Design, synthesis, stereochemical determination, molecular docking study, in silico pre-ADMET prediction and anti-proliferative activities of indole-pyrimidine derivatives as Mcl-1 inhibitors

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 (Ki = 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. Druglikeness properties and in silico pre-ADMET characters were also predicted.

Automated summary

Fourteen novel indole-pyrimidine hybrids were designed and synthesized in this study. They exhibited good abilities for targeting Mcl-1 protein, with some compounds showing dual Mcl-1/Bcl-XL or Bcl-XL/Bcl-2 inhibitory activity. The most potent derivatives as Mcl-1 inhibitors showed excellent to good anti-proliferative activities against various cancer cell lines. Additionally, druglikeness properties and in silico pre-ADMET characters were predicted for all synthesized compounds.