a-Glucosidase Inhibitors Based on Oleanolic Acid for the Treatment of Immunometabolic Disorders

Using oleanolic acid as a starting compound, a series of new oleanane-type triterpenic derivatives were synthesized via O-acylation (with nicotinic, isonicotinic, and methoxycinnamic acid acyl chlorides), N-amidation (with cyclic- or polyamines), the Mannich reaction (with secondary cyclic amines), and Claisen-Schmidt condensation (with aromatic aldehydes), and their potencies as treatments for immunometabolic disorders were investigated. The compounds were evaluated against a-glucosidase and PTP1B enzymes and LPS-stimulated murine macrophages. It was found that the target compounds are highly effective a-glucosidase inhibitors but lack activity against PTP1B. A leading compound, N-methylpiperazine methylated 2,3-indolo-oleanolic propargyl amide 15, is also a micromolar inhibitor of NO synthesis in LPS-stimulated macrophages and suppresses oxidative bursts in neutrophils with similar efficiency. These results, in addition to its ability to stimulate glucose uptake in rat fibroblasts and improve maltose tolerance in rats, allow us to consider compound 15 a promising prototype drug for the treatment of immunometabolic defects in type 2 diabetes.

Automated summary

A series of new oleanane-type triterpenic derivatives were synthesized from oleanolic acid through various reactions and were evaluated for their potential as treatments for immunometabolic disorders. The compounds showed strong inhibition against a-glucosidase enzyme but had no activity against PTP1B. One particular compound, N-methylpiperazine methylated 2,3-indolo-oleanolic propargyl amide 15, also demonstrated inhibitory effects on NO synthesis and oxidative bursts, making it a promising prototype drug for immunometabolic defects in type 2 diabetes.