SYNTHESIS AND ACETYLCHOLINESTERASE/BUTYRYLCHOLINESTERASE INHIBITION ACTIVITY OF ARECOLINE-, 4-THIAZOLIDINONE- AND PIPERIDINE- BASED CONJUGATES
Objective: The aim of the study is to design, synthesize and identification of novel acetylcholinesterase/butyrylcholinesterase (AChE/BuChE)
Methods: The AChE and BuChE inhibition activity of a library of piperidine and 4-thiazolidinone substituted arecoline derivatives are described. The
chemical structures of newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral analysis.
Results: The cholinesterase inhibition assays indicated that few of the synthesized compounds exhibited considerable activity at micromolar range
for AChE over BuChE. Compound 7c exhibited the most potent AChE inhibitory activity with an IC50 value of 6.62 Î¼M for AChE and 13.78 Î¼M for BuChE,
which is comparable to the standard Neostigmine with an IC50 2.05 Î¼M for AChE and 3.64 Î¼M for BuChE respectively.
Conclusion: Our results clearly demonstrate that arecoline-4-thiazolidinone derivatives open up a new avenue in the field of Alzheimerâ€™s disease.
Keywords: Arecoline analogs, Propylphosphonic anhydride (T3PÂ®), Acetylcholinesterase/butyrylcholinesterase inhibitor, 4-thiazolidinones.
2. Jagdeep SD, Prasad DN, Avinash CT, Rajiv G. Role of traditional medicine in neuropsychopharmacology. Asian J Pharm Clin Res 2009;2(2):72-6.
3. Blokland A. Acetylcholine: A neurotransmitter for learning and memory? Brain Res Brain Res Rev 1995;21(3):285-300.
4. Sine SM. End-plate acetylcholine receptor: Structure, mechanism, pharmacology, and disease. Physiol Rev 2012;92(3):1189-234.
5. Greig NH, Utsuki T, Yu Q, Zhu X, Holloway HW, Perry T, et al. A new therapeutic target in Alzheimerâ€™s disease treatment: Attention to butyrylcholinesterase. Curr Med Res Opin 2001;17(3):159-65.
6. Colovic MB, Krstic DZ, Lazarevic-PaÅ¡ti TD, BondÅ¾ic AM, Vasic VM. Acetylcholinesterase inhibitors: Pharmacology and toxicology. Curr Neuropharmacol 2013;11(3):315-35.
7. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimerâ€™s disease: A review of progress. J Neurol Neurosurg Psychiatry 1999;66(2):137-47.
8. Holden M, Kelly C. Use of cholinesterase inhibitors in dementia. Adv Psychiatr Treat 2002;8(2):89-96.
9. Terry AV Jr, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimerâ€™s disease-related cognitive deficits: Recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003;306(3):821-7.
10. Murray AP, Faraoni MB, Castro MJ, Alza NP, Cavallaro V. Natural AChE Inhibitors from Plants and their Contribution to Alzheimerâ€™s Disease Therapy. Curr Neuropharmacol 2013;11(4):388-413.
11. Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, et al. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: A systematic review and meta-analysis. Can Med Assoc J 2013;185(16):1393-401.
12. Adams RL, Craig PL, Parsons OA. Neuropsychology of dementia. Neurol Clin 1986;4(2):387-404.
13. Chang YF, Liu TY, Liu ST. Arecoline inhibits and destabilizes agrinâ€‘induced acetylcholine receptor cluster formation in C2C12 myotubes. Food Chem Toxicol 2013;60:391-6.
14. Bartolomeo AC, Morris H, Boast CA. Arecoline via miniosmotic pump improves AF64A-impaired radial maze performance in rats: A possible model of Alzheimerâ€™s disease. Neurobiol Learn Mem 1997;68(3):333â€‘42.
15. Asthana S, Greig NH, Holloway HW, Raffaele KC, Berardi A, Schapiro MB, et al. Clinical pharmacokinetics of arecoline in subjects with Alzheimerâ€™s disease. Clin Pharmacol Ther 1996;60(3):276-82.
16. Sadashiva CT, Chandra JN, Kavitha CV, Thimmegowda A, Subhash MN, Rangappa KS. Synthesis and pharmacological evaluation of novel N-alkyl/aryl substituted thiazolidinone arecoline analogues as muscarinic receptor 1 agonist in Alzheimerâ€™s dementia models. Eur J Med Chem 2009;44(12):4848-54.
17. Malviya M, Kumar YC, Mythri RB, Venkateshappa C, Subhash MN, Rangappa KS. Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimerâ€™s presenile dementia models. Bioorg Med Chem 2009;17(15):5526-34.
18. Sharath Kumar KS, Hanumappa A, Hegde M, Narasimhamurthy KH, Raghavan SC, Rangappa KS. Synthesis and antiproliferative effect of novel 4-thiazolidinone-, pyridine- and piperazine-based conjugates on human leukemic cells. Eur J Med Chem 2014;81:341-9.
19. Sharath Kumar KS, Swaroop TR, Harsha KB, Narasimhamurthy KH, Rangappa KS. T3PÂ®-DMSO mediated one pot cascade protocol for the synthesis of 4-thiazolidinones from alcohols. Tetrahedron Lett 2012;53:5619-23.
20. Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961;7:88-95.
21. Chandra JN, Malviya M, Sadashiva CT, Subhash MN, Rangappa KS. Effect of novel arecoline thiazolidinones as muscarinic receptor 1 agonist in Alzheimerâ€™s dementia models. Neurochem Int 2008;52(3):376-83.
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