US EPA

3358455 

Journal Article 

Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors 

Reis, J; Cagide, F; Chavarria, D; Silva, T; Fernandes, C; Gaspar, A; Uriarte, E; Remiao, F; Alcaro, S; Ortuso, F; Borges, F 

2016 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

AMER CHEMICAL SOC 

WASHINGTON 

59 

12 

5879-5893 

English 

27244485 

10.1021/acs.jmedchem.6b00527 

WOS:000378662900022 

The discovery of new chemical entities endowed with potent, selective, and reversible monoamine oxidase B inhibitory activity is a clinically relevant subject. Therefore, a small library of chromone derivatives was synthesized and screened toward human monoamine oxidase isoforms (hMAO-A and hMAO-B). The structure-activity relationships studies strengthen the importance of the amide spacer and the direct linkage of carbonyl group to the γ-pyrone ring, along with the presence of meta and para substituents in the exocyclic ring. The most potent MAO-B inhibitors were N-(3'-chlorophenyl)-4-oxo-4H-chromene-3-carboxamide (20) (IC50 = 403 pM) and N-(3',4'-dimethylphenyl)-4-oxo-4H-chromene-3-carboxamide (27) (IC50 = 669 pM), acting as competitive and noncompetitive reversible inhibitors, respectively. Computational docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed selectivity and potency. Compound 27 stands out due to its favorable toxicological profile and physicochemical properties, which pointed toward blood-brain barrier permeability, thus being a valid candidate for subsequent animal studies. 

amine oxidase (flavin containing) isoenzyme A; amine oxidase (flavin containing) isoenzyme B; carbonyl derivative; chromone derivative; monoamine oxidase B inhibitor; n (2' bromophenyl) 4 oxo 4h chromene 3 carboxamide; n (2' chlorophenyl) 4 oxo 4h chromene 3 carboxamide; n (2' hydroxyphenyl) 4 oxo 4h chromene 3 carboxamide; n (2',3' dimethylphenyl) 4 oxo 4h chromene 3 carboxamide; n (3' bromophenyl) 4 oxo 4h chromene 3 carboxamide; n (3' chlorophenyl) 4 oxo 4h chromene 3 carboxamide; n (3' hydroxyphenyl) 4 oxo 4h chromene 3 carboxamide; n (3',4' dichlorophenyl) 4 oxo 4h chromene 3 carboxamide; n (3',4' dimethylphenyl) 4 oxo 4h chromene 3 carboxamide; n (3',4',5' trichlorophenyl) 4 oxo 4h chromene 3 carboxamide; n (3',4',5' trimethylphenyl) 4 oxo 4h chromene 3 carboxamide; n (4' bromophenyl) 4 oxo 4h chromene 3 carboxamide; n (4' ethylphenyl) 4 oxo 4h chromene 3 carboxamide; n (4' ethynylphenyl) 4 oxo 4h chromene 3 carboxamide; n (4' fluorophenyl) 4 oxo 4h chromene 3 carboxamide; n (4' iodophenyl) 4 oxo 4h chromene 3 carboxamide; n (4' mercaptophenyl) 4 oxo 4h chromene 3 carboxamide; n (4' vinylphenyl) 4 oxo 4h chromene 3 carboxamide; n (m tolyl) 4 oxo 4h chromene 3 carboxamide; n (o tolyl) 4 oxo 4h chromene 3 carboxamide; n methyl n phenyl 4 oxo 4h chromene 3 carboxamide; n [4' (dimethylamino)phenyl] 4 oxo 4h chromene 3 carboxamide; o (p tolyl) 4 oxo 4h chromene 3 carboxylate; tert butyl [4 (4 oxo 4h chromene 3 carboxamide)phenyl]carbamate; unclassified drug; unindexed drug; amine oxidase (flavin containing); chromone derivative; monoamine oxidase inhibitor; Article; blood brain barrier; cell viability; crystal structure; drug absorption; drug distribution; drug excretion; drug metabolism; drug potency; enzyme inhibition; human; human cell; IC50; lipophilicity; maximum reaction velocity; molecular docking; neuroblastoma cell; structure activity relation; cell survival; chemical structure; chemistry; dose response; drug development; drug effects; metabolism; molecular model; synthesis; tumor cell culture; Cell Survival; Chromones; Dose-Response Relationship, Drug; Drug Discovery; Humans; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Structure-Activity Relationship; Tumor Cells, Cultured