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

• Published in: Bioorganic chemistry Vol. 116
• Main Authors: Elkamhawy, Ahmed, Kim, Hyeon Jeong, Elsherbeny, Mohamed H., Paik, Sora, Park, Jong-Hyun, Gotina, Lizaveta, Abdellattif, Magda H., Gouda, Noha A., Cho, Jungsook, Lee, Kyeong, Pae, Ae Nim, Park, Ki Duk, Roh, Eun Joo
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier 01.11.2021
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Life Sciences & Biomedicine; Physical Sciences; Science & Technology; INDUCED MITOCHONDRIAL DYSFUNCTION; Monoamine oxidase B; Neuroprotection; DESIGN; DRUG DISCOVERY; Benzamide; PC12 cells; MODELS; MONOAMINE-OXIDASE-B; TARGETS; SAFINAMIDE; DERIVATIVES; PARKINSONS-DISEASE
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105352

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 Nsubstituted indole-based lead compound VIII (hMAO-B IC50 = 777 nM), compound 5 (3,4-dichloro-N-(1H-indol5-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 Ki value of 7 nM. Highly effective permeability and high CNS bioavailability of compound 5 with Pe = 54.49 x 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.