Molecular docking, ADMET, molecular dynamic simulation, synthesis, and preliminary antiproliferative study of 1,2,4- thiadiazole derivatives as possible histone deacetylase inhibitors

Purpose: To develop new histone deacetylase (HDAC) inhibitors with thiadiazole moiety as a zincbinding group. Methods: Maestro software was utilized to design new HDAC inhibitors. The organic synthesis of compounds VIa-VIc was started with the Williamson reaction between benzylic halide derivatives and methyl 4-hydroxybenzoate to form ethers IIIa-IIIb. The resultant ethers were subjected to ester hydrolysis, followed by an amide reaction with 1,2,4-thiadiazol-5-amine to produce the final compound VIa-VIc. The structures of synthesized compounds were characterized using NMR and FTIR spectroscopic techniques. Anti-proliferative activity on colon cancer cells (HRT) was evaluated using MTT assay. Results: Docking study revealed that compounds VIa-VIc had in silico binding affinity for HDAC enzymes, while MTT assay showed that the IC50 values of VIa and VIc (1.00 and 1.44 µM, respectively) were comparable to IC50 of 3.00 µM for the reference compound, vorinostat used in this study. Conclusion: New potential HDAC inhibitors with a thiadiazole moiety as a possible zinc-binding group have been successfully designed, synthesized and characterized. Results from preliminary cytotoxicity evaluation were highly promising. These findings may be useful for developing novel therapeutic agents.