New semicarbazones as gorge-spanning ligands of acetylcholinesterase and potential new drugs against Alzheimer’s disease: Synthesis, molecular modeling, NMR, and biological evaluation

References

• Abraham, M. J., Murtola, T., Schulz, R., Páll, S., Smith, J. C., Hess, B., & Lindahl, E. (2015). GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1, 19–25. doi:10.1016/j.softx.2015.06.001
   Google Scholar
• Agis-Torres, A., Sollhuber, M., Fernandez, M., & Sanchez-Montero, J. M. (2014). Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for Alzheimer’s disease. Current Neuropharmacology, 12(1), 2–36. doi:10.2174/1570159X113116660047
   PubMed Web of Science ®Google Scholar
• Alvarez, A., Opazo, C., Alarcón, R., Garrido, J., & Inestrosa, N. C. (1997). Acetylcholinesterase promotes the aggregation of amyloid-β-peptide fragments by forming a complex with the growing fibrils. Journal of Molecular Biology, 272(3), 348–361. doi:10.1006/jmbi.1997.1245
   PubMed Web of Science ®Google Scholar
• Amim, R. S., Firmino, G. S., Rego, A. C., Nery, A. L., Da-Silva, S. A., de Souza, M. V., … Lessa, J. A. (2016). Cytotoxicity and leishmanicidal activity of isoniazid-derived hydrazones and 2-pyrazineformamide thiosemicarbazones. Journal of the Brazilian Chemical Society, 27(4), 769–777. doi:10.5935/0103-5053.20150330
   Web of Science ®Google Scholar
• Asis, S. E., Bruno, A. M., Molina, D. A., Conti, G. M., & Gaozza, C. H. (1996). Synthesis, DNA interaction and antineoplastic activity of semicarbazone derivatives. Farmaco (Societa Chimica Italiana: 1989), 51(6), 419–423.
   PubMedGoogle Scholar
• Auld, D. S., Kornecook, T. J., Bastianetto, S., & Quirion, R. (2002). Alzheimer’s disease and the basal forebrain cholinergic system: Relations to β-amyloid peptides, cognition, and treatment strategies. Progress in Neurobiology, 68(3), 209–245. doi:10.1016/S0301-0082(02)00079-5
   PubMed Web of Science ®Google Scholar
• Bartolini, M., Bertucci, C., Cavrini, V., & Andrisano, V. (2003). β-Amyloid aggregation induced by human acetylcholinesterase: Inhibition studies. Biochemical Pharmacology, 65(3), 407–416. doi:10.1016/S0006-2952(02)01514-9
   PubMed Web of Science ®Google Scholar
• Bartus, R. T., Dean, R., Beer, B., & Lippa, A. S. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217(4558), 408–414. doi:10.1126/science.7046051
   PubMed Web of Science ®Google Scholar
• Bharti, N., Husain, K., Garza, M. G., Cruz-Vega, D. E., Castro-Garza, J., Mata-Cardenas, B. D., … Azam, A. (2002). Synthesis and in vitro antiprotozoal activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazone derivatives. Bioorganic & Medicinal Chemistry Letters, 12(23), 3475–3478. doi:10.1016/S0960-894X(02)00703-5
   PubMed Web of Science ®Google Scholar
• Bharti, N., Sharma, S., Naqvi, F., & Azam, A. (2003). New palladium (II) complexes of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones: Synthesis, spectral studies and in vitro anti-amoebic activity. Bioorganic & Medicinal Chemistry, 11(13), 2923–2929. doi:10.1016/S0968-0896(03)00213-X
   PubMed Web of Science ®Google Scholar
• Bissantz, C., Kuhn, B., & Stahl, M. (2010). A medicinal chemist’s guide to molecular interactions. Journal of Medicinal Chemistry, 53(14), 5061–5084. doi:10.1016/S0960-894X(02)00703-5
   PubMed Web of Science ®Google Scholar
• Bolognesi, M. L., Banzi, R., Bartolini, M., Cavalli, A., Tarozzi, A., Andrisano, V., … Fato, R. (2007). novel class of quinone-bearing polyamines as multi-target-directed ligands to combat Alzheimer’s disease. Journal of Medicinal Chemistry, 50(20), 4882–4897. doi:10.1021/jm070559a
