Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design, Synthesis and Biological Evaluation of New Cycloalkyl Fused Quinolines Tethered to Isatin Schiff Bases as Cholinesterase Inhibitors

Author(s): Baswaraju Macha, Ravindra Kulkarni, Anil Kumar Garige, Rambabu Palabindala, Raghuramrao Akkinepally and Achaiah Garlapati*

Volume 25, Issue 1, 2022

Published on: 10 December, 2020

Page: [167 - 186] Pages: 20

DOI: 10.2174/1386207323666201211092138

Price: $65

Abstract

Aims and Objective: Alzheimer’s disease is now a most prevalent neurodegenerative disease of central nervous system leading to dementia in elderly population. Numerous pathological changes have been associated in the progression of Alzheimer’s disease. One of such pathological hypotheses is declined cholinergic activity which eventually leads to cognitive and memory deficits. Inhibition o f cholinesterases will apparently elevate acetyl choline levels which is benefactor on cognitive symptoms of the disease. This manuscript describes the new tacrine derivatives tethered to isatin Schiff bases through alkanoyl linker and screened for cholinesterase inhibitory activity.

Materials and Methods: Tacrine and two more cycloalkyl ring fused quinolones were synthesized and converted to N-cycloalkyl fused quinoline chloroamides. Isatin Schiff bases were also synthesized by the reaction between isatin and substituted aromatic anilines and in subsequent reaction, isatin Schiff bases were reacted with cycloalkyl fused quinolones to afford anticipated compounds 10a-i, 11a-i and 12a-i. All the compounds have been screened for acetyl- and butyrylcholinesterase inhibitory activity and in vivo behavioral studies. Binding interactions of the desired compounds have also been studied by docking them in active site of both cholinesterases.

Results: Three compounds 12d, 12e and 12h with propionyl and butyroyl linker between amine and isatin Schiff base scaffold have shown potent acetyl- and butyrylcholinesterase inhibitory activity. However most potent cholinesterase inhibitor was 13d with IC50 value of 0.71±0.004 and 1.08±0.02 μM against acetyl- and butyrylcholinesterases respectively. The hepatotoxicity of potent compounds revealed that the tested compounds were less hepatotoxic than tacrine and also exhibited encouraging in vivo behavioral studies in test animals. Docking studies of all the molecules disclosed close hydrogen bond interactions within the binding site of both cholinesterases.

Conclusion: New cycloalkyl fused quinolones tethered with alkanoyl linker to isatin Schiff bases endowed significant and potent cholinesterase inhibitory activities. Few of the compounds have also exhibited lesser hepatotoxicity and all the synthesized compounds were good in behavioral studies. Molecular docking studies also indicated close interactions in active site of cholinesterases.

Keywords: Alzheimer's disease, cholinesterase inhibitors, synthesis, behavioral studies, docking, hepatotoxicity.

