Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase

Detalhes bibliográficos
Autor(a) principal: Goulart, Paula do Nascimento
Data de Publicação: 2021
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
Texto Completo: https://tede.ufrrj.br/jspui/handle/jspui/5705
Resumo: Natural products are one of the main sources of inspiration for development of new drug prototypes candidates. Among products of natural origin, bromopyrrolic alkaloids are of great interest to medicinal chemists because they are a class of exclusively marine secondary metabolites, produced by sponges, and with diverse biological activities. The present work describes design, synthesis and evaluation, in vitro and in silico, of new guanidines and acylguanidines bromopyrrole derivatives designed as structural analogues of oroidine marine alkaloids. Structural planning was based on strategies such as bioisosterism, molecular hybridization and homologation for planning changes in the characteristic subunits of these alkaloids, such as the spacer alkyl chain and the cyclic guanidine subunit. Synthetic strategy explored the condensation reaction between the key intermediate 1-(tert-butyloxycarbonyl)-3-(4,5-dibromopyrrol-2-carbonyl)-2-methyl-2-isothiourea with different amines and subsequent removal of the protection group (N-Boc) in acid medium to obtain the target acylguanidines. The acyclic guanidinic analogs were obtained by the reaction between the intermediate 2-trichloroacetyl-4,5-dibromopyrrole, or 2-trichloroacetyl-pyrrole, and previously synthesized N,N'-bis-protected amino-alkylguanidines, and subsequent deprotection reaction in acidic medium. We synthesized 32 original compounds (68a-c; 69a-c; 50a-f; 62a-h; 62g'; 62h'; 51a-h; 51g'; 51h') in good yields, among guanidines and acylguanidines (protected and unprotected), which are synthetic analogs of oroidinic marine alkaloids, all characterized by 1H NMR and 13C NMR. In vitro screening for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, identified guanidine 68c as a non-selective inhibitor of AChE (CI50 of 22.8?M) and BuChE (CI50 of 27.3 ?M) and 50c as a selective inhibitor of BuChE (IC50 of 13.3 ?M). Acylguanidines stood out as selective BuChE inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 ?M and 3.8 ?M, respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 ?M. Structure-activity relationship showed the importance of free acylguanidine function for selective inhibition of BuChE, as well as the presence of bromine substituents in pyrrole ring. The molecular docking studies corroborated by showing the importance of bromopyrrole, acylguanidine and benzyl ring subunits for interaction with the amino acid residues in BuChE active site. Additionally, in silico evaluation of ADME and druglike properties showed that new bromopyrrole guanidines and acylguanidines have the potential for good gastrointestinal absorption and good drug-likeness properties.
id UFRRJ-1_0a9d0f0199cb7362c53ed5b732b7ef6d
oai_identifier_str oai:localhost:jspui/5705
network_acronym_str UFRRJ-1
network_name_str Biblioteca Digital de Teses e Dissertações da UFRRJ
repository_id_str
spelling Lacerda, Renata Barbosa089.126.277-67K?mmerle, Arthur Eugen053.978.487-78Lacerda, Renata BarbosaAlves, Marina AmaralRomeiro, Nelilma CorreiaTinoco, Luzineide WanderleySalles, Cristiane Martins Cardoso de124.600.037-73http://lattes.cnpq.br/3473118225634771Goulart, Paula do Nascimento2022-05-27T20:18:54Z2021-04-29GOULART, Paula do Nascimento. Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase. 2021. 214 f. Tese (Doutorado em Qu?mica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro, Serop?dica, 2021.https://tede.ufrrj.br/jspui/handle/jspui/5705Natural products are one of the main sources of inspiration for development of new drug prototypes candidates. Among products of natural origin, bromopyrrolic alkaloids are of great interest to medicinal chemists because they are a class of exclusively marine secondary metabolites, produced by sponges, and with diverse biological activities. The present work describes design, synthesis and evaluation, in vitro and in silico, of new guanidines and acylguanidines bromopyrrole derivatives designed as structural analogues of oroidine marine alkaloids. Structural planning was based on strategies such as bioisosterism, molecular hybridization and homologation for planning changes in the characteristic subunits of these alkaloids, such as the spacer alkyl chain and the cyclic guanidine subunit. Synthetic strategy explored the condensation reaction between the key intermediate 1-(tert-butyloxycarbonyl)-3-(4,5-dibromopyrrol-2-carbonyl)-2-methyl-2-isothiourea with different amines and subsequent removal of the protection group (N-Boc) in acid medium to obtain the target acylguanidines. The acyclic guanidinic analogs were obtained by the reaction between the intermediate 2-trichloroacetyl-4,5-dibromopyrrole, or 2-trichloroacetyl-pyrrole, and previously synthesized N,N'-bis-protected amino-alkylguanidines, and subsequent deprotection reaction in acidic medium. We synthesized 32 original compounds (68a-c; 69a-c; 50a-f; 62a-h; 62g'; 62h'; 51a-h; 51g'; 51h') in good yields, among guanidines and acylguanidines (protected and unprotected), which are synthetic analogs of oroidinic marine alkaloids, all characterized by 1H NMR and 13C NMR. In vitro screening for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, identified guanidine 68c as a non-selective inhibitor of AChE (CI50 of 22.8?M) and BuChE (CI50 of 27.3 ?M) and 50c as a selective inhibitor of BuChE (IC50 of 13.3 ?M). Acylguanidines stood out as selective BuChE inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 ?M and 3.8 ?M, respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 ?M. Structure-activity relationship showed the importance of free acylguanidine function for selective inhibition of BuChE, as well as the presence of bromine substituents in pyrrole ring. The molecular docking studies corroborated by showing the importance of bromopyrrole, acylguanidine and benzyl ring subunits for interaction with the amino acid residues in BuChE active site. Additionally, in silico evaluation of ADME and druglike properties showed that new bromopyrrole guanidines and acylguanidines have the potential for good gastrointestinal absorption and good drug-likeness properties.Os produtos naturais s?o uma das principais fontes de inspira??o para o desenvolvimento de novos candidatos a prot?tipos de f?rmacos. Dentre os produtos de origem natural, os alcaloides bromopirr?licos s?o de grande interesse dos qu?micos medicinais por serem uma classe de metab?litos secund?rios exclusivamente marinhos, produzidos por esponjas, e com diversas atividades biol?gicas. O presente trabalho descreve o planejamento estrutural, a s?ntese e avalia??o, in vitro e in silico, de novos derivados bromopirr?licos guanid?nicos e acilguanid?nicos desenhados como an?logos estruturais de alcaloides marinhos oroid?nicos. O planejamento estrutural se baseou em estrat?gias como o bioisosterismo, hibrida??o molecular e homologa??o para o planejamento de modifica??es nas subunidades caracter?sticas destes alcaloides, como a cadeia alqu?lica espa?adora e a subunidade guanid?nica c?clica. A estrat?gia sint?tica explorou a rea??o de condensa??o entre o intermedi?rio-chave 1-(terc-butiloxicarbonil)-3-(4,5-dibromopirrol-2-carbonil)-2-metil-2-isotioureia com diferentes aminas e posterior remo??o do grupo de prote??o (N-Boc) em meio ?cido para a obten??o das acilguanidinas alvo. Os an?logos guanid?nicos ac?clicos foram obtidos atrav?s da rea??o entre o intermedi?rio 2-tricloroacetil-4,5-dibromopirrol, ou 2-tricloroacetil-pirrol, e amino-alquilguanidinas N,N?-bis-protegidas previamente sintetizadas, e posterior rea??o de desprote??o em meio ?cido. Foram sintetizados em bons rendimentos 32 compostos originais (68a-c; 69a-c; 50a-f; 62a-h; 62g?; 62h?; 51a-h; 51g?; 51h?), entre guanidinas e acilguanidinas (protegidas e desprotegidas), an?logos sint?ticos dos alcaloides marinhos oroid?nicos, todos caracterizados por RMN de 1H e RMN de 13C. A triagem in vitro sobre as enzimas acetilcolinesterase (AChE) e butirilcolinesterase (BuChE) identificou a guanidina 68c como um inibidor n?o seletivo de AChE (CI50 de 22,8?M) e BuChE (CI50 de 27,3 ?M) e 50c como um inibidor seletivo de BuChE (CI50 de 13,3?M). As acilguanidinas se destacaram como inibidores seletivos de BuChE, principalmente as acilguanidinas livres 51a e 51g com CI50 de 4,8 ?M e 3,8 ?M, respectivamente, e 52c, 52d e 52f com inibi??o da BuChE maior que 83% a 30 ?M. A rela??o estrutura-atividade mostrou a import?ncia da fun??o acilguanidina livre para a inibi??o seletiva de BuChE, assim como a presen?a dos substituintes bromos no anel. Os estudos de docking molecular corroboraram os resultados experimentais mostrando a import?ncia das subunidades bromopirrol, acilguanidina e anel benz?lico para intera??o com os res?duos de amino?cidos presentes no s?tio ativo da BuChE. Adicionalmente, a avalia??o in silico das propriedades ADME e druglike mostrou que as novas guanidinas e acilguanidinas bromopirr?licas tem potencial para boa absor??o gastrointestinal e bom perfil drug-likeness.Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2022-05-27T20:18:54Z No. of bitstreams: 1 2021 - Paula do Nascimento Goulart.pdf: 12696775 bytes, checksum: e4efcc1c63466d6b6664c6d3318549e9 (MD5)Made available in DSpace on 2022-05-27T20:18:54Z (GMT). No. of bitstreams: 1 2021 - Paula do Nascimento Goulart.pdf: 12696775 bytes, checksum: e4efcc1c63466d6b6664c6d3318549e9 (MD5) Previous issue date: 2021-04-29CAPES - Coordena??o de Aperfei?oamento de Pessoal de N?vel Superiorapplication/pdfhttps://tede.ufrrj.br/retrieve/69493/2021%20-%20Paula%20do%20Nascimento%20Goulart.pdf.jpgporUniversidade Federal Rural do Rio de JaneiroPrograma de P?s-Gradua??o em Qu?micaUFRRJBrasilInstituto de Qu?mica1 Burger, R., & Bigler, P. (1998). COMMUNICATIONS DEPTQ : Distorsionless Enhancement by Polarization Transfer Including the Detection of Quaternary Nuclei. 534, 529?534. 2 R. Rane, N. Sahu, C. Shah, R. Karpoormath, Curr. Top. Med. Chem. 2014, 14, 253?273. 3 van Rensburg, M., Copp, B. R., & Barker, D. (2018). Synthesis and Absolute Stereochemical Reassignment of Mukanadin F: A Study of Isomerization of Bromopyrrole Alkaloids with Implications on Marine Natural Product Isolation. European Journal of Organic Chemistry, 2018(24), 3065?3074. https://doi.org/10.1002/ejoc.201800422 4 Tasdemir, D., Topaloglu, B., Perozzo, R., Brun, R., O?Neill, R., Carballeira, N.M., Zhang, X., Tonge, P.J., Linden, A., Ruedi, P., 2007. Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli. Bioorg. Med. Chem. 15, 6834?6845. 5 Richards, J., Ballard, T., Huigens, R., Melander, C., 2008. Synthesis and screening of an oroidin library against Pseudomonas aeruginosa biofilms. Chem. Biol. Chem. 9, 1267? 1279. 6 Tasdemir, D., Mallon, R., Greenstein, M., Feldberg, L., Kim, S., Collins, K., Wojciechowicz, D., Mangalindan, G., Concepcio? n, G., Harper, M., Ireland, C., 2002. Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mito gen-activated protein kinase kinase-1 (MEK-1). J. Med. Chem. 45, 529?532. 7 Paul, A.K., Robert, E.S., Moustapha, E.S.K., Rober Jr., G.H., Dan,cR., Kenneth, L.R., 1991. Bioactive bromopyrrole metabolites from the Caribbean sponge Agelas conifera. J. Org. Chem. 56, 2975-2975. 8 Tsuda, M., Yasuda, T., Fukushi, E., Kawabata, J., Sekiguchi, M., Fromont, J., Kobayashi, J., 2006. Agesamides A and B, bromopyrrole alkaloids from sponge Agelas species: application of DOSY for chemical screening of new metabolites. Org. Lett. 8, 4235?4238. 9 Rane, R.; Sahu, N,; Shah, C.; Karpoormath, R. Marine bromopyrrole alkaloids: Synthesis and diverse medicinal applications. Current Topics in Medicinal Chemistry 2014, 14, 253. 10 Forenza, S.; Minale, L.; Riccio, R. New bromo-pyrrole derivatives from sponges agelas-oroides. Chemical Communications 1971, 1129. 11 FORENZA, S.; MINALE, L.; RICCIO, R.; FATTORUSSO, E. New bromo-pyrrole derivatives from the sponge Agelas oroides. Journal of the Chemical Society D: Chemical Communications, v. 285, n. 18, p. 1129, 1971. 12Takale, B. S.; Desai, N. V.; Siddiki, A. A.; Chaudhari, H, K.; Telvekar, V. N. Synthesis and biological evaluation of pyrrole-2- carboxamide derivatives: oroidin analogues. Medicinal Chemistry Research 2014, 23, 1387. 13 Richards, J. J.; Reyes, S.; Stowe, S. D.; Tucker, A. T.; Ballard, T. E.; Mathies, L. D.; Cavanagh, J.; Melander, C. Amide isosteres of oroidin: Assessment of antibiofilm activity and C. elegans toxicity. Journal of Medicinal Chemistry 2009, 52, 4582. 14 C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney, Adv. Drug Delivery Rev., 2001, 46, 3 15 Dispon?vel em https://spongeguide.uncw.edu/myresults.php?searchtype=3&taxa=1, acessado em 18/5/2020. 16 Bharate SB, Yadav RR, Battula S, Vishwakarma RV. 2012. Meridianins: marinederived potent kinase inhibitors. MiniRev Med Chem. 12:618? 631. 17 Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Dispacamides, antihistamine alkaloids from Caribbean Agelas sponges. Tetrahedron Lett., 1996, 7, 3587- 3590. 18 Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Dispacamides, antihistamine alkaloids from Caribbean Agelas sponges. Tetrahedron Letters 1996, 37, 3587. 19 Cahn, R. S.; Ingold, C. K.; Prelog, V. Specification of molecular chirality. Angewandte Chemie International Edition 20 Vergne, C.; Appenzeller, J.; Ratinaud, C.; Martin, M.; Debitus, C.; Zaparucha, A.; Al- Mourabit, A. Debromodispacamides B and D: Isolation from the marine sponge Agelas mauritiana and stereoselective synthesis using a biomimetic proline route. Organic Letters 2008, 10, 493. 21 KOBAYASHI, J.; OHIZUMI, Y.; NAKAMURA, H.; HIRATA, Y. A Novel antagonist of serotonergic receptors, hymenidin, isolated from the okinawan marine Sponge Hymeniacidon Sp. Experientia, v. 42, n. 10, p 1176-1177, 1986. 22 MORALES, J. J.; RODRIGUEZ, A. D. The structure of clathrodin, a novel alkaloid isolated from the caribbean sea sponge Agelas clathrodes. Journal of Natural Products, v. 54, n. 2, p. 629?631, 1991. 23 ASSMANN, M.; ZEA, S.; K?CK, M. Sventrin, a new bromopyrrole alkaloid from the caribbean sponge Agelas sventres. Journal of Natural Products. v. 64, p. 1593- 1595, 2001. 24 Sun, J., Wu, J., An, B., De Voogd, N. J., Cheng, W., & Lin, W. (2018). Bromopyrrole alkaloids with the inhibitory effects against the biofilm formation of gram negative bacteria. Marine Drugs, 16(1). https://doi.org/10.3390/md16010009 25 Fattorusso, E.; Taglialatela-Scafati, O. Two novel pyrrole-imidazole alkaloids from the Mediterranean sponge Agelas oroides. Tetrahedron Letters 2000, 41, 9917. 26 Zhang, H., Khalil, Z., Conte, M. M., Plisson, F., & Capon, R. J. (2012). A search for kinase inhibitors and antibacterial agents: Bromopyrrolo-2-aminoimidazoles from a deep-water Great Australian Bight sponge, Axinella sp. Tetrahedron Letters, 53(29), 3784?3787. https://doi.org/10.1016/j.tetlet.2012.05.051 27Disponivel em http://www.faperj.br/?id=470.2.5, acessado em 14/8/2020. 28 Dispon?vel em https://www.biolib.cz/en/taxon/id299844/, acessado em 14/8/2020. 29 Chevolot, L.; Padua, S.; Ravi, B. N.; Blyth, P. C.; Scheuer, P. J. Isolation of 1-methyl- 4,5 dibromopyrrole-2-carboxilic acid its 3?- (hydantoyl)propylamide (midpacamide) from a marine sponge. Heterocycles 30 Jim?nez, C., & Crews, P. (1994). Mauritamide A and accompanying oroidin alkaloids from the sponge agelas mauritiana. Tetrahedron Letters, 35(9), 1375?1378. https://doi.org/10.1016/S0040-4039(00)76222-8 31 Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Yamashita, J.; Van Soest R. W. M.; Fusetani, N. Ageladine A: An antiangiogenic matrixmetalloproteinase inhibitor from the marine sponge Agelas nakamurai. Journal of the American Chemical Society 2003, 125, 15700. 32 Analogs, A. A. (2011). Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of. 59(May). 33 Pi?a, I. C.; White, K. N.; Cabrera, G.; Rivero, E.; Crews, P. Bromopyrrole carboxamide biosynthetic products from the Caribbean sponge Agelas dispar. Journal of Natural Products 2007, 70, 613. 34 Kusama, T.; Tanaka, N.; Takahashi- Nakaguchi, A.; Gonoi, T.; Fromont, J.; Kobayashi, J. Bromopyrrole alkaloids from a marine sponge Agelas sp. Chemical and Pharmaceutical Bulletin 2014, 62, 499. 35 Kusama, T., Tanaka, N., Takahashi-nakaguchi, A., Gonoi, T., Fromont, J., & Kobayashi, J. (2014). Bromopyrrole Alkaloids from a Marine Sponge Agelas sp . 62(May), 499?503. 36 Braekman, J. C.; Daloze, Q.; Stoller, C.; van Soest, R. W. Biochem. Syst. Ecol. 1992, 20, 417. 37 Lacerda, R. B. (2015). Bromopyrrole marine alkaloids. Revista Virtual de Quimica, 7(2), 713?729. https://doi.org/10.5935/1984-6835.20150032 38 R. J. Castellani, R. K. Rolston, and M. A. Smith, ?Alzheimer disease,? Disease-a- Month, vol. 56, no. 9, pp. 484?546, 2010. 39 ADI. Alzheimer?s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia. An analysis of prevalence, incidence, cost trends. Dispon?vel em: https://www.alz.co.uk/research/world-report-2015. Acesso em: 21/6/2020. 40 MAURER, Konrad; VOLK, Stephan; GERBALDO, Hector. Auguste D and Alzheimer's disease. The Lancet, v. 349, n. 9064, p. 1546-1549, 1997. 41 R. N. Kalaria, G. E. Maestre, R. Arizaga et al., ?Alzheimer?s disease and vascular dementia in developing countries: prevalence, management, and risk factors,? The Lancet Neurology, vol. 7, no. 9, pp. 812?826, 2008. 42 RAUK, Arvi. The chemistry of Alzheimer?s disease. Chemical Society Reviews, v. 38, n. 9, p. 2698-2715, 2009. 43 De Paula, V. J. R., Guimar?es, F. M., & Forlenza, O. V. (2009). Papel da prote?na Tau na fisiopatologia da dem?ncia frontotemporal. Revista de Psiquiatria Clinica, 36(5), 212?217. https://doi.org/10.1590/S0101-60832009000500004 44 CRAIG, Laura A.; HONG, Nancy S.; MCDONALD, Robert J. Revisiting the cholinergic hypothesis in the development of Alzheimer's disease. Neuroscience & Biobehavioral Reviews, v. 35, n. 6, p. 1397-1409, 2011. 45 HOLMES, C. Systemic inflammation and Alzheimer's disease. Neuropathology and applied neurobiology, v. 39, n. 1, p. 51-68, 2013. 46 SU, Bo; WANG, Xu; NUNOMURA, Akihiko; MOREIRA, Paula; LEE, Gon; PERRY, George; SMITH, Adrian; ZHU, Xiangyuan. Oxidative stress signaling in Alzheimer's disease. Current Alzheimer Research, v. 5, n. 6, p. 525-532, 2008. 47 GREENOUGH, Mark A.; CAMAKARIS, James; BUSH, Ashley I. Metal dyshomeostasis and oxidative stress in Alzheimer?s disease. Neurochemistry international, v. 62, n. 5, p. 540-555, 2013. 202 48Adaptado de https://pt.dreamstime.com/ilustra%C3%A7%C3%A3o-stock se%C3%A7%C3%A3o-transversal-do-c%C3%A9rebro-humano-c%C3%A9rebro saud%C3%A1vel-comparado-alzh-image85730258, acessado em 21/7/2020. 49 Elliott, C., Rojo, A. I., Ribe, E., Broadstock, M., Xia, W., Morin, P., ? Killick, R. (2018). A role for APP in Wnt signalling links synapse loss with ?-amyloid production. Translational Psychiatry, 8(1). https://doi.org/10.1038/s41398-018- 0231-6 50 Zainaghi, I. A. (2006). Fosfolipase A2, fluidez de membrana e prote?na precursora do amil?ide em plaquetas na Doen?a de Alzheimer e Comprometimento Cognitivo Leve. 1?78. 51 MCKHANN, Guy; DRACHMAN, David; FOLSTEIN, Marshall; KALTZMAN, Robert; PRICE, Donald; STADIAN, Emanuel. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS?ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology, v. 34, n. 7, p. 939-939, 1984. (4) Blennow, K.; De Leon, M. J.; Zetterberg, H. Lancet 2006, 368, 387. 52 JORM, Anthony F. Cross-national comparisons of the occurrence of Alzheimer's and vascular dementias. European archives of psychiatry and clinical neuroscience, v. 240, n. 4-5, p. 218-222, 1991. 53 LEVY-LAHAD, Ephrat; WASCO, W.; POORKAJ, P; ROMANO, D. M.; OSHIMA, J.; PETTINGELL, W. H.; YU, C. E.; JONDRO, P. D.; SCHMIDT, S. D.; WANG, K. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, v. 269, n. 5226, p. 973-977, 1995. 54 Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer?s disease. Nature. 1995;375:754-60. 55 Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, et al. Complete analysis of the presenilin 1 gene in early onset Alzheimer?s disease. Neuroreport. 1996,7:801-5 56 Bird TD. Enfermedad de Alzheimer y otras demenciais. In: Fauce AS, Braunwald EI, Wilson JB, Martin JB, Kasper DL, Hanser SL, et al. Principios de Medicina Interna. 14.ed. Madrid: McGraw-Hill Interamericana, 1998. 57 Selkoe DJ. Presenilin, Notch, and the genesis and treatment of Alzheimer?s disease. Proc Natl Acad Sci USA. 2001;98:11039-41. 58 Tamaoka A, Fraser PE, Ishii K, Sahara N, Ozawak K, Ikeda M, et al. Amyloidbetaprotein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease. Brain Rev Mol Brain Res. 1998;56:178-85. 59 Luiz Baltar. Revista Ci?ncia Hoje, edi??o 243 (2007). 60 Domise M, Didier S, Marinangeli C, Zhao H, Chandakkar P, Bu?e L, et al. AMPactivated protein kinase modulates tau phosphorylation and tau pathology in vivo. Sci Rep. 2016; 61 Sousa, B. M. (2017). Abordagem terap?utica na Doen?a de Alzheimer. Universudade Do Algarve, 60. Retrieved from https://sapientia.ualg.pt/handle/10400.1/10408 62 REITZ, Christiane; DEN HEIJER, T.; VAN DUJIN, C.; HOFMAN A.; BRETELER, M. M. B.. Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study. Neurology, v. 69, n. 10, p. 998-1005, 2007. 63 BARNES, Deborah E.; YAFFE, Kristine. The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology, v. 10, n. 9, p. 819-828, 2011. 64 GUSTAFSON, Deborah; ROTHENBERG, Elisabeth; BLENNOW, Kaj; STEEN, Bertil; SKOOG, Ingmar. An 18-year follow-up of overweight and risk of Alzheimer disease. Archives of internal medicine, v. 163, n. 13, p. 1524-1528, 2003. 65 WHITMER, Rachel; GUNDERSON, Erica; QUESENBERRY, Charles; ZHOU, Jufen; YAFFE, Kristine. