新的2-苯基喹唑啉-4（3H）-酮衍生物被设计、合成并进行生物学评估，证明它们是优秀的构象变异激酶抑制剂，在MCF-7和HepG2细胞中表现出原位细胞毒性。在建议化合物中，化合物15和18对MCF-7（IC50=1.35微米）和HepG2细胞（IC50=3.24微米）表现出有前途的抗增殖活性，与索拉非尼相当，通过原位细胞毒性测试的IC50值分别为3.04和2.93微米。将化合物15和18与索拉非尼进行比较，它们在体外VEGFR-2抑制活性显示出令人鼓舞的选择性疗效，在IC50值分别为13、67和30纳米时。各种ATP浓度下的VEGFR-2抑制结果表明，IC50值之间没有统计学上显著的差异，改善了非ATP竞争性结合。化合物15导致乳腺癌细胞凋亡，通过上调P53、Bax、caspases 3、8和9进而下调抗凋亡基因Bcl-2，在S期阻滞细胞周期55.11倍。进行了分子对接研究，以确认所设计化合物与VEGFR-2构象变异去碳基团位点的疏松结合，当与索拉非尼位姿叠加时，留下ATP结合口袋未被占据。所设计的分子显示出可重复的DFG环和变异构象位点的结合亲和力。因此，2-苯基喹唑啉-4（3H）-酮衍生物是设计诱导凋亡药物的有趣起点。©2023 Deutsche Pharmazeutische Gesellschaft。

New derivatives of 2-phenylquinazolin-4(3H)-one were designed, synthesized, and biologically evaluated as potent allosteric kinase inhibitors with in situ cytotoxicity against MCF-7 and HepG2 cells. Compounds 15 and 18 among the proposed compounds showed promising antiproliferative activity against MCF-7 (IC50 = 1.35 µM) and HepG2 cells (IC50  = 3.24 µM), comparable to sorafenib, with IC50 values of 3.04, 2.93 µM, respectively, according to in situ cytotoxicity testing. Comparing compounds 15 and 18 to sorafenib, the in vitro VEGFR-2 inhibitory activity displayed encouraging selective efficacy with IC50 values of 13, 67, and 30 nM, respectively. Results of VEGFR-2 inhibition at various ATP concentrations proved that there was no statistically significant difference between the IC50 values, which improved the non-ATP competitive binding. Compound 15 caused apoptotic breast cancer cell death with 55.11-fold cell-cycle arrest at the S-phase, where it affected the apoptosis-mediated genes through upregulating P53, Bax, caspases 3, 8, and 9 and downregulating the antiapoptotic gene Bcl-2. A molecular docking study was conducted to confirm the binding of the designed compounds to the allosteric site of VEGFR-2 in DFG-out mode, leaving the ATP-binding pocket unoccupied when superimposed to the pose of sorafenib. The designed molecules showed resealable binding affinity toward the DFG loop and the allosteric site. Hence, the 2-phenylquinazolin-4(3H)-one derivative constitutes intriguing starting points for designing apoptotic-inducing drugs.© 2023 Deutsche Pharmazeutische Gesellschaft.