RESUMO

Regulating insulin and leptin levels using a protein tyrosine phosphatase 1B (PTP1B) inhibitor is an attractive strategy to treat diabetes and obesity. Glycyrrhetinic acid (GA), a triterpenoid, may weakly inhibit this enzyme. Nonetheless, semisynthetic derivatives of GA have not been developed as PTP1B inhibitors to date. Herein we describe the synthesis and evaluation of two series of indole- and N-phenylpyrazole-GA derivatives (4a-f and 5a-f). We measured their inhibitory activity and enzyme kinetics against PTP1B using p-nitrophenylphosphate (pNPP) assay. GA derivatives bearing substituted indoles or N-phenylpyrazoles fused to their A-ring showed a 50% inhibitory concentration for PTP1B in a range from 2.5 to 10.1 µM. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 µM) than that of positive controls ursolic acid (IC50 = 5.6 µM), claramine (IC50 = 13.7 µM) and suramin (IC50 = 4.1 µM). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.

Assuntos

Inibidores Enzimáticos , Ácido Glicirretínico , Indóis , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Pirazóis , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ácido Glicirretínico/análogos & derivados , Ácido Glicirretínico/síntese química , Ácido Glicirretínico/química , Humanos , Indóis/síntese química , Indóis/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade