Design of enamides as new selective monoamine oxidase‐B inhibitors

Objectives To develop of new class of selective and reversible MAO‐B inhibitors from enamides. Methods Syntheses of the titled derivatives (AD1–AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO‐A and MAO‐B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines. Key findings Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO‐B with IC50 values of 0.11 and 0.10 µm, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µm, respectively). Most of the compounds weakly inhibited MAO‐A, with the exceptions AD9 and AD7, which had IC50 values of 4.21 and 5.95 µm, respectively. AD3 had the highest selectivity index (SI) value for MAO‐B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO‐B with Ki values of 0.044 ± 0.0036 and 0.039 ± 0.0047 µm, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO‐B; dialysis restored the activity of MAO‐B to the reference level. MTT assays revealed AD3 and AD9 were non‐toxic to normal VERO cell lines with IC50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO‐A and MAO‐B. Conclusions These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.