   PubMed Web of Science ®Google Scholar
• Carmo Carreiras, M., Mendes, E., Jesus Perry, M., Paula Francisco, A., & Marco-Contelles, J. (2013). The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Current Topics in Medicinal Chemistry, 13(15), 1745–1770. doi:10.2174/15680266113139990135
   PubMed Web of Science ®Google Scholar
• Casas, J. S., Rodrı́guez-Argüelles, M. C., Russo, U., Sánchez, A., Sordo, J., Vázquez-López, A., … Albertini, R. (1998). Diorganotin (IV) complexes of pyridoxal thiosemicarbazone: Synthesis, spectroscopic properties and biological activity. Journal of Inorganic Biochemistry, 69(4), 283–292.10.1016/S0162-0134(98)00004-X
   PubMed Web of Science ®Google Scholar
• Chierrito, T. P., Pedersoli-Mantoani, S., Roca, C., Requena, C., Sebastian-Perez, V., Castillo, W. O., … Jiménez-Barbero, J. (2017). From dual binding site acetylcholinesterase inhibitors to allosteric modulators: A new avenue for disease-modifying drugs in Alzheimer’s disease. European Journal of Medicinal Chemistry, 139, 773–791. doi:10.1016/S0162-0134(98)00004-X
   PubMed Web of Science ®Google Scholar
• Choudhary, M. I. (Ed.). (2015). Drug Design and Discovery in Alzheimer’s Disease. London: Elsevier.
   Google Scholar
• Coyle, J. T., Price, D. L., & DeLong, M. R. (1983). Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science, 219(4589), 1184–1190. doi:10.1016/j.ejmech.2017.08.051
   PubMed Web of Science ®Google Scholar
• Crismon, M. L. (1994). Tacrine: First drug approved for Alzheimer’s disease. Annals of Pharmacotherapy, 28(6), 744–751. doi:10.1177/106002809402800612
   PubMed Web of Science ®Google Scholar
• da Silva, A. W. S., & Vranken, W. F. (2012). ACPYPE – AnteChamber python parser interface. BMC Research Notes, 5(1), 367. doi:10.1186/1756-0500-5-367
   PubMedGoogle Scholar
• Dickerson, T. J., Beuscher, A. E., IV, Rogers, C. J., Hixon, M. S., Yamamoto, N., Xu, Y., … Janda, K. D. (2005). Discovery of acetylcholinesterase peripheral anionic site ligands through computational refinement of a directed library. Biochemistry, 44(45), 14845–14853. doi:10.1021/bi051613x
   PubMed Web of Science ®Google Scholar
• Dimmock, J. R., Sidhu, K. K., Thayer, R. S., Mack, P., Duffy, M. J., Reid, R. S., … Ong, A. (1993). Anticonvulsant activities of some arylsemicarbazones displaying potent oral activity in the maximal electroshock screen in rats accompanied by high protection indices. Journal of Medicinal Chemistry, 36(16), 2243–2252. doi:10.1021/jm00068a001
   PubMed Web of Science ®Google Scholar
• Eghtedari, M., Sarrafi, Y., Nadri, H., Mahdavi, M., Moradi, A., Moghadam, F. H., … Foroumadi, A. (2017). New tacrine-derived AChE/BuChE inhibitors: Synthesis and biological evaluation of 5-amino-2-phenyl-4H-pyrano [2, 3-b] quinoline-3-carboxylates. European Journal of Medicinal Chemistry, 128, 237–246. doi:10.1016/j.ejmech.2017.01.042
   PubMed Web of Science ®Google Scholar
• Ellman, G. L., Courtney, K. D., Andres, V., & Featherstone, R. M. (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology, 7(2), 88IN191–9095. doi:10.1016/0006-2952(61)90145-9
   Web of Science ®Google Scholar
• Fabián, L., Caputto, M. E., Finkielsztein, L. M., Moltrasio, G. Y., & Moglioni, A. G. (2007). Semicarbazones and copper complexes of semicarbazones and thiosemicarbazones derived from 1-indanones: Synthesis, structure and spectroscopy. Molecular Medicinal Chemistry, 12, 70–72.
