Discovery of 3,4-dichloro-N-(1H-indol-5-yl)benzamide: A highly potent, selective, and competitive hMAO-B inhibitor with high BBB permeability profile and neuroprotective action

Since there is no disease-modifying treatment discovered yet for Parkinson's disease (PD), there is still a vital need to develop novel selective monoamine oxidase B (MAO-B) inhibitors as promising therapeutically active candidates for PD patients. Herein, we report the design, synthesis, and full characterization of new twenty-six indole derivatives as potential human MAO-B (hMAO-B) selective inhibitors. Six compounds (2i, 3b–e, and 5) exhibited low micromolar to nanomolar inhibitory activities over hMAO-B; compared to our recently reported N-substituted indole-based lead compound VIII (hMAO-B IC₅₀ = 777 nM), compound 5 (3,4-dichloro-N-(1H-indol-5-yl)benzamide) exhibited 18-fold increase in potency (IC₅₀ = 42 nM). A selectivity study over hMAO-A revealed an excellent selectivity index of compound 5 (SI > 2375) with a 47-fold increase compared to rasagiline (II, a well-known MAO-B inhibitor, SI > 50). A further kinetic evaluation of compound 5 over hMAO-B showed a reversible and competitive mode of inhibition with K_i value of 7 nM. Highly effective permeability and high CNS bioavailability of compound 5 with P_e = 54.49 × 10⁻⁶ cm/s were demonstrated. Compound 5 also exhibited a low cytotoxicity profile and a promising neuroprotective effect against the 6-hydroxydopamine-induced neuronal cell damage in PC12 cells, which was more effective than that of rasagiline. Docking simulations on both hMAO-B and hMAO-A supported the in vitro data and served as further molecular evidence. Accordingly, we report the discovery of compound 5 as one of the most potent indole-based MAO-B inhibitors to date which is noteworthy to be further evaluated as a promising agent for PD treatment.