Homodimeric bis-quaternary heterocyclic ammonium salts as potent acetyl- and butyrylcholinesterase inhibitors: A systematic investigation of the influence of linker and cationic heads over affinity and selectivity

Journal of Medicinal Chemistry

Volumn 54, Issue 8, 2011, Pages 2627-2645

  Conejo García, Ana ^a   Pisani, Leonardo ^b   Del Carmen Núñez, Maria ^a   Catto, Marco ^b   Nicolotti, Orazio ^b   Leonetti, Francesco ^b   Campos, Joaquín M ^a   Gallo, Miguel A ^a   Espinosa, Antonio ^a   Carotti, Angelo ^b  

^a UNIVERSITY OF GRANADA   (Spain)

^b UNIVERSITY OF BARI   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

4 [6,7 DIMETHOXY 3,4 DIHYDROISOQUINOLIN 2(1H) YL] 1 [4 [(4 PIPERIDIN 1 YLPYRIDINIUM 1 YL)METHYL]BENZYL]PYRIDINIUM DIBROMIDE; ACETYLCHOLINESTERASE; CHOLINESTERASE; CHOLINESTERASE INHIBITOR; HETEROCYCLIC COMPOUND; PYRIDINIUM DERIVATIVE; QUATERNARY AMMONIUM DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; DRUG POTENCY; DRUG SYNTHESIS; ENZYME SPECIFICITY; IC 50; MOLECULAR MODEL; NONHUMAN; REACTION ANALYSIS;

ACETYLCHOLINESTERASE; BUTYRYLCHOLINESTERASE; CATIONS; CHOLINESTERASE INHIBITORS; DIMERIZATION; HETEROCYCLIC COMPOUNDS; MODELS, MOLECULAR; QUATERNARY AMMONIUM COMPOUNDS;

EID: 79955449571     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm101299d     Document Type: Article

References (44)

1. Gentry, M. K.; Doctor, B. P. Alignment of Amino Acid Sequences of Acetylcholinesterases and Butyrylcholinesterases. In Cholinesterases: Structure, Function, Mechanism, Genetics and Cell Biology; Massoulié, J., Bacou, F., Barnard, E. A., Chatonnet, A., Doctor, B. P., Quinn, D. M., Eds.; American Chemical Society: Washington, DC, 1991; pp 394 - 398.
2. Saxena, A.; Redman, A. M.; Jiang, X.; Lockridge, B. P.; Doctor, B. P. Differences in Active Site Gorge Dimensions of Cholinesterases Revealed by Binding of Inhibitors to Human Butyrylcholinesterase Biochemistry 1997, 36, 14642-14651 (Pubitemid 27524384)
3. Sussman, J. L.; Harel, M.; Frolow, F.; Oefner, C.; Goldman, A.; Toker, L.; Silman, I. Atomic Structure of Acetylcholinesterase from Torpedo californica: A Prototypic Acetylcholine-Binding Protein Science 1991, 253, 872-879 (Pubitemid 21917225)
4. Inestrosa, N. C.; Alvarez, A.; Perez, C. A.; Moreno, R. D.; Vicente, M.; Linker, C.; Casanueva, O. I.; Soto, C.; Garrido, J. Acetylcholinesterase Accelerates Assembly of Amyloid-beta-peptides into Alzheimer's Fibrils: Possible Role of the Peripheral Site of the Enzyme Neuron 1996, 16, 881-891 (Pubitemid 26124065)
5. Kryger, G.; Silman, I.; Sussman, J. L. Structure of Acetylcholinesterase Complexed with E2020 (Aricept): Implications for the Design of New Anti-Alzheimer Drugs Structure 1999, 7, 297-307 (Pubitemid 29159689)
6. Rama Sastry, B. V. Anticholinergic Drugs. In Burger's Medicinal Chemistry and Drug Discovery, 6 th ed.; Abraham, D. J., Ed.; Wiley: New York, 2003; pp 109 - 166.
7. Bevan, D. R.; Donati, F.; Kopman, A. F. Reversal of Neuromuscular Blockade Anesthesiology 1992, 77, 785-805
8. Meriggioli, M. N.; Sanders, D. B. Autoimmune Myasthenia Gravis: Emerging Clinical and Biological Heterogeneity Lancet 2009, 8, 475-490
9. McKinnon, S. J.; Goldberg, L. D.; Peeples, P.; Walt, J. G.; Bramley, T. J. Current Management of Glaucoma and the Need for Complete Therapy Am. J. Manag. Care 2008, 14, S20-S27
10. García-Carrasco, M.; Escárcega, R. O.; Fuentes-Alexandro, S.; Riebeling, C.; Cervera, R. Therapeutic Options in Autoimmune Myasthenia Gravis Autoimmun. Rev. 2007, 6, 373-378 (Pubitemid 46824097)
11. Pisani, L.; Catto, M.; Giangreco, I.; Leonetti, F.; Nicolotti, O.; Stefanachi, A.; Cellamare, S.; Carotti, A. Design, Synthesis and Biological Evaluation of Coumarin Derivatives Tethered to an Edrophonium-like Fragment as Highly Potent and Selective Dual Binding Site Acetylcholinesterase Inhibitors ChemMedChem 2010, 5, 1616-1630
12. Leonetti, F.; Catto, M.; Nicolotti, O.; Pisani, L.; Cappa, A.; Stefanachi, A.; Carotti, A. Homo- and Hetero-Bivalent Edrophonium-like Ammonium Salts as Highly Potent, Dual Binding Site AChE Inhibitors Bioorg. Med. Chem. 2008, 16, 7450-7456
13. Campos, J.; Núñez, M. C.; Conejo-García, A.; Sánchez-Martín, R. M.; Hernández-Alcoceba, R.; Rodríguez-González, A.; Lacal, J. C.; Gallo, M. A.; Espinosa, A. QSAR-Derived Choline Kinase Inhibitors: How Rational Can Antiproliferative Drug Design Be? Curr. Med. Chem. 2003, 10, 1095-1112 (Pubitemid 36758224)
14. Campos, J. M.; Sánchez-Martín, R. M.; Conejo-García, A.; Entrena, A.; Gallo, M. A.; Espinosa, A. (Q)SAR Studies To Design New Human Choline Kinase Inhibitors as Antiproliferative Drugs Curr. Med. Chem. 2006, 13, 1231-1248
15. Campos, J.; Núñez, M. C.; Rodríguez, V.; Entrena, A.; Hernández-Alcoceba, R.; Fernández, F.; Lacal, J. C.; Gallo, M. A.; Espinosa, A. LUMO Energy of Model Compounds of Bispyridinium Compounds as an Index for the Inhibition of Choline Kinase Eur. J. Med. Chem. 2001, 36, 215-225 (Pubitemid 32406197)
