Synthesis of Novel 2,3-Dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl) inden-1-one Derivatives as Acetyl Cholinesterase Inhibitors

Author(s): Salekoppal B.B. Prasad, Sachin Mysore, C.S. Ashok Raj, Kanchugarakoppalu S. Rangappa, K. Mahadevaiah, Channapillekoppal S.A. Kumar*

Journal Name: Current Bioactive Compounds

Volume 16 , Issue 3 , 2020

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Graphical Abstract:


Background: Novel carboxamides and thioureas of 2,3-dihydro-5,6-dimethoxy-2-((piperidin- 4-yl)methyl) inden-1-one were synthesized and their potential anticholinesterase activities were evaluated. The inhibition potency of the compounds 17a-j and 19a-j against AChE was measured and evaluated using Ellman’s spectrophotometric method. Among carboxamides series, compound 17f, 17i, 17j and among thiourea series, compound 19a, 19b were found to be the most active.

Methods: The scaffold 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl) inden-1-one 16, key intermediate of drug donepezil has been synthesised in three steps and derivatised as carboxamides and thioureas for SAR studies. Compounds 17a-j and 19a-j were characterised by 1H NMR and LCMS. The inhibitory activity and antiamnesic effect were studied using different sources such as electric eel AChE, human serum AChE and rat brain homogenate AChE.

Results: The results of bioassays indicated that among all the synthesized compounds tested, five compounds 17f, 17i, 17j, 19a and 19b shows IC50 at a dose of 67, 42, 64, 52 and 63 nM respectively against electric eel, human serum and rat brain homogenate, which lead to the suggestion that compound 17i might be considered to be a potent AChE inhibitor.

Conclusion: Derivatives of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one with different substitutions were synthesised and tested for their AChE activity. The order of potency is 17i>17j>17f and 19a>19b. The other compounds screened failed to elicit any inhibition of acetyl cholinesterase from rat brain homogenate. It may be concluded from this study that, for effective binding and blocking the AChE activity, molecule needs to bind with peripheral site and active site of the enzyme. Therefore, it can be summarized that by changing the functional group and substitution in the scaffold 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one needs to be studied for better AChE inhibitory activity in future research.

Keywords: Donepezil, carboxamide, thiourea, electric eel AChE, human serum AChE and rat brain homogenate AChE.