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Current Alzheimer Research, v. 4, n. 2, p. 103-109, 2007. 66 MAYEUX, Richard. Epidemiology of neurodegeneration. Annual review of neuroscience, v. 26, n. 1, p. 81-104, 2003. 67 LAUNER, Lenore; ROSS, Webster; PETROVITCH, Helen; MASAKI, Kamal; FOLEY, Dan; WHITE, Lon; HAVLIK, Richard. Midlife blood pressure and dementia: the Honolulu?Asia aging study?. Neurobiology of aging, v. 21, n. 1, p. 49-55, 2000. 68 BARNES, Deborah E.; YAFFE, Kristine. The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology, v. 10, n. 9, p. 819-828, 2011. 69 NOTKOLA, Irma-Leena; SULKAVA, R.; PEKKANEN, J.; ERKINJUNTTI, T.; EHNHOLM, C.; KIVINEN, P.; TUOMILEHTO, J.; NISSINEN, A. Serum total cholesterol, apolipoprotein E {FC12} e4 allele, and Alzheimer?s disease. Neuroepidemiology, v. 17, n. 1, p. 14-20, 1998. 70 IRIZARRY, M. C.; GUROL, M. E.; RAJU, S.; DIAZ-ARRASTIA, R.; LOCASCIO, J. J.; TENNIS M.; HYMAN, B. T.; GROWDON, J. H.; GREENBERG, S. M.; BOTTIGLIERI, T. Association of homocysteine with plasma amyloid ? protein in aging and neurodegenerative disease. Neurology, v. 65, n. 9, p. 1402-1408, 2005. 71 MIU, A. C.; BENGA, O. J. Aluminum and Alzheimer's disease: A new lookAlzheimer's Dis. 2006, 10, 179. Journal of Alzheimer's Disease, v. 10, no. 2-3, pp. 179-201, 2006. 72 LOEF, Martin; MENDOZA, Luisa Fernanda; WALACH, Harald. Lead (Pb) and the risk of Alzheimer?s disease or cognitive decline: a systematic review. Toxin Reviews, v. 30, n. 4, p. 103-114, 2011. 73 MUTTER, Joachim; CURTH, Annika; NAUMANN, Johannes; DETH, Richard; WALACH, Harald. Does inorganic mercury play a role in Alzheimer's disease? A systematic review and 155 an integrated molecular mechanism. Journal of Alzheimer's Disease, v. 22, n. 2, p. 357-374, 2010. 74 NERI, Luciano; HEWITT, David. Aluminium, Alzheimer's disease, and drinking water. The Lancet, v. 338, n. 8763, p. 390, 1991. 75 TOMLJENOVIC, Lucija. Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link?. Journal of Alzheimer's Disease, v. 23, n. 4, p. 567-598, 2011. 76 BONDY, Stephen C. The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology, v. 31, n. 5, p. 575-581, 2010. 77 LINDSAY, Joan; LAURIN, Danielle; VERREAULT, Ren?; H?BERT, R?jean; HELLIWELL, Barbara; HILL, Gerry; MCDOWELL, Ian. Risk factors for Alzheimer?s disease: a prospective analysis from the Canadian Study of Health and Aging. American journal of epidemiology, v. 156, n. 5, p. 445-453, 2002. 78 VALENZUELA, M.; BRAYNE, C.; SACHDEV, P.; WILCOCK, G. Medical Research Council Cognitive Function and Ageing Study. Cognitive lifestyle and long-term risk of dementia and survival after diagnosis in a multicenter population-based cohort. Am J Epidemiol, v. 173, n. 9, p. 1004-12, 2011. 79 MORRIS, M. C. The role of nutrition in Alzheimer?s disease: epidemiological evidence. European Journal of Neurology, v. 16, p. 1-7, 2009. 80 TAEPAVARAPRUK, Pornnarin; SONG, Cai. Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin?1? administrations: effects of omega?3 fatty acid EPA treatment. Journal of neurochemistry, v. 112, n. 4, p. 1054-1064, 2010. 81 DEWEERDT, Sarah. Prevention: activity is the best medicine. Nature, v. 475, n. 7355, p. S16-S17, 2011. 82 Sousa, M. (2017). Abordagem Terap?utica na Doen?a de Alzheimer. 83 RANG, R.; DALE, M. M.; RITTER, J. M.; FLOWER, R. J.; HENDERSON, G. Farmacologia. Elsevier Brasil, 2015. 84 K?SA, Peter; RAKONCZAY, Zoltan; GULYA, Karoly. The cholinergic system in Alzheimer's disease. Progress in neurobiology, v. 52, n. 6, p. 511-535, 1997. 85 Adaptado de https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/65- neurons-and-synapses/neurotransmitters.html, acessado em 09/6/2020. 86 HARDY, John; ALLSOP, David. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends in pharmacological sciences, v. 12, p. 383- 388, 1991. 87 HARDY, John; SELKOE, Dennis J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. science, v. 297, n. 5580, p. 353-356, 2002. 88 RAJASEKHAR, K.; GOVINDARAJU, Thimmaiah. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease. RSC advances, v. 8, n. 42, p. 23780-23804, 2018. 89 Serenki A, Vital MB. A doen?a de Alzheimer: aspectos fisiopatol?gicos e farmacol?gicos. Rev Psiquiatr. Rio Gd. Sul [Internet]. 2008 Terapia antiamiloide na doen?a de Alzheimer Rev Soc Bras Clin Med. 2018 abr-jun;16(2):127-31 131 90 Forlenza OV. Tratamento farmacol?gico da doen?a de Alzheimer. Rev Psiquiatr Cl?n [Internet]. 2005 [citado 2015 nov 02];32(3): 137-48. Dispon?vel em: http://www.scielo.br/pdf/rpc/v32n3/ a06v32n3.pdf 91 Costa IP. Neurobiologia da doen?a de Alzheimer [conclus?o de curso]. Rio Claro: Universidade Estadual Paulista, Instituto de Bioci?ncias de Rio Claro; 2013 [citado 2015 nov 02]. 38p. Dispon?vel em: http://hdl.handle.net/11449/118771 92 LEVY, E.; CARMAN, M. D.; FERNANDEZ-MADRID, I.J.; POWER, M.D.; LIEBERBURG, I.; VAN DUINEN, S.G.; FRANGIONE, B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science, 248(4959), p. 1124-1126, 1990. 93 CHEIGNON, C.; TOMAS, M., BONNEFONT-ROUSSELOT, D.; FALLER, P.; HUREAU, C.; COLLIN, F. Oxidative stress and the amyloid beta peptide in Alzheimer?s Disease. Redox Biology, 14, p. 450-464, 2017. 94 SOREGHAN, B.; KOSMOSKI, J.; GLABE, C. Surfactant properties of Alzheimer's A beta peptides and the mechanism of amyloid aggregation. Journal of Biological Chemistry, 269(46), p. 28551-28554, 1994. 95 SAIDO, T.; LEISSRING, M. A. Proteolytic degradation of amyloid ?-protein. Cold Spring Harbor Perspectives in Medicine, 2(6), p. a006379, 2012. 96 DANYSZ, W.; PARSONS, C.G. Alzheimer's disease, ??amyloid, glutamate, NMDA receptors and memantine?searching for the connections. British journal of pharmacology, 167(2), p. 324-352, 2012. 97 YAMADA, M.; CHIBA, T.; SASABE, J., NAWA, M., TAJIMA, H., NIIKURA, T.; NISHIMOTO, I. Implanted cannula-mediated repetitive administration of A?25?35 into the mouse cerebral ventricle effectively impairs spatial working memory. Behavioural brain research, 164(2), p. 139-146, 2005. 98 HARDY, J.A.; HIGGINS, G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science, 256(5054), p. 184, 1992. 99 RAJASEKHAR, K.; GOVINDARAJU, T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease. RSC advances, v. 8, n. 42, p. 23780-23804, 2018. 100 LUO, W.; RODINA, A.; CHIOSIS, G. Heat shock protein 90: translation from cancer to Alzheimer's disease treatment?. BMC Neuroscience, v. 9, n. 2, p. S7, 2008. 101 Adaptado de CITRON, Martin. Alzheimer's disease: strategies for disease modification. Nature reviews Drug discovery, v. 9, n. 5, p. 387, 2010. 102 LANSDALL, Claire J. An effective treatment for Alzheimer's disease must consider both amyloid and tau. Bioscience Horizons: The International Journal of Student Research, v. 7, 2014. 103 SELKOE, Dennis J.; HARDY, John. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine, v. 8, n. 6, p. 595-608, 2016. 104 BLOOM, George S. Amyloid-? and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology, v. 71, n. 4, p. 505-508, 2014. 105 FALLER, P.; HUREAU, C.; LA PENNA, G. Metal ions and intrinsically disordered proteins and peptides: from Cu/Zn amyloid-? to general principles. Accounts of chemical research, v. 47, n. 8, p. 2252-2259, 2014. 106 LEE, S. J. C.; NAM, E.; LEE, H. J.; SAVELIEFF, M. G.; LIM, M. H. Towards an understanding of amyloid-? oligomers: characterization, toxicity mechanisms, and inhibitors. Chemical Society Reviews, v. 46, n. 2, p. 310-323, 2017. 107 SAVELIEFF, M. G.; LEE, S.; LIU, Y.; LIM, M. H. Untangling amyloid-?, tau, and metals in Alzheimer?s disease. ACS chemical biology, v. 8, n. 5, p. 856-865, 2013. 108 ZHENG, Wei; MONNOT, Andrew D. Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacology & therapeutics, v. 133, n. 2, p. 177-188, 2012. 109 JOMOVA, Klaudia; VONDRAKOVA, D.; LAWSON, M.; VALKO, M. Metals, oxidative stress and neurodegenerative disorders. Molecular and cellular biochemistry, v. 345, n. 1-2, p. 91-104, 2010. 110 PENDERGRASS, James C.; HALEY, Boyd E.; VIMY, Murray J. Tubulin in Rat Brain: Similarity to a Molecular Lesion in Alzheimer Diseased Brain. Neurotoxicology, v. 18, n. 2, p. 315-324, 1997. 111BONDA, David J.; LEE, H. G.; BLAIR, J. A.; ZHU, X.; PERRY, G.; SMITH, M. A. Role of metal dyshomeostasis in Alzheimer's disease. Metallomics, v. 3, n. 3, p. 267-270, 2011. 112 BARNHAM, Kevin J.; MASTERS, Colin L.; BUSH, Ashley I. Neurodegenerative diseases and oxidative stress. Nature reviews Drug discovery, v. 3, n. 3, p. 205-214, 2004. 113 UTTARA, B.; SINGH, A. V.; ZAMBONI, P.; MAHAJAN, R. T. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Current neuropharmacology, v. 7, n. 1, p. 65-74, 2009. 114 SIES, H. Oxidative stress: a concept in redox biology and medicine. Redox biology, v. 4, p. 180-183, 2015. 115 RANG, R.; DALE, M. M.; RITTER, J. M.; FLOWER, R. J.; HENDERSON, G. Farmacologia. Elsevier Brasil, 2015. 116 VALKO, Marian; LEIBTFRITZ, D.; MONCOL, J.; CRONIN, M. T.; MAZUR, M.; TELSER, J. Free radicals and antioxidants in normal physiological functions and human disease. The international journal of biochemistry & cell biology, v. 39, n. 1, p. 44- 84, 2007. 117 NUNOMURA, Akihiko; CASTELLANI, R. J.; ZHU, X.; MOREIRA, P. I.; PERRY, G.; SMITH, M. A. Involvement of oxidative stress in Alzheimer disease. Journal of neuropathology & experimental neurology, v. 65, n. 7, p. 631-641, 2006. 118 BENEVENTO, Carlos Eduardo. Disfun??o mitocondrial induzida por pept?deos betaamil?ide. 2011. 119 Adaptado de Luque-contreras, D., Carvajal, K., Toral-rios, D., Franco-bocanegra, D., & Campos-pe?a, V. (2014). Oxidative Stress and Metabolic Syndrome : Cause or Consequence of Alzheimer ? s Disease ? 2014. 120 FISH, Paul V.; STEADMAN, David; BAYLE, Elliott; WHITING, Paul. New approaches for the treatment of Alzheimer?s disease. Bioorganic & medicinal chemistry letters, v. 29, n. 2, p. 125-133, 2019. 121 SERENIKI, Adriana; VITAL, Maria Aparecida Barbato Fraz?o. A doen?a de Alzheimer: aspectos fisiopatol?gicos e farmacol?gicos. Revista de psiquiatria do Rio Grande do Sul, v. 30, n. 1, p. 0-0, 2008. 122 DINGLEDINE, R.; McBAIN, C. J.; & McNAMARA, J. O. Excitatory amino acid recepos in epilepsy. TiPS (Special Report) 49-53,1991. 123 Meldrum BS. Excitotoxicity and epileptic brain damage. Epilepsy Res. 1991; 10: 55- 61. Review. 124 Lipton SA, Rosemberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. New Engl J Med 1994; 330:613-622. 125 MARAGAKIS, N.J. & ROTHSTEIN, J.D. Glutamate transporters: animal models to neurologic disease. Neurobiology of Disease. 15:461-473, 2004. 126 Tansey, E. M. Henry Dale and the discovery of acetylcholine. Comptes Rendus Biologies 2006, 329, 419. 127 Peters, B. H.; Levin, H. S. Effects of physostigmine and lecithin on memory in Alzheimer disease. Annals of Neurology 1979, 6, 219. 128 Kumar, V.; Becker, R. E. Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent for Alzheimer's disease. International journal of clinical pharmacology, therapy, and toxicology 1989, 27, 478. 129 Li, Q.; He, S.; Chen, Y.; Feng, F.; Qu, W.; Sun, H. Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer's disease. European Journal of Medicinal Chemistry 2018, 158, 463. 130 Onor, M. L.; Trevisiol, M.; Aguglia, E. Rivastigmine in the treatment of Alzheimer?s disease: an update. Clinical Interventions in Aging 2007, 2, 17. 131 Razay, G.; Wilcock, G. K. Galantamine in Alzheimer's disease. Expert Review of Neurotherapeutics 2008, 8, 9. 132 Pacheco, G.; Palacios-Esquivel, R.; Moss, D. E. Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. Journal of Pharmacology and Experimental Therapeutics 1995, 274, 767 133 Summers, W. K.; Majovski, L. V.; Marsh, G. M.; Tachild, K.; Kling, A.; Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. The New England journal of Medicine 1986, 315, 1241. 134 Watkins, P. B.; Zimmerman, H. J.; Knapp, M. J.; Gracon, S. I.; Lewis, K. W. Hepatotoxic Effects of Tacrine Administration in Patients With Alzheimer's Disease. Journal of the American Medical Association 1994, 271, 992. 135 Crismon, M. l. Tacrine: First Drug Approved for Alzheimer's Disease. The Annals of Pharmacotherapy 1994, 28, 744. 136 Szeto, J. Y.; Lewis, S. J. Current Treatment Options for Alzheimer's Disease and Parkinson's Disease Dementia. Current Neuropharmacology 2016, 14, 326. 137 Blennow. K.; De Leon, M. J.; Zetterberg, H. Alzheimer's disease. Lancet 2006, 368, 387. 138 Weinstock, M. Selectivity of cholinesterase inhibition. CNS drugs 1999, 12, 307. 139 Jann, M. W.; Shirley, K. L.; Small, G. W. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clinical pharmacokinetics 2002, 41, 719. 140 Bores, G. M.; Kosley, R. W. Galanthamine derivatives for the treatment of Alzheimer's disease. Drugs of the Future 1996, 21, 621. 141 Samochocki, M.; H?ffle, A.; Fehrenbacher, A.; Jostock, R.; Ludwig, J.; Christner, C.; Radina, M.; Zerlin, M.; Ullmer, C.; Pereira, E. F. R.; L?bbert, H.; Albuquerque, E. X.; Maelicke, A. Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. Journal of Pharmacology and Experimental Therapeutics 2003, 305, 1024 142 MASSOULI?, Jean; PEZZEMENTI, Leo; SUZANNE, Bon, KREJCI, Eric; VALETTE, Fran?ois-Marie. Molecular and cellular biology of cholinesterases. Progress in neurobiology, v. 41, n. 1, p. 31-91, 1993. 143 NICOLET, Yvain; LOCKRIDGE, Oksana; MASSON, Patrick; FONTECILLACAMPS, Juan; NACHON, Florian. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. Journal of Biological Chemistry, v. 278, n. 42, p. 41141-41147, 2003. 144 SHAFFERMAN, A.; KRONMAN C.; FLASHNER, Y.; LEITNER, M; GROSFELD, H.; ORDENTLICH, A; GOZES, Y; COHEN, S.; ARIEN, N; BARAK, D. Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. Journal of Biological Chemistry, v. 267, n. 25, p. 17640-17648, 1992. 145 BERGMANN, Felix; WILSON, Irwin B.; NACHMANSOHN, David. Acetylcholinesterase IX. Structural features determining the inhibition by amino acids and related compounds. Journal of Biological Chemistry, v. 186, n. 2, p. 693-703, 1950. 146 WILSON, Irwin B.; BERGMANN, Felix. Acetylcholinesterase VIII. Dissociation constants of the active groups. Journal of Biological Chemistry, v. 186, n. 2, p. 683- 692, 1950. 147 WILSON, Irwin B.; BERGMANN, Felix; NACHMANSOHN, David. Acetylcholinesterase X. Mechanism of the catalysis of acylation reactions. Journal of Biological Chemistry, v. 186, n. 2, p. 781-790, 1950. 148 Dispon?vel em https://www.rcsb.org/structure/4ey4 149 Dispon?vel em https://www.rcsb.org/structure/1p0i 150 Harel, M.; Quinn, D.; Nair, H.; Silman, I.; Sussman, J. The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetylcholinesterase. Journal of the American Chemical Society 1996, 118, 2340. 151 Ferreira?Vieira, T.; Guimaraes, I.; Silva, F.; Ribeiro, F. Alzheimer?s disease: Targeting the Cholinergic System. Current Neuropharmacology 2016, 14, 101. 152 Greenblatt, H.M., Kryger, G., Lewis, T., Silman, I., Sussman, J.L., 1999. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett. 463, 321?326. 153 Bar-On, P., Millard, C.B., Harel, M., Dvir, H., Enz, A., Sussman, J.L., Silman, I., 2002a. Kinetic and Structural Studies on the Interaction of Cholinesterases with the AntiAlzheimer Drug Rivastigmine,. Biochemistry (Mosc.) 41, 3555?3564. doi:10.1021/bi020016x 154 Greenblatt, H.M., Kryger, G., Lewis, T., Silman, I., Sussman, J.L., 1999. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett. 463, 321?326. 155 Spencer, C.M., Noble, S., 1998. Rivastigmine. A review of its use in Alzheimer?s disease. Drugs Aging 13, 391?411. 156 Cheung, J., Rudolph, M.J., Burshteyn, F., Cassidy, M.S., Gary, E.N., Love, J., Franklin, M.C., Height, J.J., 2012a. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem. 55, 10282?10286. doi:10.1021/jm300871x 157 MESULAM, M. M.; GUILLOZET, A.; SHAW, P.; LEVEY, A.; DUYSEN, E. G.; LOCKRIDGE, O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience, 110(4), p. 627-639, 2002. 158 Chatonnet, A.; Lockridge, O. Comparison of butyrylcholinesterase and acetylcholinesterase. Biochemical Journal 1989, 260, 625. 159 Mack, A.; Robitzki, A. The key role of butyrylcholinesterase during neurogenesis and neural disorders: an antisense-5'butyrylcholinesterase-DNA study. Progress in Neurobiology 2000, 60, 607. 160 Mendel, B.; Rudney, H. Studies on cholinesterase: 1. Cholinesterase and pseudocholinesterase. Biochemical Journal 1943, 37, 59. [CrossRef] [PubMed] 161 Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. 2006:101?124. doi:10.1017/S1461145705005833. 162 Demencia: A Public Health Priority.; 2012:112. Available at: http://apps.who.int/iris/bitstream/10665/75263/1/9789241564458_eng.pdf. Accessed October 6, 2013. 163 Mushtaq, F.; Greig, N. H.; Khan, J. A.; Kamal, M. A.; Status of acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease and type 2 diabetes mellitus. CNS & Neurological Disorders - Drug Targets 2014, 13, 1432. 164 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. Current Medical Research and Opinion 2001, 17, 159. 165 STEPHENSON, J.; CZEPULKOWSKI, B.; HIRST, W.; MUFTI, G. J. Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Leuk Res, v. 20, p. 235-241, 1996. 166 DARVESH, S.; HOPKINS, D. A.; GEULA, C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci, v. 4, p. 131-138, 2003. 167 M. Barbosa, O. Rios, M. Vel?squez, J. Villalobos, J. Ehrmanns, Acetylcholinesterase and butyrylcholinesterase histochemical activities and tumor cell growth in several brain tumors, Surg. Neurol. 55 (2001) 106?112. 168 M. Syed, C. Fenoglio-Preiser, K.A. Skau, G.F. Weber, Acetylcholinesterase supports anchorage independence in colon cancer., Clin. Exp. Metastasis. 25 (2008) 787?798. 169 Benyamin B, Middelberg RP, Lind PA, Valle AM, Gordon S, Nyholt DR, et al. GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors. Hum Mol Genet. 2011;20(22):4504-14. 170 Furtado-Alle L, Andrade FA, Nunes K, Mikami LR, Souza RL, Chautard-Freire-Maia EA. Association of variants of the -116 site of the butyrylcholinesterase BCHE gene to enzyme activity and body mass index. Chem Biol Interact. 2008;175(1-3):115-8. 171 Boberg DR, Furtado-Alle L, Souza RL, Chautard-Freire-Maia EA. Molecular forms of butyrylcholinesterase and obesity. Genet Mol Biol. 2010;33(3):452-4 172 Arun K. Ghosh and Margherita Brindisi. Journal of Medicinal Chemistry 2015, 58, 2895. 173 Colovi?, M. B.; Krsti?, D. Z.; Lazarevi?-Pa?ti, T. D.; Bond?i?, A. M.; Vasi?, V. M. Acetylcholinesterase inhibitors: pharmacology and toxicology. Current Neuropharmacology 2013, 11, 315. 174 Darvesh, S.; Darvesh, K. V.; McDonald, R. S. Mataija, D.; Walsh, R.; Oksana Lockridge?, M.; Martin, E. Carbamates with differential mechanism of inhibition toward acetylcholinesterase and butyrylcholinesterase. Journal of Medicinal Chemistry 2008, 51, 4200. 175 Jones, M.; Wang, J.; Harmon, S.; Kling, B.; Heilmann, J.; Gilmer, J. F. Novel Selective Butyrylcholinesterase Inhibitors Incorporating Antioxidant Functionalities as Potential Bimodal Therapeutics for Alzheimer's Disease. Molecules 2016, 21, 440. 176 Garg, V.; Maurya, R. K.; Thanikachalam, P. V.; Bansal, G.; Monga, V. An insight into the medicinal perspective of synthetic analogs of indole: A review. European Journal of Medicinal Chemistry 2019, 180, 562. 177 Purgatorio, R.; de Candia, M.; Catto, M.; Carrieri, L.; De Palma, A.; Toma, M.; Ivanova, O. A.; Voskressensky, L. G.; Altomarea, C. D. Investigating 1,2,3,4,5,6- hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer's disease. European Journal of Medicinal Chemistry 2019, 177, 414. 178 Vel?k, J.; Baliharov?, V.; Fink-Gremmels, J.; Bull, S.; Lamka, J.; Sk?lov?, L. Benzimidazole drugs and modulation of biotransformation enzymes. Research in Veterinary Science 2004, 76, 95. 179 Ajani, O. O.; Aderohunmu, D. V.; Ikpo, C. O.; Adedapo, A. E.; Olanrewaju, I. O. Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine. Archiv der Pharmazie (Weinheim) 2016, 349, 475. 180 Zhu J, Wu CF, Li X, et al. Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg Med Chem. 2013;21(14):4218-4224. 181 Gopi, C.; Dhanaraju, M. D. Recent Progress in Synthesis, Structure and Biological Activities of Phenothiazine Derivatives. Review Journal of Chemistry 2019, 9, 95. 182 Gonz?lez-Mu?oz, G. C.; Arce, M. P.; L?pez, B.; P?rez, C.; Villarroy, M.; L?pez, M. G.; Garc?a, A. G.; Conde, S.; Rodr?guez-Franco, M. I. Old phenothiazine and dibenzothiadiazepine derivatives for tomorrow's neuroprotective therapies against neurodegenerative diseases. European Journal of Medicinal Chemistry 2010, 45, 6152. 183 Gonz?lez-Mu?oz, G. C.; Arce, M. P.; L?pez, B.; P?rez, C.; Romero, A.; del Barrio, L.; Mart?n-de-Saavedra, M. D.; Ejea, J.; L?on, R.; Villarroya, M.; L?pez, M. G.; Garc?a, A. G.; Conde, S.; Rodr?guez-Franco, M. I. N-acylaminophenothiazines: neuroprotective agents displaying multifunctional activities for a potential treatment of Alzheimer's disease. European Journal of Medicinal Chemistry 2011, 46, 2224. 184 Marella, A.; Tanwar, O. P.; Saha, R.; Ali, M. R.; Srivastava, S.; Akhter, M.; Shaquiquzzaman, M.; Alam, M. M. Quinoline: A versatile heterocyclic. Saudi pharmaceutical journal 2013, 21, 1. 185 Knez, D.; Brus, B.; Coquelle, N.; Sosi?, I.; ?ink, R.; Brazzolotto, X.; Mravljak, J.; Colletier, J. P.; Gobec. S. Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents. Bioorganic and Medicinal Chemistry 2015, 23, 4442. 186 Kumar, V.; Becker, R. E. Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent for Alzheimer's disease. International journal of clinical pharmacology, therapy, and toxicology 1989, 27, 478. 187 Chen, Y.; Sun, J.; Huang, Z.; et al. NO-donating tacrine derivatives as potential butyrylcholinesterase inhibitors with vasorelaxation activity. Bioorganic and Medicinal Chemistry Letters 2013, 23, 3162. 