Sustainable Synthesis of 3‐(1 <i>H</i> ‐Indol‐3‐yl)propionic Acid Derivatives with Anti‐Alzheimer Activity

A biocatalytic approach was applied to synthesizing esters and amides derived from 2-(1H-indol-3-yl)acetic (IAA), 3-(1H-indol-3-yl)propionic (IPA), and 4-(1H-indol-3-yl)butanoic (IBA) acids. Thirty-seven derivatives were obtained through lipase catalysis in mild reaction conditions with good to excellent yields and a reduced environmental impact. The scope of the reaction was explored in terms of enzyme source, solvent, temperature, substrate-to-nucleophile and enzyme-to-substrate ratios, and substrate versatility. Ten representative derivatives were evaluated as potential anti-Alzheimer's disease (AD) agents using Caenorhabditis elegans models. Among them, octyl 3-(1H-indol-3-yl)propanoate (6e), N-butyl-3-(1H-indol-3-yl)propanamide (10a), and (S)-N-(2-hydroxypropyl)-3-(1H-indol-3-yl)propanamide (13c) emerged as the most promising candidates, demonstrating significant improvements in AD pathology, including enhanced locomotion and mitochondrial function. In addition, the obtained compounds showed no toxicity in Vero cells, making them potential lead drug candidates.