期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 12, 页码 5879-5893出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00527
关键词
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资金
- Foundation for Science and Technology (FCT)
- FEDER/COMPETE2020 [UID/QUI/00081/2015, POCI-01-0145-FEDER-006980]
- COST action [CA15135]
- FCT [SFRH/BD/96033/2013, SFRH/BPD/74491/2010, SFRH/BD/108119/2015, SFRH/BD/79671/2011, SFRH/BD/98519/2013, SFRH/BPD/93331/2013]
- FEDER/COMPETE funds [SFRH/BD/96033/2013, SFRH/BPD/74491/2010, SFRH/BD/108119/2015, SFRH/BD/79671/2011, SFRH/BD/98519/2013, SFRH/BPD/93331/2013]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/79671/2011, SFRH/BD/108119/2015, SFRH/BD/98519/2013, SFRH/BD/96033/2013] Funding Source: FCT
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 gamma-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.
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