Indole- and Pyrazole-Glycyrrhetinic Acid Derivatives as PTP1B Inhibitors: Synthesis, In Vitro and In Silico Studies

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 mu M. The trifluoromethyl derivative of indole-GA (4f) exhibited non-competitive inhibition of PTP1B as well as higher potency (IC50 = 2.5 mu M) than that of positive controls ursolic acid (IC50 = 5.6 mu M), claramine (IC50 = 13.7 mu M) and suramin (IC50 = 4.1 mu M). Finally, docking and molecular dynamics simulations provided the theoretical basis for the favorable activity of the designed compounds.

Automated summary

Regulating insulin and leptin levels through inhibiting PTP1B with GA derivatives is a promising strategy for treating diabetes and obesity. In this study, indole- and N-phenylpyrazole-GA derivatives were synthesized and evaluated for their inhibitory activity against PTP1B. Among them, the trifluoromethyl derivative of indole-GA showed non-competitive inhibition and higher potency compared to positive controls, providing a theoretical basis for their favorable activity.