Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase
and COX for Treatment of Alzheimer’s Disease

Sukhvir      Kaur; Richa      Minhas; Shivam      Mishra; Birpal      Kaur; Yogita      Bansal; Gulshan      Bansal

doi:10.2174/1871524922666220428134001

Abstract

Background: A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues.

Objective: The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models.

Methods: The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, ¹H-NMR, ¹³C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation.

Results: Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil.

Conclusion: The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.

Keywords: NsCOXi, Alzheimer’s disease, acetylcholinesterase inhibitor, hybrid, benzimidazole, ibuprofen, naproxen.

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[1] 
Martorana, A.; Esposito, Z.; Koch, G. Beyond the cholinergic hypothesis: Do current drugs work in Alzheimer’s disease? CNS Neurosci. Ther.,  2010, 16(4), 235-245.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00175.x] [PMID:  20560995] 
[2] 
Hansen, R.A.; Gartlehner, G.; Lohr, K.N.; Kaufer, D.I. Functional outcomes of drug treatment in Alzheimer’s disease: A systematic review and meta-analysis. Drugs Aging,  2007, 24(2), 155-167.
[http://dx.doi.org/10.2165/00002512-200724020-00007] [PMID:  17313203] 
[3] 
Medina-Franco, J.L.; Giulianotti, M.A.; Welmaker, G.S.; Houghten, R.A. Shifting from the single to the multitarget paradigm in drug dis-covery. Drug Discov. Today,  2013, 18(9-10), 495-501.
[http://dx.doi.org/10.1016/j.drudis.2013.01.008] [PMID:  23340113] 
[4] 
Zhang, C.; Wang, Y.; Wang, D.; Zhang, J.; Zhang, F. NSAID exposure and risk of Alzheimer’s disease: An updated meta-analysis from cohort studies. Front. Aging Neurosci.,  2018, 10, 83.
[http://dx.doi.org/10.3389/fnagi.2018.00083] [PMID:  29643804] 
[5] 
Etminan, M.; Gill, S.; Samii, A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: Systematic review and meta-analysis of observational studies. BMJ,  2003, 327(7407), 128.
[http://dx.doi.org/10.1136/bmj.327.7407.128] [PMID:  12869452] 
[6] 
Wang, J.; Tan, L.; Wang, H.F.; Tan, C.C.; Meng, X.F.; Wang, C.; Tang, S.W.; Yu, J.T. Anti-inflammatory drugs and risk of Alzheimer’s disease: An updated systematic review and meta-analysis. J. Alzheimers Dis.,  2015, 44(2), 385-396.
[http://dx.doi.org/10.3233/JAD-141506] [PMID:  25227314] 
[7] 
McGeer, P.L.; McGeer, E.G. NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies. Neurobiol. Aging,  2007, 28(5), 639-647.
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.03.013] [PMID:  16697488] 
[8] 
Azam, F.; Alabdullah, N.H.; Ehmedat, H.M.; Abulifa, A.R.; Taban, I.; Upadhyayula, S. NSAIDs as potential treatment option for preventing amyloid β toxicity in Alzheimer’s disease: An investigation by docking, molecular dynamics, and DFT studies. J. Biomol. Struct. Dyn.,  2018, 36(8), 2099-2117.
[http://dx.doi.org/10.1080/07391102.2017.1338164] [PMID:  28571516] 
[9] 
Young, S.; Fabio, K.; Guillon, C.; Mohanta, P.; Halton, T.A.; Heck, D.E.; Flowers, R.A., II; Laskin, J.D.; Heindel, N.D. Peripheral site acetylcholinesterase inhibitors targeting both inflammation and cholinergic dysfunction. Bioorg. Med. Chem. Lett.,  2010, 20(9), 2987-2990.
[http://dx.doi.org/10.1016/j.bmcl.2010.02.102] [PMID:  20347302] 
[10] 
River-Auty, J.; Mater, E.A.; Peters, R.; Lawrence, B.C.; David, B. Antiinflammatories in Alzheimer’s disease-potential therapy or spurious correlate? Brain Commun.,  2020, 2(2), fcaa109.
[11] 
Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: A review. Bioorg. Med. Chem.,  2012, 20(21), 6208-6236.
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID:  23031649] 
[12] 
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol.,  1961, 7(2), 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID:  13726518] 
[13] 
Minhas, R.; Bansal, G.; Bansal, Y. Novel coupled molecules from active structural motifs of synthetic and natural origin as immunosup-pressants. Med. Chem.,  2020, 16(4), 544-554.
[http://dx.doi.org/10.2174/1573406415666190409111459] [PMID:  30963980] 
[14] 
Xie, W.L.; Chipman, J.G.; Robertson, D.L.; Erikson, R.L.; Simmons, D.L. Expression of a mitogen-responsive gene encoding prostaglan-din synthase is regulated by mRNA splicing. Proc. Natl. Acad. Sci. USA,  1991, 88(7), 2692-2696.
[http://dx.doi.org/10.1073/pnas.88.7.2692] [PMID:  1849272] 
[15] 
Reines, S.A.; Block, G.A.; Morris, J.C.; Liu, G.; Nessly, M.L.; Lines, C.R.; Norman, B.A.; Baranak, C.C. Rofecoxib Protocol 091 Study Group. Rofecoxib: No effect on Alzheimer’s disease in a 1-year, randomized, blinded, controlled study. Neurology,  2004, 62(1), 66-71.
[http://dx.doi.org/10.1212/WNL.62.1.66] [PMID:  14718699] 
[16] 
Ohkawa, H.; Ohishi, N.; Yagi, K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem.,  1979, 95(2), 351-358.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID:  36810] 
[17] 
Beutler, E.; Duron, O.; Kelly, B.M. Improved method for the determination of blood glutathione. J. Lab. Clin. Med.,  1963, 61, 882-888.
[PMID:  13967893] 

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DOI https://dx.doi.org/10.2174/1871524922666220428134001	Print ISSN 1871-5249
Publisher Name Bentham Science Publisher	Online ISSN 1875-6166

Central Nervous System Agents in Medicinal Chemistry

Design, Synthesis and Evaluation of Benzimidazole Hybrids to Inhibit Acetylcholinesterase and COX for Treatment of Alzheimer’s Disease

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