In vitro Anti-acetylcholinesterase Evaluation and Molecular Docking Modeling of Some α‑amino Phosphonate Derivatives

Abstract

The overuse of organophosphorus insecticides has resulted in the rise of pest resistance to these chemicals, thus making it necessary to develop new insecticides for global agriculture. In this investigation, we examined the anti-acetylcholinesterase (AChE) activity of certain α-amino phosphonate derivatives via both in vitro experiments and molecular docking modeling. The tested compounds demonstrated notable efficacy against the Drosophila melanogaster AChE enzyme. The compound Diethyl(2,4‑dichlorophenyl) (2,4‑dichlorophenylamino) methylphosphonate (M2), which contained two Cl- substituents on each ring, exhibited a significant concentration-dependent inhibition of the enzyme with an LC₅₀ of 220 µg/ml. Additionally, at concentrations of 500 and 1000 µg/ml, Diethyl (2,4‑dichloropheny l) (2‑hydroxyophenylamino) methylphosphonate (M4) reduced the enzyme activity by 45.7 and 84.6%, respectively. Moreover, the four molecules displayed in silico affinity towards Dm-AChE as observed in the experimental assay. Notably, M2 demonstrated the highest affinity towards the enzyme, with two oxygen atoms in the molecule forming hydrogen bonds with SER-238 and HIS-480. The estimated free binding energy and inhibition constant for M2 were determined to be –10.04 kcal/mol and Ki = 43.83 nM, respectively. In addition, M4 exhibited an affinity of –9.36 kcal/mol and Ki = 137.7 nM. Further studies on the formulation and efficacy of these α-amino phosphonate derivatives are needed to serve as novel high-performance pesticides.

Keywords:

α‑amino phosphonate, AChE, in silico, molecular docking.