A hybrid pharmacophore approach was used to design and synthesize a series of coumarin derivatives bearing 2-methylbiphenyl moiety, which were evaluated for their in vitro anticancer activities against four cancer cell lines(MCF-7, A549, H460 and HT29) and PD-1/PD-L1 inhibitory activities. Moreover, several compounds with excellent anticancer activities were selected to evaluate the cytotoxicities against one normal cell line(HEK-293). The most promising compound 11o showed the best anticancer activities against the four tested cancer cell lines with the IC50 values of 6.45, 8.65, 6,57 and 8.13 μmol/L, respectively, and displayed weak cytotoxicity on the normal cell(HEK-293). Furthermore, screening of PD-1/PD-L1inhibitory activity revealed that compound 11o could effectively inhibit the binding of PD-1/PD-L1, and the binding interactions of compound 11o with PD-L1 protein were explored by molecular docking. All above evidences showed that compound 11o might be worthy of further study as a valuable leading compound for the treatment of cancer.

中文翻译：

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具有2-甲基联苯部分的香豆素衍生物的设计，合成，生物活性和分子对接研究

使用杂交药效团方法设计和合成了一系列带有2-甲基联苯部分的香豆素衍生物，并对其在体外对四种癌细胞系（MCF-7，A549，H460和HT29）和PD-1的抗癌活性进行了评估。 / PD-L1抑制活性。此外，选择了几种具有优异抗癌活性的化合物来评估对一种正常细胞系（HEK-293）的细胞毒性。最有前途的化合物11o对四种测试的癌细胞系表现出最佳的抗癌活性，其IC50值分别为6.45、8.65、6,57和8.13μmol/ L，并且对正常细胞（HEK-293）的细胞毒性较弱。此外，对PD-1 / PD-L1抑制活性的筛选显示化合物11o可有效抑制PD-1 / PD-L1的结合，通过分子对接研究了化合物11o与PD-L1蛋白的结合相互作用。以上所有证据表明，化合物11o作为治疗癌症的有价值的领先化合物可能值得进一步研究。