Monoamine Oxidase Isoform-Dependent Tautomeric Influence in the Recognition of 3,5-Diaryl Pyrazole Inhibitors

Abstract

A series of 3,5-diaryl pyrazoles were prepared and assayed for their ability to inhibit reversibly monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds show inhibitory activity with concentration values in the nanomolar range. A computational work was carried out on the two most selective inhibitors that have tautomeric pyrazole forms. The binding free energies of these compounds for each MAO isoform were influenced by the tautomeric equilibria.

The State of the Art of Pyrazole Derivatives as Monoamine Oxidase Inhibitors and Antidepressant/Anticonvulsant Agents

“…In addition to the good results of activity and selectivity (Table 2), the importance of this scaffold is related to the influence of the active site recognition of the tautomeric forms of pyrazole in modulating the biological activity [14]. As reported in Table 2, some 3,5-diarylpyrazoles showed inhibitory activity at concentration values in the nanomolar range.…”

“…As regards the C5 position, only compounds bearing a 4-bromophenyl enhanced their biological activity (6,14).…”

“…Compounds 12-17 were highly selective towards BuChE. Of the selective inhibitors of rat liver MAO-B (11)(12)(13)(14)(15)(16)(17), compound 11 was selective for AChE while 12-17 were selective for BuChE. The hydroxy substitution in the ortho position of phenyl ring at C3 position, an electron rich substitution (Cl> OCH 3 > OH, in order of decreasing activity) in the para position of phenyl ring at C5, and the presence of unsubstituted phenyl ring at N1 were optimal for the activity.…”

Monoamine oxidase inhibitory activities of heterocyclic chalcones

“…In fact, chalcones have been used in the synthesis of pyrazoline derivatives as part of an effort to discover novel MAO inhibitors. [23][24][25][26][27][28][29][30] Literature reports that, with the appropriate substitution, chalcones themselves are, however, high potency MAO-B inhibitors. For example, synthetic chalcone 2 inhibits human MAO-B with an IC 50 value of 0.0044 lM.…”

Interactions between pyrazole derived enantiomers and Chiralcel OJ: Prediction of enantiomer absolute configurations and elution order by molecular dynamics simulations

“…It is well-known that mobile phase has significant influence on the separation of enantiomers by HPLC [35,36]. At room temperature (25°), Fig.…”