   Google Scholar
• Neto, D. C. F., de Souza Ferreira, M., da Conceição Petronilho, E., Lima, J. A., de Azeredo, S. O. F., Brum, J. D. O. C., … Villar, J. D. F. (2017). A new guanylhydrazone derivative as a potential acetylcholinesterase inhibitor for Alzheimer’s disease: Synthesis, molecular docking, biological evaluation and kinetic studies by nuclear magnetic resonance. RSC Advances, 7(54), 33944–33952. doi:10.1039/C7RA04180B
   Web of Science ®Google Scholar
• Guex, N., & Peitsch, M. C. (1997). SWISS-MODEL and the Swiss-Pdb viewer: An environment for comparative protein modeling. Electrophoresis, 18(15), 2714–2723. doi:10.1002/elps.1150181505
   PubMed Web of Science ®Google Scholar
• Gupta, S., & Mohan, C. G. (2014). Dual binding site and selective acetylcholinesterase inhibitors derived from integrated pharmacophore models and sequential virtual screening. BioMed Research International, Article ID 291214. doi:10.1155/2014/291214
   Web of Science ®Google Scholar
• Halgren, T. A. (1996). Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions. Journal of Computational Chemistry, 17(5–6), 520–552. doi:10.1002/(SICI)1096-987X(199604)17:5/6<520::AID-JCC2>3.0.CO;2-W
   Web of Science ®Google Scholar
• Hall, I. H., Lackey, C. B., Kistler, T. D., Durham, R. W., Jr, Jouad, E. M., Khan, M., … Bouet, G. M. (2000). Cytotoxicity of copper and cobalt complexes of furfural semicarbazone and thiosemicarbazone derivatives in murine and human tumor cell lines. Die Pharmazie, 55(12), 937–941.
   PubMed Web of Science ®Google Scholar
• Hehre, W. J., Deppmeier, B. J., & Klunzinger, P. E. (1999). PC spartan pro. Irvine: Wavefunction..
   Google Scholar
• Heilbronn, E. D. I. T. H. (1961). Inhibition of cholinesterases by tetrahydroaminacrin. Acta Chemica Scandinavic, 15(6), 1386–1390.10.3891/acta.chem.scand.15-1386
   Google Scholar
• Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38. doi:10.1016/0263-7855(96)00018-5
   PubMedGoogle Scholar
• Inestrosa, N. C., Alvarez, A., Perez, C. A., Moreno, R. D., Vicente, M., Linker, C., … Garrido, J. (1996). Acetylcholinesterase accelerates assembly of amyloid-β-peptides into Alzheimer’s fibrils: Possible role of the peripheral site of the enzyme. Neuron, 16(4), 881–891. doi:10.1016/S0896-6273(00)80108-7
   PubMed Web of Science ®Google Scholar
• Jackisch, R., Förster, S., Kammerer, M., Rothmaier, A. K., Ehret, A., Zentner, J., & Feuerstein, T. J. (2009). Inhibitory potency of choline esterase inhibitors on acetylcholine release and choline esterase activity in fresh specimens of human and rat neocortex. Journal of Alzheimer’s Disease, 16(3), 635–647. doi:10.3233/JAD-2009-1008
   PubMed Web of Science ®Google Scholar
• Johnson, G., & Moore, S. W. (2006). The peripheral anionic site of acetylcholinesterase: Structure, functions and potential role in rational drug design. Current Pharmaceutical Design, 12(2), 217–225. doi:10.2174/138161206775193127
   PubMed Web of Science ®Google Scholar
• Jorgensen, W. L., Maxwell, D. S., & Tirado-Rives, J. (1996). Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. Journal of the American Chemical Society, 118(45), 11225–11236. doi:10.1021/ja9621760
   Web of Science ®Google Scholar
• Katzman, R. (1976). The prevalence and malignancy of Alzheimer disease: A major killer. Archives of Neurology, 33(4), 217–218. doi:10.1001/archneur.1976.00500040001001
