Novel Triazole-Quinoline Derivatives as Selective Dual Binding Site Acetylcholinesterase Inhibitors

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. Currently, the only strategy for palliative treatment of AD is to inhibit acetylcholinesterase (AChE) in order to increase the concentration of acetylcholine in the synaptic cleft. Evidence indicates that AChE also interacts with the β-amyloid (Aβ) protein, acting as a chaperone and increasing the number and neurotoxicity of Aβ fibrils. It is known that AChE has two binding sites: the peripheral site, responsible for the interactions with Aβ, and the catalytic site, related with acetylcholine hydrolysis. In this work, we reported the synthesis and biological evaluation of a library of new tacrine-donepezil hybrids, as a potential dual binding site AChE inhibitor, containing a triazole-quinoline system. The synthesis of hybrids was performed in four steps using the click chemistry strategy. These compounds were evaluated as hAChE and hBChE inhibitors, and some derivatives showed IC 50 values in the micro-molar range and were remarkably selective towards hAChE. Kinetic assays and molecular modeling studies confirm that these compounds block both catalytic and peripheral AChE sites. These results are quite interesting since the triazole-quinoline system is a new structural scaffold for AChE inhibitors. Furthermore, the synthetic approach is very efficient for the preparation of target compounds, allowing a further fruitful new chemical library optimization.

Antimicrobial Activity of Quinoline-Based Hydroxyimidazolium Hybrids

“…In summary, the hybrid 7b represents a promising molecule showing significant antibacterial effect against S. aureus (5 µM) and M. tuberculosis H37R (24 µM), for which the study of its mechanism of action should be undertaken to assess its potential development as an anti-infective agent. In this direction, some previous reports indicated that quinoline hybrids, along with other nitrogen-containing heterocycles have shown to bind to heme and hemozoin unities, but also DNA, acetylcholinesterase, or to affect prostaglandin production [29][30][31][32][33]. The hits discovered in this study open the door for the exploration of a focused library of compounds and to deepen the study of their antimicrobial mechanism of action.…”

Synthesis, Antibacterial Activity and DFT Calculation of Naphtopyrano, Furo and Pyrazolo [3,2,e] [1,2,4]Triazolo-[1,5-c]Pyrimidine Derivatives

“…"2-Amino-3-cyano-4-methylfuran 1, 2-amino-3-cyano-pyrans 2, 1-Phenyl-3-thiomethyl-5-aminopyrazole-4-carbonitrile 3" were selected as our primary starting material for this synthesis and were prepared by methods taken from the literature [21][22][23], the reactivity of the cyanoacetic acid hydrazone has been already reported by the present authors [24,28]. Compound 1, 2 and 3 reacted with excess of ethyl orthoester to yield iminoethers 4, 5 and 6 (Scheme 2), which were known to react with compounds containing -NH 2 moiety such as hydrazides [4,[25][26][27][28][29].…”

“…Pyranotriazolopyrimidine derivatives have attracted a great deal of interest due to their biological activities and their potential applications as pharmacological agents. Several derivatives of the pyranotriazolopyrimidine exhibit platelet anti-aggregating activity and local "inhibition of influenza, virus sialidase and mutagenic activity [1], anti-genotoxic activity [2], antimicrobial activity [3], AChE or acetylhydrolase inhibition [4], and antifungal [5,6]". Moreover pyranotriazolopyrimidine derivatives are well known antigenotoxic, [7] and in the agrochemical field, showing herbicidal activity [8].…”

Crystal structures of 6-chloroindan-1-one and 6-bromoindan-1-one exhibit different intermolecular packing interactions

“…6-Haloindan-1-ones have featured in the synthesis of biologically or pharmacologically active compounds. In recent examples, 6-chloroindan-1-one (I) has been employed in the total synthesis of the anticancer natural product chartarin (Unzner et al, 2016), and in the synthesis of triazole-quinoline derivatives that are acetylcholinesterase inhibitors relevant to the treatment of Alzheimer's disease (Mantoani et al, 2016). 6-Bromoindan-1one has been used as the starting material for the synthesis of small molecules that inhibit cell entry by HIV-1 (Melillo et al, 2016), and both 6-chloroindan-1-one and 6-bromoindan-1-one have been used as the starting material for the preparation of C-7 substituted 3,4-dihydroisoquinolin-1(2H)-one analogues that selectively inhibit unique poly-ADP-ribose polymerases (Morgan et al, 2015).…”