16. Conejo-García, A.; Báñez-Coronel, M.; Sánchez-Martín, R.; Rodríguez-González, A.; Ramos, A.; Ramírez de Molina, A.; Espinosa, A.; Gallo, M. A.; Campos, J.; Lacal, J. C. Influence of the Linker in Bispyridium Compounds on the Inhibition of Human Choline Kinase J. Med. Chem. 2004, 47, 5433-5440 (Pubitemid 39386296)
17. Sánchez-Martín, R.; Campos, J. M.; Conejo-García, A.; Cruz-López, O.; Báñez-Coronel, M.; Rodríguez- González, A.; Gallo, M. A.; Lacal, J. C.; Espinosa, A. Symmetrical Bis-Quinolinium Compounds: New Human Choline Kinase Inhibitors with Antiproliferative Activity against the HT-29 Cell Line J. Med. Chem. 2005, 48, 3354-3363 (Pubitemid 40628054)
18. Campos, J.; Núñez, M. C.; Sánchez, R. M.; Gómez-Vidal, J. A.; Rodríguez-González, A.; Báñez, M.; Gallo, M. A.; Lacal, J. C.; Espinosa, A. Quantitative Structure-Activity Relationships for a Series of Symmetrical Bisquaternary Anticancer Compounds Bioorg. Med. Chem. 2002, 10, 2215-2231 (Pubitemid 34450913)
19. + Channel-Blocking Activity of Dequalinium Analogues Having Semirigid Linkers J. Med. Chem. 1996, 39, 4247-4254 (Pubitemid 26339835)
20. Conejo-García, A.; Campos, J.; Sánchez-Martín, R. M.; Gallo, M. A.; Espinosa, A. Bispyridinium Cyclophanes: Novel Templates for Human Choline Kinase Inhibitors J. Med. Chem. 2003, 46, 3754-3757 (Pubitemid 36992208)
21. Conejo-García, A.; Campos, J.; Sánchez, R. M.; Rodríguez-González, A.; Lacal, J. C.; Gallo, M. A.; Espinosa, A. Choline Kinase Inhibitory Effect and Antiproliferative Activity of New 1,1′,1′′-(Benzene-1,3,5-triylmethylene)tris{4-[(disubstituted) amino]pyridinium} Tribromides Eur. J. Med. Chem. 2003, 38, 109-116 (Pubitemid 36197859)
22. Conejo-García, A.; Campos, J.; Sánchez, R. M.; Rodríguez-González, A.; Lacal, J. C.; Gallo, M. A.; Espinosa, A. Synthesis and NMR Studies on a C3-Symmetrical Triquinoline Triscationic Bicyclophane J. Org. Chem. 2005, 70, 5748-5751 (Pubitemid 40980792)
23. Tao, B.; Huang, T. L.; Zhang, Q.; Jackson, L.; Queener, S. F.; Donkor, I. O. Synthesis and Anti- Pneumocystis carinii Activity of Conformationally Restricted Analogues of Pentamidine Eur. J. Med. Chem. 1999, 34, 531-538
24. Neset, S.; Hope, H.; Undheim, K. Stereoselective Synthesis of Cyclopropane-1,2-bis(glycine) Derivatives Tetrahedron 1997, 53, 10459-10470 (Pubitemid 27303845)
25. Wenner, W. Bis(bromomethyl) Compounds J. Org. Chem. 1952, 17, 523-528
26. Cram, D. J.; Steinberg, H. Macro Rings. I. Preparation and Spectra of the Paracyclophanes J. Am. Chem. Soc. 1951, 73, 5691-5704
27. Raston, I.; Wennerström, O. [2(6)]Paracyclophanes-Large Ring Compounds with Extended pi-Systems Acta Chem. Scand. 1982, B36, 655-660
28. Drefahl, G.; Ploetner, G. Untersuchungen über Stilbene, XVIII. Polyphenyl-polyene Chem. Ber. 1958, 91, 1274-1280
29. Ellman, G. L.; Courtney, K. D.; Andres, V., Jr.; Feartherstone, R. M. A New and Rapid Colorimetric Determination of Acetylcholinesterase Activity Biochem. Pharmacol. 1961, 7, 88-95
30. 1-40 Aggregation in Vitro Bioorg. Med. Chem. 2008, 16, 4810-4822 (Pubitemid 351625896)
31. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.; Taylor, R. D. Improved Protein-Ligand Docking Using GOLD Proteins 2003, 52, 609-623 (Pubitemid 37034158)
32. Hong, B. S.; Allali-Hassani, A.; Tempel, W.; Finerty, P. J., Jr.; MacKenzie, F.; Dimov, S.; Vedadi, M.; Park, H. Crystal Structures of Human Choline Kinase Isoforms in Complex with Hemicholinium-3: Single Amino Acid near the Active Site Influences Inhibitor Sensitivity J. Biol. Chem. 2010, 285, 16330-16340
33. Case, D. A.; Darden, T. A.; Cheatham, T. E., III; Simmerling, C. L.; Wang, J.; Duke, R. E.; Luo, R.; Crowley, M.; Walker, R. C.; Zhang, W.; Merz, K. M.; Wang, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Kolossváry, I.; Wong, K. F.; Paesani, F.; Vanicek, J.; Wu, X.; Brozell, S. R.; Steinbrecher, T.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.; Mathews, D. H.; Seetin, M. G.; Sagui, C.; Babin, V.; Kollman, P. A. AMBER, version 10; University of California: San Francisco, CA, 2008.
