In this study, fourteen novel indole-pyrimidine hybrids were designed and synthesized. Their chemical structures were confirmed using different spectroscopic techniques (¹H NMR, ¹³C NMR, IR and mass). Their (E) stereochemical configuration was determined theoretically (MM2 property) and experimentally using 2D NMR technique (NOESY experiment). The prepared compounds were subjected to preliminary biological studies as Mcl-1 inhibitors. Most of the compounds exhibited good abilities for targeting Mcl-1 protein, especially, 7d, 7e, 7i and 7k (K_i = 11.19–15.21 nM). These derivatives were further evaluated against Bcl-XL and Bcl-2 proteins. Some compounds were found to have dual Mcl-1/Bcl-XL such as 7i, or Bcl-XL/Bcl-2 inhibitory activity as 7d.

The most potent derivatives as Mcl-1 inhibitors were chosen as representative examples for determination of in-vitro anti-proliferative activity against PC-3, K-562 and MDA-MB-231 cell lines. They possessed excellent to good anti-proliferative activities. All of the synthesized compounds were docked into Mcl-1 active site. Drug-likeness properties and in silico pre-ADMET characters were also predicted.

在这项研究中，设计并合成了 14 种新型吲哚-嘧啶杂化物。使用不同的光谱技术（¹ H NMR、¹³ C NMR、IR 和质量）确认了它们的化学结构。它们的 ( E ) 立体化学构型是通过理论（MM2 特性）和实验使用 2D NMR 技术（NOESY 实验）确定的。将制备的化合物作为 Mcl-1 抑制剂进行初步生物学研究。大多数化合物表现出良好的靶向 Mcl-1 蛋白的能力，尤其是7d、7e、7i和7k (K _i = 11.19–15.21 nM）。针对 Bcl-XL 和 Bcl-2 蛋白进一步评估了这些衍生物。发现一些化合物具有双重 Mcl-1/Bcl-XL 如7i或 Bcl-XL/Bcl-2 抑制活性如7d。

选择最有效的衍生物作为 Mcl-1 抑制剂作为确定对 PC-3、K-562 和 MDA-MB-231 细胞系的体外抗增殖活性的代表性实例。它们具有极好的抗增殖活性。所有合成的化合物都停靠在 Mcl-1 活性位点。还预测了药物相似性和计算机模拟前 ADMET 特征。