Design, Synthesis, and Biological Evaluation of N-Acyl Pregnane Alkaloid Ester Derivatives as Acetylcholinesterase and α-Glucosidase Inhibitors.

Authors

Wenyu Li, Yafang Chen, Mingjiang Lu, Juan Zou, Xiang Yu, Kang He

Published in

Chemistry & biodiversity. Volume 23. Issue 8. Pages e71552.

Abstract

To discover novel potential enzyme inhibitors based on natural products, a series of N-acyl pregnane alkaloid ester derivatives were designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE) and α-glucosidase. The bioassay test results revealed that the target compounds generally showed more potent inhibition against α-glucosidase than against AChE. Notably, compounds 6e and 6i demonstrated significant α-glucosidase inhibitory activity, with IC₅₀ values of 29.85 µM and 38.11 µM (acarbose IC₅₀: 16.49 µM), respectively, and exhibited low cytotoxicity toward Thle-2 cells, with IC₅₀ values of 112.70 µM and 73.65 µM, respectively. Structure-activity relationship (SAR) analysis indicated that derivatives bearing an N-tigloyl group and nitro or pyridine substituents at the C-20 position contributed to enhanced α-glucosidase inhibition. Enzyme kinetics confirmed that 6e and 6i function as reversible, noncompetitive inhibitors of α-glucosidase. Molecular docking studies further illustrated that both compounds bind to the lateral surface of the α‑glucosidase through hydrogen bonds and hydrophobic interactions, rather than occupying the catalytic active site. These findings highlight that 6e and 6i exhibit certain inhibitory activity, providing a basis for the design of subsequent derivatives.

PMID:
42555857
Bibliographic data and abstract were imported from PubMed on 06 Aug 2026.

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