Design and Synthesis of Novel β-Naphthol Dithiocarbamate Hybrids: A Convergent Multifaceted Approach Towards AChE and Amyloid-β Inhibition for Alzheimer's Disease.

Abstract

Alzheimer's disease (AD) is an irreversible and chronic neurodegenerative disease, posing a growing global health burden, necessitating the development of multitarget-directed ligands (MTDLs) to combat its complex, multifactorial pathology. In this research, a new series of β-naphthol-based dithiocarbamate derivatives (5a-5g) were designed, synthesized using a rational drug design approach, and their structures were elucidated using FTIR, UV, and NMR spectra analysis. Reportedly, compound 5d showed characteristic C-N, C = S, and C-S vibrations in FTIR, while distinct aromatic and piperidinyl proton signals were detected in NMR. The compounds were screened for pre-ADME, molecular docking, and DFT study. The in silico studies predicted favorable binding capabilities against acetylcholinesterase (AChE) and amyloid-β (Aβ) targets. The antioxidant and biochemical estimation of the synthesized β-naphthol-based dithiocarbamate derivatives was evaluated using several in vitro assays, among which compound 5d exhibited the highest free radical scavenging activity and anti-AChE activity (IC₅₀ = 3.54 ± 0.98 µg/mL). Neurobehavioral activity showed improved learning and memory during behavioral assessments of the streptozotocin (STZ)-induced rat model. Compound 5d (30 mg/kg) improved learning and memory in STZ-induced rats, supported by enhanced antioxidant enzyme levels and reduced oxidative stress markers. It also decreased Aβ_1-42 and AChE contents, with histopathological findings confirming significant neuroprotection in the hippocampus. The neuroprotective action of the β-naphthol-based dithiocarbamate derivative is likely associated with its combined antioxidant, cholinergic, and anti-Aβ properties. Collectively, these findings will provide a strong rationale for the futuristic clinical applicability of 5d as a potent therapeutic candidate for AD.