RESUMO
A series of (1H-1,2,3-triazol-4-yl)methoxybenzaldehyde derivatives containing an anthraquinone moiety were synthesized and identified as novel xanthine oxidase inhibitors. Among them, the most promising compounds 1h and 1k were obtained with IC50 values of 0.6µM and 0.8µM, respectively, which were more than 10-fold potent compared with allopurinol. The Lineweaver-Burk plot revealed that compound 1h acted as a mixed-type xanthine oxidase inhibitor. SAR analysis showed that the benzaldehyde moiety played a more important role than the anthraquinone moiety for inhibition potency. The basis of significant inhibition of xanthine oxidase by 1h was rationalized by molecular modeling studies.
Assuntos
Antraquinonas/química , Benzaldeídos/química , Inibidores Enzimáticos/química , Xantina Oxidase/antagonistas & inibidores , Benzaldeídos/síntese química , Benzaldeídos/metabolismo , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Triazóis/química , Xantina Oxidase/metabolismoRESUMO
A series of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives (1a-j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D-phenylalanine derivatives (1d and 1i) and the L/D-tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L-phenylalanine derivative 1d (IC50 = 3.0 µm) and the D-phenylalanine derivative 1i (IC50 = 2.9 µm) presented the highest potency and were both more potent than the positive control allopurinol (IC50 = 8.1 µm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D-amino acid derivative presented equal or greater potency compared to its L-enantiomer; and the 9,10-anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation.