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

Fifteen multiconjugated dienones () 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 , with an IC value of 2.82 nM, most effectively inhibited MAO-B, like (IC = 3.22 nM), followed by , , and (IC = 4.02, 4.24, and 4.89 nM, respectively). The selectivity index values of and for MAO-B over MAO-A were 7361.5 and 1780.5, respectively. Compounds and were competitive reversible inhibitors of MAO-B, with values of 1.10 ± 0.20 and 3.0 ± 0.27 nM, respectively. Cytotoxic studies showed that , , , and exhibited low toxicities on Vero cells, with IC 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, , , , and decreased cell damage in HO-induced cells via a significant scavenging effect of reactive oxygen species. Molecular modeling was performed to rationalize the potential inhibitory activities of , , , and 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.