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Published on:June 2018
Indian Journal of Pharmaceutical Education and Research, Submitted; 52(4):644-654
Original Article | doi:10.5530/ijper.52.4.75

Design, Synthesis and Evaluation of 4-Aminopyridine Analogues as Cholinesterase Inhibitors for Management of Alzheimer’s Diseases


Authors and affiliation (s):

Shashi Kant Singh1, Saurabh Kumar Sinha2, Mrunal Krishnarao Shirsat*3

1Faculty of Pharmacy, Pacific Academy of Higher Education and Research University, Udaipur, Rajasthan, INDIA.

2Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, INDIA.

3Faculty of Pharmacy, Pacific Academy of Higher Education and Research University, Udaipur, Rajasthan, INDIA.

Abstract:

Introduction: Alzheimer’s disease (AD) is a slowly progressive devasting neurodegenerative disorder of central nervous system manifested by deterioration of memory, cognitive functions, behaviour change and impairment in performing activities of daily life. Neurochemical studies of patients suffering from AD demonstrate selective loss of cholinergic neurons, low concentration of acetylcholine (Ach) in the selective areas of brain such as cortex and hippocampus. Objective: A series of new semicarbazones of 4-aminopyridine has been designed, synthesized and evaluated for cognition enhancing activities through the inhibition of acetylcholinesterase (AChE) and by passive avoidance model. Material and Methods: In the present study, ten new 4-Aminopyridine analogues were synthesized and characterized by analytic methods such as UV, IR, NMR, elemental analysis and for their inhibitory role on Acetylcholinesterase activity by applying the molecular docking studies and performed enzyme kinetics study by Ellman’s spectrophotometric method. The synthesized analogues were then evaluated for antiamnesic and cognition enhancing activities by passive avoidance test. Results: The results illustrated a significant cognition enhancing effect on passive avoidance test with a significant reversal of scopolamine-induced amnesia, which is comparable with standard drug rivastigmine. The in-vitro study of synthesized analogues showed maximum activity of compound-3 and compound-9 compared to standard drug rivastigmine, whereas its enzyme kinetic study revealed a non-competitive inhibition of acetylcholinesterase (AChE) is held responsible to a possible interaction of analogue with the peripheral anionic site (PAS) of AChE and was also confirmed by molecular docking studies. Conclusion: On the basis of present study, we are concluding that hydroxyl substituted Compound 3 and 9 identified as most potent drug which can leads to the discovery and development of new Cognition enhancers in near future.

Key words: 4-aminopyridine, Acetylcholinesterase, Passive avoidance test, Rivastigmine.

 

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The Official Journal of Association of Pharmaceutical Teachers of India (APTI)
(Registered under Registration of Societies Act XXI of 1860 No. 122 of 1966-1967, Lucknow)

Indian Journal of Pharmaceutical Education and Research (IJPER) [ISSN-0019-5464] is the official journal of Association of Pharmaceutical Teachers of India (APTI) and is being published since 1967.

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IJPER uses reference linking service using Digital Object Identifiers (DOI) by Crossref. Articles from the year 2013 are being assigned DOIs for its permanent URLs