Evaluation of nitrocatechol chalcone and pyrazoline derivatives as inhibitors of catechol-O-methyltransferase and monoamine oxidase

[Display omitted] •Nitrocatechol chalcones and their pyrazoline derivatives were synthesised.•This is the first report of COMT inhibition by pyrazoline compounds.•The most potent COMT inhibitor exhibits an IC50 of 0.048 µM.•This is more potent than the reference COMT inhibitor, entacapone (IC50 = 0.23 μM).•Pyrazolines may be useful leads for the future design of antiparkinsonian therapy. Literature reports that chalcones inhibit the monoamine oxidase (MAO) enzymes, mostly with specificity for the MAO-B isoform, while nitrocatechol compounds are established inhibitors of catechol–O-methyltransferase (COMT). Based on this, nitrocatechol derivatives of chalcone have been proposed to represent dual-target-directed compounds that may inhibit both MAO-B and COMT. Both these enzymes play key roles in the metabolism of dopamine and levodopa, and inhibitors are thus relevant to the treatment of Parkinson’s disease. The present study expands on the discovery of dual MAO-B/COMT inhibitors by synthesising additional nitrocatechol derivatives of chalcones which include heterocyclic derivatives, and converting them to the corresponding pyrazoline derivatives. The newly synthesised chalcone and pyrazoline compounds were evaluated as inhibitors of human MAO and rat COMT, and the inhibition potencies were expressed as IC50 values. A pyrazoline derivative, compound 8b, was the most potent COMT inhibitor with an IC50 value of 0.048 μM. This is more potent than the reference COMT inhibitor, entacapone, which has an IC50 value of 0.23 μM. The results indicated that the pyrazoline derivatives (IC50 = 0.048–0.21 µM) are more potent COMT inhibitors than the chalcones (IC50 = 0.14–0.29 µM). Unfortunately, the chalcone and pyrazoline derivatives were weak MAO inhibitors with IC50 values > 41.4 µM. This study concludes that the nitrocatechol derivatives investigated here are promising COMT inhibitors, while not being suitable as MAO inhibitors. Using molecular docking, potential binding modes and interactions of selected inhibitors with COMT are proposed.