New Multifunctional Benzannulated 1,8‐Naphthyridine Derivatives: Targeting Cholinesterase Inhibition and Oxidative Stress via Synthetic, Computational, and Biological Approaches

ABSTRACT

A series of new benzo[ b ][1,8]naphthyridine derivatives ( 3a–g ) was synthesized and biologically evaluated as multifunctional antioxidant and cholinesterase inhibitory agents. The target compounds were prepared through a multi‐step strategy involving amination followed by Friedländer‐type condensation with activated methylene compounds. In vitro evaluation using the Ellman method revealed notable inhibitory activity against acetylcholinesterase (AChE, IC ₅₀  = 2.29–9.51 µM) and butyrylcholinesterase (BChE, IC ₅₀  = 11.37–67.21 µM). Compound 3e emerged as the most active dual inhibitor of AChE (IC ₅₀  = 2.29 µM) and BChE (IC ₅₀  = 11.37 µM), whereas compounds 3b , 3c , and 3g were inactive toward BChE, highlighting strong AChE selectivity with selectivity indices up to 8.04. The antioxidant activity of the derivatives was assessed using β‐carotene–linoleic acid, CUPRAC, and superoxide DMSO alkaline assays. Several compounds exhibited significant antioxidant potential, with compound 3d showing the strongest lipid peroxidation inhibition (IC ₅₀  = 0.13 ± 0.02 mM). whereas compounds 3a (0.33 ± 0.01 mM) and 3b (0.063 ± 0.025 mM) displayed superoxide scavenging activity comparable to α‐tocopherol. Structure–activity relationship analysis indicated that electron‐donating substituents enhanced radical stabilization and reducing power. Density functional theory (DFT) calculations at the B3LYP/6‐311 G(d,p) level revealed that electron‐withdrawing substituents reduced HOMO–LUMO gaps and increased electrophilicity and charge‐transfer ability. Overall, the combined biological, docking, and theoretical results findings highlight the naphthyridine scaffold as a promising platform for the development of multifunctional agents targeting neurodegenerative disorders.