   PubMedGoogle Scholar
• Knapp, M. J., Knopman, D. S., Solomon, P. R., Pendlebury, W. W., Davis, C. S., Gracon, S. I., … Baumel, B. (1994). A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. Jama, 271(13), 985–991. doi:10.1001/jama.1994.03510370037029
   PubMed Web of Science ®Google Scholar
• Konrath, E. L., Neves, B. M., Lunardi, P. S., dos Santos Passos, C., Simões-Pires, A., Ortega, M. G., … Henriques, A. T. (2012). Investigation of the in vitro and ex vivo acetylcholinesterase and antioxidant activities of traditionally used Lycopodium species from South America on alkaloid extracts. Journal of Ethnopharmacology, 139(1), 58–67. doi:10.1016/j.jep.2011.10.042
   PubMed Web of Science ®Google Scholar
• Kontoyianni, M., McClellan, L. M., & Sokol, G. S. (2004). Evaluation of docking performance: comparative data on docking algorithms. Journal of Medicinal Chemistry, 47(3), 558–565. doi:10.1021/jm0302997
   PubMed Web of Science ®Google Scholar
• Kuca, K., Soukup, O., Maresova, P., Korabecny, J., Nepovimova, E., Klimova, B., … França, T. C. C. (2016). Current approaches against Alzheimer’s disease in clinical trials. Journal of the Brazilian Chemical Society, 27(4), 641–649. doi:10.5935/0103-5053.20160048
   Web of Science ®Google Scholar
• Lambert, C., Beraldo, H., Lievre, N., Garnier-Suillerot, A., Dorlet, P., & Salerno, M. (2013). Bis (thiosemicarbazone) copper complexes: Mechanism of intracellular accumulation. JBIC Journal of Biological Inorganic Chemistry, 18(1), 59–69. doi:10.1007/s00775-012-0949-1
   PubMed Web of Science ®Google Scholar
• Lineweaver, H., & Burk, D. (1934). The determination of enzyme dissociation constants. Journal of the American Chemical Society, 56(3), 658–666. doi:10.1021/ja01318a036
   Google Scholar
• Lipinski, C. A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods, 44(1), 235–249. doi:10.1016/S1056-8719(00)00107-6
   PubMed Web of Science ®Google Scholar
• Lipinski, C. A. (2004). Lead-and drug-like compounds: The rule-of-five revolution. Drug Discovery Today: Technologies, 1(4), 337–341. doi:10.1016/j.ddtec.2004.11.007
   PubMedGoogle Scholar
• Marquis, J. K. (1990). Pharmacological significance of acetylcholinesterase inhibition by tetrahydroaminoacridine. Biochemical Pharmacology, 40(5), 1071–1076. doi:10.1016/0006-2952(90)90495-7
   PubMed Web of Science ®Google Scholar
• Mufson, E. J., Counts, S. E., Perez, S. E., & Ginsberg, S. D. (2008). Cholinergic system during the progression of Alzheimer’s disease: Therapeutic implications. Expert Review of Neurotherapeutics, 8(11), 1703–1718. doi:10.1586/14737175.8.11.1703
   PubMedGoogle Scholar
• Murphy, M. P., & LeVine, H., III (2010). Alzheimer’s disease and the amyloid-β peptide. Journal of Alzheimer’s Disease, 19(1), 311–323. doi:10.3233/JAD-2010-1221
   PubMed Web of Science ®Google Scholar
• O’Brien, R. J., & Wong, P. C. (2011). Amyloid precursor protein processing and Alzheimer’s disease. Annual Review of Neuroscience, 34, 185–204. doi:10.1146/annurev-neuro-061010-113613
   PubMed Web of Science ®Google Scholar
• Pacheco, G., Palacios-Esquivel, R., & Moss, D. E. (1995). Cholinesterase inhibitors proposed for treating dementia in Alzheimer’s disease: Selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. Journal of Pharmacology and Experimental Therapeutics, 274(2), 767–770.
