Kumar_2018_Eur.J.Med.Chem_150_87

Novel multifunctional 3,6-Diphenyl-1,4-bis(phenylsulfonyl)piperazine-2,5-dione derivatives were designed and synthesized for the treatment of Alzheimer's disease (AD). The designed scaffold has blood brain barrier penetrating ability, acetylcholinesterase (AChE) and matrix metalloproteinase-2 (MMP-2) inhibition potential. Compounds 52 and 46 showed very significant inhibition against AChE, IC50=32.45+/-0.044, 28.65+/-0.029, BuChE, IC50=157.95+/-0.264, 160.58+/-0.082 and MMP-2, IC50=36.83+/-0.015, 19.57+/-0.005 (nM). In the enzyme kinetics study, lead molecule 46 showed non-competitive inhibition of AChE with Ki=7nM and competitive inhibition of MMP-2 with Ki=20nM. Compounds 52 and 46 inhibited AChE-induced Abeta aggregation at 20muM. The compounds also exhibited in-vitro antioxidant potential in DPPH assay. Further, compound 46 was found to be a promising neuroprotective agent in MC65cells. Lead molecule 46 significantly enhanced working memory in scopolamine induced amnesia animal model at dose of 5mg/kg dose. The mitochondrial membrane potential was restored in animals when treated with compounds 52 and 46.