The polyphenol - altilisol from Artocarpus altilis leaves exhibits angiotensin-I converting enzyme inhibitory activity

Abstract

Angiotensin-I converting enzyme (ACE) plays a central role in blood pressure regulation and is a key target in the treatment of hypertension. Although clinically used ACE inhibitors are effective, they are often associated with adverse effects, prompting the search for safer, plant-derived alternatives. In this study, a polyphenolic compound, altilisol (C₂₉H₃₈O₅; 2-(4-(3,7-dimethyloctyl)-2,3-dihydroxybenzylidene)-4‑hydroxy-7-propoxy-2,3-dihydro-1H-inden-1-one)propan-1-one; m/z 466.62) was isolated from Artocarpus altilis leaf extract using bioassay-guided fractionation. Altilisol exhibited potent ACE inhibitory activity in a concentration-dependent manner, with an IC₅₀ of 60.12±0.223 μM. Fluorescence-based interaction studies and molecular docking analyses confirmed that altilisol directly binds to ACE, with strong binding affinities for both the N- and C-domains. Specifically, docking predicted binding affinities of -7.8 and -5.9 kcal/mol for chains A and B of the N-domain, and -7.3 kcal/mol for the C-domain, along with key hydrogen bond interactions involving Gly382, Tyr369, Tyr338 and His353. In silico ADMET profiling further supported drug-likeness of altilisol, satisfying Lipinski's Rule of Five. However, its moderate bioavailability score and poor solubility suggest the need for structural optimization or advance formulation strategies to enhance its pharmacokinetic properties. Overall, altilisol emerges as a promising natural ACE inhibitor with potential therapeutic application in hypertension and related cardiovascular disorders.