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

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.
Abdelrahman Hamdi 1,  Walaa M Elhusseiny 1,  Dina I A Othman 1,  Abdullah Haikal 2,  Ahmed H Bakheit 3,  Adel S El-Azab 3,  Mohamed H M Al-Agamy 4,  Alaa A-M Abdel-Aziz 5
Affiliations

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.

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