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

• Published in: Bioorganic chemistry 2024-02, Vol.143, p.107062
• Main Authors: Mohamed, Abeer A, El-Hddad, Sanadelaslam S A, Aljohani, Ahmed K B, Khedr, Fathalla, Alatawi, Omar M, Keshek, Doaa E, Ahmed, Sahar, Alsulaimany, Marwa, Almadani, Sara A, El-Adl, Khaled, Hanafy, Noura S
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors - antagonists & inhibitors; Humans; Lung Neoplasms - drug therapy; Molecular Docking Simulation; Molecular Structure; Mutation; Protein Kinase Inhibitors; Quinazolines - chemistry; Quinazolines - pharmacology; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors
• ISSN: 1090-2120

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 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  = 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 prolonging from 41.66 to 53.99 μM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFR 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  = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFR activity with IC  = 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.