188 Fang, L.; Kraus, B.; Lehmann, J.; Heilmann, J.; Zhang, Y.; Decker, M. Design and synthesis of tacrine-ferulic acid hybrids as multi-potent anti-Alzheimer drug candidates. Bioorganic and Medicinal Chemistry Letters 2008, 18, 2905. 189 Benchekroun, M.; Bartolini, M.; Egea, J.; et al. Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids. ChemMedChem. 2015;10(3):523-539. 190 Bozorov, K.; Zhao, J.; Aisa, H. A. 1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview. Bioorganic and Medicinal Chemistry 2019, 27, 3511. 191 Xu, M.; Peng, Y.; Zhu, L.; Wang, S.; Ji, J.; Rakesh, K. P. Triazole derivatives as inhibitors of Alzheimer's disease: Current developments and structure-activity relationships. European Journal of Medicinal Chemistry 2019, 180, 656. 192 Khan, I.; Bakht, S. M.; Ibrar, A.; Abbas, S.; Hameed, S.; White, J. M.; Rana, U. A.; Zaib, S.; Shahid, M.; Iqbal, J. Exploration of a library of triazolothiadiazole and triazolothiadiazine compounds as a highly potente and selective family of cholinesterase and monoamine oxidase inhibitors: design, synthesis, Xray diffraction analysis and molecular docking studies. RSC Advances 2015, 5, 21249. 193 Santos, S. N.; Souza, G. A.; Pereira, T. M.; Franco, D. P.; Del Cistia, C. N.; Sant'Anna, C. M. R.; Lacerda, R. B.; Kummerle, A. E. Regioselective microwave synthesis and derivatization of 1,5-diaryl-3-amino-1,2,4-triazoles and a study of their cholinesterase inhibition properties. RSC Advances 2019, 9, 20356 194 Brazzolotto, X. (2019). ChemComm. 1, 3765?3768. https://doi.org/10.1039/c9cc01330j 195 Hickey, S. M., Ashton, T. D., & Pfeffer, M. (n.d.). Asian journal yanmei.pdf. 196 Costa, P. R. R.; Pilli, R. A.; Pinheiro, S.; Vasconcelos, M. L. A. A.; Subst?ncias Carboniladas e seus Derivados, Bookman: Porto Alegre, 2003. 197 ELLMAN, G. L.; COURTNEY, K. D.; ANDRES JR, V.; FEATHERSTONE, R. M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical pharmacology, v. 7, n. 2, p. 88-95, 1961. 198 Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(October 2016), 1?13. https://doi.org/10.1038/srep42717 199 Williams, A. D.; Lemke, T. L. Foye?s Principles of Medicinal Chemistry, 5th ed.; Lippincott Williams & Wilkins: United States of America, 2002. 200 Leung, M. R., van Bezouwen, L. S., Schopfer, L. M., Sussman, J. L., Silman, I., Lockridge, O., & Zeev-Ben-Mordehai, T. (2018). Cryo-EM structure of the native butyrylcholinesterase tetramer reveals a dimer of dimers stabilized by a superhelical assembly. Proceedings of the National Academy of Sciences of the United States of America, 115(52), 13270?13275. https://doi.org/10.1073/pnas.1817009115 201 https://www.tandfonline.com/doi/full/10.1080/14756366.2019.1571270 202 https://pubs.rsc.org/en/content/articlepdf/2019/ra/c9ra04105b 203 https://www.tandfonline.com/doi/full/10.1080/14756366.2019.1571270 204 https://pubs.rsc.org/en/content/articlepdf/2019/ra/c9ra04105b 205 HICKEY, M. S. et al. An Optimised Synthesis of 2-[2,3-Bis(tertbutoxycarbonyl) guanidino]ethylamine. Synlett, v. 23, p. 1779-1782, 2012. 206 GUERRITZ, S. et al. Acyl Guanidine Inhibitors of ?-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution- Phase Library Synthesis. Journal Of Medicinal Chemistry, n. 55, p. 9208?9223, 2012. 207 WANG, M. et al. Design, synthesis and antifungal activities of novel pyrrole alkaloid analogs. European Journal Of Medicinal Chemistry, v. 46, n. 5, p. 1463-1472, 2011. 208 KONIG, B.; SPATH, A. Ditopic Crown Ethet-Guanidinium Ion Receptors for the Molecular Recognition of Amino Acids and Small Peptides. Tetrahedron, v. 66, p. 1859- 1873, 2010. 209 Luo, S., Xu, S., Liu, J., Ma, F., & Zhu, Y. Z. (2020). Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations. European Journal of Medicinal Chemistry, 200, 112469. https://doi.org/10.1016/j.ejmech.2020.112469acilguanidinasguanidinasalcaloides marinhosqu?mica medicinalButirilcolinesteraseacylguanidinesguanidinesmarine alkaloidsmedicinal chemistryQu?micaAcilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesteraseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFRRJinstname:Universidade Federal Rural do Rio de Janeiro (UFRRJ)instacron:UFRRJTHUMBNAIL2021 - Paula do Nascimento Goulart.pdf.jpg2021 - Paula do Nascimento Goulart.pdf.jpgimage/jpeg1966http://localhost:8080/tede/bitstream/jspui/5705/4/2021+-+Paula+do+Nascimento+Goulart.pdf.jpg9d539a86aef96848b3ad927c9cdc1754MD54TEXT2021 - Paula do Nascimento Goulart.pdf.txt2021 - Paula do Nascimento Goulart.pdf.txttext/plain256573http://localhost:8080/tede/bitstream/jspui/5705/3/2021+-+Paula+do+Nascimento+Goulart.pdf.txtac05eb1ad1bc39a4b52eda79c5298536MD53ORIGINAL2021 - Paula do Nascimento Goulart.pdf2021 - Paula do Nascimento Goulart.pdfapplication/pdf12696775http://localhost:8080/tede/bitstream/jspui/5705/2/2021+-+Paula+do+Nascimento+Goulart.pdfe4efcc1c63466d6b6664c6d3318549e9MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-82089http://localhost:8080/tede/bitstream/jspui/5705/1/license.txt7b5ba3d2445355f386edab96125d42b7MD51jspui/57052022-05-30 13:24:03.117oai:localhost: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Biblioteca Digital de Teses e Dissertaçõeshttps://tede.ufrrj.br/PUBhttps://tede.ufrrj.br/oai/requestbibliot@ufrrj.br||bibliot@ufrrj.bropendoar:2022-05-30T16:24:03Biblioteca Digital de Teses e Dissertações da UFRRJ - Universidade Federal Rural do Rio de Janeiro (UFRRJ)false
dc.title.por.fl_str_mv Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
title Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
spellingShingle Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
Goulart, Paula do Nascimento
acilguanidinas
guanidinas
alcaloides marinhos
qu?mica medicinal
Butirilcolinesterase
acylguanidines
guanidines
marine alkaloids
medicinal chemistry
Qu?mica
title_short Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
title_full Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
title_fullStr Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
title_full_unstemmed Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
title_sort Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase
author Goulart, Paula do Nascimento
author_facet Goulart, Paula do Nascimento
author_role author
dc.contributor.advisor1.fl_str_mv Lacerda, Renata Barbosa
dc.contributor.advisor1ID.fl_str_mv 089.126.277-67
dc.contributor.advisor-co1.fl_str_mv K?mmerle, Arthur Eugen
dc.contributor.advisor-co1ID.fl_str_mv 053.978.487-78
dc.contributor.referee1.fl_str_mv Lacerda, Renata Barbosa
dc.contributor.referee2.fl_str_mv Alves, Marina Amaral
dc.contributor.referee3.fl_str_mv Romeiro, Nelilma Correia
dc.contributor.referee4.fl_str_mv Tinoco, Luzineide Wanderley
dc.contributor.referee5.fl_str_mv Salles, Cristiane Martins Cardoso de
dc.contributor.authorID.fl_str_mv 124.600.037-73
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/3473118225634771
dc.contributor.author.fl_str_mv Goulart, Paula do Nascimento
contributor_str_mv Lacerda, Renata Barbosa
K?mmerle, Arthur Eugen
Lacerda, Renata Barbosa
Alves, Marina Amaral
Romeiro, Nelilma Correia
Tinoco, Luzineide Wanderley
Salles, Cristiane Martins Cardoso de
dc.subject.por.fl_str_mv acilguanidinas
guanidinas
alcaloides marinhos
qu?mica medicinal
Butirilcolinesterase
topic acilguanidinas
guanidinas
alcaloides marinhos
qu?mica medicinal
Butirilcolinesterase
acylguanidines
guanidines
marine alkaloids
medicinal chemistry
Qu?mica
dc.subject.eng.fl_str_mv acylguanidines
guanidines
marine alkaloids
medicinal chemistry
dc.subject.cnpq.fl_str_mv Qu?mica
description Natural products are one of the main sources of inspiration for development of new drug prototypes candidates. Among products of natural origin, bromopyrrolic alkaloids are of great interest to medicinal chemists because they are a class of exclusively marine secondary metabolites, produced by sponges, and with diverse biological activities. The present work describes design, synthesis and evaluation, in vitro and in silico, of new guanidines and acylguanidines bromopyrrole derivatives designed as structural analogues of oroidine marine alkaloids. Structural planning was based on strategies such as bioisosterism, molecular hybridization and homologation for planning changes in the characteristic subunits of these alkaloids, such as the spacer alkyl chain and the cyclic guanidine subunit. Synthetic strategy explored the condensation reaction between the key intermediate 1-(tert-butyloxycarbonyl)-3-(4,5-dibromopyrrol-2-carbonyl)-2-methyl-2-isothiourea with different amines and subsequent removal of the protection group (N-Boc) in acid medium to obtain the target acylguanidines. The acyclic guanidinic analogs were obtained by the reaction between the intermediate 2-trichloroacetyl-4,5-dibromopyrrole, or 2-trichloroacetyl-pyrrole, and previously synthesized N,N'-bis-protected amino-alkylguanidines, and subsequent deprotection reaction in acidic medium. We synthesized 32 original compounds (68a-c; 69a-c; 50a-f; 62a-h; 62g'; 62h'; 51a-h; 51g'; 51h') in good yields, among guanidines and acylguanidines (protected and unprotected), which are synthetic analogs of oroidinic marine alkaloids, all characterized by 1H NMR and 13C NMR. In vitro screening for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, identified guanidine 68c as a non-selective inhibitor of AChE (CI50 of 22.8?M) and BuChE (CI50 of 27.3 ?M) and 50c as a selective inhibitor of BuChE (IC50 of 13.3 ?M). Acylguanidines stood out as selective BuChE inhibitors, mainly free acylguanidines 51a and 51g with IC50 of 4.8 ?M and 3.8 ?M, respectively, and 52c, 52d and 52f with BuChE inhibition greater than 83% at 30 ?M. Structure-activity relationship showed the importance of free acylguanidine function for selective inhibition of BuChE, as well as the presence of bromine substituents in pyrrole ring. The molecular docking studies corroborated by showing the importance of bromopyrrole, acylguanidine and benzyl ring subunits for interaction with the amino acid residues in BuChE active site. Additionally, in silico evaluation of ADME and druglike properties showed that new bromopyrrole guanidines and acylguanidines have the potential for good gastrointestinal absorption and good drug-likeness properties.
publishDate 2021
dc.date.issued.fl_str_mv 2021-04-29
dc.date.accessioned.fl_str_mv 2022-05-27T20:18:54Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.citation.fl_str_mv GOULART, Paula do Nascimento. Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase. 2021. 214 f. Tese (Doutorado em Qu?mica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro, Serop?dica, 2021.
dc.identifier.uri.fl_str_mv https://tede.ufrrj.br/jspui/handle/jspui/5705
identifier_str_mv GOULART, Paula do Nascimento. Acilguanidinas e guanidinas an?logas de alcaloides bromopirr?licos, planejadas como inibidores seletivos de butirilcolinesterase. 2021. 214 f. Tese (Doutorado em Qu?mica) - Instituto de Qu?mica, Universidade Federal Rural do Rio de Janeiro, Serop?dica, 2021.