« Previous Next »
Graphical Abstract

[1]
Cohen, S.I.A.; Arosio, P.; Presto, J.; Kurudenkandy, F.R.; Biverstal, H.; Dolfe, L.; Dunning, C.; Yang, X.; Frohm, B.; Vendruscolo, M.; Johansson, J.; Dobson, C.M.; Fisahn, A.; Knowles, T.P.J.; Linse, S. A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers. Nat. Struct. Mol. Biol., 2015, 22(3), 207-213.
[http://dx.doi.org/10.1038/nsmb.2971] [PMID: 25686087]
[2]
World Alzheimer Report, 2015.http://www.worldalzreport2015. org/
[3]
Boutajangout, A.; Wisniewski, T. Tau-based therapeutic approaches for Alzheimer’s disease - a mini-review. Gerontology, 2014, 60(5), 381-385.
[http://dx.doi.org/10.1159/000358875] [PMID: 24732638]
[4]
Amemori, T.; Jendelova, P.; Ruzicka, J.; Urdzikova, L.M.; Sykova, E. Alzheimer’s disease: mechanism and approach to cell therapy. Int. J. Mol. Sci., 2015, 16(11), 26417-26451.
[http://dx.doi.org/10.3390/ijms161125961] [PMID: 26556341]
[5]
Scarpini, E.; Cogiamanian, F. Alzheimer’s disease: from molecular pathogenesis to innovative therapies. Expert Rev. Neurother., 2003, 3(5), 619-630.
[http://dx.doi.org/10.1586/14737175.3.5.619] [PMID: 19810962]
[6]
Gella, A.; Durany, N. Oxidative stress in Alzheimer disease. Cell Adhes. Migr., 2009, 3(1), 88-93.
[http://dx.doi.org/10.4161/cam.3.1.7402] [PMID: 19372765]
[7]
Romero, A.; Cacabelos, R.; Oset-Gasque, M.J.; Samadi, A.; Marco-Contelles, J. Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer’s disease. Bioorg. Med. Chem. Lett., 2013, 23(7), 1916-1922.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.017] [PMID: 23481643]
[8]
Meng, Q.; Ru, J.; Zhang, G.; Shen, C.; Schmitmeier, S.; Bader, A. Re-evaluation of tacrine hepatotoxicity using gel entrapped hepatocytes. Toxicol. Lett., 2007, 168(2), 140-147.
[http://dx.doi.org/10.1016/j.toxlet.2006.11.009] [PMID: 17166674]
[9]
Singh, M.; Kaur, M.; Chadha, N.; Silakari, O. Hybrids: a new paradigm to treat Alzheimer’s disease. Mol. Divers., 2016, 20(1), 271-297.
[http://dx.doi.org/10.1007/s11030-015-9628-9] [PMID: 26328942]
[10]
Spilovska, K.; Korabecny, J.; Nepovimova, E.; Dolezal, R.; Mezeiova, E.; Soukup, O.; Kuca, K. Multitarget tacrine hybrids with neuroprotective properties to confront alzheimer’s disease. Curr. Top. Med. Chem., 2017, 17(9), 1006-1026.
[http://dx.doi.org/10.2174/1568026605666160927152728] [PMID: 27697055]
[11]
Li, S.Y.; Jiang, N.; Xie, S.S.; Wang, K.D.; Wang, X.B.; Kong, L.Y. Design, synthesis and evaluation of novel tacrine-rhein hybrids as multifunctional agents for the treatment of Alzheimer’s disease. Org. Biomol. Chem., 2014, 12(5), 801-814.
[http://dx.doi.org/10.1039/C3OB42010H] [PMID: 24310227]
[12]
Xie, S.S.; Wang, X.; Jiang, N.; Yu, W.; Wang, K.D.; Lan, J.S.; Li, Z.R.; Kong, L.Y. Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer’s disease. Eur. J. Med. Chem., 2015, 95, 153-165.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.040] [PMID: 25812965]
[13]
Rodríguez-Franco, M.I.; Fernández-Bachiller, M.I.; Pérez, C.; Hernández-Ledesma, B.; Bartolomé, B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J. Med. Chem., 2006, 49(2), 459-462.
[http://dx.doi.org/10.1021/jm050746d] [PMID: 16420031]
[14]
Fancellu, G.; Chand, K.; Tomás, D.; Orlandini, E.; Piemontese, L.; Silva, D.F.; Cardoso, S.M.; Chaves, S.; Santos, M.A. Novel tacrine-benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 211-226.
[http://dx.doi.org/10.1080/14756366.2019.1689237] [PMID: 31760822]
[15]
Rajeshwari, R.; Chand, K.; Candeias, E.; Cardoso, S.M.; Chaves, S.; Santos, M.A. New multitarget hybrids bearing tacrine and phenylbenzothiazole motifs as potential drug candidates for alzheimer’s disease. Molecules, 2019, 24(3), 1-15.
[http://dx.doi.org/10.3390/molecules24030587] [PMID: 30736397]
[16]
Riazimontazer, E.; Sadeghpour, H.; Nadri, H.; Sakhteman, A.; Tüylü Küçükkılınç, T.; Miri, R.; Edraki, N. Design, synthesis and biological activity of novel tacrine-isatin Schiff base hybrid derivatives. Bioorg. Chem., 2019, 89.
[http://dx.doi.org/10.1016/j.bioorg.2019.103006] [PMID: 31158577]
[17]
