Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona

Detalhes bibliográficos
Autor(a) principal: Ferreira, Welisson da Silva
Data de Publicação: 2014
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
Texto Completo: https://rima.ufrrj.br/jspui/handle/20.500.14407/10174
Resumo: O desenvolvimento deste trabalho faz parte de uma linha de pesquisa que visa utilizar produtos naturais abundantes e accessíveis, que já possuam atividades biológicas relevantes descritas, como matéria-prima e fonte inspiradora de estruturas na síntese de novos derivados e análogos com potencial antifúngico e antichagásico. A piperina, extraída da pimenta do reino, bem como alguns derivados e análogos, preparados pelo nosso grupo de pesquisa, demonstraram efeito tóxico sobre o Trypanosoma cruzi, agente etiológico da Doença de Chagas. Além da atividade tóxica frente a protozoários, também é descrita para este produto natural a atividade antifúngica, entre outras. Descrevemos aqui o planejamento, a síntese e a caracterização de 19 novos derivados e análogos da piperina, bem como a avaliação da atividade destes contra epimastigotas do T. cruzi, contra cepas do fungo Cryptococcus neoformans e a avaliação da citotoxicidade frente a células humanas. Para todos os compostos preparados foi homologado o heterociclo da classe 1,3,4-oxadiazol-2-tiona, descrito como unidade farmacofórica para a atividade antifúngica. Os resultados obtidos nas avaliações biológicas realizadas indicam que os derivados 89 e 90 apresentam as melhores atividades contra o T. cruzi. O derivado 90 apresenta o melhor perfil antifúngico, apresentando atividade comparável ao fármaco fluconazol nos ensaios realizados. Estudos sobre a interferência destes compostos no perfil lipídico da membrana do T. cruzi e do C. neoformans, sugerem que este possa ser um dos mecanismos de ação destes derivados. O conjunto de resultados descritos, indicam que os derivados 89 (insaturado) e 90 (saturado), ambos com 4 carbonos na cadeia espaçadora e com estruturas mais semelhantes à amida natural, apresentam as melhores atividades antiparasitária e antifúngica, respectivamente, validando o planejamento realizado neste trabalho.
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spelling Ferreira, Welisson da SilvaLima, Marco Edilson Freire de88020266704http://lattes.cnpq.br/8392420706762318Coelho, Fernando Antônio SantosDias, Ayres GuimarãesNimrichter, LeonardoGraebin, Cedric Stephan08754329728http://lattes.cnpq.br/23994641115064272023-12-21T18:58:27Z2023-12-21T18:58:27Z2014-11-14Ferreira, Welisson da Silva. Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona. 2014. [251 f]. Tese( Programa de Pós-Graduação em Química) - Universidade Federal Rural do Rio de Janeiro, [Seropédica-RJ] .https://rima.ufrrj.br/jspui/handle/20.500.14407/10174O desenvolvimento deste trabalho faz parte de uma linha de pesquisa que visa utilizar produtos naturais abundantes e accessíveis, que já possuam atividades biológicas relevantes descritas, como matéria-prima e fonte inspiradora de estruturas na síntese de novos derivados e análogos com potencial antifúngico e antichagásico. A piperina, extraída da pimenta do reino, bem como alguns derivados e análogos, preparados pelo nosso grupo de pesquisa, demonstraram efeito tóxico sobre o Trypanosoma cruzi, agente etiológico da Doença de Chagas. Além da atividade tóxica frente a protozoários, também é descrita para