Synthesis and biological evaluation of O4′-benzyl-hispidol derivatives and analogs as dual monoamine oxidase-B inhibitors and anti-neuroinflammatory agents

• Published in: Bioorganic & medicinal chemistry 2024-08, Vol.110, p.117826, Article 117826
• Main Authors: Hassan, Ahmed H.E., Choi, Yeonwoo, Kim, Rium, Kim, Hyeon Jeong, Almatary, Aya M., El-Sayed, Selwan M., Lee, Yeongae, Lee, Jong Kil, Park, Ki Duk, Lee, Yong Sup
• Format: Article
• Language: English
• Subjects: Anti-neuroinflammatory; Hispidol; Hybrid molecules; MAO-B; Natural products derivatives
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2024.117826

[Display omitted] •Hybridization of the privileged benzyloxyphenyl fragment with hispidol suggested O4′-benzyl-hispidol derivatives as dual MAO-B/neuroinflammation inhibitors.•O4′-Benzyl-hispidol derivatives are more potential MAO-B inhibitors than analogous O3′-Benzyl derivatives.•Compound 2e demonstrates sub-micromolar MAO-B IC50 and >264 selectivity index.•Compound 2e inhibits BV2 cells induced production of nitric oxide.•Compound 2e might be a promising lead compound. Design, synthesis, and biological evaluation of two series of O4′-benzyl-hispidol derivatives and the analogous corresponding O3′-benzyl derivatives aiming to develop selective monoamine oxidase-B inhibitors endowed with anti-neuroinflammatory activity is reported herein. The first O4′-benzyl-hispidol derivatives series afforded several more potentially active and MAO-B inhibitors than the O3′-benzyl derivatives series. The most potential compound 2e of O4′-benzyl derivatives elicited sub-micromolar MAO-B IC50 of 0.38 µM with a selectivity index >264 whereas most potential compound 3b of O3′-benzyl derivatives showed only 0.95 MAO-B IC50 and a selectivity index >105. Advancement of the most active compounds showing sub-micromolar activities to further cellular evaluations of viability and induced production of pro-neuroinflammatory mediators confirmed compound 2e as a potential lead compound inhibiting the production of the neuroinflammatory mediator nitric oxide significantly by microglial BV2 cells at 3 µM concentration without significant cytotoxicity up to 30 µM. In silico molecular docking study predicted plausible binding modes with MAO enzymes and provided insights at the molecular level. Overall, this report presents compound 2e as a potential lead compound to develop potential multifunctional compounds.