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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Research Article

Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

Author(s): Martin Krátký*, Šárka Štěpánková, Michaela Brablíková, Katarína Svrčková, Markéta Švarcová and Jarmila Vinšová

Volume 20, Issue 23, 2020

Page: [2106 - 2117] Pages: 12

DOI: 10.2174/1568026620666200819155503

Price: $65


Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment.

Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors.

Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery.

Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes.

Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

Keywords: Acetylcholinesterase, Butyrylcholinesterase, 1, 2-diacylhydrazine, Enzyme inhibition, Hydrazides, Hydrazones.

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Narang, R.; Narasimhan, B.; Sharma, S. A review on biological activities and chemical synthesis of hydrazide derivatives. Curr. Med. Chem., 2012, 19(4), 569-612.
[] [PMID: 22204327]
Popiołek, Ł. Hydrazide-hydrazones as potential antimicrobial agents: overview of the literature since 2010. Med. Chem. Res., 2017, 26(2), 287-301.
[] [PMID: 28163562]
Rahim, F.; Ullah, H.; Taha, M.; Wadood, A.; Javed, M.T.; Rehman, W.; Nawaz, M.; Ashraf, M.; Ali, M.; Sajid, M.; Ali, F.; Khan, M.N.; Khan, K.M. Synthesis and in vitro acetylcholinesterase and butyrylcholinesterase inhibitory potential of hydrazide based Schiff bases. Bioorg. Chem., 2016, 68, 30-40.
[] [PMID: 27441832]
Al-Aboudi, A.; Al-Qawasmeh, R.A.; Shahwan, A.; Mahmood, U.; Khalid, A.; Ul-Haq, Z. In-silico identification of the binding mode of synthesized adamantyl derivatives inside cholinesterase enzymes. Acta Pharmacol. Sin., 2015, 36(7), 879-886.
[] [PMID: 25937631]
Sıcak, Y.; Oruç-Emre, E.E.; Öztürk, M.; Taşkın-Tok, T.; Karaküçük-Iyidoğan, A. Novel fluorine-containing chiral hydrazidehydrazones: Design, synthesis, structural elucidation, antioxidant and anticholinesterase activity, and in silico studies. Chirality, 2019, 31(8), 603-615.
[] [PMID: 31222828]
Parlar, S.; Sayar, G.; Tarikogullari, A.H.; Karadagli, S.S.; Alptuzun, V.; Erciyas, E.; Holzgrabe, U. Synthesis, bioactivity and molecular modeling studies on potential anti-Alzheimer piperidinehydrazidehydrazones. Bioorg. Chem., 2019, 87, 888-900.
[] [PMID: 30538051]
Huang, D.; Lüthi, U.; Kolb, P.; Cecchini, M.; Barberis, A.; Caflisch, A. In silico discovery of β-secretase inhibitors. J. Am. Chem. Soc., 2006, 128(16), 5436-5443.
[] [PMID: 16620115]
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]
Greig, N.H.; Utsuki, T.; Yu, Q.; Zhu, X.; Holloway, H.W.; Perry, T.; Lee, B.; Ingram, D.K.; Lahiri, D.K. A new therapeutic target in Alzheimer’s disease treatment: attention to butyrylcholinesterase. Curr. Med. Res. Opin., 2001, 17(3), 159-165.
[] [PMID: 11900310]
Ferreira-Vieira, T.H.; Guimaraes, I.M.; Silva, F.R.; Ribeiro, F.M. Alzheimer’s disease: targeting the cholinergic system. Curr. Neuropharmacol., 2016, 14(1), 101-115.
[] [PMID: 26813123]
Shaikh, S.; Verma, A.; Siddiqui, S.; Ahmad, S.S.; Rizvi, S.M.D.; Shakil, S.; Biswas, D.; Singh, D.; Siddiqui, M.H.; Shakil, S.; Tabrez, S.; Kamal, M.A. Current acetylcholinesterase-inhibitors: a neuroinformatics perspective. CNS Neurol. Disord. Drug Targets, 2014, 13(3), 391-401.
[] [PMID: 24059296]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7, 42717.
