Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson’s disease

[Display omitted] •Novel dopamine metabolism enzyme inhibitors were designed based on the pharmacophore fusion strategy.•C12 demonstrates good inhibitory activity against COMT.•C12 indicated acceptable brain exposure levels and protective effects against MPP+ induced damage in SH-SY5Y cells.•C12 can effectively elevate dopamine levels and ameliorate the motor abilities of subacute PD mice induced by MPTP. Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson’s disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC50 = 0.37 μM), metal chelation ability, and BBB permeability. Furthermore, results from in vivo biological activity evaluations indicate that C12 can improve dopamine levels and ameliorate MPTP-induced PD symptoms in mice. Preliminary in vivo and in vitro study results highlight the potential of compound C12 in PD treatment.