este produto natural a atividade antifúngica, entre outras. Descrevemos aqui o planejamento, a síntese e a caracterização de 19 novos derivados e análogos da piperina, bem como a avaliação da atividade destes contra epimastigotas do T. cruzi, contra cepas do fungo Cryptococcus neoformans e a avaliação da citotoxicidade frente a células humanas. Para todos os compostos preparados foi homologado o heterociclo da classe 1,3,4-oxadiazol-2-tiona, descrito como unidade farmacofórica para a atividade antifúngica. Os resultados obtidos nas avaliações biológicas realizadas indicam que os derivados 89 e 90 apresentam as melhores atividades contra o T. cruzi. O derivado 90 apresenta o melhor perfil antifúngico, apresentando atividade comparável ao fármaco fluconazol nos ensaios realizados. Estudos sobre a interferência destes compostos no perfil lipídico da membrana do T. cruzi e do C. neoformans, sugerem que este possa ser um dos mecanismos de ação destes derivados. O conjunto de resultados descritos, indicam que os derivados 89 (insaturado) e 90 (saturado), ambos com 4 carbonos na cadeia espaçadora e com estruturas mais semelhantes à amida natural, apresentam as melhores atividades antiparasitária e antifúngica, respectivamente, validando o planejamento realizado neste trabalho.Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPQThis work is part of a research program that aims to use abundant and accessible natural products that show relevant biological activities as starting material and source of inspiring in the synthesis of new derivatives and analogues with antifungal and/or antichagasic potential. Piperine, extracted from black pepper as well as some derivatives and analogues prepared by our research group, showed toxic effect against Trypanosoma cruzi, the etiologic agent of Chagas disease. Apart its toxic activity against protozoa, it is also described antifungal activity for this natural product, among others. We describe herein the design, synthesis and the characterization of 19 new derivatives and analogues of piperine as well as the evaluation of their activities against epimastigotes of T. cruzi and as well as strains of the fungus Cryptococcus neoformans. The cytotoxicity of all the synthesized compounds were evaluated of against human cells. In the structure of all the prepared compounds has been inserted the 1,3,4-oxadiazole-2-thione portion, described as pharmacophoric unit for antifungal activity. The biological results obtained indicate that the oxadiazolic derivatives 89 and 90 show the best activity against T. cruzi epimastigotes. The derivative 90 showed the best antifungal profile, comparable to fluconazole. Studies on the interference of these compounds on lipid profile of the T. cruzi membrane and C. neoformans, suggest that this may be one of the mechanisms of action of these derivatives. The assembly of results described herein indicate that the derivatives 89 (unsaturated) and 90 (saturated), both with 4 carbons in the spacer chain and most similar structures to the natural amide, featuring the best antiparasitic and antifungal activities, respectively, validating the molecular planning done in this studyapplication/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de Ciências ExatasQuímica OrgânicaSíntese OrgânicaPiperaceaeFungicidasTrypanossoma CruziCryptococcus neoformansOrganic ChemistryOrganic SynthesisFungicidesQuímicaPlanejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-TionaPlanning, synthesis and evaluation of the antifungal and trypanocidal activities of piperine and 1,3,4-Oxadiazol-2-Tione nucleus derivativesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisABE, F.; NAGAFUJI, S.; OKAWA, M.; KINJO, J.; AKAHANE, H.; OGURA, T.; MARTINEZ-ALFARO, M. A.; REYES-CHILPA, R. Trypanocidal Constituents in Plants: Evaluation of some Mexican plants for their Trypanocidal activity and active constituents in the seeds of Persea Americana. Biol. Pharm. Bull. 28(7): 1314-1317, 2005. ABORAIA, A. S., ABDEL-RAHMAN, H. M. Novel 5-(2-hydroxyphenyl)-3- substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents. Bioorg. Med. Chem. 14: 1236-1246, 2005. ABORAIA, A. S.; ABDEL-RAHMAN, H. M.; MAHFOUZ, N. M.; EL-GENDY, M. A. Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents. Bioorg. Med. Chem. 14: 1236-1246, 2006. AGGARWAL, N.; KUMAR, R.; DUREJA, P.; KHURANA, J. M. Synthesis of novel nalidixic acid-based derivatives as potent antibacterial agents. Chem. Biol. Drug. Des. 79: 384-397, 2012. ALMASIRAD, A.; SHAFIEE, A.; ABDOLLAHI, M.; NOEPARAST, A.; SHAHROKHINEJAD, N.; VOUSOOGHI, N.; TABATABAI, S. A.; KHORASAMI, R. Synthesis and analgesic activity of new 1,3,4-oxadiazoles and 1,2,4-triazoles. Med. Chem. Res. 20: 435-442, 2011. ALMAZIRAD, A.; VOUSOOGHI, N.; TABATABAI, S. A. KEBRIAEEZADEH, A.; SHAFIEE, A. Synthesis, anticonvulsivant and muscle relaxant activities of substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole. Acta. Chim. Slov. 54: 317-324, 2007. AMIR, M.; SHIKHA, K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino)phenyl]acetic acid derivatives. Eur. J. Med. Chem. 39: 535-545, 2004. 230 ANDERSON, T. M.; CLAY, M. C.; CIOFFI, A. G.; DIAZ, K. A.; HISAO, G. S.; TUTTLE, M. D.; NIEUWKOOP. A. J.; COMELLAS, G.; MARYUM, N.; WANG, S.; UNO, B. E.; WILDEMAN, E. L.; GONEN, T.; RIENSTRA, C. M.; BURKE, M. D. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat. Chem. Biol. 10: 400-406, 2014. ATAL, C. K.; ZUTSHI, U.; RAO, P. G. Scientific evidence on the role of ayurvedic herbals on bioavailability of drugs. J. Ethnopharm. 4(2): 229-232, 1981. BANO, G.; RAINA, R. K.; ZUTSHI, U.; BEDI, K. L.; JOHRI, R. K.; SHARMA, S. C. Effect of piperine on bioavailability and pharmacokinetics of propanolol and theophylline in healthy-volunteers. Eur. J. Clin. Pharm. 41(6): 615-617, 1991. BARCHIESI, F.; SCHIMIZZI, A. M.; NAJVAR, L. K.; BOCANEGRA, R.; CASELLI, F.; DI-CESARE, S.; GIANNINI, D, DI-FRANCESCO, L. F.; GIACOMETTI, A.; CARLE, F.; SCALISE, G.; GRAYBILL, J. R. Interactions of posaconazole and flucytosine against Cryptococcus neoformans. Antimicrob. Agents. Chemother. 45(5): 1355-1359, 2001. BLICKE, F. F. The Mannich reactions. Organic Reactions. 1(10): 303-341, 1942. BRAMMER, K. W.; FARROW, P. R.; FAULKNER, J. K. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev. Infect. Dis. 12(S3): 318-326, 1990. BRENER, Z., ANDRADE, Z. A. Trypanosoma cruzi e a doença de Chagas. Guanabara Koogan, Rio de Janeiro, 1979. BUCHANAN, K. L.; MURPHY, J. W. What makes Cryptococcus neoformans a pathogen?. Emerg. Infect. Dis. 4(1): 71-83, 1998. BUSSE, O. Uber parasitare Zelleinschlusse und ihre Zuchtung. Zentralbl. Bakteriol. 16: 175-180, 1894. 