DESIGN, SYNTHESIS, DOCKING STUDIES AND BIOLOGICAL EVALUATION OF NOVEL HYDROXAMIC AND CARBOXYLIC ACID DERIVATIVES AS HISTONE DEACETYLASE ENZYME INHIBITORS

摘要

A new series of hydroxamic (5a-5j) and carboxylic acid analogs (4a-4j) based on the 1, 3, 4-thiadiazole scaffold was designed and synthesized to explore its potential as new antitumor agents. The chemical structures of the compounds were confirmed based on TLC, IR, sup1/supH NMR, and 13C NMR analysis. Molecular docking studies showed that the target compounds correctly dock into the binding pocket of histone deacetylase inhibitor (PDB Code 1w22 reference compound), while their bioavailability / drug-likeness was predicted to be acceptable. The predicted physicochemical were compared with those of a reference compound. Biological results revealed that the structural modifications proposed significantly affected inhibitory potency as well as selectivity for HDAC inhibitors. Most target compounds were significantly more active specifically 5a, 5b, 5e with ICsub50/sub values in the low micromolar or, the most active compounds in the series. Selected compounds were tested on the viability of MDA-MB-231 (breast cancer cell) and K562 (chronic myelogenous leukemia cell), A549 (human lung cancer), PC3 (Prostate cancer cell lines) using MTT assay.