Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFRWT and EGFRT790M: design, synthesis, ADMET and molecular docking

Ahmed K B Aljohani; Khaled El-Adl; Basmah Almohaywi; Omar M Alatawi; Marwa Alsulaimany; Ahmed El-Morsy; Sara A Almadani; Hussam Y Alharbi; Majed S Aljohani; Felemban Athary Abdulhaleem M; Hanan E M Osman; Samy Mohamady

doi:10.1039/d4ra00502c

Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFR^WT and EGFR^T790M: design, synthesis, ADMET and molecular docking

RSC Adv. 2024 Mar 6;14(12):7964-7980. doi: 10.1039/d4ra00502c.

Authors

Affiliations

¹ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University Al-Madinah Al-Munawarah 41477 Saudi Arabia eladlkhaled74@azhar.edu.eg khaled.eladl@hu.edu.eg eladlkhaled74@yahoo.com.
² Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development Cairo Egypt.
³ Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Nasr City 11884 Cairo Egypt.
⁴ Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University Abha 61421 Saudi Arabia.
⁵ Department of Chemistry, Faculty of Science, University of Tabuk Tabuk 47512 Saudi Arabia.
⁶ Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University Medina 42353 Saudi Arabia.
⁷ Pharmaceutical Chemistry Department, College of Pharmacy, The Islamic University Najaf Iraq.
⁸ Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University Medina 42353 Saudi Arabia.
⁹ Department of Chemistry, Faculty of Science, Taibah University Yanbu Saudi Arabia.
¹⁰ Biology Department, Faculty of Science, Umm Al-Qura University Makkah 21955 Saudi Arabia.
¹¹ Botany and Microbiology Department, Al-Azhar University Cairo 11651 Egypt.
¹² Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt Cairo Egypt.

Abstract

Fifteen new iodoquinazoline derivatives, 5a,b to 18, are reported in this study and their anticancer evaluation as dual inhibitors of EGFR^WT and EGFR^T790M. The new derivatives were designed according to the target of structural requirements of receptors. Cytotoxicity of our compounds was evaluated against MCF-7, A549, HCT116 and HepG2 cell lines using MTT assay. Compounds 18, 17 and 14b showed the highest anticancer effects with IC₅₀ = 5.25, 6.46, 5.68 and 5.24 μM, 5.55, 6.85, 5.40 and 5.11 μM and 5.86, 7.03, 6.15 and 5.77 μM against HepG2, MCF-7, HCT116 and A549 cell lines, respectively. The eight highly effective compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 were inspected against VERO normal cell lines to evaluate their cytotoxicity. Our conclusion was that compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 possessed low toxicity against VERO normal cells with IC₅₀ increasing from 43.44 to 52.11 μM. All compounds were additionally assessed for their EGFR^WT and EGFR^T790M inhibitory activities. Additionally, their ability to bind with EGFR^WT and EGFR receptors was confirmed by molecular docking. Compound 17 exhibited the same inhibitory activity as erlotinib. Compounds 10, 13, 14b, 16 and 18 excellently inhibited VEGFR-2 activity with IC₅₀ ranging from 0.17 to 0.50 μM. Moreover, compounds 18, 17, 14b and 16 remarkably inhibited EGFR^T790M activity with IC₅₀ = 0.25, 0.30, 0.36 and 0.40 μM respectively. As planned, compounds 18, 17 and 14b showed excellent dual EGFR^WT/EGFR^T790M inhibitory activities. Finally, our compounds 18, 17 and 14b displayed good in silico ADMET calculated profiles.