Castellani, R.J.; Rolston, R.K.; Smith, M.A. Alzheimer disease. Dis. Mon., 2010, 56(9), 484-546.
[] [PMID: 20831921]
Terry, A.V., Jr; Buccafusco, J.J. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J. Pharmacol. Exp. Ther., 2003, 306(3), 821-827.
[] [PMID: 12805474]
Perl, D.P. Neuropathology of Alzheimer’s disease. Mt. Sinai J. Med., 2010, 77(1), 32-42.
[] [PMID: 20101720]
Yurttaş, L.; Kaplancıklı, Z.A.; Özkay, Y. Design, synthesis and evaluation of new thiazole-piperazines as acetylcholinesterase inhibitors. J. Enzyme Inhib. Med. Chem., 2013, 28(5), 1040-1047.
[] [PMID: 22871134]
Altintop, M.D.; Kaplancikli, Z.A.; Ozdemir, A.; Turan-Zitouni, G.; Temel, H.E.; Akalın, G. Synthesis and anticholinesterase activity and cytotoxicity of novel amide derivatives. Arch. Pharm. (Weinheim), 2012, 345(2), 112-116.
[] [PMID: 22006836]
Turan-Zitouni, G.; Ozdemir, A.; Kaplancikli, Z.A.; Altintop, M.D.; Temel, H.E.; Çiftçi, G.A. Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors. J. Enzyme Inhib. Med. Chem., 2013, 28(3), 509-514.
[] [PMID: 22299580]
Massoud, F.; Léger, G.C. Pharmacological treatment of Alzheimer disease. Can. J. Psychiatry, 2011, 56(10), 579-588.
[] [PMID: 22014690]
Winslow, B.T.; Onysko, M.K.; Stob, C.M.; Hazlewood, K.A. Treatment of Alzheimer disease. Am. Fam. Physician, 2011, 83(12), 1403-1412.
[PMID: 21671540]
Colović, M.B.; Krstić, D.Z.; Lazarević-Pašti, T.D.; Bondžić, A.M.; Vasić, V.M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr. Neuropharmacol., 2013, 11(3), 315-335.
[] [PMID: 24179466]
Perry, E.K.; Tomlinson, B.E.; Blessed, G.; Bergmann, K.; Gibson, P.H.; Perry, R.H. Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. BMJ, 1978, 2(6150), 1457-1459.
[] [PMID: 719462]
Klockgether, T.; Wüllner, U.; Steinbach, J.P.; Petersen, V.; Turski, L.; Löschmann, P.A. Effects of the antiparkinsonian drug budipine on central neurotransmitter systems. Eur. J. Pharmacol., 1996, 301(1-3), 67-73.
[] [PMID: 8773448]
Fletcher, S.R.; Burkamp, F.; Blurton, P.; Cheng, S.K.; Clarkson, R.; O’Connor, D.; Spinks, D.; Tudge, M.; van Niel, M.B.; Patel, S.; Chapman, K.; Marwood, R.; Shepheard, S.; Bentley, G.; Cook, G.P.; Bristow, L.J.; Castro, J.L.; Hutson, P.H.; MacLeod, A.M. 4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists. J. Med. Chem., 2002, 45(2), 492-503.
[] [PMID: 11784153]
Willoughby, C.A.; Berk, S.C.; Rosauer, K.G.; Degrado, S.; Chapman, K.T.; Gould, S.L.; Springer, M.S.; Malkowitz, L.; Schleif, W.A.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen, R.; Holmes, K.; Lineberger, J.; Carella, A.; Carver, G.; Emini, E.A. Combinatorial synthesis of CCR5 antagonists. Bioorg. Med. Chem. Lett., 2001, 11(24), 3137-3141.
[] [PMID: 11720860]
Yang, L.; Morriello, G.; Patchett, A.A.; Leung, K.; Jacks, T.; Cheng, K.; Schleim, K.D.; Feeney, W.; Chan, W.W.; Chiu, S.H.; Smith, R.G. 1-[2(R)-(2-amino-2-methylpropionylamino)-3-(1H-indol-3-yl)propionyl]- 3-benzylpiperidine-3(S)-carboxylic acid ethyl ester (L-163,540): a potent, orally bioavailable, and short-duration growth hormone secretagogue. J. Med. Chem., 1998, 41(14), 2439-2441.
[] [PMID: 9651148]
Ramalingan, C.; Balasubramanian, S.; Kabilan, S.; Vasudevan, M. Synthesis and microbiological evaluation of spiro piperidinyl heterocycles. Med. Chem. Res., 2003, 12(1), 41-44.
Ramalingan, C.; Balasubramanian, S.; Kabilan, S.; Vasudevan, M. Synthesis and study of antibacterial and antifungal activities of novel 1-[2-(benzoxazol-2-yl)ethoxy]- 2,6-diarylpiperidin-4-ones. Eur. J. Med. Chem., 2004, 39(6), 527-533.
[] [PMID: 15183911]
Amat, M.; Hidalgo, J.; Bosch, J. Corrigendum. Synthesis of enantiopure 3,4-disubstituted piperidines. An asymmetric synthesis of (+)-paroxetine. Tet. Symmetry (Basel), 1996, 7, 1591-1594.
Contreras, J.M.; Parrot, I.; Sippl, W.; Rival, Y.M.; Wermuth, C.G. Design, synthesis, and structure-activity relationships of a series of 3-[2-(1-benzylpiperidin-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors. J. Med. Chem., 2001, 44(17), 2707-2718.
[] [PMID: 11495583]
Yan, P.Y.; Shi, B.W.; Guo, H.G.; Zhe, S.Q. Synthesis and studies on anticonvulsant and antibacterial activities of 1-alkyl-4-(4H-1,2,4-triazol-4-yl)piperidine derivatives. Lett. Drug Des. Discov., 2014, 11(9), 1070-1078.
Behjat, P.; Mohammad, M.; Setareh, M.; Loghman, F.; Hamid, N.; Alireza, M.; Esmat, T.K.; Ali, A.; Alireza, F. Synthesis and antiacetylcholinesterase activity evaluation of new 2-aryl benzofuran derivatives. Lett. Drug Des. Discov., 2016, 13(9), 897-902.
Padmanilayam, M.; Scorneaux, B.; Dong, Y.; Chollet, J.; Matile, H.; Charman, S.A.; Creek, D.J.; Charman, W.N.; Tomas, J.S.; Scheurer, C.; Wittlin, S.; Brun, R.; Vennerstrom, J.L. Antimalarial activity of N-alkyl amine, carboxamide, sulfonamide, and urea derivatives of a dispiro-1,2,4-trioxolane piperidine. Bioorg. Med. Chem. Lett., 2006, 16(21), 5542-5545.
[] [PMID: 16931006]
Reddy, P.A.; Woodward, K.E.; McIlheran, S.M.; Hsiang, B.C.; Latifi, T.N.; Hill, M.W.; Rothman, S.M.; Ferrendelli, J.A.; Covey, D.F. Synthesis and anticonvulsant activities of 3,3-dialkyl- and 3-alkyl-3-benzyl-2-piperidinones (delta-valerolactams) and hexahydro-2H-azepin-2-ones (epsilon-caprolactams). J. Med. Chem., 1997, 40(1), 44-49.
[] [PMID: 9016327]
Hill, M.W.; Reddy, P.A.; Covey, D.F.; Rothman, S.M. Inhibition of voltage-dependent sodium channels by the anticonvulsant γ-aminobutyric acid type A receptor modulator, 3-benzyl-3-ethyl-2-piperidinone. J. Pharmacol. Exp. Ther., 1998, 285(3), 1303-1309.
[PMID: 9618437]
Prasad, S.B.; Kumar, Y.C.; Kumar, C.S.; Sadashiva, C.T.; Vinaya, K.; Rangappa, K.S. Synthesis of Novel 3-Aryl-N-Methyl-1,2,5,6-Tetrahydropyridine Derivatives by Suzuki coupling: As Acetyl Cholinesterase Inhibitors. Open Med. Chem. J., 2007, 1, 4-10.
[] [PMID: 19662135]
Ananda Kumar, C.S.; Prasad, S.B.; Vinaya, K.; Chandrappa, S.; Thimmegowda, N.R.; Ranganatha, S.R.; Swarup, S.; Rangappa, K.S. Synthesis and antiproliferative activity of substituted diazaspiro hydantoins: a structure-activity relationship study. Invest. New Drugs, 2009, 27(2), 131-139.
[] [PMID: 18607541]

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Article Details

Year: 2020
Published on: 11 June, 2020
Page: [348 - 357]
Pages: 10
DOI: 10.2174/1573407214666181113112352
Price: $65

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