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

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 IC 50 value of 2.82 nM, most effectively inhibited MAO-B, like MK12 (IC 50 = 3.22 nM), followed by MK5 , MK13 , and MK14 (IC 50 = 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 IC 50 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 H 2 O 2 -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.