   PubMed Web of Science ®Google Scholar
• Pajouhesh, H., & Lenz, G. R. (2005). Medicinal chemical properties of successful central nervous system drugs. NeuroRX, 2(4), 541–553. doi:10.1602/neurorx.2.4.541
   PubMedGoogle Scholar
• Paul, S., Jeon, W. K., Bizon, J. L., & Han, J. S. (2015). Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment. Frontiers in Aging Neuroscience, 7, Article 43. doi:10.3389/fnagi.2015.00043
   Web of Science ®Google Scholar
• Pavan, F. R., Maia, P. I. D. S., Leite, S. R., Deflon, V. M., Batista, A. A., Sato, D. N., … Leite, C. Q. (2010). Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: Anti-mycobacterium tuberculosis activity and cytotoxicity. European Journal of Medicinal Chemistry, 45(5), 1898–1905. doi:10.1016/j.ejmech.2010.01.028
   PubMed Web of Science ®Google Scholar
• Prince, M. J., Wu, F., Guo, Y., Robledo, L. M. G., O’Donnell, M., Sullivan, R., & Yusuf, S. (2015). The burden of disease in older people and implications for health policy and practice. The Lancet, 385(9967), 549–562. doi:10.1016/S0140-6736(14)61347-7
   PubMed Web of Science ®Google Scholar
• Raghav, N., & Kaur, R. (2015). Chalcones, semicarbazones and pyrazolines as inhibitors of cathepsins B, H and L. International Journal of Biological Macromolecules, 80, 710–724. doi:10.1016/j.ijbiomac.2015.07.029
   PubMed Web of Science ®Google Scholar
• Reyes, A. E., Perez, D. R., Alvarez, A., Garrido, J., Gentry, M. K., Doctor, B. P., & Inestrosa, N. C. (1997). A monoclonal antibody against acetylcholinesterase inhibits the formation of amyloid fibrils induced by the enzyme. Biochemical and Biophysical Research Communications, 232(3), 652–655. doi:10.1006/bbrc.1997.6357
   PubMed Web of Science ®Google Scholar
• Rocha, G. B., Freire, R. O., Simas, A. M., & Stewart, J. J. (2006). RM1: A reparameterization of AM1 for H, C, N, O, P, S, F, Cl, Br, and I. Journal of Computational Chemistry, 27(10), 1101–1111. doi:10.1002/jcc.20425
   PubMed Web of Science ®Google Scholar
• Romero, A., Cacabelos, R., Oset-Gasque, M. J., Samadi, A., & Marco-Contelles, J. (2013). Novel tacrine-related drugs as potential candidates for the treatment of Alzheimer’s disease. Bioorganic & Medicinal Chemistry Letters, 23(7), 1916–1922. doi:10.1016/j.bmcl.2013.02.017
   PubMed Web of Science ®Google Scholar
• Rosini, M., Simoni, E., Bartolini, M., Cavalli, A., Ceccarini, L., Pascu, N., … Tumiatti, V. (2008). Inhibition of acetylcholinesterase, β-amyloid aggregation, and NMDA receptors in Alzheimer’s disease: A promising direction for the multi-target-directed ligands gold rush. Journal of Medicinal Chemistry, 51(15), 4381–4384. doi:10.1021/jm800577j
   PubMed Web of Science ®Google Scholar
• Shan, W. J., Huang, L., Zhou, Q., Meng, F. C., & Li, X. S. (2011). Synthesis, biological evaluation of 9-N-substituted berberine derivatives as multi-functional agents of antioxidant, inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation. European Journal of Medicinal Chemistry, 46(12), 5885–5893. doi:10.1016/j.ejmech.2011.09.051
   PubMed Web of Science ®Google Scholar
• Singh, S. K., Srivastav, S., Yadav, A. K., Srikrishna, S., & Perry, G. (2015). Overview of Alzheimer’s disease and some therapeutic approaches targeting Aβ by using several synthetic and herbal compounds. Oxidative Medicine and Cellular Longevity, Article ID 7361613. doi:10.1155/2016/7361613
   Web of Science ®Google Scholar
• Sinha, S. K., & Shrivastava, S. K. (2013). Synthesis, evaluation and molecular dynamics study of some new 4-aminopyridine semicarbazones as an antiamnesic and cognition enhancing agents. Bioorganic & Medicinal Chemistry, 21(17), 5451–5460. doi:10.1016/j.bmc.2013.06.003
   PubMed Web of Science ®Google Scholar
• Soares, R. O., Echevarria, A., Bellieny, M. S., Pinho, R. T., de Leo, R. M., Seguins, W. S., … Leon, L. L. (2011). Evaluation of thiosemicarbazones and semicarbazones as potential agents anti-trypanosoma cruzi. Experimental Parasitology, 129(4), 381–387. doi:10.1016/j.exppara.2011.08.019