231 CASADEVALL, A.; CLEARE, W.; FELDMESSER, M.; GLATMAN-FREEDMAN, A.; GOLDMAN, D. L.; KOZEL, T. R.; LENDVAI, N.; MUKHERJEE, J. PIROFSKI, L. A.; RIVERA, J.; ROSAS, A. L.; SCHARFF, M. D. Characterization of murine monoclonal antibody to Cryptococcus neoformans polysaccharide that is a candidate for human therapeutic studies. Antimicrob. Agents Chemother. 42: 1437-1446, 1998. CASADEVALL, A.; PERFECT, J. R. Cryptococcus Neoformans. ASM Press. 1998. CASALINUOVO, I. A.; DI-FRANCESCO, P.; GARACI, E. Fluconazole resistence in Candida albicans: A review of mecanisms. Eur. Rev. Med. Pharmacol. Sc. 8: 69-77, 2004. CHAGAS, C. Nova tripanozomiaze humana. “Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen. n. sp, ajente etiolójico de nova entidade mórbida do homem”. Mem. Inst. Oswaldo Cruz. 1: 159-218, 1909. CHIOU, C.; GROLL, A.; WALSH, T. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist. 5: 120-135, 2000. CHOI, J. Y.; PODUST, L. M.; ROUSH, W. R. Drug strategies targenting CYP51 in neglected tropical diseases. Chem. Rev. 2014 (no prelo; doi:10.1021/cr5003134) COURA, J. R., VIÑAS, P. A. Chagas disease a new worldwide challenge. Nature. 465(7301): S6-7, 2010. COURNIA, Z.; ULLMANN, G. M.; SMITH, J. C. Differential effects of cholesterol, ergosterol and lanosterol on a dipalmitoyl phosphatidylcholine membrane: a molecular dynamics simulation study. J. Phys. Chem. 111: 1786-1801, 2007. DABIRI, M.; SALEHI, P.; BAGHBANZADEH, M.; BAHRAMNEJAD, M. A facile procedure for the one-pot synthesis of unsymmetrical 2,5-disubstituted 1,3,4- oxadiazoles. Tetrah. Lett. 47(39): 6983-6986, 2006. 232 DASH, S.; KUMAR, B. A.; SINGH, J.; MAITY, B. C.; MAITY, T. K. Synthesis of some novel 3,5-disubstituted 1,3,4-oxadiazole derivatives and anticancer activity on EAC animal model. Med. Chem. Res. 20(8): 1206-1213, 2011. DE-SARRO, A.; LA-CAMERA, E.; FERA, M. T. New and investigational triazole agents for the treatment of invasive fungal infections. J. Chemother. 20: 661-671, 2008. DESAI, N. C.; DODIYA, A. M.; RAJPARA, K. M.; RUPALA, Y. M. Synthesis and antimicrobial screening of 1,3,4-oxadiazole and clubbed thiophene derivatives. J. Sau. Chem. Soc. 18: 255-261, 2014. DOCAMPO, R.; MORENO, S. N.; TURRENS, J. F.; KATZIN, A. M.; GONZALEZCAPPA, S. M.; STOPPANI, A. O. Biochemical and ultrastructural alterations produced by miconazole and econazole in Trypanosoma cruzi. Mol. Biochem. Parasitol. 3: 169- 180, 1981. DONNICI, C. L.; NOGUEIRA, L. J.; ARAUJO, M. H.; OLIVEIRA, S. R. MAGALHÃES, T. F. F.; LOPES, M. T. P.; ARAUJO, A. C.; STOIANOFF, M. A. R. In vitro studies of the activity of dithiocarbamate organoruthenium complexes against clinically relevant fungal pathogens. Molecules. 19: 5402-5420, 2014. DUSCHAK, V.G.; COUTO, A. S. An Insight on Targets and Patented Drugs for Chemotherapy of Chagas Disease. Recent Patents on Anti-Infective Drug Discovery, 2: 19-51, 2007. EL-EMAM, A.; AL-DEEB, O.A.; AL-OMAR, M.; LEHMAN, J., Synthesis, antimicrobial, and anti-HIV activity of certain 5-(1-adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones, Bioorg. Med. Chem., 12, 5107-5113, 2004. ELOY, F.; LENAERS, R. Synthèse d’amino-oxadiazoles-1,2,4. Helv. Chim. Acta. 49(4): 1430-1432, 1966. 233 ESTRELA. J. L. V., GUEDES, R. N. C., MALTHA, C. R. A., FASOLIN, M. Toxicidade de amidas análogas à piperina a larvas de Ascia monuste orseis Godart e Spodoptera frugiperda. Neotrop. Entomol. 