Development of Novel Pyridine and Pyrimidine Clubbed Bisindoles as Inhibitors of AKT Pathway

Indoles and their derivatives have long been studied for their anticancer properties. Breast cancer has been treated using indole‐3‐carbinol, Indirubins, and many other naturally occurring indoles as well as their synthesized equivalents. It has been determined that the AKT pathway is a prospective target for therapeutic strategies in the treatment of breast cancer. The dysregulation of AKT pathway frequently promotes cell proliferation, survival, and resistance to apoptosis. We synthesized a novel group of bisindole clubbed pyridine and pyrimidine derivatives 5(a–l) using water as the solvent and thiamine hydrochloride as the catalyst. Compounds 5 a, 5 c, 5 d, 5 e, and 5 f are the most active against MCF‐7 cells, with an IC50 values of 2.48±0.39, 1.35±0.13, 3.36±0.53, 4.05±0.61 and 1.91±0.28 μM, respectively. Further, in silico docking of the active compound 5 c had the highest binding energy of −10.59 kcal/mol. Additionally, molecular dynanamics simulations were performed for better understanding the mode of interaction of ligand and protein. In conclusion, we have synthesized bisindoles using thiamine hydrochloride as a catalyst that target AKT pathway in breast cancer cells. Novel Bisindoles as Inhibitors of AKT in Human Breast Cancer Cells: Pyridine/pyrimidine substituted aldehydes were obtained by Suzuki coupling reactions and further treated with indoles to yield bisindole derivatives. AKT2 targeting compounds were assayed for its cytotoxic activity against MCF‐7 cells, in silico docking and molecular dynamics simulations.