Synthesis, Molecular Docking, and Preliminary Evaluation of 2‐(1,2,3‐Triazoyl)benzaldehydes As Multifunctional Agents for the Treatment of Alzheimer's Disease

Abstract

We described here our results on the use of thiourea as a ligand in the copper catalysed azide‐alkyne cycloaddition (CuAAC) of 2‐azidobenzaldehyde with alkynes. Reactions were performed reacting 2‐azidobenzaldehyde with a range of terminal alkynes using 10 mol % of copper iodide as a catalyst, 20 mol % of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 °C under nitrogen atmosphere. The corresponding 2‐(1H‐1,2,3‐triazoyl)‐benzaldehydes (2‐TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: β‐secretase (BACE), glycogen synthase kinase (GSK‐3β) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5 a (2‐(4‐phenyl‐1H‐1,2,3‐triazol‐1‐yl)benzaldehyde), 5 b (2‐(4‐(p‐tolyl)‐1H‐1,2,3‐triazol‐1‐yl)benzaldehyde), and 5 d (2‐(4‐(4‐(tert‐butyl)phenyl)‐1H‐1,2,3‐triazol‐1‐yl)benzaldehyde) were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation. Due the antioxidant potential ally to the affinity with BACE, GSK‐3β and AChE, compound 5 b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5 b (1 mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK‐3β expression.

Synthesis ofα‐Hydroxyphosphonates Containing Functionalized 1,2,3‐Triazoles

“…With the purpose of investigating the generality of our protocol regarding the presence of carbonyl groups in the triazole counterpart, functionalized 1,2,3‐triazoles were used as starting materials in the Abramov reaction with diethyl phosphite 2 a (Scheme 5). The starting functionalized triazoles 1 i – m were prepared through the organocatalytic reaction between the azide 4 a and functionalized β ‐keto compounds, as previously described [59] . The carbonyl‐containing 1,2,3‐triazoles were suitable substrates for the reaction, and the desired products containing ester ( 3 o ), ketone ( 3 p ) and amide groups ( 3 q – s ) were obtained in moderate to good yields (Scheme 5, 50–84 %).…”

“…Based on the aforementioned characteristics of α ‐hydroxyphosphonates, and the efforts to generate new synthetic routes to prepare 1,2,3‐triazole compounds, [57–59] we disclose a solvent‐free synthesis of a series of α ‐hydroxyphosphonates hybridized with the 1,2,3‐triazole heterocycle via Abramov reaction (Scheme 1). The 1,2,3‐triazole starting materials were prepared by the copper‐catalyzed azide‐alkyne cycloaddition reaction (CuAAC) from carbonyl azides and terminal alkynes, according to our previous report [60] .…”

Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease

“…Among them, we identified 12 inhibitors of tau and Ab aggregation with the inhibitory potency exceeding 50%. Most compounds with such dual inhibitory activity are tacrine (5,17,20,(27)(28)(29)(30) and N-benzylpiperidine (16, 37-39) derivatives. Tacrine is a widely used scaffold in the AD therapy research 40 .…”

“…Thus, a combination of these activities in one molecule may be a reasonable step towards effective slowing down of AD progression. The most explored multifunctional ligands combine anticholinesterase activity with anti-aggregation properties resulting from inhibition of b-secretase or modulation of c-secretase and direct inhibition of processes of aggregation of Ab and tau proteins [15][16][17][18] . Also, many G-protein coupled receptors are explored in combination with anticholinesterase activity, among them cannabinoid receptors CB 1 and CB 2 19-22 , histamine H 3 receptors [23][24][25] or serotonin 5-HT 1A 26 , 5-HT 4 , and 5-HT 6 receptors [27][28][29][30][31] .…”

Synthesis of 4-Arylselanyl-1H-1,2,3-triazoles from Selenium-Containing Carbinols

“…Triazoles are a significant class of heterocycles which have received considerable attention because of their application in materials science, medicinal chemistry and organic synthesis [1][2][3]. Particularly, 1,2,3-triazoles derivatives exhibit a broad spectrum of biological properties, such as anti-inflammatory, antifungal, antibacterial, anticancer, antivirus and antituberculosis [4][5][6][7][8][9][10][11][12][13]. 1,2,3-Triazoles derivatives are an important connecting group, linking a broad range of substituted substrates in a simple fashion, being used as peptide mimetics [14,15].…”