Synthesis and evaluation of novel carbamate-substituted flavanone derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents

Abstract

This study was designed to synthesize and evaluate flavanone derivatives with phenylcarbamate moiety as potent acetylcholinesterase (AChE) inhibitors and anti-amnestic agents for management of AD. The synthesis of carbamate-substituted flavanone derivatives involved base-catalysed Claisen-Schmidt condensation reaction of 2-hydroxy acetophenone/2-hydroxy-4,6-dimethoxyacetophenone with differently substituted benzaldehydes to yield differently substituted chalcones that underwent intra-molecular oxidative cyclization on refluxing with glacial acetic acid to yield flavanone compounds. Thereafter, refluxing of flavanone compounds with phenyl isocyanate in the presence of petroleum-ether and triethylamine provided phenyl carbamate-substituted flavanone derivatives. The synthesized compounds were screened in vitro for AChE inhibitory activity with donepezil as the standard drug. The most potent test compound (5f′) was evaluated in vivo for memory restorative actions in scopolamine (0.4 mg/kg)-induced amnesia in mice by Morris water maze test. All the compounds exhibited AChE inhibitory activity with carbamate substituted 5,7-dimethoxyflavanone derivatives (5a′–5g′) being the most potent compounds with IC50 ranging from 21.5 ± 1.8 to 9.9 ± 1.6 nM. Compound 5f′ also ameliorated scopolamine-induced amnesia in mice in terms of restoration of time spent in target quadrant and escape latency time. It may be concluded that phenylcarbamate-substituted 5,7-dimethoxyflavanones may be a promising structural template for the development of novel AChE inhibitors in managing amnestic disorders including AD.