Potential role of hydrazinyl 1,2,4-triazoles derivatives as acetylcholinesterase inhibitors: synthesis, biological evaluation, kinetics mechanism and molecular docking and simulation studies

In the current study, total six hydrazinyl 1,2,4-triazoles derivatives (5a-5f) are reported. A new series of pyridine substituted 1,2,4-triazoles was synthesized and tested for in vitro studies, acetylcholinesterase (AChE) inhibition assay, kinetics mechanism studies and chemical characterization (1HNMR and 13CNMR analysis). The acetylcholinesterase inhibition activity of the compound 5f (IC50 +/- SEM = 0.0249 +/- 0.01 mu M) was maximum as compared to the rest of the derivatives. Results of kinetics mechanism showed that synthetic compound (5f) had inhibitory effect on enzyme in a competitive manner and its Ki Value was 0.025 mu M. These findings were also supported by molecular docking studies to rule out the binding interactions in the molecules. In addition, comprehensive molecular dynamics simulations were performed to investigate the stability of protein-ligand complex. It was revealed that RMSD fluctuations demonstrated stable pattern. The data showed that almost all derivatives are best inhibitors of AChE in comparison to neostigmine. Therefore, it can be suggested that these derivatives must be explored further at molecular level so that their role can be identified as lead molecules in drug discovery for the management of age related neurodegenerative diseases.

Automated summary

In this study, a new series of pyridine substituted 1,2,4-triazoles was synthesized and evaluated for their acetylcholinesterase (AChE) inhibition activity. Compound 5f showed the strongest inhibition activity with an IC50 value of 0.0249 μM. The kinetics mechanism studies revealed that compound 5f competitively inhibited the enzyme, and its Ki value was determined to be 0.025 μM. Molecular docking and molecular dynamics simulations supported these findings and demonstrated the stability of the protein-ligand complex. These derivatives have great potential as lead molecules for drug discovery in the management of age-related neurodegenerative diseases.