url https://tede.ufrrj.br/jspui/handle/jspui/5705
dc.language.iso.fl_str_mv por
language por
dc.relation.references.por.fl_str_mv 1 Burger, R., & Bigler, P. (1998). COMMUNICATIONS DEPTQ : Distorsionless Enhancement by Polarization Transfer Including the Detection of Quaternary Nuclei. 534, 529?534. 2 R. Rane, N. Sahu, C. Shah, R. Karpoormath, Curr. Top. Med. Chem. 2014, 14, 253?273. 3 van Rensburg, M., Copp, B. R., & Barker, D. (2018). Synthesis and Absolute Stereochemical Reassignment of Mukanadin F: A Study of Isomerization of Bromopyrrole Alkaloids with Implications on Marine Natural Product Isolation. European Journal of Organic Chemistry, 2018(24), 3065?3074. https://doi.org/10.1002/ejoc.201800422 4 Tasdemir, D., Topaloglu, B., Perozzo, R., Brun, R., O?Neill, R., Carballeira, N.M., Zhang, X., Tonge, P.J., Linden, A., Ruedi, P., 2007. Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli. Bioorg. Med. Chem. 15, 6834?6845. 5 Richards, J., Ballard, T., Huigens, R., Melander, C., 2008. Synthesis and screening of an oroidin library against Pseudomonas aeruginosa biofilms. Chem. Biol. Chem. 9, 1267? 1279. 6 Tasdemir, D., Mallon, R., Greenstein, M., Feldberg, L., Kim, S., Collins, K., Wojciechowicz, D., Mangalindan, G., Concepcio? n, G., Harper, M., Ireland, C., 2002. Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mito gen-activated protein kinase kinase-1 (MEK-1). J. Med. Chem. 45, 529?532. 7 Paul, A.K., Robert, E.S., Moustapha, E.S.K., Rober Jr., G.H., Dan,cR., Kenneth, L.R., 1991. Bioactive bromopyrrole metabolites from the Caribbean sponge Agelas conifera. J. Org. Chem. 56, 2975-2975. 8 Tsuda, M., Yasuda, T., Fukushi, E., Kawabata, J., Sekiguchi, M., Fromont, J., Kobayashi, J., 2006. Agesamides A and B, bromopyrrole alkaloids from sponge Agelas species: application of DOSY for chemical screening of new metabolites. Org. Lett. 8, 4235?4238. 9 Rane, R.; Sahu, N,; Shah, C.; Karpoormath, R. Marine bromopyrrole alkaloids: Synthesis and diverse medicinal applications. Current Topics in Medicinal Chemistry 2014, 14, 253. 10 Forenza, S.; Minale, L.; Riccio, R. New bromo-pyrrole derivatives from sponges agelas-oroides. Chemical Communications 1971, 1129. 11 FORENZA, S.; MINALE, L.; RICCIO, R.; FATTORUSSO, E. New bromo-pyrrole derivatives from the sponge Agelas oroides. Journal of the Chemical Society D: Chemical Communications, v. 285, n. 18, p. 1129, 1971. 12Takale, B. S.; Desai, N. V.; Siddiki, A. A.; Chaudhari, H, K.; Telvekar, V. N. Synthesis and biological evaluation of pyrrole-2- carboxamide derivatives: oroidin analogues. Medicinal Chemistry Research 2014, 23, 1387. 13 Richards, J. J.; Reyes, S.; Stowe, S. D.; Tucker, A. T.; Ballard, T. E.; Mathies, L. D.; Cavanagh, J.; Melander, C. Amide isosteres of oroidin: Assessment of antibiofilm activity and C. elegans toxicity. Journal of Medicinal Chemistry 2009, 52, 4582. 14 C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney, Adv. Drug Delivery Rev., 2001, 46, 3 15 Dispon?vel em https://spongeguide.uncw.edu/myresults.php?searchtype=3&taxa=1, acessado em 18/5/2020. 16 Bharate SB, Yadav RR, Battula S, Vishwakarma RV. 2012. Meridianins: marinederived potent kinase inhibitors. MiniRev Med Chem. 12:618? 631. 17 Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Dispacamides, antihistamine alkaloids from Caribbean Agelas sponges. Tetrahedron Lett., 1996, 7, 3587- 3590. 18 Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Dispacamides, antihistamine alkaloids from Caribbean Agelas sponges. Tetrahedron Letters 1996, 37, 3587. 19 Cahn, R. S.; Ingold, C. K.; Prelog, V. Specification of molecular chirality. Angewandte Chemie International Edition 20 Vergne, C.; Appenzeller, J.; Ratinaud, C.; Martin, M.; Debitus, C.; Zaparucha, A.; Al- Mourabit, A. Debromodispacamides B and D: Isolation from the marine sponge Agelas mauritiana and stereoselective synthesis using a biomimetic proline route. Organic Letters 2008, 10, 493. 21 KOBAYASHI, J.; OHIZUMI, Y.; NAKAMURA, H.; HIRATA, Y. A Novel antagonist of serotonergic receptors, hymenidin, isolated from the okinawan marine Sponge Hymeniacidon Sp. Experientia, v. 42, n. 10, p 1176-1177, 1986. 22 MORALES, J. J.; RODRIGUEZ, A. D. The structure of clathrodin, a novel alkaloid isolated from the caribbean sea sponge Agelas clathrodes. Journal of Natural Products, v. 54, n. 2, p. 629?631, 1991. 23 ASSMANN, M.; ZEA, S.; K?CK, M. Sventrin, a new bromopyrrole alkaloid from the caribbean sponge Agelas sventres. Journal of Natural Products. v. 64, p. 1593- 1595, 2001. 24 Sun, J., Wu, J., An, B., De Voogd, N. J., Cheng, W., & Lin, W. (2018). Bromopyrrole alkaloids with the inhibitory effects against the biofilm formation of gram negative bacteria. Marine Drugs, 16(1). https://doi.org/10.3390/md16010009 25 Fattorusso, E.; Taglialatela-Scafati, O. Two novel pyrrole-imidazole alkaloids from the Mediterranean sponge Agelas oroides. Tetrahedron Letters 2000, 41, 9917. 26 Zhang, H., Khalil, Z., Conte, M. M., Plisson, F., & Capon, R. J. (2012). A search for kinase inhibitors and antibacterial agents: Bromopyrrolo-2-aminoimidazoles from a deep-water Great Australian Bight sponge, Axinella sp. Tetrahedron Letters, 53(29), 3784?3787. https://doi.org/10.1016/j.tetlet.2012.05.051 27Disponivel em http://www.faperj.br/?id=470.2.5, acessado em 14/8/2020. 28 Dispon?vel em https://www.biolib.cz/en/taxon/id299844/, acessado em 14/8/2020. 29 Chevolot, L.; Padua, S.; Ravi, B. N.; Blyth, P. C.; Scheuer, P. J. Isolation of 1-methyl- 4,5 dibromopyrrole-2-carboxilic acid its 3?- (hydantoyl)propylamide (midpacamide) from a marine sponge. Heterocycles 30 Jim?nez, C., & Crews, P. (1994). Mauritamide A and accompanying oroidin alkaloids from the sponge agelas mauritiana. Tetrahedron Letters, 35(9), 1375?1378. https://doi.org/10.1016/S0040-4039(00)76222-8 31 Fujita, M.; Nakao, Y.; Matsunaga, S.; Seiki, M.; Itoh, Y.; Yamashita, J.; Van Soest R. W. M.; Fusetani, N. Ageladine A: An antiangiogenic matrixmetalloproteinase inhibitor from the marine sponge Agelas nakamurai. Journal of the American Chemical Society 2003, 125, 15700. 32 Analogs, A. A. (2011). Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of. 59(May). 33 Pi?a, I. C.; White, K. N.; Cabrera, G.; Rivero, E.; Crews, P. Bromopyrrole carboxamide biosynthetic products from the Caribbean sponge Agelas dispar. Journal of Natural Products 2007, 70, 613. 34 Kusama, T.; Tanaka, N.; Takahashi- Nakaguchi, A.; Gonoi, T.; Fromont, J.; Kobayashi, J. Bromopyrrole alkaloids from a marine sponge Agelas sp. Chemical and Pharmaceutical Bulletin 2014, 62, 499. 35 Kusama, T., Tanaka, N., Takahashi-nakaguchi, A., Gonoi, T., Fromont, J., & Kobayashi, J. (2014). Bromopyrrole Alkaloids from a Marine Sponge Agelas sp . 62(May), 499?503. 36 Braekman, J. C.; Daloze, Q.; Stoller, C.; van Soest, R. W. Biochem. Syst. Ecol. 1992, 20, 417. 37 Lacerda, R. B. (2015). Bromopyrrole marine alkaloids. Revista Virtual de Quimica, 7(2), 713?729. https://doi.org/10.5935/1984-6835.20150032 38 R. J. Castellani, R. K. Rolston, and M. A. Smith, ?Alzheimer disease,? Disease-a- Month, vol. 56, no. 9, pp. 484?546, 2010. 39 ADI. Alzheimer?s Disease International. World Alzheimer Report 2015: The Global Impact of Dementia. An analysis of prevalence, incidence, cost trends. Dispon?vel em: https://www.alz.co.uk/research/world-report-2015. Acesso em: 21/6/2020. 40 MAURER, Konrad; VOLK, Stephan; GERBALDO, Hector. Auguste D and Alzheimer's disease. The Lancet, v. 349, n. 9064, p. 1546-1549, 1997. 41 R. N. Kalaria, G. E. Maestre, R. Arizaga et al., ?Alzheimer?s disease and vascular dementia in developing countries: prevalence, management, and risk factors,? The Lancet Neurology, vol. 7, no. 9, pp. 812?826, 2008. 42 RAUK, Arvi. The chemistry of Alzheimer?s disease. Chemical Society Reviews, v. 38, n. 9, p. 2698-2715, 2009. 43 De Paula, V. J. R., Guimar?es, F. M., & Forlenza, O. V. (2009). Papel da prote?na Tau na fisiopatologia da dem?ncia frontotemporal. Revista de Psiquiatria Clinica, 36(5), 212?217. https://doi.org/10.1590/S0101-60832009000500004 44 CRAIG, Laura A.; HONG, Nancy S.; MCDONALD, Robert J. Revisiting the cholinergic hypothesis in the development of Alzheimer's disease. Neuroscience & Biobehavioral Reviews, v. 35, n. 6, p. 1397-1409, 2011. 45 HOLMES, C. Systemic inflammation and Alzheimer's disease. Neuropathology and applied neurobiology, v. 39, n. 1, p. 51-68, 2013. 46 SU, Bo; WANG, Xu; NUNOMURA, Akihiko; MOREIRA, Paula; LEE, Gon; PERRY, George; SMITH, Adrian; ZHU, Xiangyuan. Oxidative stress signaling in Alzheimer's disease. Current Alzheimer Research, v. 5, n. 6, p. 525-532, 2008. 47 GREENOUGH, Mark A.; CAMAKARIS, James; BUSH, Ashley I. Metal dyshomeostasis and oxidative stress in Alzheimer?s disease. Neurochemistry international, v. 62, n. 5, p. 540-555, 2013. 202 48Adaptado de https://pt.dreamstime.com/ilustra%C3%A7%C3%A3o-stock se%C3%A7%C3%A3o-transversal-do-c%C3%A9rebro-humano-c%C3%A9rebro saud%C3%A1vel-comparado-alzh-image85730258, acessado em 21/7/2020. 49 Elliott, C., Rojo, A. I., Ribe, E., Broadstock, M., Xia, W., Morin, P., ? Killick, R. (2018). A role for APP in Wnt signalling links synapse loss with ?-amyloid production. Translational Psychiatry, 8(1). https://doi.org/10.1038/s41398-018- 0231-6 50 Zainaghi, I. A. (2006). Fosfolipase A2, fluidez de membrana e prote?na precursora do amil?ide em plaquetas na Doen?a de Alzheimer e Comprometimento Cognitivo Leve. 1?78. 51 MCKHANN, Guy; DRACHMAN, David; FOLSTEIN, Marshall; KALTZMAN, Robert; PRICE, Donald; STADIAN, Emanuel. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS?ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology, v. 34, n. 7, p. 939-939, 1984. (4) Blennow, K.; De Leon, M. J.; Zetterberg, H. Lancet 2006, 368, 387. 52 JORM, Anthony F. Cross-national comparisons of the occurrence of Alzheimer's and vascular dementias. European archives of psychiatry and clinical neuroscience, v. 240, n. 4-5, p. 218-222, 1991. 53 LEVY-LAHAD, Ephrat; WASCO, W.; POORKAJ, P; ROMANO, D. M.; OSHIMA, J.; PETTINGELL, W. H.; YU, C. E.; JONDRO, P. D.; SCHMIDT, S. D.; WANG, K. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science, v. 269, n. 5226, p. 973-977, 1995. 