Synthesis, Structural Characterization, and Investigation of Biological Effects of Novel Benzothiazole-Triazole Derivatives Designed as AKT Kinase Inhibitors.

Breast cancer (BC) is one of the most common cancers in women worldwide, and the need for new, more effective treatment options remains. The PI3K/Akt signaling pathway and the aromatase enzyme are among the molecular targets that play a critical role in the development and progression of BC. In this study, novel benzothiazole-triazole derivatives were synthesized, and their structures were confirmed using NMR and HRMS analyses. The cytotoxic activities of the eight synthesized compounds in the MCF-7 BC cell line were evaluated using the MTT method, with NIH/3T3 cells used as a healthy cell model. The IC50 values of the compounds ranged from 10.186 to 52.020 μM, with compounds 5b, 5f, and 5h showing the highest activity. Selectivity index results revealed that compound 5h (SI = 5.986) exhibited the optimal selectivity profile along with strong anticancer activity. In enzyme inhibition studies, compound 5h showed a strong inhibitory effect on Akt1, exhibiting activity close to the reference inhibitor with an IC50 value of 0.209 ± 0.011 μM. However, the lack of significant inhibition of aromatase enzymes indicated that the compound displayed a more selective inhibitory profile towards Akt1. Mechanistic studies revealed that compound 5h induced apoptotic cell death in MCF-7 cells, disrupted mitochondrial membrane potential, and caused high levels of caspase-3 activation. Furthermore, molecular docking and molecular dynamics simulations showed that the compound formed stable interactions in the Akt1 and PI3K active sites, supporting the experimental results. The findings indicate that compound 5h is a promising anticancer candidate that targets the PI3K/Akt signaling pathway.