Novel coumarin-pyridazine hybrids as selective MAO-B inhibitors for the Parkinson's disease therapy.
Bioorg Chem
; 104: 104203, 2020 11.
Article
em En
| MEDLINE
| ID: mdl-32932120
ABSTRACT
The 3-pyridazinylcoumarin scaffold was previously reported as an efficient core for the discovery of reversible and selective inhibitors of MAO-B, a validated drug target for PD therapy which also plays an important role in the AD progress. Looking for its structural optimization, novel compounds of hybrid structure coumarin-pyridazine, differing in polarizability and lipophilicity properties, were synthesized and tested against the two MAO isoforms, MAO-A and MAO-B (compounds 17a-f and 18a-f). All the designed compounds selectively inhibited the MAO-B isoenzyme, exhibiting many of them IC50 values ranging from sub-micromolar to nanomolar grade and lacking neuronal toxicity. The 7-bromo-3-(6-bromopyridazin-3-yl)coumarin (18c), the most potent compound of these series (IC50 = 60 nM), was subjected to further in vivo studies in a reserpine-induced mouse PD model. The obtained results suggest a promising potential for 18c as antiparkinsonian agent. Molecular modeling studies also provided valuable information about the enzyme-drug interactions and the potential pharmacokinetic profile of the novel compounds.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Piridazinas
/
Fármacos Neuroprotetores
/
Cumarínicos
/
Monoaminoxidase
/
Inibidores da Monoaminoxidase
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2020
Tipo de documento:
Article