Pharma / Biotech

Design, synthesis and evaluation of pyrazole bearing α-aminophosphonate derivatives as potential acetylcholinesterase inhibitors against Alzheimer's disease.



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Design, synthesis and evaluation of pyrazole bearing α-aminophosphonate derivatives as potential acetylcholinesterase inhibitors against Alzheimer’s disease.

Bioorg Chem. 2020 Jan 15;96:103589

Authors: Shaikh S, Dhavan P, Pavale G, Ramana MMV, Jadhav BL

Abstract
A series of novel scaffold of N-substituted pyrazole derived α-aminophosphonates were designed, synthesized and evaluated for their anti-cholinesterase activity. Porcine pancreatic lipase (PPL) was used as a catalyst for the organic transformation. Compounds 4ah and 4bh proved to be more potent than the standard drug tacrine, rivastigmine and galantamine for AChE inhibition activity with IC50 value between 0.055 ± 0.143 µM and 0.017 ± 0.02 µM respectively. BuChE activity of the synthesized derivatives possessed moderate to weak inhibition potency. 4bhshows a comparable activity to Rivastigmine against BuChE (IC50 = 6.331 ± 0.17). The compounds did not show any cytotoxicity against HEK-293 cells when compared to standard drugs. Cell viability assay using N2a cell showed compounds 4ah and 4bh showed comparable results to positive control rivastigmine. In addition, these compounds showed promising antioxidant activities against DPPH and H2O2 scavenging. Both 4ah and 4bh showed mixed-type inhibition which supported by molecular docking studies by acting as a dual site inhibitor. The predicted ADME showed good pharmacokinetics as predicted by QikProp. DNA cleavage studies and DNA protection assay of active compounds were also performed. 4bh did not show any damage to DNA and was protective in nature.

PMID: 31978679 [PubMed – as supplied by publisher]

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