Combining the Pharmacophore Features of Coumarins and 1,4-Substituted 1,2,3-Triazoles to Design New Acetylcholinesterase Inhibitors: Fast and Easy Generation of 4-Methylcoumarins/1,2,3-triazoles Conjugates via Click Chemistry

Abstract

Coumarins are a large class of compounds that display a range of interesting biological properties, being considered privileged structures because of the ability of their 2H-chromen-2-one nuclei to bind to multiple pharmacological targets. We hypothesized that the linkage of a second pharmacophore nucleus to the 2H-chromen-2-one core, the 1,2,3-triazole moiety, would entail more selective and pharmacologically active coumarins. Therefore, we describe the synthesis of fourteen 4-methylcoumarins/1,4-substituted 1,2,3-triazole conjugates, which were predicted by in silico methods to inhibit acetylcholinesterase (AChE) and proved to be moderate in vitro inhibitors of this enzyme. Molecular docking simulations suggest that the most active of these compounds has a putative binding mode similar to donepezil, both occupying the peripheral anionic site of AChE, which is associated with the secondary noncholinergic functions of the enzyme. This highlights the potential of this series for further optimization in the search of new coumarins for the treatment of Alzheimer's disease.

Application of triazoles in the structural modification of natural products

“…In 2016, Torres et al. 156 screened the in vitro acetylcholinesterase inhibitor activity of a novel series of 1,2,3-triazole-linked coumarin hybrids. The most prominent compound was coumarin 83 (triazole and 4-methylcoumarins) ( Figure 21 ), and this compound inhibited nearly 60% of the acetylcholinesterase activity at a concentration of 200 µmol/L.…”

Micellization-induced amplified fluorescence response for highly sensitive detection of heparin in serum

“…Precursor 2 and amphiphilic building block 1 were prepared in a good yield using the synthetic methods described in the literature 34,35 .…”

1-[2-(4-Methyl-7-coumarinyloxy)ethyl]-4-(5-{1-[2-(4-methyl-7-coumarinyloxy)ethyl]-1H-1,2,3-triazol-4-yl}pentyl)-1H-1,2,3-triazole

“…Chemical shifts (δ) are given in parts per million downfield from tetramethylsilane. 7-(2-Azidoethoxy)-4-methyl-2H-chromen-2-one (1) was synthesized according to reported methods [10] and coupled with commercial 1,8-nonadiyne (2) by using the copper(I)-catalyzed alkyne-azide cycloaddition reaction, in good yields and with complete regioselectivity (Scheme 1).…”

“…The reaction mixture was partitioned between H2O and EtOAc, the aqueous phase was extracted with EtOAc three times. The organic phase was dried over MgSO4, filtered, concentrated, and the residue purified by column chromatography with a CH2Cl2/EtOAc gradient [10]. Yield 67%; mp 168 °C; 1 Supplementary Materials: 1 H, 13 C-NMR and HRMS spectra for compound 3 and the molfiles can be found at http://www.mdpi.com/1422-8599/2016/2/M894.…”