Affiliation:
1. Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy Taibah University Medina Saudi Arabia
2. Pharmaceutical Chemistry Department, Faculty of Pharmacy Omar Almukhtar University Libya
3. Department of Pharmacology and Toxicology, Faculty of Pharmacy Omar Almukhtar University Al‐Bayda Libya
4. Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy Taibah University Al‐Madinah Al‐Munawarah Saudi Arabia
5. Department of Pharmaceutical Chemistry, College of Pharmacy King Khalid University Abha Saudi Arabia
6. Department of Chemistry, Faculty of Science University of Tabuk Tabuk Saudi Arabia
7. Department of Pharmacology and Toxicology, College of Pharmacy Taibah University Medina Saudi Arabia
8. Department of Chemistry, Faculty of Science Taibah University Yanbu Saudi Arabia
9. Chemistry Department, Faculty of Pharmacy Heliopolis University for Sustainable Development Cairo Egypt
10. Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys) Al‐Azhar University Cairo Egypt
Abstract
AbstractNovel inhibitors of epidermal growth factor receptor (EGFR)T790M/vascular endothelial growth factor receptor‐2 (VEGFR‐2) were synthesized based on the iodoquinazoline scaffold linked to different heteroaromatic, aromatic, and/or aliphatic moieties. The novel derivatives were in vitro examined for anticancer activities against A549, HCT116, michigan cancer foundation‐7 (MCF‐7), and HepG2 cells. Molecular modeling was applied to discover their orientation of binding with both VEGFR‐2 and EGFR active sites. Compounds 8d, 8c, 6d, and 6c indicated the highest cytotoxicity with IC50 = 6.00, 6.90, 6.12 and 6.24 µM, 7.05, 7.35, 6.80, and 6.80 µM, 5.75, 7.50, 6.90, and 6.95 µM, and 6.55, 7.88, 7.44, and 7.10 µM against the A549, HepG2, HCT116, and MCF‐7 cell lines, correspondingly. The cytotoxicity against normal VERO (normal african green monkey kidney cells) of the extremely active eight compounds 6a–d and 8a–d was evaluated. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 45.66–51.83 μM. Furthermore, inhibition assays for both the EGFRT790M and VEGFR‐2 enzymes were done for all compounds. Remarkable inhibition of EGFRT790M activity was achieved with compounds 6d, 8d, 6c, and 8c at IC50 = 0.35, 0.42, 0.48, and 0.50 µM correspondingly. Moreover, remarkable inhibition of VEGFR‐2 activity was achieved with compounds 8d, 8c, 6d, and 6c at IC50 = 0.92, 0.95, 1.00, and 1.20 µM correspondingly. As planned, derivatives 6d, 8d, 6c, and 8c presented exceptional inhibition of both EGFRT790M/VEGFR‐2 activities. Finally, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were made for the highly active four compounds 6c, 6d, 8c, and 8d in comparison with erlotinib and sorafenib as reference standards.