Synthesis, antitumor, and apoptosis-inducing activities of novel 5-arylidenethiazolidine-2,4-dione derivatives: Histone deacetylases inhibitory activity and molecular docking study

Abdelrahman Hamdi; Walaa M Elhusseiny; Dina I A Othman; Abdullah Haikal; Ahmed H Bakheit; Adel S El-Azab; Mohamed H M Al-Agamy; Alaa A-M Abdel-Aziz

doi:10.1016/j.ejmech.2022.114827

Synthesis, antitumor, and apoptosis-inducing activities of novel 5-arylidenethiazolidine-2,4-dione derivatives: Histone deacetylases inhibitory activity and molecular docking study

Eur J Med Chem. 2022 Dec 15:244:114827. doi: 10.1016/j.ejmech.2022.114827. Epub 2022 Oct 5.

Authors

Abdelrahman Hamdi¹, Walaa M Elhusseiny¹, Dina I A Othman¹, Abdullah Haikal², Ahmed H Bakheit³, Adel S El-Azab³, Mohamed H M Al-Agamy⁴, Alaa A-M Abdel-Aziz⁵

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
² Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
³ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi Arabia.
⁴ Department of Pharmaceutics and Microbiology, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh, 11451, Saudi Arabia. Electronic address: almoenes@ksu.edu.sa.

PMID: 36242988
DOI: 10.1016/j.ejmech.2022.114827

Abstract

The antitumor activity of the newly synthesized 5-arylidenethiazolidine-2,4-dione derivatives 18a-f and 19a-f was investigated, compared to doxorubicin (IC₅₀ = 4.17-8.87 μM) and SAHA (IC₅₀ = 2.70-7.11 μM). Among the tested molecules, compounds 18b, 18c, 18f, 19d, and 19e displayed the highest antitumor activity against cancer cell lines (IC₅₀ = 3.16-28.94 μM). Further, compounds 18b, 18c, 18f, and 19d were tested as Histone deacetylases (HDACs) inhibitors compared with Entinostat (IC₅₀ = 0.093-0.75 μM). Compounds 18b, 18c, 18f, and 19d inhibited HDAC1, HDAC2, HDAC8, and HDAC6 enzymes with IC₅₀ values ranging from 0.144 to 1.741 μM. In addition, compound 18b caused apoptosis via a mitochondrial-mediated pathway and led to cell cycle arrest at the G1 phase. It also increased caspases-3 and caspases-7 by 5.2-3.9 and 9.1-3.7 folds, respectively. The molecular docking analysis of compounds 18b and 18c revealed that they could bind to the active sites of HDAC1, HDAC2, HDAC8, and HDAC6 like co-crystallized inhibitors.

Keywords: Antitumor activity; Cell cycle arrest; Histone deacetylases; Molecular docking; Thiazolidine-2,4-dione; Urea.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis
Cell Line, Tumor
Cell Proliferation
Drug Design*
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology
Histone Deacetylases / metabolism
Molecular Docking Simulation
Structure-Activity Relationship

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Histone Deacetylases