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

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.

A synthetically benign one-pot construction of enamino-xanthene dyes

“…In solution these tautomeric equilibria depend strongly on some structural factors such as substitution pattern and intramolecular hydrogen bonding, and are also markedly influenced by temperature, light and solvent effects. 19 However, Schiff bases of THB with aromatic amines ( 14 , R = aryl), 20 hydrazines ( 14 , R = NR 1 R 2 ) 21 and hydrazides ( 14 , R = COR 1 ), 22 (thio)semicarbazides ( 14 , R = NHCONH 2 or NHCSNH 2 ), dithiocarbazides ( 14 , R = NHCSS-R 1 ) and carbohydrazides, 22 show exclusively imine structures in solution.…”

Syntheses, Complexation and Biological Activity of Aminopyridines: A Mini-Review

“…The reaction showed below in figure 30 represents the semicarbazones of 4-aminopyridine synthesis. Singh and co-workers opined that the in-vitro study of synthesized analogues showed maximum activity of compounds compared to standard drug rivastigmine [52]. They reported that the enzyme kinetic study revealed a non-competitive inhibition of acetylcholinesterase (AChE) and is responsible for the possible interaction of the analogue with the peripheral anionic site (PAS) of AChE, which was however confirmed by molecular docking studies.…”

“…The synthesis of semicarbazones of 4-aminopyridine was obtained by the reaction of 5ml of glacial acetic acid solution of 4-aminopyridine and NaCNO in 25ml of warm water was conducted by Singh et al [52]. The mixture was stirred and allowed to stand for 4 hours, thereafter; the product was obtained by filtration, washed with water, dried in an oven below the melting point and recrystallized from ethanol to afford key intermediate.…”

“…Also, simple or complex structures with a grafted moiety of aminopyridine have been reported to be effective as antitumor, antidiabetic, antimicrobial, antiviral, analgesic, anti-inflammatory, antiparasitic, antimalarial, antihistaminic anticonvulsant, etc. [52]. 2-Aminopyridine derivatives have attracted considerable interest recently, though well known for a long time, because of their applications in various fields, especially in pharmaceutical research.…”

Inhibitory potential of nitrogen, oxygen and sulfur containing heterocyclic scaffolds against acetylcholinesterase and butyrylcholinesterase

“…The hydroxyl group of one of these compounds' phenyl rings was observed forming an H-bond with Tyr-70 in docking studies, and Tyr-70 appears to play a dual role in the active centre: (a) its hydroxyl appears to maintain the functional orientation of Phe-288 and Tyr-70 by hydrogen bonding, and (b) its aromatic moiety appears to maintain the functional orientation of the anionic subsite Trp-84. Compounds 286 and 287 were discovered as the most potent species in an AChE inhibition and passive avoidance test, which could lead to the discovery of new cognition enhancers soon 281 ( Table 13 ).…”