Abstract
A series of uncharged salicylaldehyde oximes were synthesized and evaluated for the reactivation of organophosphorus (OP) nerve agents simulants Diethylchlorophosphonate (DCP) & Diethylcyanophosphonate (DCNP) and pesticides (paraoxon & malaoxon) inhibited electric eel Acetylcholinesterase (AChE). The computational software Swiss ADME and molinspiration were used to unfold the probability of drug-likeness properties of the oximes derivatives. Substituted aromatic oximes with diethylamino or bromo group with free hydroxyl group ortho to oxime moiety were found efficient to regenerate the enzymatic activity in in-vitro AChE assay. The alkylation of the ortho hydroxyl group of derivatives led to the loss of reactivation potential. The derivatives with a hydroxyl group and without oxime group and vice versa did not show significant reactivation potency against tested OP toxicants. Further, we also evaluated the reactivation potential of these selected molecules on the rat brain homogenate against different OPs inhibited ChE and found maximum reactivation potency of oxime 2e. The in-vitro results were further validated by molecular docking and dynamic studies which showed that the hydroxyl group interacted with serine amino acids in the catalytic anionic site of AChE enzyme and was stable up to 200 ns consequently providing proper orientation to oxime moiety for reactivating the OP inhibited enzyme. It has thus been proved by the structure-activity relationship of oximes derivatives that hydroxyl group ortho to oxime is essential for reactivating OP inhibited electric eel AChE. Amongst the twenty-one oximes derivatives, 2e was found to be most active in regenerating the paraoxon, malaoxon, DCP and DCNP inhibited AChE enzyme.
Acknowledgement
Ashima Thakur, Jayant Patwa, and Suyash Pant would like to acknowledge the Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers Government of India for the award of Junior and Senior Research Fellowship. The authors are thankful to CIF for providing spectral data. Suyash Pant also would like to acknowledge NIPER-Kolkata for providing the computational facility.
Author contributions
All authors contributed to the study conception, design, material preparation, data collection and analysis. The first draft of the manuscript was written by Ashima Thakur, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Ethical approval
The animals were given humane care as per the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India, and prior permission was taken from the Institutional Animal Ethics Committee of the National Institute of Pharmaceutical Education and Research, Raebareli (NIPER/RBL/IAEC/10/March 2018).
Disclosure statement
No potential conflict of interest was reported by the author(s).