TXCA-mediated synthesis of halogenated 4-aminocoumarins derivatives under mild conditions and in silico evaluation against Alzheimer's disease-related protein targets

Abstract

A highly efficient and selective protocol for the halogenation of the C─H bond of 4-aminocoumarin derivatives is reported. This shows that the use of trihaloisocyanuric acids in the synthesis of aminocoumarin derivatives consists of obtaining pharmacologically important compounds using new strategies and transformations. The proposed method has a broad substrate scope and uses ethyl acetate as the solvent. The reaction scope evaluation of 4-aminocoumarins with different structural characteristics showed that the reaction tolerates electron-withdrawing groups (compounds 3d–f and 8c–e) and electron-donating groups (compounds 3b-c, 3g, 5, 7, and 8b). A sterically hindered group attached to the nitrogen at C4 was also tolerated in the bromination reaction (compound 3h), as well as an alkyl group (compound 7) and even the absence of a substituent on the nitrogen (compound 5). Molecular docking results show that, among the compounds tested, compound 3h stands out. Its predicted interactions with acetylcholinesterase (AChE), monoamine oxidase B (MAO-B), β-secretase enzyme (BACE), and N-methyl-D-aspartate receptors (NMDAR) suggest a promising profile for inhibiting these neurochemical enzymes and antagonizing glutamatergic NMDAR, potentially contributing to therapeutic strategies for neurodegenerative diseases such as Alzheimer’s disease.