Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies

Hamad M Alkahtani; Mohammed M Alanazi; Fadilah Sfouq Aleanizy; Fulwah Yahya Alqahtani; Ali Alhoshani; Fawaz E Alanazi; Abdulrahman A Almehizia; Ashraf N Abdalla; Mashael G Alanazi; Adel S El-Azab; Alaa A-M Abdel-Aziz

doi:10.1016/j.jsps.2019.04.003

Synthesis, anticancer, apoptosis-inducing activities and EGFR and VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies

Saudi Pharm J. 2019 Jul;27(5):682-693. doi: 10.1016/j.jsps.2019.04.003. Epub 2019 Apr 3.

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
² Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
³ Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁴ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
⁵ Department of Pharmacology and Toxicology, National Center for Research, Khartoum, Sudan.
⁶ Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
⁷ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Abstract

A new series of 5,5-diphenylhydantoin derivatives containing benzylidene or isatin (4-19) was synthesized. Their anticancer activity against HeLa, a cervical cancer cell line, A549, a lung cancer cell line, and MDA-MB-231, a breast cancer cell line, was evaluated. Compounds 13, 16, 17 and 18 exhibited potent anticancer activity with average IC₅₀ values against the tested cell lines of 109, 59, 81 and 113 μM, respectively. Compound 16 showed potent EGFR and VEGFR2 inhibitory activity with IC₅₀ values of 6.17 and 0.09 μM, respectively. In addition, compound 16 induced caspase-dependent apoptosis and reactive oxygen species (ROS) production at 5 and 10 μM. Moreover, a molecular docking simulation was performed for compound 16 and sunitinib to predict the protein-ligand interactions with the active site of VEGFR2.

Keywords: 5,5-Diphenylhydantoin; Apoptosis; EGFR; Isatin; Molecular docking; VEGFR2.