32, 343, 2003. FAO. Food and Agriculture of the United Nations. Statistical Databases. Disponível em: <http://faostat.fao.org/faostat > Acesso em: 9 de janeiro de 2014. FERREIRA, C.; SOARES, D. C.; BARRETO-JUNIOR, C. B.; NASCIMENTO, M. T.; FREIRE-DE-LIMA, L.; DELORENZI, J. C.; LIMA, M. E. F.; ATELLA, G. C.; FOLLY, E.; CARVALHO, T. M. Leishmanicidal effects of piperine, its derivatives, and analogues on Leishmania amazonensis. Phytochemistry. 72: 2155-2164, 2011. FERREIRA, W. S., FRANKLIM, T. N., LOPES, N. D., DE LIMA, M. E. F. Piperina, seus Análogos e Derivados: Potencial como Antiparasitários. Rev. Vir. Quim. 4(3): 208- 224, 2012. FERREIRA, W. S.; FREIRE-DE-LIMA, L.; SARAIVA, V. B.; ALISSON-SILVA, F.; MENDONÇA-PREVIATO, L.; PREVIATO, J. O.; ECHEVARRIA, A.; LIMA, M. E. Novel 1,3,4-thiadiazolium-2-phenylamine chlorides derived from natural piperine as trypanocidal agents: chemical and biological studies. Bioorg. Med. Chem. 16(6): 2984- 2991, 2008. FOLCH, J.; LEES, M.; SLOANE-STANLEY, G. H. A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226: 497-509, 1957. FRANKLIM, T. N.; FREIRE-DE-LIMA, L.; DINIZ, J. N. S.; PREVIATO, J. O.; CASTRO, R. N.; MENDONÇA-PREVIATO, L.; LIMA, M. E. F. Desing, synthesis and trypanocidal evaluation of novel 1,2,4-triazoles-3-thiones derived from natural piperine. Molecules. 18: 6366-6382, 2013. FRASER, J. A.; GILES, S. S.; WENINK, E. C.; GEUNES-BOYER, S. G.; WRIGHT, J. R.; DIEZMANN, S.; ALLEN, A.; STAJICH, J. E.; DIETRICH, F. E.; PERFECT, J. R.; HEITMAN, J. Same-sex mating and origin of the Vancouver Island Cryptococcus gattii outbreak. Nature. 437: 1360-1364, 2005. 234 FREITAS, J. J. R.; SILVA, E. E.; REGUEIRA, J. L. L. F.; DE-ALMEIDA, S. A.; CAVALCANTE, P. M. M.; OLIVEIRA, R. N.; FREITAS J. R. 1,2,4-oxadiazóis: Síntese e aplicações. Rev. Vir. Quim. 4(6): 670-691, 2012. FRIES, B. C.; GOLDMAN, D. L.; CHERNIAK, R.; JU, R.; CASADAVALL, A. Phenotypic Switching in Cryptococcus neoformans: Results in changes in cellular morphology and glucuronoxylomannan structure. Infect. Immun. 67(11): 6076-6083, 1999. GARCIA-HERMOSO, D.; JANBON, G.; DROMER, F. Epidemiological evidence for dormant Cryptococcus neoformans infection. J. Clin. MIcrobiol. 37: 3204-3209, 1999. GHANI, U.; ULLAH, N. New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-oxadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2-(3H)-thiones, 4-amino-1,2,4- triazole-5(4H)-thiones and substituted hydrazides to the dicopper active site. Bioorg. Med. Chem. 18: 4042-4048, 2010. GIRI, S.; SINGH, H.; YADAV, L. D. S. Studies in oxadiazoles: Synthesis of some 2- mercapto-1,3,4-oxadiazoles and related compounds as potential fungicides. Agr. Biol. Chem. 40(1): 17-21, 1976. GRECCO, S. S.; REIMÃO, J. Q.; TEMPONE, A. G.; SARTORELLI, P.; ROMOFF, P.; FERREIRA, M. J. P.; FAVERO, O. A.; LAGO, J. H. G. Isolation of na antileishmanial and antitrypanosomal flavanone from leaves of Baccharis retusa. Prarasitol. Res. 106: 1245-1248, 2010. GUIMARAES, C. R. W; BOGER, D. L.; JORGENSEN, W. L. Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations. J. Am. Chem. Soc. 127(49): 17377-17384, 2005. GUPTA, S. K.; BANSAL, P.; BHARDWAJ, R. K.; VELPANDIAN, T. Comparative anti-nociceptive, anti-inflamatory and toxicity profile of nimesulide vs nimesulide and piperine combination. Pharmacol. Res. 41(6): 657-662, 2000. 235 GURGEL-GONÇALVES, R., GALVÃO, C., COSTA, J., PETERSON, A. T. Geographic Distribution of Chagas Disease Vectors in Brazil Based on Ecological Niche Modeling. J. Trop. Med. 2012: 1-15, 2012. HAINES, T. H. Do sterols reduce proton and sodium leaks through lipid bilayers? Prog. Lipid Res. 40: 299-324, 2001. HARSANYI, K.; KISS, P.; KORBONITS, D.; MALYATA, I. R. The synthesis of an antitussive action derivative of 1,2,4-oxadiazole, 3-(2,2-diphenylethyl)-5-(2- piperidinoethyl)-1,2,4-oxadiazole. Arzneim. Forsch. 