Design, synthesis and biological evaluation of novel antipyrine based alpha-aminophosphonates as anti-Alzheimer and anti-inflammatory agent

Herein, a series of novel antipyrine based alpha-aminophosphonates derivatives were synthesized and characterized. The synthesized derivatives were subjected for in vitro cholinesterase inhibition, enzyme kinetic studies, protein denaturation assay, proteinase inhibitory assay and cell viability assay. For cholinesterase inhibition, the results inferred that the test compounds possess better AChE activity (0.46 to 6.67 mu M) than BuChE (2.395 to 12.47 mu M). Compound 4j inhibited both AChE and BuChE (IC50 = 0.475 +/- 0.12 mu M and 2.95 +/- 0.16 mu M, respectively), implying that it serves as a dual AChE/BuChE inhibitor. Also, kinetic studies revealed that compound 4j exhibits mixed-type inhibition against both AChE and BuChE, with K-i values of 3.003 mu M and 5.750 mu M, respectively. Further, protein denaturation and proteinase inhibitory assays were used to test in vitro anti-inflammatory potential. It was found that compound 4o exhibited highest activity against protein denaturation (IC50 = 42.64 +/- 0.19 mu M) and proteinase inhibition (IC50 = 37.57 +/- 0.19 mu M) when compared to diclofenac. In addition, cell viability assay revealed that active compounds possess no cytotoxicity against N2a cell and RAW 264.7 macrophages. Finally, molecular docking experiments for AChE, BuChE, and COX-2 were conducted to better understand the binding modes of active compounds. Communicated by Ramaswamy H. Sarma