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P4‐009: Design, Synthesis and Molecular Docking Studies of Some Novel Potential Piperazine Derivatives for the Improvement of Cognitive Dysfunction
Author(s) -
Piplani Poonam,
Danta Chhanda Charan
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.2098
Subject(s) - aché , pharmacology , chemistry , docking (animal) , dementia , cognition , piperazine , ic50 , neuroprotection , in vivo , acetylcholinesterase , psychology , medicine , neuroscience , enzyme , biochemistry , in vitro , biology , nursing , disease , microbiology and biotechnology
Background: Cognitive dysfunction (CD) is an impairment of the brain’s functions that are related to memory, attention, intellect etc. It also includes aging associated cognitive decline,mild cognitive decline and cognitive impairment no dementia (CIND). Cognitive dysfunction has become a major public health concern because of its increasing prevalence and financial costs of care. Methods:Series of novel piperazine derivatives have been designed, synthesized and evaluated for cognition enhancing activity. The synthesized compounds were screened for their in vitroAChE inhibition and reversal of scopolamine induced memory deficit in a passive avoidance stepdown animal model in mice. ADME properties were predicted using cheminformatics tools. The antiradical activity was evaluated by DPPH method. Enzyme kinetics and molecular docking studies were carried out to elucidate the mechanism of AChE inhibition. Results: All the compounds exhibited excellent IC50 values with potential dual binding site inhibition activity. The IC50 values and inhibition constants of the most promising compounds 1d and 3c were found to be 2.23 mM, 1.05 mM, 14.38 mMand 6.93 mM respectively. They potentially reversed the scopolamine induced memory deficit at a dose of 1.0 mg/kg i.p. in mice. Furthermore, 1d and 3c showed high CNS penetration and brain AChE inhibition in ex vivo experiments in mice. Additionally, these compounds also showed free radical scavenging activity. Conclusions:The present study focused on the development of piperazine based new chemical entities that can be well received for the treatment of cognitive dysfunction manifested in various neurological disorders. The study put forward two lead molecules 1d and 3c that exhibited appreciable acetylcholinesterase inhibitory potential. Further elaborations in this domain of research can bring out novel compounds that can revolutionize the paradigm of treatment of neurodegenerative disorders.