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

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, IC50 = 2.29-9.51 µM) and butyrylcholinesterase (BChE, IC50 = 11.37-67.21 µM). Compound 3e emerged as the most active dual inhibitor of AChE (IC50 = 2.29 µM) and BChE (IC50 = 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 (IC50 = 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.