16 (5): 615-617, 1966. HULL, C. M.; HEITMAN, J. Genetics of Cryptococcus neoformans. Annu. Rev. Genet. 36: 557-615, 2002. IKAN, R. In: Natural Products: A Laboratory Guide, Academic Press, 2nd Edition: 233- 238, 1991. IZUMI, E.; UEDA-NAKAMURA, T.; DIAS-FILHO, B. P.; VEIGA-JUNIOR, V. F.; NAKAMURA, C. V. Natural products and Chagas’ disease: a review of plant compounds studied for activity against Trypanosoma cruzi. Nat. Prod. Rep. 28: 809- 823, 2011. JAMES, N. D.; GROWCOTT, J. W. Zibotentan. Drug. Fut. 34(8): 624, 2009. KAPLANCIKLI, Z. A. Synthesis of some oxadiazole derivatives as new anticandidal agents. Molecules. 16: 7662-7671, 2011. JAYAKANTHAN, M.; CHANDRASEKAR, S.; MUTHUKUMARAN, J.; MATHUR, P. P. Analysis of CYP3A4-HIV-1 protease drugs interactions by computational methods for Highly Active Antiretroviral Therapy in HIV/AIDS. J. Mol. Graphics Modell. 28(5): 455-463, 2010. 236 JOHRI, R. K.; THUSU, N.; KHAJURIA, A.; ZUTSHI, U. Piperine-mediated changes in the permeability of rat intestinal epithelial-cells the status of gamma-glutamyl transpeptidase activity, uptake of amino-acid and lipid-peroxidation. Biochem. Pharmacol. 43(7): 1401-1407, 1992. KANTHIAH, S.; KALUSALINGAM, A.; VELAYUTHAM, R.; VIMALA, A. T.; BEYATRICKS, J. 5-(2-aminophenyl)-1,3,4-oxadiazole-2(3H)-thione derivatives: synthesis, characterization and antimicrobial evaluation. Int. J. Pharm. Sc. Rev. Res. 6(1): 64-67, 2011. KAPIL, A. Piperine: a potent inhibitor of Leishmania donovani promastigotes in vitro, Planta Medica. 59: 474, 1993. KAPPE, C.O.; DALLINGER, D. Controlled microwave heating in modern organic synthesis: highlights from the 2004-2008 literature. Molecular Diversity, 13(2): 71-193, 2009. KATZ, R. L.; LUKEMAN, J. M. The comparative diagnostic accuracy of cancer-cell deterction obtained with Ficoll-Hypaque gradient separation and standard centrifugation technics on body-cavity fluids. Amer. J. Clin. Pathol. 74: 18-24, 1980. KOPARIR, M.; CETIN, A.; CANSIZ, A. 5-Furan-2yl[1,3,4]oxadiazole-2-thiol, 5-furan- 2yl-4H[1,2,4]triazole-3-thiol and their thiol-thione tautomerism. Molecules. 10: 475- 480, 2005. KOUL, S.; KOUL, J. L.; TANEJA, S. C.; DHAR, K. L.; JAMWAL, D. S.; SINGH, K.; REEN, R. R.; SINGH, J. Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities. J. Bioorg. Med. Chem. 8(1): 251-268, 2000. KUMAR, R.; KHOKARA, S. L. Chemistry and common synthetic route of 1,3,4- oxadiazole: Na important heterocyclic moiety in medicinal chemistry. Int. J. Inst. Pharm. Life Sc. 2(5): 126-143, 2012. 237 LEPESHEVA, G. I.; VILLALTA, F.; WATERMAN, M. R. Targeting Trypanosoma cruzi Sterol 14α-Demethylase (CYP51). Advances in Parasitology. 75: 65-87, 2011. LEPESHEVA, G. I.; WATERMAN, M. R. Sterol 14α-Demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochem. Biophys. Acta. 1770: 467-477, 2007. LEPESHEVA, G. I.; ZAITSEYA, N. G.; NES, W. D.; ZHOU, W.; ARASE, M.; LIU, J. CYP51 from Trymanosoma cruzi: A phyla-specific residue in the B’ helix defines substrate preferences of sterol 14-α-demethylase. J. Biol. Chem. 281: 3577-3585, 2006. LEUNG, D.; DU, W.; HARDOWIN, C.; CHENG, H.; HWANG, I.; CRAVATT, B. F.; BOGER, D. L. