Design, synthesis, in silico studies, and biological evaluation of novel pyrimidine-5-carbonitrile derivatives as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

Abdulrahman M Saleh; Hazem A Mahdy; Mohamed Ayman El-Zahabi; Ahmed B M Mehany; Mohamed M Khalifa; Ibrahim H Eissa

doi:10.1039/d3ra04182d

Design, synthesis, in silico studies, and biological evaluation of novel pyrimidine-5-carbonitrile derivatives as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers

RSC Adv. 2023 Jul 24;13(32):22122-22147. doi: 10.1039/d3ra04182d. eCollection 2023 Jul 19.

Authors

Abdulrahman M Saleh^{1

2}, Hazem A Mahdy¹, Mohamed Ayman El-Zahabi¹, Ahmed B M Mehany², Mohamed M Khalifa¹, Ibrahim H Eissa¹

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt Ibrahimeissa@azhar.edu.eg Hazem_hady2001@azhar.edu.eg MohamedKhalifa2321.el@azhar.edu.eg.
² Zoology Department, Faculty of Science (Boys), Al-Azhar University Cairo 11884 Egypt.

Abstract

A novel series of pyrimidine-5-carbonitrile derivatives bearing benzylidene and hydrazone moieties with different linkers (spacers) were designed and synthesized as possible inhibitors of the vascular endothelial growth factor receptor-2 (VEGFR-2). The newly synthesized compounds were evaluated in vitro for their cytotoxic activities against two human cancer cell lines namely colon cancer (HCT-116) and breast cancer (MCF-7) using sorafenib as a standard anticancer drug. Compounds 9d, 11e, 12b, and 12d showed higher cytotoxic activities than sorafenib with IC₅₀ values ranging from 1.14 to 10.33 μM. In particular, compound 11e exhibited excellent activities against HCT-116 and MCF-7 with IC₅₀ values of 1.14 and 1.54 μM, respectively. Moreover, compound 11e exhibited about 47.32-fold cytotoxic activity against normal human fibroblast (WI-38) cells, lower than the cytotoxicity against the cancer cells. Compounds 11e and 12b were the most potent VEGFR-2 inhibitors with IC₅₀ values of 0.61 and 0.53 μM, respectively, compared to sorafenib. Bedsides, compound 11e arrested the HCT-116 cell growth at S and sub-G1 phases, induced a significant increase in the apoptotic cells, and caused remarkable decrease in the levels of TNF-α, IL-6, and caspase-3. Finally, the binding patterns of the target derivatives were investigated through the docking study against the proposed molecular target (VEGFR-2, PDB ID 1YWN). The results of molecular docking studies showed similar binding modes to sorafenib against VEGFR-2. In addition, molecular dynamic simulations revealed the stability of compound 11e in the active site for 100 ns.