Synthesis, In vitro and In silico Evaluation of a Series of Pyrazolines as New Anticholinesterase Agents

Author(s): Mehlika Dilek Altıntop*

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 5 , 2020

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Pyrazolines, electron-rich nitrogen carriers, are of great importance due to their potential applications for the treatment of many diseases including inflammation, infectious diseases and neurodegenerative disorders.

Objectives: The purpose of this work was to synthesize new pyrazoline derivatives and evaluate their anticholinesterase effects.

Methods: 1-Aryl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (1-7) were synthesized via the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(piperidin-1-yl)phenyl]prop-2- en-1-one with arylhydrazine hydrochloride derivatives in acetic acid, whereas 1-aryl-5-[4- (morpholin-4-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (8-14) were obtained by the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one with arylhydrazine hydrochloride derivatives in acetic acid. Their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were determined using a modification of Ellman’s spectrophotometric method. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were performed using Schrödinger’s Maestro molecular modeling package.

Results: In general, piperidine derivatives were found to be more effective than morpholine derivatives on cholinesterases (ChEs). 1-Phenyl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)- 4,5-dihydro-1H-pyrazole (1) and 1-(4-cyanophenyl)-5-[4-(piperidin-1-yl)phenyl]-3-(3,4- dimethoxyphenyl)-4,5-dihydro-1H-pyrazole (7) were identified as the most effective AChE inhibitors in this series with 40.92% and 38.98%, respectively. Compounds 1 and 7 were docked into the active site of human AChE (PDB code: 4EY7). Both the compounds were found to be capable of forming π-π stacking interactions with Trp286. Based on in silico ADME studies, these compounds are expected to have reasonable oral bioavailability.

Conclusion: In the view of this work, the structural modification of the identified agents is going on for the generation of new anticholinesterase agents with enhanced efficacy.

Keywords: Acetylcholinesterase, molecular docking, piperidine, pyrazoline, anticholinesterase agents, ADME.

