Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

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

Rusul Mohammed Hasan Ali, Ayad A Al-Hamashi

Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Baghdad, Iraq;

For correspondence:- Ayad Al-Hamashi Email: a.alhamashi@copharm.uobaghdad.edu.iq Tel:+647732892787

Accepted: 9 July 2024 Published: 31 July 2024

Citation: Ali RM, Al-Hamashi AA. Molecular docking, ADMET, molecular dynamic simulation, synthesis, and preliminary antiproliferative study of 1,2,4-thiadiazole derivatives as possible histone deacetylase inhibitors. Trop J Pharm Res 2024; 23(7):1069-1076 doi: 10.4314/tjpr.v23i7.4

© 2024 The authors.
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Abstract

Purpose: To develop new histone deacetylase (HDAC) inhibitors with thiadiazole moiety as a zinc-binding 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.

Keywords: Histone deacetylase, Molecular docking, Vorinostat, Thiadiazole