Rullo_2026_Eur.J.Med.Chem_316_118961

Neuroinflammatory process is a key factor in multifaceted neurodegenerative disorders, as proved by the increased levels of pro-inflammatory mediators, primarily released by microglia and astrocytes. Following a multitarget strategy, we aimed at identifying dual inhibitors of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO B). Both enzymes emerged as promising targets for tuning the inflammatory response within the central nervous system (CNS). Here we describe the synthesis, in vitro biological evaluation, and drug-likeness characterization of a series of 16 methoxy-bearing coumarin derivatives. Among them, compound 9 behaved as a well-balanced dual-acting inhibitor (hBChE, IC50 = 557 nM; hMAO B, IC50 = 142 nM) capable of mitigating interleukin-6 release from stimulated human microglia clone 3 (HMC3) cells in a dose-dependent manner and of counteracting 6-hydroxydopamine (6-OHDA) toxicity in SH-SY5Y lines. Moreover, X-ray crystal structures of 9 in both hBChE and hMAO B were solved at 2.36 A and 1.60 A resolution, respectively.