Naphthalene-4H-Chromene Molecular Hybrids as Dual Cholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline associated with cholinergic dysfunction. Herein, we have designed and synthesized series of 4-(naphthalen-1-yl)-4H-chromene derivatives 4(a-n) by a one-pot three-component reaction with adequate synthetic yield and purity. Naphthalene-chromene hybrids were synthesized by formation of two C─C bonds and one C─O bond in a single synthetic step. All synthesized compounds were tested for safety and efficacy using in vitro and in vivo studies. Compounds were found devoid of cytotoxicity in BV-2 cells. Most of the synthesized compounds have shown moderate to good inhibitory activity against cholinesterase enzymes. These compounds were found to be more selective towards acetylcholinesterase (AChE) compared to butyrylcholinesterase (BuChE). Compound 4 m has shown highest inhibitory potency against AChE (AChE, IC50 = 1.08 µM; BuChE, IC50 = 82.59 µM). The prototype compound (4 m) from in-vitro screening was found to be safe in acute oral toxicity followed by histopathological analysis. Compound 4 m was evaluated for in vivo efficacy in scopolamine-induced cognitive impairment model in mice. It significantly reversed the cognitive deficit in neurobehavioral tests. Pre-treatment with 4 m have balanced key biochemical markers involved in the oxidative stress and cognitive functions. The compound 4 m alleviated neuronal tissue damage caused by scopolamine as indicated in the histological study. Molecular docking analysis also reconfirmed the binding affinity of 4 m at cholinesterase enzymes. Taken together, these findings supported the emergence of 4 m as a potential cholinesterase inhibitor for the treatment of AD.