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

Abstract

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 α-glucosidase and PTP1B enzymes and LPS-stimulated murine macrophages. It was found that the target compounds are highly effective α-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.

New Dipterocarpol‐Based Molecules with α‐Glucosidase Inhibitory and Hypoglycemic Activity

“…Earlier, the same effect was observed for methyl 2-furfurylidene betulonates and 3-oxo-β-sitosterol with IC 50 values of 0.25 μM and 38.95 μM. [39,41] The furfurylidenes of 20-oxo-lupanes with IC 50 values of 1.76 μM were 97-more active than acarbose. [40] Modification of C2 position by introducing benzylidene fragment 3 b (IC 50 176.1 μM) led to an increase in activity in comparison with the native dipterocarpol.…”

“…Based on these data and as a part of our ongoing studies on the structural modification of natural triterpenoids to get the promising AGIs for the treatment of immunometabolic disorders [39][40][41] , dipterocarpol arylidene derivatives were synthesized and their antidiabetic activity was evaluated.…”