   PubMed Web of Science ®Google Scholar
• Soares, S. F. D. C. X., Vieira, A. A., Delfino, R. T., & Figueroa-Villar, J. D. (2013). NMR determination of Electrophorus electricus acetylcholinesterase inhibition and reactivation by neutral oximes. Bioorganic & Medicinal Chemistry, 21(18), 5923–5930. doi:10.1016/j.bmc.2013.05.063
   PubMed Web of Science ®Google Scholar
• Sriram, D., Yogeeswari, P., Dhakla, P., Senthilkumar, P., & Banerjee, D. (2007). N-Hydroxythiosemicarbazones: Synthesis and in vitro antitubercular activity. Bioorganic & Medicinal Chemistry Letters, 17(7), 1888–1891. doi:10.1016/j.bmcl.2007.01.037
   PubMed Web of Science ®Google Scholar
• Sussman, J. L., Harel, M., Frolow, F., Oefner, C., Goldman, A., Toker, L., & Silman, I. (1991). Atomic structure of acetylcholinesterase from Torpedo californica: A prototypic acetylcholine-binding protein. Science, 253(5022), 872–879.10.1126/science.1678899
   PubMed Web of Science ®Google Scholar
• Takeuchi, K., & Wagner, G. (2006). NMR studies of protein interactions. Current Opinion in Structural Biology, 16(1), 109–117. doi:10.1016/j.sbi.2006.01.006
   PubMed Web of Science ®Google Scholar
• Thomsen, R., & Christensen, M. H. (2006). MolDock: A new technique for high-accuracy molecular docking. Journal of Medicinal Chemistry, 49(11), 3315–3321. doi:10.1021/jm051197e
   PubMed Web of Science ®Google Scholar
• Veerapandian, M., Marimuthu, M., Ilangovan, P., Ganguly, S., Yun, K. S., Kim, S., & An, J. (2010). Analytical and biological characterization of quinazoline semicarbazone derivatives. Medicinal Chemistry Research, 19(3), 283–298. doi:10.1007/s00044-009-9191-y
   Web of Science ®Google Scholar
• Vieira, R. P., Rocha, L., Teixeira, L. R., Sinisterra, R. D., Coelho, M. M., & Beraldo, H. (2010). Benzaldeído Semicarbazona: Um Perfil de Atividades do Candidato a Fármaco que Alia Simplicidade Estrutural a um Amplo Perfil de Atividades. Revista Virtual de Química, 2(1), 2–9. doi:10.5935/1984-6835.20100002
   Google Scholar
• Walters, W. P., & Murcko, M. A. (2002). Prediction of ‘drug-likeness’. Advanced Drug Delivery Reviews, 54(3), 255–271.10.1016/S0169-409X(02)00003-0
   PubMed Web of Science ®Google Scholar
• Warren, J. D., Woodward, D. L., & Hargreaves, R. T. (1977). 4-Substituted semicarbazones of mono-and dichlorobenzaldehydes as antihypertensive agents. Journal of Medicinal Chemistry, 20(11), 1520–1521. doi:10.1016/S0169-409X(02)00003-0
   PubMed Web of Science ®Google Scholar
• Whitehouse, P. J., Price, D. L., Struble, R. G., Clark, A. W., Coyle, J. T., & Delon, M. R. (1982). Alzheimer’s disease and senile dementia: Loss of neurons in the basal forebrain. Science, 215(4537), 1237–1239. doi:10.1126/science.7058341
   PubMed Web of Science ®Google Scholar
• Wilson, R. S., Segawa, E., Boyle, P. A., Anagnos, S. E., Hizel, L. P., & Bennett, D. A. (2012). The natural history of cognitive decline in Alzheimer’s disease. Psychology and Aging, 27(4), 1008. doi:10.1037/a0029857
   PubMed Web of Science ®Google Scholar
• Wong, O. T., Hall, I. H., & Chapman, J. M. (1989). The hypolipidemic activity of l-N-3-methylphthalimido-butan-3-semicarbazone in rodents. Pharmaceutical Research, 6(3), 230–234. doi:10.1023/A:1015965517279
   PubMed Web of Science ®Google Scholar
• Zernov, V. V., Balakin, K. V., Ivaschenko, A. A., Savchuk, N. P., & Pletnev, I. V. (2003). drug discovery using support vector machines. The Case studies of drug-likeness, agrochemical-likeness, and enzyme inhibition predictions. Journal of Chemical Information and Computer Sciences, 43(6), 2048–2056. doi:10.1021/ci0340916
   PubMedGoogle Scholar
• Zhao, Y., & Lukiw, W. J. (2015). Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer’s disease (AD). Journal of Nature and Science, 1(7), pii: e138.
   Google Scholar