Dual functional cholinesterase and carbonic anhydrase inhibitors for the treatment of Alzheimer's disease: Design, synthesis, in vitro, and in silico evaluations of coumarin-dihydropyridine derivatives

Abstract

Alzheimer's disease (AD) is a complex, progressive, and predominant form of cognitive disorders. The useful effect of cholinesterase (ChE) inhibitors in treatment of AD has been well-documented. In addition to ChE inhibitors, several studies confirmed that inhibition of human carbonic anhydrases (hCAs) can be help to AD treatment. In an attempt to introduce of potent ChE and hCA inhibitors, new coumarin-dihydropyridine derivatives (6a-m) were designed based on the molecular hybridization of effective pharmacophores. A simple synthetic route consisting of three steps was used to synthesis of title compounds 6a-m. The latter compounds were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and two important isoforms of hCA including hCA I and hCA II. The results of in vitro assays exhibited that compounds 6b, 6f, and 6i were the most promising derivatives against AChE and BChE and the most potent compounds against studied hCAs were compounds 6g, 6i, and 6j. Furthermore, the most potent compounds were subjected to in silico screening using Autodock software and preADMET online software to identify the binding modes and prediction of pharmacokinetic property, respectively.