54 Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer?s disease. Nature. 1995;375:754-60. 55 Hutton M, Busfield F, Wragg M, Crook R, Perez-Tur J, Clark RF, et al. Complete analysis of the presenilin 1 gene in early onset Alzheimer?s disease. Neuroreport. 1996,7:801-5 56 Bird TD. Enfermedad de Alzheimer y otras demenciais. In: Fauce AS, Braunwald EI, Wilson JB, Martin JB, Kasper DL, Hanser SL, et al. Principios de Medicina Interna. 14.ed. Madrid: McGraw-Hill Interamericana, 1998. 57 Selkoe DJ. Presenilin, Notch, and the genesis and treatment of Alzheimer?s disease. Proc Natl Acad Sci USA. 2001;98:11039-41. 58 Tamaoka A, Fraser PE, Ishii K, Sahara N, Ozawak K, Ikeda M, et al. Amyloidbetaprotein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease. Brain Rev Mol Brain Res. 1998;56:178-85. 59 Luiz Baltar. Revista Ci?ncia Hoje, edi??o 243 (2007). 60 Domise M, Didier S, Marinangeli C, Zhao H, Chandakkar P, Bu?e L, et al. AMPactivated protein kinase modulates tau phosphorylation and tau pathology in vivo. Sci Rep. 2016; 61 Sousa, B. M. (2017). Abordagem terap?utica na Doen?a de Alzheimer. Universudade Do Algarve, 60. Retrieved from https://sapientia.ualg.pt/handle/10400.1/10408 62 REITZ, Christiane; DEN HEIJER, T.; VAN DUJIN, C.; HOFMAN A.; BRETELER, M. M. B.. Relation between smoking and risk of dementia and Alzheimer disease: the Rotterdam Study. Neurology, v. 69, n. 10, p. 998-1005, 2007. 63 BARNES, Deborah E.; YAFFE, Kristine. The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology, v. 10, n. 9, p. 819-828, 2011. 64 GUSTAFSON, Deborah; ROTHENBERG, Elisabeth; BLENNOW, Kaj; STEEN, Bertil; SKOOG, Ingmar. An 18-year follow-up of overweight and risk of Alzheimer disease. Archives of internal medicine, v. 163, n. 13, p. 1524-1528, 2003. 65 WHITMER, Rachel; GUNDERSON, Erica; QUESENBERRY, Charles; ZHOU, Jufen; YAFFE, Kristine. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Current Alzheimer Research, v. 4, n. 2, p. 103-109, 2007. 66 MAYEUX, Richard. Epidemiology of neurodegeneration. Annual review of neuroscience, v. 26, n. 1, p. 81-104, 2003. 67 LAUNER, Lenore; ROSS, Webster; PETROVITCH, Helen; MASAKI, Kamal; FOLEY, Dan; WHITE, Lon; HAVLIK, Richard. Midlife blood pressure and dementia: the Honolulu?Asia aging study?. Neurobiology of aging, v. 21, n. 1, p. 49-55, 2000. 68 BARNES, Deborah E.; YAFFE, Kristine. The projected effect of risk factor reduction on Alzheimer's disease prevalence. The Lancet Neurology, v. 10, n. 9, p. 819-828, 2011. 69 NOTKOLA, Irma-Leena; SULKAVA, R.; PEKKANEN, J.; ERKINJUNTTI, T.; EHNHOLM, C.; KIVINEN, P.; TUOMILEHTO, J.; NISSINEN, A. Serum total cholesterol, apolipoprotein E {FC12} e4 allele, and Alzheimer?s disease. Neuroepidemiology, v. 17, n. 1, p. 14-20, 1998. 70 IRIZARRY, M. C.; GUROL, M. E.; RAJU, S.; DIAZ-ARRASTIA, R.; LOCASCIO, J. J.; TENNIS M.; HYMAN, B. T.; GROWDON, J. H.; GREENBERG, S. M.; BOTTIGLIERI, T. Association of homocysteine with plasma amyloid ? protein in aging and neurodegenerative disease. Neurology, v. 65, n. 9, p. 1402-1408, 2005. 71 MIU, A. C.; BENGA, O. J. Aluminum and Alzheimer's disease: A new lookAlzheimer's Dis. 2006, 10, 179. Journal of Alzheimer's Disease, v. 10, no. 2-3, pp. 179-201, 2006. 72 LOEF, Martin; MENDOZA, Luisa Fernanda; WALACH, Harald. Lead (Pb) and the risk of Alzheimer?s disease or cognitive decline: a systematic review. Toxin Reviews, v. 30, n. 4, p. 103-114, 2011. 73 MUTTER, Joachim; CURTH, Annika; NAUMANN, Johannes; DETH, Richard; WALACH, Harald. Does inorganic mercury play a role in Alzheimer's disease? A systematic review and 155 an integrated molecular mechanism. Journal of Alzheimer's Disease, v. 22, n. 2, p. 357-374, 2010. 74 NERI, Luciano; HEWITT, David. Aluminium, Alzheimer's disease, and drinking water. The Lancet, v. 338, n. 8763, p. 390, 1991. 75 TOMLJENOVIC, Lucija. Aluminum and Alzheimer's disease: after a century of controversy, is there a plausible link?. Journal of Alzheimer's Disease, v. 23, n. 4, p. 567-598, 2011. 76 BONDY, Stephen C. The neurotoxicity of environmental aluminum is still an issue. Neurotoxicology, v. 31, n. 5, p. 575-581, 2010. 77 LINDSAY, Joan; LAURIN, Danielle; VERREAULT, Ren?; H?BERT, R?jean; HELLIWELL, Barbara; HILL, Gerry; MCDOWELL, Ian. Risk factors for Alzheimer?s disease: a prospective analysis from the Canadian Study of Health and Aging. American journal of epidemiology, v. 156, n. 5, p. 445-453, 2002. 78 VALENZUELA, M.; BRAYNE, C.; SACHDEV, P.; WILCOCK, G. Medical Research Council Cognitive Function and Ageing Study. Cognitive lifestyle and long-term risk of dementia and survival after diagnosis in a multicenter population-based cohort. Am J Epidemiol, v. 173, n. 9, p. 1004-12, 2011. 79 MORRIS, M. C. The role of nutrition in Alzheimer?s disease: epidemiological evidence. European Journal of Neurology, v. 16, p. 1-7, 2009. 80 TAEPAVARAPRUK, Pornnarin; SONG, Cai. Reductions of acetylcholine release and nerve growth factor expression are correlated with memory impairment induced by interleukin?1? administrations: effects of omega?3 fatty acid EPA treatment. Journal of neurochemistry, v. 112, n. 4, p. 1054-1064, 2010. 81 DEWEERDT, Sarah. Prevention: activity is the best medicine. Nature, v. 475, n. 7355, p. S16-S17, 2011. 82 Sousa, M. (2017). Abordagem Terap?utica na Doen?a de Alzheimer. 83 RANG, R.; DALE, M. M.; RITTER, J. M.; FLOWER, R. J.; HENDERSON, G. Farmacologia. Elsevier Brasil, 2015. 84 K?SA, Peter; RAKONCZAY, Zoltan; GULYA, Karoly. The cholinergic system in Alzheimer's disease. Progress in neurobiology, v. 52, n. 6, p. 511-535, 1997. 85 Adaptado de https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/65- neurons-and-synapses/neurotransmitters.html, acessado em 09/6/2020. 86 HARDY, John; ALLSOP, David. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends in pharmacological sciences, v. 12, p. 383- 388, 1991. 87 HARDY, John; SELKOE, Dennis J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. science, v. 297, n. 5580, p. 353-356, 2002. 88 RAJASEKHAR, K.; GOVINDARAJU, Thimmaiah. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease. RSC advances, v. 8, n. 42, p. 23780-23804, 2018. 89 Serenki A, Vital MB. A doen?a de Alzheimer: aspectos fisiopatol?gicos e farmacol?gicos. Rev Psiquiatr. Rio Gd. Sul [Internet]. 2008 Terapia antiamiloide na doen?a de Alzheimer Rev Soc Bras Clin Med. 2018 abr-jun;16(2):127-31 131 90 Forlenza OV. Tratamento farmacol?gico da doen?a de Alzheimer. Rev Psiquiatr Cl?n [Internet]. 2005 [citado 2015 nov 02];32(3): 137-48. Dispon?vel em: http://www.scielo.br/pdf/rpc/v32n3/ a06v32n3.pdf 91 Costa IP. Neurobiologia da doen?a de Alzheimer [conclus?o de curso]. Rio Claro: Universidade Estadual Paulista, Instituto de Bioci?ncias de Rio Claro; 2013 [citado 2015 nov 02]. 38p. Dispon?vel em: http://hdl.handle.net/11449/118771 92 LEVY, E.; CARMAN, M. D.; FERNANDEZ-MADRID, I.J.; POWER, M.D.; LIEBERBURG, I.; VAN DUINEN, S.G.; FRANGIONE, B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science, 248(4959), p. 1124-1126, 1990. 93 CHEIGNON, C.; TOMAS, M., BONNEFONT-ROUSSELOT, D.; FALLER, P.; HUREAU, C.; COLLIN, F. Oxidative stress and the amyloid beta peptide in Alzheimer?s Disease. Redox Biology, 14, p. 450-464, 2017. 94 SOREGHAN, B.; KOSMOSKI, J.; GLABE, C. Surfactant properties of Alzheimer's A beta peptides and the mechanism of amyloid aggregation. Journal of Biological Chemistry, 269(46), p. 28551-28554, 1994. 95 SAIDO, T.; LEISSRING, M. A. Proteolytic degradation of amyloid ?-protein. Cold Spring Harbor Perspectives in Medicine, 2(6), p. a006379, 2012. 96 DANYSZ, W.; PARSONS, C.G. Alzheimer's disease, ??amyloid, glutamate, NMDA receptors and memantine?searching for the connections. British journal of pharmacology, 167(2), p. 324-352, 2012. 97 YAMADA, M.; CHIBA, T.; SASABE, J., NAWA, M., TAJIMA, H., NIIKURA, T.; NISHIMOTO, I. Implanted cannula-mediated repetitive administration of A?25?35 into the mouse cerebral ventricle effectively impairs spatial working memory. Behavioural brain research, 164(2), p. 139-146, 2005. 98 HARDY, J.A.; HIGGINS, G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science, 256(5054), p. 184, 1992. 99 RAJASEKHAR, K.; GOVINDARAJU, T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease. RSC advances, v. 8, n. 42, p. 23780-23804, 2018. 100 LUO, W.; RODINA, A.; CHIOSIS, G. Heat shock protein 90: translation from cancer to Alzheimer's disease treatment?. BMC Neuroscience, v. 9, n. 2, p. S7, 2008. 101 Adaptado de CITRON, Martin. Alzheimer's disease: strategies for disease modification. Nature reviews Drug discovery, v. 9, n. 5, p. 387, 2010. 102 LANSDALL, Claire J. An effective treatment for Alzheimer's disease must consider both amyloid and tau. Bioscience Horizons: The International Journal of Student Research, v. 7, 2014. 103 SELKOE, Dennis J.; HARDY, John. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO molecular medicine, v. 8, n. 6, p. 595-608, 2016. 104 BLOOM, George S. Amyloid-? and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA neurology, v. 71, n. 4, p. 505-508, 2014. 105 FALLER, P.; HUREAU, C.; LA PENNA, G. Metal ions and intrinsically disordered proteins and peptides: from Cu/Zn amyloid-? to general principles. Accounts of chemical research, v. 47, n. 8, p. 2252-2259, 2014. 106 LEE, S. J. C.; NAM, E.; LEE, H. J.; SAVELIEFF, M. G.; LIM, M. H. Towards an understanding of amyloid-? oligomers: characterization, toxicity mechanisms, and inhibitors. Chemical Society Reviews, v. 46, n. 2, p. 310-323, 2017. 107 SAVELIEFF, M. G.; LEE, S.; LIU, Y.; LIM, M. H. Untangling amyloid-?, tau, and metals in Alzheimer?s disease. ACS chemical biology, v. 8, n. 5, p. 856-865, 2013. 108 ZHENG, Wei; MONNOT, Andrew D. Regulation of brain iron and copper homeostasis by brain barrier systems: implication in neurodegenerative diseases. Pharmacology & therapeutics, v. 133, n. 2, p. 177-188, 2012. 109 JOMOVA, Klaudia; VONDRAKOVA, D.; LAWSON, M.; VALKO, M. Metals, oxidative stress and neurodegenerative disorders. Molecular and cellular biochemistry, v. 345, n. 1-2, p. 91-104, 2010. 