Premium
2‐Phenyloxazole‐4‐carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B
Author(s) -
Di Paolo Maria L.,
Christodoulou Michael S.,
Calogero Alessandra M.,
Pinzi Luca,
Rastelli Giulio,
Passarella Daniele,
Cappelletti Graziella,
Dalla Via Lisa
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900261
Subject(s) - chemistry , selectivity , monoamine oxidase , amide , carboxamide , monoamine oxidase b , stereochemistry , monoamine oxidase a , docking (animal) , non competitive inhibition , gene isoform , monoamine neurotransmitter , biochemistry , pharmacology , enzyme , biology , receptor , serotonin , medicine , gene , nursing , catalysis
A series of 2‐phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO‐B isoform. The most potent and selective derivatives are characterized by inhibition constant ( K i ) values in the sub‐micromolar range and a good selectivity index ( K i MAO‐A / K i MAO‐B >50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)‐differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2‐(2‐hydroxyphenyl)‐ N ‐phenyloxazole‐4‐carboxamide (compound 4 a ) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF‐differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity.