the MTT cell viability assay indicate that the IC50 of 6b is 0.66 μM while the IC50 of vorinostat is 1.48 μM.