34. Phillips, J. C.; Braun, R.; Wang, W.; Gumbart, J.; Tajkhorshid, E.; Villa, E.; Chipot, C.; Skeel, R. D.; Kale, L.; Schulten, K. Scalable Molecular Dynamics with NAMD J. Comput. Chem. 2005, 26, 1781-1802 (Pubitemid 43078511)
35. Barril, X.; Orzoco, M.; Luque, F. J. Predicting Relative Binding Free Energies of Tacrine-Huperzine A Hybrids as Inhibitors of Acetylcholinesterase J. Med. Chem. 1999, 42, 5110-5119 (Pubitemid 30020262)
36. Piazzi, L.; Rampa, A.; Bisi, A.; Gobbi, S.; Belluti, F.; Cavalli, A.; Bartolini, M.; Andrisano, V.; Valenti, P.; Recanatini, M. 3-(4-{[Benzyl(methyl) amino]methyl}-phenyl)-6,7-dimethoxy-2 H -2-chromenone (AP2238) Inhibits Both Acetylcholinesterase and Acetylcholinesterase-Induced β-Amyloid Aggregation: A Dual Function Lead for Alzheimer's Disease Therapy J. Med. Chem. 2003, 46, 2279-2282 (Pubitemid 36637912)
37. Campiani, G.; Fattorusso, C.; Butini, S.; Gaeta, A.; Agnusdei, M.; Gemma, S.; Persico, M.; Catalanotti, B.; Savini, L.; Nacci, V.; Novellino, E.; Holloway, H. W.; Greig, N. H.; Belinskaya, T.; Fedorko, J. M.; Saxena, A. Development of Molecular Probes for the Identification of Extra Interaction Sites in the Mid-Gorge and Peripheral Sites of Butyrylcholinesterase (BuChE). Rational Design of Novel, Selective, and Highly Potent BuChE Inhibitors J. Med. Chem. 2005, 48, 1919-1929 (Pubitemid 40396322)
38. Cheng, Y.; Cheng, X.; Radić, Z.; McCammon, J. A. Acetylcholinesterase: Mechanisms of Covalent Inhibition of Wild-Type and H447I Mutant Determined by Computational Analysis J. Am. Chem. Soc. 2007, 129, 6562-6570 (Pubitemid 46799354)
39. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. Further Development of a Genetic Algorithm for Ligand Docking and Its Application to Screening Combinatorial Libraries. In Rational Drug Design, Novel Methodology and Practical Applications; Parrill, A. L.; Reddy, M. R., Eds.; American Chemical Society: Washington, DC, 1999; pp 271 - 291.
40. Camps, P.; Formosa, X.; Galdeano, C.; Gómez, T.; Muñoz Torrero, D.; Ramírez, L.; Viayna, E.; Gómez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.; Bartolini, M.; Mancini, F.; Andrisano, V.; Bidon-Chanal, A.; Huertas, Ó.; Dafni, T.; Luque, F. J. Tacrine-Based Dual Binding Site Acetylcholinesterase Inhibitors as Potential Disease-Modifying Anti-Alzheimer Drug Candidates Chem.-Biol. Interact. 2010, 187, 411-415
41. Muñoz-Ruiz, P.; Rubio, L.; Garcia-Palomero, E.; Dorronsoro, I.; del Monte-Millan, M.; Valenzuela, R.; Usan, P.; de Austria, C.; Bartolini, M.; Andrisano, V.; Bidon-Chanal, A.; Orozco, M.; Luque, F. J.; Medina, M.; Martinez, A. Design, Synthesis, and Biological Evaluation of Dual Binding Site Acetylcholinesterase Inhibitors: New Disease-Modifying Agents for Alzheimer's Disease J. Med. Chem. 2005, 48, 7223-7233 (Pubitemid 41743636)
42. Hartshorn, M. J.; Verdonk, M. L.; Chessari, G.; Brewerton, S. C.; Mooij, W. T. M.; Mortenson, P. N.; Murray, C. W. Diverse, High-Quality Test Set for the Validation of Protein-Ligand Docking Performance J. Med. Chem. 2007, 50, 726-741 (Pubitemid 46332985)
43. Hernandez-Alcoceba, R.; Fernandez, F.; Lacal, J. C. In Vivo Antitumor Activity of Choline Kinase Inhibitors: A Novel Target for Anticancer Drug Discovery Cancer Res. 1999, 59, 3112-3118 (Pubitemid 29316010)
44. Ramirez de Molina, A.; Penalva, V.; Lucas, L.; Lacal, J. C. Regulation of Choline Kinase Activity by Ras Proteins Involves Ral-GDS and PI3K Oncogene 2002, 21, 937-994