Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer's disease

Abstract

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

Design, synthesis, in silico and biological evaluations of novel polysubstituted pyrroles as selective acetylcholinesterase inhibitors against Alzheimer’s disease

“…Donepezil, galantamine, and rivastigmine, as well as huperzine A are approved AChE inhibitors that increase acetylcholine levels at synapses and improve neurotransmission. In this context, search for novel AChE inhibitors ongoing and novel scaffolds including dioxane-4,6-dione 9 , thiourea 10,11 , arylisoxazole 12 , thio methyltriazole were developed 10,[13][14][15][16] .…”

Investigation of biological activities of two cultivars of Cicer arietinum proteins mass associated with Alzheimer's disease

“…The fluorescence assay of thioflavin T (ThT) was applied to evaluate βA aggregation 27 . Inhibition of βA accumulation was analyzed based on fluorescence emission of ThT.…”

Synthesis and antiproliferative activity of 1H-1,2,3-triazole-4H-chromene-d-glucose hybrid compounds with dual inhibitory activity against EGFR/VEGFR-2 and molecular docking studies

“…The free energy of binding was evaluated using the MMGBSA method 42 and Prime (v5.4) 43 implemented in Schrodinger 2021–2. This method includes a combination of OPLS4 force-field 36 molecular mechanics energies, a VSGB 2.1 prime energy polar solvation model, and a non-polar solvation term comprising the non-polar solvent-accessible surface area and van der Waals interactions.…”

“…Based on this, it is clear that both EGFR/HER2 and VEGFR-2 play a critical role in tumour growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously, representing a promising approach for cancer treatment. To look for compounds that exhibit the multi-targeting activity of 1 H -1,2,3-triazoles containing glucose-conjugated chromene-triazole, 42 in this work, we synthesized some new hybrid compounds having 4 H -chromene and 1 H -1,2,3-triazole rings conjugated to a d -glucose moiety. The rational for the structural design of these hybrid compounds is presented in Fig.…”