Zhang, C.; Du, Q.Y.; Chen, L.D.; Wu, W.H.; Liao, S.Y.; Yu, L.H.; Liang, X.T. Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer’s disease. Eur. J. Med. Chem., 2016, 116, 200-209.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.077] [PMID: 27061983]
[18]
Ozgun, D.O.; Yamali, C.; Gul, H.I.; Taslimi, P.; Gulcin, I.; Yanik, T.; Supuran, C.T. Inhibitory effects of isatin Mannich bases on carbonic anhydrases, acetylcholinesterase, and butyrylcholinesterase. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1498-1501.
[http://dx.doi.org/10.3109/14756366.2016.1149479] [PMID: 26928426]
[19]
Hanish Singh, J.C.; Alagarsamy, V.; Diwan, P.V.; Sathesh Kumar, S.; Nisha, J.C.; Narsimha Reddy, Y. Neuroprotective effect of Alpinia galanga (L.) fractions on Aβ(25-35) induced amnesia in mice. J. Ethnopharmacol., 2011, 138(1), 85-91.
[http://dx.doi.org/10.1016/j.jep.2011.08.048] [PMID: 21911048]
[20]
Almoazen, H.; Bhattacharjee, H.; Samsa, A.C.; Pate, S. Stability of mesna in ReadyMed infusion devices. Ann. Pharmacother., 2010, 44(1), 224-225.
[http://dx.doi.org/10.1345/aph.1M390] [PMID: 20028956]
[21]
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, 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[22]
Goodarzi, Z.; Mele, B.; Guo, S.; Hanson, H.; Jette, N.; Patten, S.; Pringsheim, T.; Holroyd-Leduc, J. Guidelines for dementia or Parkinson’s disease with depression or anxiety: A systematic review. BMC Neurol., 2016, 16(1), 244-248.
[http://dx.doi.org/10.1186/s12883-016-0754-5] [PMID: 27887589]
[23]
Conrad, C.D.; Lupien, S.J.; Thanasoulis, L.C.; McEwen, B.S. The effects of type I and type II corticosteroid receptor agonists on exploratory behavior and spatial memory in the Y-maze. Brain Res., 1997, 759(1), 76-83.
[http://dx.doi.org/10.1016/S0006-8993(97)00236-9] [PMID: 9219865]
[24]
Buresová, O.; Bures, J.; Oitzl, M.S.; Zahálka, A. Radial maze in the water tank: an aversively motivated spatial working memory task. Physiol. Behav., 1985, 34(6), 1003-1005.
[http://dx.doi.org/10.1016/0031-9384(85)90028-9] [PMID: 4059369]
[25]
Shear, D.A.; Dong, J.; Haik-Creguer, K.L.; Bazzett, T.J.; Albin, R.L.; Dunbar, G.L. Chronic administration of quinolinic acid in the rat striatum causes spatial learning deficits in a radial arm water maze task. Exp. Neurol., 1998, 150(2), 305-311.
[http://dx.doi.org/10.1006/exnr.1998.6767] [PMID: 9527900]
[26]
Barros, D.M.; Izquierdo, L.A.; Mello e Souza, T.; Ardenghi, P.G.; Pereira, P.; Medina, J.H.; Izquierdo, I. Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats. Behav. Brain Res., 2000, 114(1-2), 183-192.
[http://dx.doi.org/10.1016/S0166-4328(00)00226-6] [PMID: 10996059]
[27]
Bornschein, R.L.; Hastings, L.; Manson, J.M. Behavioral toxicity in the offspring of rats following maternal exposure to dichloromethane. Toxicol. Appl. Pharmacol., 1980, 52(1), 29-37.
[http://dx.doi.org/10.1016/0041-008X(80)90244-6] [PMID: 7361313]
[28]
Garofalo, P.; Colombo, S.; Lanza, M.; Revel, L.; Makovec, F. CR 2249: a new putative memory enhancer. Behavioural studies on learning and memory in rats and mice. J. Pharm. Pharmacol., 1996, 48(12), 1290-1297.
[http://dx.doi.org/10.1111/j.2042-7158.1996.tb03938.x] [PMID: 9004193]
[29]
Adewale, O.B.; Adekeye, A.O.; Akintayo, C.O.; Onikanni, A.; Saheed, S. Carbon tetrachloride (CCl4)-induced hepatic damage in experimental Sprague Dawley rats: Antioxidant potential of Xylopia aethiopica. J. Phyto. Pharmacology., 2014, 3, 118-123.
[30]
Al-Harbi, N.O.; Imam, F.; Nadeem, A.; Al-Harbi, M.M.; Iqbal, M.; Ahmad, S.F.; Ahmad, S.F. Carbon tetrachloride-induced hepatotoxicity in rat is reversed by treatment with riboflavin. Int. Immunopharmacol., 2014, 21(2), 383-388.
[http://dx.doi.org/10.1016/j.intimp.2014.05.014] [PMID: 24874442]
[31]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[32]
Cosconati, S.; Forli, S.; Perryman, A.L.; Harris, R.; Goodsell, D.S.; Olson, A.J. Virtual screening with autodock: theory and practice. Expert Opin. Drug Discov., 2010, 5(6), 597-607.
[http://dx.doi.org/10.1517/17460441.2010.484460] [PMID: 21532931]

Rights & Permissions Print Cite
Article Metrics
30
4
1
1
© 2024 Bentham Science Publishers | Privacy Policy