Conjugated Dienones from Differently Substituted Cinnamaldehyde as Highly Potent Monoamine Oxidase‑B Inhibitors: Synthesis, Biochemistry, and Computational Chemistry

• Published in: ACS omega Vol. 7; no. 9; pp. 8184 - 8197
• Main Authors: Mathew, Bijo, Oh, Jong Min, Abdelgawad, Mohamed A, Khames, Ahmed, Ghoneim, Mohammed M, Kumar, Sunil, Nath, Lekshmi R, Sudevan, Sachithra Thazhathuveedu, Parambi, Della Grace Thomas, Agoni, Clement, Soliman, Mahmoud E. S, Kim, Hoon
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 08.03.2022
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.2c00397

Fifteen multiconjugated dienones (MK1–MK15) were synthesized and evaluated to determine their inhibitory activities against monoamine oxidases (MAOs) A and B. All derivatives were found to be potent and highly selective MAO-B inhibitors. Compound MK6, with an IC50 value of 2.82 nM, most effectively inhibited MAO-B, like MK12 (IC50 = 3.22 nM), followed by MK5, MK13, and MK14 (IC50 = 4.02, 4.24, and 4.89 nM, respectively). The selectivity index values of MK6 and MK12 for MAO-B over MAO-A were 7361.5 and 1780.5, respectively. Compounds MK6 and MK12 were competitive reversible inhibitors of MAO-B, with K i values of 1.10 ± 0.20 and 3.0 ± 0.27 nM, respectively. Cytotoxic studies showed that MK5, MK6, MK12, and MK14 exhibited low toxicities on Vero cells, with IC50 values of 218.4, 149.1, 99.96, and 162.3 μg/mL, respectively, which were much higher than those for their effective nanomolar-level concentrations. Also, MK5, MK6, MK12, and MK14 decreased cell damage in H2O2-induced cells via a significant scavenging effect of reactive oxygen species. Molecular modeling was performed to rationalize the potential inhibitory activities of MK5, MK6, MK12, and MK14 toward MAO-B and their possible binding mechanisms, showing high-affinity binding pocket interactions and conformation perturbations of the compounds with MAO-B, which were interpreted as the conformational dynamics of MAO-B. This study concluded that all the compounds tested were more potent MAO-B inhibitors than the reference drugs, and leading compounds could be further explored for their effectiveness in various kinds of neurodegenerative disorders.