Synthesis of novel hybrids of 1,2,3-triazoles-hydrazone: targeting cholinesterases and Alzheimer's related genes

Abstract

Aim: A new series of 1,2,3-triazole-hydrazone derivatives were developed to evaluate their anti-Alzheimer's activity. Materials & methods: All compounds were screened toward cholinesterases via the modified Ellman's method. The toxicity assay on SH-SY5Y cells was performed using the MTT assay, and the expression levels of GSK-3α, GSK-3β, DYRK1 and CDK5 were assessed in the presence of compounds 6m and 6p.Results:6m and 6p; acting as mixed-type inhibitors, exhibited promising acetylcholinesterase and butyrylcholinesterase inhibitory activity, respectively. 6m demonstrated no toxicity under tested concentrations on the SH-SY5Y cells and positively impacted neurodegenerative pathways. Notably, 6m displayed a significant downregulation in mRNA levels of GSK-3α, GSK-3β and CDK5.Conclusion: The target compounds could be considered in developing anti-Alzheimer's disease agents.

Keywords: 1,2,3-Triazoles; AChE; Alzheimer's; BChE; CDK5; GSK-3α; GSK-3β; Hydrazones.

Graphical abstract

Figure 1.

Kinetic study. (A) Lineaweaver-Burk plot for the inhibition of AChE by compound 6m. (B) Lineaweaver–Burk plot for the inhibition of AChE by compound 6p.

Figure 2.

Binding position of compound 6m in the AChE active site.

Figure 3.

Binding position of compound 6p in the BChE active site.

Figure 4.

Cytotoxicity of 6m and 6p after 72 h exposure determined by MTT assay. Data represents the mean ± SEM.

Figure 5.

Gene expression measurements. GSK-3α (A), GSK-3β (B), DYRK1 (C), and CDK5 (D) gene expression on SH-SY5Y cells after 72 h treatment with 6m (25 μM) or 6p (10 μM).

Figure 6.

Design of target 1,2,3-triazoles-hydrazone hybrids 6a–p.

Figure 7.

Synthesis of 1,2,3-triazoles-hydrazone derivatives 6.