RESUMO
The present study investigates the monoamine oxidase (MAO) inhibition properties of a series of ten 5-aryl-1,3,4-oxadiazol-2-ylbenzenesulfonamides. The target compounds were synthesized by dehydration of the corresponding N,N'-diacylhydrazines with phosphorus oxychloride to yield the 1,3,4-oxadiazole cycle with concomitant transformation of the sulfonamide to the sulfonyl chloride group. Treatment with aqueous ammonia in acetonitrile regenerated the target sulfonamides. The results of the enzymology document that these compounds are potent and specific MAO-B inhibitors with the most potent compound exhibiting an IC50 value of 0.0027⯵M. An analysis of the structure-activity relationships shows that the 4-benzenesulfonamides are significantly more potent MAO-B inhibitors than the corresponding 3-benzenesulfonamides, and that the corresponding N,N'-diacylhydrazine synthetic precursors are weak MAO inhibitors. Although MAO inhibition by oxadiazole compounds are known, this is the first report of nanomolar MAO inhibition potencies recorded for sulfonamide derivatives. MAO-B specific inhibitors such as those discovered here may be of interest in the treatment of neurodegenerative disorders such as Parkinson's disease.
Assuntos
Antidepressivos/química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Sulfonamidas/síntese química , Sequência de Aminoácidos , Antidepressivos/metabolismo , Benzoatos/química , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Isomerismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores da Monoaminoxidase/metabolismo , Oxidiazóis/química , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Zonisamida/química , BenzenossulfonamidasRESUMO
Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile.