Iodoquinazoline-derived VEGFR-2 and EGFR T790M dual inhibitors: Design, synthesis, molecular docking and anticancer evaluations.

Autor: Mohamed AA; Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt; Egyptian Drug Authority (EDA), 51 Wezaret El-Zeraa St, Dokki, Giza, A. R., Egypt., El-Hddad SSA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Omar Almukhtar University, Libya., Aljohani AKB; Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia., Khedr F; Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt., Alatawi OM; Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk 47512, Saudi Arabia., Keshek DE; Department of Biology, Jumum College University, Umm Al-Qura University, P.O Box7388, Makkah 21955, Sudia Arabia; Agriculture Genetic Engineering Research Institute (AGERI), Agriculture Research Centre, Giza, Egypt., Ahmed S; Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt., Alsulaimany M; Department of Pharmacognosy & Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia., Almadani SA; Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia., El-Adl K; Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt; Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt. Electronic address: eladlkhaled74@yahoo.com., Hanafy NS; Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2024 Feb; Vol. 143, pp. 107062. Date of Electronic Publication: 2023 Dec 25.
DOI: 10.1016/j.bioorg.2023.107062
Abstrakt: Herein, we report the synthesis of a series of new fourteen iodoquinazoline derivatives 7a-c to 13a-e and their evaluation as potential anticancer agents via dual targeting of EGFR T790M and VEGFR-2. The new derivatives were designed according to the target receptors structural requirements. The compounds were evaluated for their cytotoxicity against HepG2, MCF-7, HCT116 and A549 cancer cell lines using MTT assay. Compound 13e showed the highest anticancer activities with IC 50  = 5.70, 7.15, 5.76 and 6.50 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Compounds 7c, 9b and 13a-d exhibited very good anticancer effects against the tested cancer cell lines. The highly effective six derivatives 7c, 10, 13b, 13c, 13d and 13e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Our conclusion revealed that compounds 7c, 10, 13b, 13c, 13d and 13e possessed low toxicity against VERO normal cells with IC 50 prolonging from 41.66 to 53.99 μM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFR T790M and VEGFR-2. Also, their ability to bind with both EGFR and VEGFR-2 receptors was examined by molecular modeling. Compounds 13e, 13d, 7c and 13c excellently inhibited VEGFR-2 activity with IC 50  = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFR T790M activity with IC 50  = 0.30, 0.35, 0.45 and 0.47 µM respectively. Finally, our derivatives 7b, 13d and 13e showed good in silico calculated ADMET profile.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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