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Bistable and Water‐Operable Hemiindigo Photoswitches Allow Optical Control of Acetylcholinesterase Activity with Visible Light

Year: 2025

Type: article

Abstract: While photopharmacology enables precise spatiotemporal control over drug activity, its widespread reliance on UV‐responsive molecules often hinders preclinical and clinical advancements. Thus, alternative scaffolds can offer promising advantages over the commonly used azobenzene family. In this study, we introduce the first hemiindigo‐based photopharmacological agents, which are capable of isomer‐dependent human acetylcholinesterase inhibition in the nanomolar range. These hemiindigo photoswitches exhibit highly favorable properties: They are fully functional in aqueous medium with good photoisomerization quantum yields, respond exclusively to blue‐to‐orange visible light (415–590 nm), and maintain high stability in their metastable form, even in physiological buffers. Notably, indoxyl N‐methylation emerged as a key structural feature for optimizing photophysical properties, as demonstrated through crystallography and a theoretical model describing the photochemical pathways governing photoisomerization. Overall, this study paves the way for broader exploration and future applications of the largely overlooked hemiindigo scaffold in photopharmacology.

Source: ChemistryEurope

DOI: 10.1002/ceur.202500221