110 PENDERGRASS, James C.; HALEY, Boyd E.; VIMY, Murray J. Tubulin in Rat Brain: Similarity to a Molecular Lesion in Alzheimer Diseased Brain. Neurotoxicology, v. 18, n. 2, p. 315-324, 1997. 111BONDA, David J.; LEE, H. G.; BLAIR, J. A.; ZHU, X.; PERRY, G.; SMITH, M. A. Role of metal dyshomeostasis in Alzheimer's disease. Metallomics, v. 3, n. 3, p. 267-270, 2011. 112 BARNHAM, Kevin J.; MASTERS, Colin L.; BUSH, Ashley I. Neurodegenerative diseases and oxidative stress. Nature reviews Drug discovery, v. 3, n. 3, p. 205-214, 2004. 113 UTTARA, B.; SINGH, A. V.; ZAMBONI, P.; MAHAJAN, R. T. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Current neuropharmacology, v. 7, n. 1, p. 65-74, 2009. 114 SIES, H. Oxidative stress: a concept in redox biology and medicine. Redox biology, v. 4, p. 180-183, 2015. 115 RANG, R.; DALE, M. M.; RITTER, J. M.; FLOWER, R. J.; HENDERSON, G. Farmacologia. Elsevier Brasil, 2015. 116 VALKO, Marian; LEIBTFRITZ, D.; MONCOL, J.; CRONIN, M. T.; MAZUR, M.; TELSER, J. Free radicals and antioxidants in normal physiological functions and human disease. The international journal of biochemistry & cell biology, v. 39, n. 1, p. 44- 84, 2007. 117 NUNOMURA, Akihiko; CASTELLANI, R. J.; ZHU, X.; MOREIRA, P. I.; PERRY, G.; SMITH, M. A. Involvement of oxidative stress in Alzheimer disease. Journal of neuropathology & experimental neurology, v. 65, n. 7, p. 631-641, 2006. 118 BENEVENTO, Carlos Eduardo. Disfun??o mitocondrial induzida por pept?deos betaamil?ide. 2011. 119 Adaptado de Luque-contreras, D., Carvajal, K., Toral-rios, D., Franco-bocanegra, D., & Campos-pe?a, V. (2014). Oxidative Stress and Metabolic Syndrome : Cause or Consequence of Alzheimer ? s Disease ? 2014. 120 FISH, Paul V.; STEADMAN, David; BAYLE, Elliott; WHITING, Paul. New approaches for the treatment of Alzheimer?s disease. Bioorganic & medicinal chemistry letters, v. 29, n. 2, p. 125-133, 2019. 121 SERENIKI, Adriana; VITAL, Maria Aparecida Barbato Fraz?o. A doen?a de Alzheimer: aspectos fisiopatol?gicos e farmacol?gicos. Revista de psiquiatria do Rio Grande do Sul, v. 30, n. 1, p. 0-0, 2008. 122 DINGLEDINE, R.; McBAIN, C. J.; & McNAMARA, J. O. Excitatory amino acid recepos in epilepsy. TiPS (Special Report) 49-53,1991. 123 Meldrum BS. Excitotoxicity and epileptic brain damage. Epilepsy Res. 1991; 10: 55- 61. Review. 124 Lipton SA, Rosemberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. New Engl J Med 1994; 330:613-622. 125 MARAGAKIS, N.J. & ROTHSTEIN, J.D. Glutamate transporters: animal models to neurologic disease. Neurobiology of Disease. 15:461-473, 2004. 126 Tansey, E. M. Henry Dale and the discovery of acetylcholine. Comptes Rendus Biologies 2006, 329, 419. 127 Peters, B. H.; Levin, H. S. Effects of physostigmine and lecithin on memory in Alzheimer disease. Annals of Neurology 1979, 6, 219. 128 Kumar, V.; Becker, R. E. Clinical pharmacology of tetrahydroaminoacridine: a possible therapeutic agent for Alzheimer's disease. International journal of clinical pharmacology, therapy, and toxicology 1989, 27, 478. 129 Li, Q.; He, S.; Chen, Y.; Feng, F.; Qu, W.; Sun, H. Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer's disease. European Journal of Medicinal Chemistry 2018, 158, 463. 130 Onor, M. L.; Trevisiol, M.; Aguglia, E. Rivastigmine in the treatment of Alzheimer?s disease: an update. Clinical Interventions in Aging 2007, 2, 17. 131 Razay, G.; Wilcock, G. K. Galantamine in Alzheimer's disease. Expert Review of Neurotherapeutics 2008, 8, 9. 132 Pacheco, G.; Palacios-Esquivel, R.; Moss, D. E. Cholinesterase inhibitors proposed for treating dementia in Alzheimer's disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. Journal of Pharmacology and Experimental Therapeutics 1995, 274, 767 133 Summers, W. K.; Majovski, L. V.; Marsh, G. M.; Tachild, K.; Kling, A.; Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. The New England journal of Medicine 1986, 315, 1241. 134 Watkins, P. B.; Zimmerman, H. J.; Knapp, M. J.; Gracon, S. I.; Lewis, K. W. Hepatotoxic Effects of Tacrine Administration in Patients With Alzheimer's Disease. Journal of the American Medical Association 1994, 271, 992. 135 Crismon, M. l. Tacrine: First Drug Approved for Alzheimer's Disease. The Annals of Pharmacotherapy 1994, 28, 744. 136 Szeto, J. Y.; Lewis, S. J. Current Treatment Options for Alzheimer's Disease and Parkinson's Disease Dementia. Current Neuropharmacology 2016, 14, 326. 137 Blennow. K.; De Leon, M. J.; Zetterberg, H. Alzheimer's disease. Lancet 2006, 368, 387. 138 Weinstock, M. Selectivity of cholinesterase inhibition. CNS drugs 1999, 12, 307. 139 Jann, M. W.; Shirley, K. L.; Small, G. W. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clinical pharmacokinetics 2002, 41, 719. 140 Bores, G. M.; Kosley, R. W. Galanthamine derivatives for the treatment of Alzheimer's disease. Drugs of the Future 1996, 21, 621. 141 Samochocki, M.; H?ffle, A.; Fehrenbacher, A.; Jostock, R.; Ludwig, J.; Christner, C.; Radina, M.; Zerlin, M.; Ullmer, C.; Pereira, E. F. R.; L?bbert, H.; Albuquerque, E. X.; Maelicke, A. Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors. Journal of Pharmacology and Experimental Therapeutics 2003, 305, 1024 142 MASSOULI?, Jean; PEZZEMENTI, Leo; SUZANNE, Bon, KREJCI, Eric; VALETTE, Fran?ois-Marie. Molecular and cellular biology of cholinesterases. Progress in neurobiology, v. 41, n. 1, p. 31-91, 1993. 143 NICOLET, Yvain; LOCKRIDGE, Oksana; MASSON, Patrick; FONTECILLACAMPS, Juan; NACHON, Florian. Crystal structure of human butyrylcholinesterase and of its complexes with substrate and products. Journal of Biological Chemistry, v. 278, n. 42, p. 41141-41147, 2003. 144 SHAFFERMAN, A.; KRONMAN C.; FLASHNER, Y.; LEITNER, M; GROSFELD, H.; ORDENTLICH, A; GOZES, Y; COHEN, S.; ARIEN, N; BARAK, D. Mutagenesis of human acetylcholinesterase. Identification of residues involved in catalytic activity and in polypeptide folding. Journal of Biological Chemistry, v. 267, n. 25, p. 17640-17648, 1992. 145 BERGMANN, Felix; WILSON, Irwin B.; NACHMANSOHN, David. Acetylcholinesterase IX. Structural features determining the inhibition by amino acids and related compounds. Journal of Biological Chemistry, v. 186, n. 2, p. 693-703, 1950. 146 WILSON, Irwin B.; BERGMANN, Felix. Acetylcholinesterase VIII. Dissociation constants of the active groups. Journal of Biological Chemistry, v. 186, n. 2, p. 683- 692, 1950. 147 WILSON, Irwin B.; BERGMANN, Felix; NACHMANSOHN, David. Acetylcholinesterase X. Mechanism of the catalysis of acylation reactions. Journal of Biological Chemistry, v. 186, n. 2, p. 781-790, 1950. 148 Dispon?vel em https://www.rcsb.org/structure/4ey4 149 Dispon?vel em https://www.rcsb.org/structure/1p0i 150 Harel, M.; Quinn, D.; Nair, H.; Silman, I.; Sussman, J. The X-ray structure of a transition state analog complex reveals the molecular origins of the catalytic power and substrate specificity of acetylcholinesterase. Journal of the American Chemical Society 1996, 118, 2340. 151 Ferreira?Vieira, T.; Guimaraes, I.; Silva, F.; Ribeiro, F. Alzheimer?s disease: Targeting the Cholinergic System. Current Neuropharmacology 2016, 14, 101. 152 Greenblatt, H.M., Kryger, G., Lewis, T., Silman, I., Sussman, J.L., 1999. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett. 463, 321?326. 153 Bar-On, P., Millard, C.B., Harel, M., Dvir, H., Enz, A., Sussman, J.L., Silman, I., 2002a. Kinetic and Structural Studies on the Interaction of Cholinesterases with the AntiAlzheimer Drug Rivastigmine,. Biochemistry (Mosc.) 41, 3555?3564. doi:10.1021/bi020016x 154 Greenblatt, H.M., Kryger, G., Lewis, T., Silman, I., Sussman, J.L., 1999. Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution. FEBS Lett. 463, 321?326. 155 Spencer, C.M., Noble, S., 1998. Rivastigmine. A review of its use in Alzheimer?s disease. Drugs Aging 13, 391?411. 156 Cheung, J., Rudolph, M.J., Burshteyn, F., Cassidy, M.S., Gary, E.N., Love, J., Franklin, M.C., Height, J.J., 2012a. Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J. Med. Chem. 55, 10282?10286. doi:10.1021/jm300871x 157 MESULAM, M. M.; GUILLOZET, A.; SHAW, P.; LEVEY, A.; DUYSEN, E. G.; LOCKRIDGE, O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience, 110(4), p. 627-639, 2002. 158 Chatonnet, A.; Lockridge, O. Comparison of butyrylcholinesterase and acetylcholinesterase. Biochemical Journal 1989, 260, 625. 159 Mack, A.; Robitzki, A. The key role of butyrylcholinesterase during neurogenesis and neural disorders: an antisense-5'butyrylcholinesterase-DNA study. Progress in Neurobiology 2000, 60, 607. 160 Mendel, B.; Rudney, H. Studies on cholinesterase: 1. Cholinesterase and pseud
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidade Federal Rural do Rio de Janeiro
dc.publisher.program.fl_str_mv Programa de P?s-Gradua??o em Qu?mica
dc.publisher.initials.fl_str_mv UFRRJ
dc.publisher.country.fl_str_mv Brasil
dc.publisher.department.fl_str_mv Instituto de Qu?mica
publisher.none.fl_str_mv Universidade Federal Rural do Rio de Janeiro
dc.source.none.fl_str_mv reponame:Biblioteca Digital de Teses e Dissertações da UFRRJ
instname:Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron:UFRRJ
instname_str Universidade Federal Rural do Rio de Janeiro (UFRRJ)
instacron_str UFRRJ
institution UFRRJ
reponame_str Biblioteca Digital de Teses e Dissertações da UFRRJ
collection Biblioteca Digital de Teses e Dissertações da UFRRJ
bitstream.url.fl_str_mv http://localhost:8080/tede/bitstream/jspui/5705/4/2021+-+Paula+do+Nascimento+Goulart.pdf.jpg
http://localhost:8080/tede/bitstream/jspui/5705/3/2021+-+Paula+do+Nascimento+Goulart.pdf.txt
http://localhost:8080/tede/bitstream/jspui/5705/2/2021+-+Paula+do+Nascimento+Goulart.pdf
http://localhost:8080/tede/bitstream/jspui/5705/1/license.txt
bitstream.checksum.fl_str_mv 9d539a86aef96848b3ad927c9cdc1754
ac05eb1ad1bc39a4b52eda79c5298536
e4efcc1c63466d6b6664c6d3318549e9
7b5ba3d2445355f386edab96125d42b7
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
repository.name.fl_str_mv Biblioteca Digital de Teses e Dissertações da UFRRJ - Universidade Federal Rural do Rio de Janeiro (UFRRJ)
repository.mail.fl_str_mv bibliot@ufrrj.br||bibliot@ufrrj.br
_version_ 1800313550237859840

Registros relacionados