Novel tetrazole annulation on benzopyridodiazepine derivatives as inhibitor of tropomyosin kinase B (TrkB): rational design, synthesis, biological evaluation, SAR, and in silico studies

Abstract

Tropomyosin kinase B (TrkB) is an attractive target for cancer treatment and is emerging as a target for the treatment of neurological disorders, specifically epilepsy, due to its role in regulating neuronal degeneration and inflammation. However, current medications frequently suffer from toxicity, resistance, and poor metabolism. In the present study, four new series of tetrazole annulated benzopyridodiazepine derivatives (26 examples) were synthesized in two steps: intramolecular cyclization with various sets of amines to produce benzopyridodiazepinone derivatives, and then, in the second step, the tetrazole ring was introduced by the reaction of imidoyl chloride with azide. All four synthesized series were assessed for in vitro inhibitory activity against tropomyosin kinase (TrkB) using both enzyme and cellular assays. To further evaluate the biological efficacy of the synthesized derivatives, we conducted ROS measurements, fluorescence-based microscopy, and flow cytometry to determine the mode of action and the induction of apoptosis. Molecular docking, ADMET, and DFT studies supported the binding at the TrkB site and suggested favorable pharmacokinetic profiles. Overall, the results indicate that the synthesized compounds are highly promising candidates, especially 14h, which shows significant inhibition of TrkB in neuroblastoma cells. Thus, the tetrazole annulated benzopyridodiazepine is an interesting molecule for exploration in the management of cancer and neurological disorders.