Multi-target directed ligands design of 1-O-Acetylbritannilactone derivatives: Dual anti-neuroinflammatory and acetylcholinesterase inhibitory activities

Abstract

Alzheimer’s disease, a progressive neurodegenerative disorder of the central nervous system, presents a complex pathological mechanism that limits the efficacy of conventional single-target drugs. Utilizing the unique advantages of natural products in multi-target intervention, this study employed the active component 1-O-acetylbritannilactone (ABL) from Inula britannica L. as the parent structure. Guided by the multi-target directed ligands (MTDLs) strategy, four novel derivatives (ABL-1 to ABL-4) were successfully designed and synthesized by introducing acetylcholinesterase (AChE) inhibitory pharmacophores into the ABL scaffold. In vitro pharmacological evaluation demonstrated that ABL-2, ABL-3, and ABL-4 not only preserved the anti-neuroinflammatory activity of the parent compound but also endowed compound ABL with AChE inhibitory potency. Notably, ABL-4 displayed the most promising dual efficacy profile, achieving an AChE inhibition rate of 40.09 ± 0.73 % at 30 μM and an anti-neuroinflammatory activity (EC₅₀ = 8.43 ± 0.5 μM). Molecular docking simulations revealed that the dual-target synergistic mechanism of ABL derivatives arises from hydrogen bonding and π-π stacking interactions with key residues of both AChE and inducible nitric oxide synthase (iNOS). This work not only validates the feasibility of the MTDLs strategy in optimizing natural product scaffolds but also provides a structurally novel lead compound with significant potential for developing multi-target anti-AD therapeutics.