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

• Published in: Bioorganic chemistry Vol. 116; p. 105352
• 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, Nim Pae, Ae, Park, Ki Duk, Roh, Eun Joo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2021
• Subjects: Animals; Benzamide; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Discovery; Humans; Molecular Structure; Monoamine Oxidase - metabolism; Monoamine oxidase B; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; Neuroprotection; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oxidopamine - antagonists & inhibitors; Oxidopamine - pharmacology; Parkinson’s disease; PC12 Cells; Rats; Structure-Activity Relationship; Monoamine oxidase B; Neuroprotection; Benzamide; PC12 cells; Parkinson’s disease
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105352

[Display omitted] •Nanomolar inhibition (IC50 = 42 nM) over hMAO-B was detected by compound 5.•Compound 5 displayed a competitive and reversible hMAO-B mode of inhibition.•Compound 5 showed a highly effective permeability and high CNS bioavailability.•Compound 5 showed a low cytotoxicity profile and a promising neuroprotective effect. 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 Ki value of 7 nM. Highly effective permeability and high CNS bioavailability of compound 5 with Pe = 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.