Unveiling Pyridocarbazole Fused with Carbamate as MAO-B Inhibitors using In silico and In vitro approaches

Alzheimer’s disease (AD) a neurodegenerative disorder is one of the most prevalent diseases characterized by multifactorial etiology, including amyloid plaques, tau tangles, as well as neuronal loss. Current therapeutic options are limited and often only provide symptomatic relief. In pursuit of novel therapeutic agents, pyrido-carbazole fused with carbamate (PCC) hybrids were rationally designed and synthesized based on literature and clinically approved candidates. The study involved a comprehensive approach to evaluating these hybrids. Pharmacokinetic and acute toxicity profiles were assessed, followed by molecular modeling to predict a plausible monoamine oxidase B(MAO-B) interactions and in vitro MAO-B inhibition assay. The synthesized hybrids exhibited a range of inhibitory activities against MAO-B, falling at low micromolar concentrations. Notably, compound 4e demonstrated potent and well-balanced activity against MAO-B with an IC₅₀ value of 4.51μM, approaching the efficacy of the standard drug selegiline of IC₅₀ 2.93μM. The percentage inhibition of 4e was higher than the selegiline at a 100 μM concentration. The molecular modeling studies indicated that 4e interacted with the MAO-B catalytic site. These findings highlight the potential of compound 4e as a promising candidate for AD therapy, given its potent MAO-B inhibition, an excellent pharmacokinetic profile, and low toxicity.