A novel series of substituted chalcones were designed and synthesized to be evaluated as selective human MAO-B inhibitors. A combination of either methylsulfonyl or trifluoromethyl substituents on the aromatic ketone moiety with a benzodioxol ring on the other end of the chalcone scaffold was investigated. The compounds were tested for their inhibitory activities on both human MAO-A and B. All compounds appeared to be selective MAO-B inhibitors with Ki values in the micromolar to submicromolar range. Molecular modeling studies have been performed to get insight into the binding mode of the synthesized compounds to human MAO-B active site. Display omitted •Novel chalcone analogs were designed and synthesized as human MAO-B reversible inhibitors.•The inhibitors bind with micromolar to submicromolar potency.•The molecular scaffold determines high MAO-A/MAO-B selectivity.•A double conformation in MAO-B active site is predicted by molecular docking.