The in silico and in vitro analysis of donepezil derivatives for Anopheles acetylcholinesterase inhibition

Abstract

Current studies on Anopheles anticholinesterase insecticides are focusing on identifying agents with high selectivity towards Anopheles over mammalian targets. Acetylcholinesterase (AChE) from electric eel is often used as the bioequivalent enzyme to study ligands designed for activity and inhibition in human. In this study, previously identified derivatives of a potent AChE, donepezil, that have exhibited low activity on electric eel AChE were assessed for potential AChE-based larvicidal effects on four African malaria vectors; An. funestus, An. arabiensis, An. gambiae and An. coluzzii. This led to the identification of four larvicidal agents with a lead molecule, 1-benzyl-N-(thiazol-2-yl) piperidine-4-carboxamide 2 showing selectivity for An. arabiensis as a larvicidal AChE agent. Differential activities of this molecule on An. arabiensis and electric eel AChE targets were studied through molecular modelling. Homology modelling was used to generate a three-dimensional structure of the An. arabiensis AChE for this binding assay. The conformation of this molecule and corresponding interactions with the AChE catalytic site was markedly different between the two targets. Assessment of the differences between the AChE binding sites from electric eel, human and Anopheles revealed that the electric eel and human AChE proteins were very similar. In contrast, Anopheles AChE had a smaller cysteine residue in place of bulky phenylalanine group at the entrance to the catalytic site, and a smaller aspartic acid residue at the base of the active site gorge, in place of the bulky tyrosine residues. Results from this study suggest that this difference affects the ligand orientation and corresponding interactions at the catalytic site. The lead molecule 2 also formed more favourable interactions with An. arabiensis AChE model than other Anopheles AChE targets, possibly explaining the observed selectivity among other assessed Anopheles species. This study suggests that 1-benzyl-N-(thiazol-2-yl) piperidine-4-carboxamide 2 may be a lead compound for designing novel insecticides against Anopheles vectors with reduced toxic potential on humans.

Ginsenoside Rg1 attenuates D‐galactose‐induced neural stem cell senescence via the Sirt1‐Nrf2‐BDNF pathway

“…It is due to the limited regenerative capacity of the adult nervous system and the death or irreversible dysfunction of the neural cells (Achilleos & Trainor, 2012; Fauser et al, 2021; Matsubara et al, 2021). Currently, the drugs approved by the Food and Drug Administration (FDA) such as MDA receptor antagonists, levodopa, and donepezil are used to prolong neurodegeneration by supplementing neurotransmitters and neurotrophic factors (Gao et al, 2022; Honorio et al, 2022; Nagai et al, 2022; Osmaniye et al, 2023; Rants'o et al, 2022; Safarpour et al, 2022). Unfortunately, the adverse effects of these drugs have gradually been revealed (Audira et al, 2020; Hagiwara‐Nagasawa et al, 2021; Kurihara et al, 2022; Morris et al, 2021; Rus et al, 2022; Wang, Zong, et al, 2022).…”