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity. Bioorg. Med. Chem. Lett. 15(5): 1423-1428, 2005. LIAO, J.; YANG, F.; ZHANG, L.; CHAI, X.; ZHAO, Q.; YU, S.; ZOU, Y.; MENG, Q.; WU, Q. Synthesis and biological evalution of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents. Arch. Pharm. Res. 1-10, 2014. LIMA, L. M.; BARREIRO, E. J. Bioisosterism: A useful strategy for molecular modification and drug disign. Curr. Med. Chem. 12: 23-49, 2005. LIMA, J. S. S.; OLIVEIRA, R. B.; ROCHA, W.; OLIVEIRA, P. C.; UARTEZANI, W. Z. Análise espacial de atributos químicos do solo e da produção da cultura pimenta-doreino (Piper nigrum). Idesia (Chile). 28(2): 31-39, 2010. LIN, Z. X.; HOULT, J. R. S.; BENNET, D. C.; RAMAN, A. Stimulation of mouse melanocyte proliferation by Piper nigrum fruit extract and its main alkaloid, piperine. Planta Med. 65(7): 600-603, 1999. 238 LOURINHO, M. P.; COSTA, C. A. S.; SOUZA, L. C.; SOUZA, L. C.; NETOS, C. F. O. Conjuntura da pimenta do reino no mercado nacional e na região norte do Brasil. Enc. Biosf. 10(18): 1016-1031, 2014. LUIZE, P. S.; UEDA-NAKAMURA, T.; DIAS-FILHO, B. P.; CORTEZ, D. A. G.; NAKAMURA, C. V. Activity of Neolignans isolated from Piper regnellii (Miq.) C. DC. var. pallescens (C. DC.) YUNCK against Trypanosoma cruzi. Biol. Pharm. Bull. 29(10): 2126-2130, 2006. MA, H.; MAY, R. C. Virulence in Cryptococcus Species. Adv. Appl. Microbiol. 67: 131-190, 2009. MA, L.; XIAO, Y.; LI, C.; XIE, Z. L.; LI, D. D.; WANG, Y. T.; MA, H. T.; ZHU, H. L.; WANG, M. H.; YE, Y. H. Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan. Bioorg. Med. Chem. 21(21): 6763-6770, 2013. MACAEV, F.; RUSU, G.; POGREBNOI, S.; GUDIMA, A.; STINGACI, E.; VLAD, L.; SHVETS, N.; KANDEMIRLI, F.; DIMOGLO, A.; REYNOLDS, R. Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure-anti mycobacterial activities. Bioorg. Med. Chem. 13: 4842-4850, 2005. MARCH, J. Advanced Organic Chemistry-Reactions, Mecanism and Structure. John Willey and Sons. 3ºed: 388, 437-8, 1099, 1100 e 1101, 1985. MAYEKAR, A. N.; YATHIRAJAN, H. S.; NARAYANA, B.; SAROJINI, B. K.; KUMARI, N. S. Synthesis and antimicrobial studies on new substituted 1,3,4- oxadiazole derivatives bearing 6-bromonaphthalene moiety. Int. J. Chem. 2(1): 38-54, 2010. MBWAMBO, Z. H.; KAPINGU, M. C.; MOSHI, M. J.; MACHUMI, F.; APERS, S.; COS, P.; FERREIRA, D.; MARAIS, J. P.; VANDEN-BERGHE, D.; MAES, L.; VLIETINCK, A.; PIETERS, L. A. Antiparasitic activity of some xanthones and 239 biflavonoids from the root bark of Garcinia livingstonei. J. Nat. Prod. 69(3): 369-372, 2006. MCFADDEN, D. C.; CASADEVALL, A. Capsule and melanin synthesis in Cryptococcus neoformans. Med. Mycol. 39: 19-30, 2001. MEANWELL, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54: 2529-2591, 2011. MEGHWAL, M.; GOSWAMI, T. K. Piper nigrum and Piperine: An update. Phytother. Res. 27(8): 1121-1130, 2013. MELO, J. L. R.; ECHEVARRIA, A. Sistemas enzimáticos de Tripanossomatídeos como Potenciais alvos quimioterápicos. Rer. Virt. Quim. 4(4): 374-392, 2012. MENDOZA, D. T.; URENA-GONZALEZ, L. D.; ORTEGA-BARRIA, E.; CAPSON, T. L.; RIOS, L. C. Five new cassane diterpenes from Myrospermum frutescens with activity against Trypanosoma cruzi. J. Nat. Prod. 66(7): 928-932, 2003. MITCHELL, T. G.; PERFECTS, J. R. Cryptococcosis in the era of AIDS-100 years after the discovery of Cryptococcus neoformans. Clin. Microbiol. Rev. 8(4): 515-548, 1995. MORETTI, C.; SAUVAIN, M.; LAVAUD, C.; MASSIOT, G.; BRAVO, J. A.; MUÑOZ, V. A novel antiprotozoal aminosteroid from Saracha punctata. J. Nat. Prod. 61: 1390-1393, 1998. MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J. Immun. Meth. 65(1): 55-63, 1983. NAVEENA, C. S.; BOJA, P.; KUMARI, N. S. Synthesis, characterization and antimicrobial activity of some disubstituted 1,3,4-oxadiazoles carrying 2- (aryloxymethyl)phenyl moiety. Eur. J. Med. Chem. 45: 4708-4719, 2010. 