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

Abstract

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.

Research status of indole-modified natural products

“…Enzyme kinetics experiments showed that compound 24 (Ki: 3.9 μM) is a noncompetitive inhibitor with stronger binding ability to the enzyme than suramin (Ki: 7.1 μM). 48 Oleanolic acid is a pentacyclic triterpenoid natural product derived from the fruit of Ligustrum lucidum and has pharmacological activities such as inhibition of glucosidase, 49 anti-oxidant, 50 and anti-hyaluronidase. 50 Therefore, researchers modified the C2 and C3 positions of oleanolic acid to obtain compounds with better pharmacological activity.…”

“…Enzyme kinetics experiments showed that compound 24 (Ki: 3.9 μM) is a non-competitive inhibitor with stronger binding ability to the enzyme than suramin (Ki: 7.1 μM). 48…”

Design, Sythesis, Characterization, Molecular Docking Studies, and Possible Biolological Activities of Novel Pyrazine Fused Indole Derivatives

“…Anti-Diabetics-Glucose diffusion inhibitory study: A series of novel pyrazine fused Indole derivatives II-(4a-4l) were evaluated for antidiabetic-glucose diffusion inhibitory activity was decisive by incubating a solution of maltose substrate with Tris volume of buffer pH 8.0 and different concentrations of compounds II-(4a-4l) at 35 0 C. The reaction was commencing by adding 𝛼glucosidase enzyme into the reaction mixture followed by incubation at 35 0 C. Then the reaction was determined by the addition of a colorimetric reagent like DNSA [17]. Ethanol was used as control and it was prepared using the alike procedure replacing the lead molecules.…”

Glycyrrhizic Acid and Its Derivatives: Promising Candidates for the Management of Type 2 Diabetes Mellitus and Its Complications

“…Interestingly, 18α-GA and 18β-GA were identified as competitive PTP1B inhibitors [ 82 , 83 ]. Two other derivatives of GA, namely, indole- and N-phenylpyrazole-GA, also showed potent non-competitive inhibition of PTP1B [ 84 ].…”