Abstract
The tetrahydroquinoline ring system is a unit found in many biologically active natural products and pharmacologically relevant therapeutic agents. A new series of bistetrahydroquinolines (bis-THQs) was synthesized using imino Diels-Alder reactions between dialdehydes, anilines and N-vinyl-2-pyrrolidone (NVP). The notable features of this procedure are mild reaction conditions, greater selectivity and good yields of products. In addition, the inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of some selected derivatives is reported. The feasible binding modes of these active compounds, within AChE and BuChE binding sites, were predicted by molecular docking experiments and their binding affinity was estimated by means of free energy calculations through the MM-GBSA approximation.
Highlights
Heterocyclic compounds, especially nitrogen heterocycles, are the most important class of compounds in the pharmaceutical and agrochemical industries [1]
AChE catalyzes the hydrolysis of acetylcholine, decreasing its availability in the synaptic space [17], and inhibitors of AChE have been used as palliative drugs for Alzheimer’s disease (AD), including synthetic compounds as tacrine [18], donepezil [19], galanthamine [20] and rivastigmine [21], which have all been proven to improve a little the situation of AD patients
We propose the following possible mechanism to explain the product formation (Scheme 2). This procedure allows a cycloaddition reaction between substituted anilines 1 and dialdehydes 2, generating a double Schiff base, which is activated by the presence of BiCl3 as Lewis acid, and by double imino Diels-Alder cycloaddition with VNP leads to the formation of the bis-THQs
Summary
Heterocyclic compounds, especially nitrogen heterocycles, are the most important class of compounds in the pharmaceutical and agrochemical industries [1]. The THQ nucleus has been found to possess a wide range of biological activities, including psychotropic activity [3], anti-allergenic [4], antitumoral [5], antimalarial [6], anti-bacterial [7], antifungal [8,9], cardiovascular activity [10], antiviral activity [11,12], etc These kind of molecules can act as γ-secretase inhibitors for the treatment of Alzheimer’s disease [13], as platelet aggregation inhibitors [14] and modulators of HIV transcription [15]. Alzheimer’s disease (AD), characterized by progressive cognitive impairment, has been raising much interest as the most common cause of dementia in elderly people It is a multifactorial disorder involving the malfunction of different biochemical pathways in which certain enzymes play a key role [16]. The main purposes of our work were: first, to develop a simple and efficient synthesis protocol for bis-THQ derivatives with several degrees of structural diversity; second, to study their biological activity as inhibitors of the enzymes AChE and BuChE and third, to explain their binding modes of interaction with those molecular targets, aiming in particular at estimating the binding free energy of the compounds
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