Lett Drug Des Discov Gulhan T-Z. 15 414 2018 10.2174/1570180814666170704144917 Gulhan T-Z.; Fighting against Alzheimer’s Disease: Synthesis of new pyrazoline and benzothiazole derivatives as new acetylcholinesterase and MAO inhibitors. Lett Drug Des Discov 2018,15(4),414-427 Hum Mol Genet Crews L. 19 R12 2010 10.1093/hmg/ddq160 Crews L.; Masliah E.; Molecular mechanisms of neurodegeneration in Alzheimer’s disease. Hum Mol Genet 2010,19(R1),R12-R20 BioMed Res Int Lu R-C. 2014 10.1155/2014/435203 Lu R-C.; Heat shock protein 70 in Alzheimer’s disease. BioMed Res Int 2014 Lett Drug Des Discov Maryam N. 15 1131 2018 10.2174/1570180815666180115144608 Maryam N.; Design, Synthesis and Characterization of Novel Urolithin Derivatives as Cholinesterase Inhibitor Agents. Lett Drug Des Discov 2018,15(11),1131-1140 Eur J Med Chem Chen S-C. 147 194 2018 10.1016/j.ejmech.2018.02.002 Chen S-C.; Qiu G.L.; Li B.; Shi J.B.; Liu X.H.; Tang W.J.; Tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one scaffold derivatives: Synthesis and biological evaluation as selective BuChE inhibitors. Eur J Med Chem 2018,147,194-204 Science Hardy J. 297 353 2002 10.1126/science.1072994 Hardy J.; Selkoe D.J.; The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002,297(5580),353-356 Vitam Horm Weisman D. 74 505 2006 10.1016/S0083-6729(06)74020-1 Weisman D.; Hakimian E.; Ho G.J.; Interleukins, inflammation, and mechanisms of Alzheimer’s disease. Vitam Horm 2006,74,505-530 Curr Med Chem Bajda M. 18 4949 2011 10.2174/092986711797535245 Bajda M.; Guzior N.; Ignasik M.; Malawska B.; Multi-target-directed ligands in Alzheimer’s disease treatment. Curr Med Chem 2011,18(32),4949-4975 Pharmacol Res Sonkusare S.K. 51 1 2005 10.1016/j.phrs.2004.05.005 Sonkusare S.K.; Kaul C.L.; Ramarao P.; Dementia of Alzheimer’s disease and other neurodegenerative disorders--memantine, a new hope. Pharmacol Res 2005,51(1),1-17 Ann Intern Med Raina P. 148 379 2008 10.7326/0003-4819-148-5-200803040-00009 Raina P.; Santaguida P.; Ismaila A.; Patterson C.; Cowan D.; Levine M.; Booker L.; Oremus M.; Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008,148(5),379-397 Nat Rev Neurol De Strooper B. 6 99 2010 10.1038/nrneurol.2009.218 De Strooper B.; Vassar R.; Golde T.; The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010,6(2),99-107 Alzheimers Res Ther Vassar R. 6 89 2014 10.1186/s13195-014-0089-7 Vassar R.; BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther 2014,6(9),89 Bioorg Med Chem Lett Fobare W.F. 17 5353 2007 10.1016/j.bmcl.2007.08.010 Fobare W.F.; Solvibile W.R.; Robichaud A.J.; Malamas M.S.; Manas E.; Turner J.; Hu Y.; Wagner E.; Chopra R.; Cowling R.; Jin G.; Bard J.; Thiophene substituted acylguanidines as BACE1 inhibitors. Bioorg Med Chem Lett 2007,17(19),5353-5356 Eur J Med Chem Iraji A. 141 690 2017 10.1016/j.ejmech.2017.09.057 Iraji A.; Firuzi O.; Khoshneviszadeh M.; Tavakkoli M.; Mahdavi M.; Nadri H.; Edraki N.; Miri R.; Multifunctional iminochromene-2H-carboxamide derivatives containing different aminomethylene triazole with BACE1 inhibitory, neuroprotective and metal chelating properties targeting Alzheimer’s disease. Eur J Med Chem 2017,141,690-702 Bioorg Med Chem Edraki N. 21 2396 2013 10.1016/j.bmc.2013.01.064 Edraki N.; Firuzi O.; Foroumadi A.; Miri R.; Madadkar-Sobhani A.; Khoshneviszadeh M.; Shafiee A.; Phenylimino-2H-chromen-3-carboxamide derivatives as novel small molecule inhibitors of β-secretase (BACE1). Bioorg Med Chem 2013,21(8),2396-2412 J Med Chem Gerritz S.W. 55 9208 2012 10.1021/jm300931y Gerritz S.W.; Zhai W.; Shi S.; Zhu S.; Toyn J.H.; Meredith J.E.; Iben L.G.; Burton C.R.; Albright C.F.; Good A.C.; Tebben A.J.; Muckelbauer J.K.; Camac D.M.; Metzler W.; Cook L.S.; Padmanabha R.; Lentz K.A.; Sofia M.J.; Poss M.A.; Macor J.E.; Thompson L.A.; Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis. J Med Chem 2012,55(21),9208-9223 Bioorg Chem Iraji A. 77 223 2018 10.1016/j.bioorg.2018.01.017 Iraji A.; Firuzi O.; Khoshneviszadeh M.; Nadri H.; Edraki N.; Miri R.; Synthesis and structure-activity relationship study of multi-target triazine derivatives as innovative candidates for treatment of Alzheimer’s disease. Bioorg