Aljohani Ahmed K B, El-Adl Khaled, Almohaywi Basmah, Alatawi Omar M, Alsulaimany Marwa, El-Morsy Ahmed, Almadani Sara A, Alharbi Hussam Y, Aljohani Majed S, Abdulhaleem M Felemban Athary, Osman Hanan E M, Mohamady Samy
Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University Al-Madinah Al-Munawarah 41477 Saudi Arabia
Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development Cairo Egypt.
RSC Adv. 2024 Mar 6;14(12):7964-7980. doi: 10.1039/d4ra00502c.
Fifteen new iodoquinazoline derivatives, 5a,b to 18, are reported in this study and their anticancer evaluation as dual inhibitors of EGFR and EGFR. 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 IC = 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 IC increasing from 43.44 to 52.11 μM. All compounds were additionally assessed for their EGFR and EGFR inhibitory activities. Additionally, their ability to bind with EGFR 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 IC ranging from 0.17 to 0.50 μM. Moreover, compounds 18, 17, 14b and 16 remarkably inhibited EGFR activity with IC = 0.25, 0.30, 0.36 and 0.40 μM respectively. As planned, compounds 18, 17 and 14b showed excellent dual EGFR/EGFR inhibitory activities. Finally, our compounds 18, 17 and 14b displayed good ADMET calculated profiles.
本研究报告了15种新型碘喹唑啉衍生物，即5a、b至18，并对其作为表皮生长因子受体（EGFR）和表皮生长因子受体（EGFR）双重抑制剂的抗癌活性进行了评估。这些新型衍生物是根据受体结构要求的靶点设计的。使用MTT法评估了我们化合物对MCF-7、A549、HCT116和HepG2细胞系的细胞毒性。化合物18、17和14b表现出最高的抗癌效果，对HepG2、MCF-7、HCT116和A549细胞系的半数抑制浓度（IC）分别为5.25、6.46、5.68和5.24 μM，5.55、6.85、5.40和5.11 μM，以及5.86、7.03、6.15和5.77 μM。对8种高效化合物10、13、14a、14b、15、16、17和18进行了针对VERO正常细胞系的检测，以评估它们的细胞毒性。我们的结论是，化合物10、13、14a、14b、15、16、17和18对VERO正常细胞具有低毒性，IC从43.44 μM增加到52.11 μM。此外，对所有化合物的EGFR和EGFR抑制活性进行了评估。另外，通过分子对接证实了它们与EGFR和EGFR受体结合的能力。化合物17表现出与厄洛替尼相同的抑制活性。化合物10、13、14b、16和18对血管内皮生长因子受体-2（VEGFR-2）活性具有出色的抑制作用，IC范围为0.17至0.50 μM。此外，化合物18、17、14b和16对EGFR活性具有显著抑制作用，IC分别为0.25、0.30、0.36和0.40 μM。如预期的那样，化合物18、17和14b表现出出色的EGFR/EGFR双重抑制活性。最后，我们的化合物18、17和14b显示出良好的药物代谢动力学（ADMET）预测特征。
