Exploration of a new class of monoamine oxidase B inhibitors by assembling benzyloxy pharmacophore on halogenated chalcones

Eight derivatives of benzyloxy-derived halogenated chalcones (BB1--BB8) were synthesized and tested for their ability to inhibit monoamine oxidases (MAOs). MAO-A was less efficiently inhibited by all compounds than MAO-B. Additionally, the majority of the compounds displayed significant MAO-B inhibitory activities at 1 mu M with residual activities of less than 50%. With an IC50 value of 0.062 mu M, compound BB4 was the most effective in inhibiting MAO-B, followed by compound BB2 (IC50 = 0.093 mu M). The lead molecules showed good activity than the reference MAO-B inhibitors (Lazabemide IC50 = 0.11 mu M and Pargyline Pargyline IC50 = 0.14). The high selectivity index (SI) values for MAO-B were observed in compounds BB2 and BB4 (430.108 and 645.161, respectively). Kinetics and reversibility experiments revealed that BB2 and BB4 were reversible competitive MAO-B inhibitors with K-i values of 0.030 +/- 0.014 and 0.011 +/- 0.005 mu M, respectively. Swiss target prediction confirmed the high probability in the targets of MAO-B for both compounds. Hypothetical binding mode revealed that the BB2 or BB4 is similarly oriented to the binding cavity of MAO-B. Based on the modelling results, BB4 showed a stable confirmation during the dynamic simulation. From these results, it was concluded that BB2 and BB4 were potent selective reversible MAO--B inhibitors and they can be considered drug candidates for treating related neurodegenerative diseases such as Parkinson's disease.