Chem 2018,77,223-235 J Med Chem Malamas M.S. 52 6314 2009 10.1021/jm9006752 Malamas M.S.; Erdei J.; Gunawan I.; Barnes K.; Johnson M.; Hui Y.; Turner J.; Hu Y.; Wagner E.; Fan K.; Olland A.; Bard J.; Robichaud A.J.; Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors. J Med Chem 2009,52(20),6314-6323 Bioorg Med Chem Lett Malamas M.S. 21 5164 2011 10.1016/j.bmcl.2011.07.057 Malamas M.S.; Erdei J.; Gunawan I.; Barnes K.; Hui Y.; Johnson M.; Robichaud A.; Zhou P.; Yan Y.; Solvibile W.; Turner J.; Fan K.Y.; Chopra R.; Bard J.; Pangalos M.N.; New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: exploring the S2′ region. Bioorg Med Chem Lett 2011,21(18),5164-5170 J Neurochem Ghosh A.K. 120 71 2012 10.1111/j.1471-4159.2011.07476.x Ghosh A.K.; Brindisi M.; Tang J.; Developing β-secretase inhibitors for treatment of Alzheimer’s disease. J Neurochem 2012,120(Suppl. 1),71-83 J Med Chem Qu W. 50 3380 2007 10.1021/jm070467l Qu W.; Kung M.P.; Hou C.; Oya S.; Kung H.F.; Quick assembly of 1,4-diphenyltriazoles as probes targeting β-amyloid aggregates in Alzheimer’s disease. J Med Chem 2007,50(14),3380-3387 Eur J Med Chem Delgado O. 97 719 2015 10.1016/j.ejmech.2014.12.034 Delgado O.; Delgado F.; Vega J.A.; Trabanco A.A.; N-Bridged 5,6-bicyclic pyridines: Recent applications in central nervous system disorders. Eur J Med Chem 2015,97,719-731 Expert Opin Ther Pat Kethiri R.R. 24 745 2014 10.1517/13543776.2014.907275 Kethiri R.R.; Bakthavatchalam R.; Leucine-rich repeat kinase 2 inhibitors: A review of recent patents (2011 - 2013). Expert Opin Ther Pat 2014,24(7),745-757 J Med Chem Al-Tel T.H. 54 8373 2011 10.1021/jm201181f Al-Tel T.H.; Semreen M.H.; Al-Qawasmeh R.A.; Schmidt M.F.; El-Awadi R.; Ardah M.; Zaarour R.; Rao S.N.; El-Agnaf O.; Design, synthesis, and qualitative structure-activity evaluations of novel β-secretase inhibitors as potential Alzheimer’s drug leads. J Med Chem 2011,54(24),8373-8385 J Med Chem Maillard M.C. 50 776 2007 10.1021/jm061242y Maillard M.C.; Hom R.K.; Benson T.E.; Moon J.B.; Mamo S.; Bienkowski M.; Tomasselli A.G.; Woods D.D.; Prince D.B.; Paddock D.J.; Emmons T.L.; Tucker J.A.; Dappen M.S.; Brogley L.; Thorsett E.D.; Jewett N.; Sinha S.; John V.; Design, synthesis, and crystal structure of hydroxyethyl secondary amine-based peptidomimetic inhibitors of human β-secretase. J Med Chem 2007,50(4),776-781 Bioorg Chem Gurjar A.S. 57 90 2014 10.1016/j.bioorg.2014.09.002 Gurjar A.S.; Andrisano V.; Simone A.D.; Velingkar V.S.; Design, synthesis, in silico and in vitro screening of 1,2,4-thiadiazole analogues as non-peptide inhibitors of beta-secretase. Bioorg Chem 2014,57,90-98 Eur J Med Chem Azimi S. 138 729 2017 10.1016/j.ejmech.2017.06.040 Azimi S.; Zonouzi A.; Firuzi O.; Iraji A.; Saeedi M.; Mahdavi M.; Edraki N.; Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis. Eur J Med Chem 2017,138,729-737 Arch Pharm (Weinheim) Edraki N. 348 330 2015 10.1002/ardp.201400322 Edraki N.; Firuzi O.; Fatahi Y.; Mahdavi M.; Asadi M.; Emami S.; Divsalar K.; Miri R.; Iraji A.; Khoshneviszadeh M.; Firoozpour L.; Shafiee A.; Foroumadi A.; N-(2-(Piperazin-1-yl)phenyl)arylamide derivatives as β-Secretase (BACE1) inhibitors: Simple synthesis by UGI four-component reaction and biological evaluation. Arch Pharm (Weinheim) 2015,348(5),330-337 Biochem Pharmacol Ellman G.L. 7 88 1961 10.1016/0006-2952(61)90145-9 Ellman G.L.; Courtney K.D.; Andres V.; Feather-Stone R.M.; A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961,7(2),88-95 Eur J Med Chem Kumar D. 150 87 2018 10.1016/j.ejmech.2018.02.078 Kumar D.; Gupta S.K.; Ganeshpurkar A.; Gutti G.; Krishnamurthy S.; Modi G.; Singh S.K.; Development of piperazinediones as dual inhibitor for treatment of Alzheimer’s disease. Eur J Med Chem 2018,150,87-101 Arch Pharm (Weinheim) Badran M.M. 343 590 2010 10.1002/ardp.200900226 Badran M.M.; Abdel Hakeem M.; Abuel-Maaty S.M.; El-Malah A.; Abdel Salam R.M.; Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer’s disease. Arch Pharm (Weinheim) 2010,343(10),590-601

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [574 - 584]
Pages: 11
DOI: 10.2174/1570180816666190618111023
Price: $65

Article Metrics

PDF: 28