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Published:
Mar 31, 2025Keywords:
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Main Article Content
Molecular docking, ADMET, molecular dynamic simulation, synthesis, and preliminary antiproliferative study of 1,2,4- thiadiazole derivatives as possible histone deacetylase inhibitors
Abstract
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.