[] [PMID: 28256516]
Sultan, S.; Ashiq, U.; Jamal, R.A.; Mahroof-Tahir, M.; Shaikh, Z.; Shamshad, B.; Lateef, M.; Iqbal, L. Vanadium(V) complexes with hydrazides and their spectroscopic and biological properties. Biometals, 2017, 30(6), 873-891.
[] [PMID: 28994011]
Young, D.; Shaber, S.; Avila-Adame, C.; Breaux, N.; Ruiz, J.; Siddall, T.; Webster, J. Fungicidal compositions including hydrazone derivatives and copper. WO 2010083318 A2 DOW AGROSCIENCES Llc. 2010.
Kuriakose, D.; Prathapachandra Kurup, M.R. Crystal structures and supramolecular architectures of ONO donor hydrazone and solvent exchangeable dioxidomolybdenum(VI) complexes derived from 3,5-diiodosalicyaldehyde-4-methoxybenzoylhydrazone: Hirshfeld surface analysis and interaction energy calculations. Polyhedron, 2019, 170, 749-761.
Wei, Y.; Wang, F. Crystal structures of new 4-hydroxy-N′-(3,5-diiodo-2-hydroxybenzylidene)benzohydrazidemethanol and 4-hydroxy-N′-(2-methoxynaphth-1-ylmethylene) benzohydrazide dimethanol solvate. J. Struct. Chem., 2011, 52, 755-759.
Bailey, L.; Gylfe, Å.; Elofsson, M.; Wolf-Watz, H.; Nordström, P. Innate Pharmaceuticals Ab. Method and means for preventing and inhibiting respiratory disease, atherosclerosis and osteoporosis caused by Chlamydia pneumoniae infection. WO 2006132583 A1 2006.
Buu-Hoi, N.P.; Xuong, N.D.; Nam, N.H.; Binon, F.; Royer, R. Tuberculostatic hydrazides and their derivatives. J. Chem. Soc., 1953, 1953, 1358-1364.
Zdrazilova, P.; Stepankova, S.; Komers, K.; Ventura, K.; Cegan, A. Half-inhibition concentrations of new cholinesterase inhibitors. Z. Natforsch. C J. Biosci., 2004, 59(3-4), 293-296.
[] [PMID: 15241943]
Sinko, G.; Calić, M.; Bosak, A.; Kovarik, Z. Limitation of the Ellman method: cholinesterase activity measurement in the presence of oximes. Anal. Biochem., 2007, 370(2), 223-227.
[] [PMID: 17716616]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[] [PMID: 15264254]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[] [PMID: 19499576]
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.
[] [PMID: 19399780]
Filali, I.; Belkacem, M.A.; Ben Nejma, A.; Souchard, J.P.; Ben Jannet, H.; Bouajila, J. Synthesis, cytotoxic, anti-lipoxygenase and anti-acetylcholinesterase capacities of novel derivatives from harmine. J. Enzyme Inhib. Med. Chem. 2016, 31(sup1), 23-33.
[] [PMID: 27028352]
Krátký, M.; Baranyai, Z.; Štěpánková, Š.; Svrčková, K.; Švarcová, M.; Stolaříková, J.; Horváth, L.; Bősze, S.; Vinšová, J. N-Alkyl-2-[4-(trifluoromethyl)benzoyl]hydrazine-1-carboxamides and their analogues: synthesis and multitarget biological activity. Molecules, 2020, 25(10), 2268.
[] [PMID: 32408517]
Mahar Doan, K.M.; Humphreys, J.E.; Webster, L.O.; Wring, S.A.; Shampine, L.J.; Serabjit-Singh, C.J.; Adkison, K.K.; Polli, J.W. Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. J. Pharmacol. Exp. Ther., 2002, 303(3), 1029-1037.
[] [PMID: 12438524]
Rankovic, Z. CNS drug design: balancing physicochemical properties for optimal brain exposure. J. Med. Chem., 2015, 58(6), 2584-2608.
[] [PMID: 25494650]
Daina, A.; Zoete, V. A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem, 2016, 11(11), 1117-1121.
[] [PMID: 27218427]
Olender, D.; Żwawiak, J.; Zaprutko, L. Multidirectional efficacy of biologically active nitro compounds included in medicines. Pharmaceuticals (Basel), 2018, 11(2), 54.
[] [PMID: 29844300]

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