240 NOBREGA, A. A.; GARCIA, M. H.; TATTOO, E.; OBARA, M. T.; COSTA, E.; SOBEL, J.; ARAUJO, W. N. Oral transmission of Chagas disease by consumption of açaí palm fruit, Brazil. Emerging Infectious Diseases. 15(4): 653-655, 2009. OGATA, M.; ATOBE, H.; KUSHIDA, H.; YAMAOTO, K. In vitro sensitivity of mycoplasmas isolated from various animals and sewage to antibiotics and nitrofurans. J. Antibiot. 24: 443-451, 1971. OLIVEIRA, C. S.; LIRA, B. F.; BARBOSA-FILHO, J. M.; LORENZO, J. G. F.; ATHAYDE-FILHO, P. F. Synthetic approaches and pharmacological activity of 1,3,4- oxadiazoles: A review of the literature from 2000-2012. Molecules. 17: 10192-10231, 2012. OLIVEIRA, R. G.; ALENCAR-FILHO, E. B.; VASCONCELLOS, M. L. A. A. A influencia da piperina na biodisponibilidade de fármacos: Uma abordagem molecular. Quim. Nova. 37(1): 69-73, 2014. PARMAR, V. S., JAIN, S. C., BISHT, K. S., JAIN., TANEJA, P., JHA, A., TYAGI, O. D., PRASAD, A. K., WENGEL, J., OLSEN, C. E., BOLL, P. M. Phytochemistry of the genus Piper. Phytochem. 46(4): 597-673, 1997. PASSOS L. A. C.; GUARALDO, A. M. A.; BARBOSA, R. L.; DIAS, V. L.; PEREIRA, K. S.; SCHMIDT. F. L.; FRANCO, R. M. B.; ALVES, D. P. Sobrevivência e infectividade do Trypanosoma cruzi na polpa de açaí: estudo in vitro e in vivo. Epidemiol. Serv. Saúde. 21(2): 223-232, 2012. PENA-DIAZ, J.; MONTALVETTI, A.; FLORES, C. L.; CONSTAN, A.; HURTADOGUERRO, R.; DE SOLZA, W. Mitochondrial localization of the mevalonate pathway enzyme 3-Hydroxy-3-methyl-glutaryl-CoA redutase in the Trypanosomatidae. Mol. Biol. Cell. 15: 1356-1363, 2004. 241 PERES, L. A. B.; DELFINO, V. D. A.; MOCELIN, A. J.; TUTIDA, L. A.; FAVERO, M. E.; MATSUO, T. Padronização do teste do MTT em modelo de preservação a frio como instrumento de avaliação da viabilidade celular renal. J. Bras. Nefrol. 30(1): 48- 53, 2008. PETRIKKOS, G.; SKIADA, A. Recent advances in anti-fungal chemotherapy. Int. J. Anti-microb. Agents. 30: 108-117, 2007. PINAZO, M. J.; ESPINOSA, G.; GALLEGO, M.; LOPES-CHEJADE, P. L.; URBINA, J. A.; GASCON, J. Successful treatment with posaconazol of a patient with chronic Chagas disease and systemic lupus erythematosus. Am. J. Trop. Med. Hyg. 82: 583-587, 2010. PINTO, E.; AFONSO, C.; DUARTE, S.; VALE-SILVA, L.; COSTA, E.; SOUSA, E.; PINTO, M. Antifungal activity of xanthones: evaluation of their effect on ergosterol biosynthesis by high-performance liquid chromatography. Chem. Biol. Drug. Des. 77(3): 212-222, 2011. PLATEL, K.; SRINIVASAN, K. Influence of dietary spices or their active principles on pancreatic digestive enzymes in albino rats. Nahrung. 44(1): 42-46, 2000. RAAY, B.; MEDDA, S.; MUKHOPADHYAY, S. BASU, M. K. Targetin of piperine intercalated in mannose-coated liposomes in experimental leishmaniasis. Indian J. Biochem. Biopharmacol. 36(4): 248-251, 1999. RAJAPAKNE, H. A.; ZHU, H.; YOUNG, M. B.; MOTT, B. T. A mild and efficient one pot synthesis of 1,3,4-oxadiazoles from carboxylic acids and acyl hidrazides. Tetrahedron Lett. 47: 4827-4830, 2006. RAMAPRASAD, G. C.; KALLURAYA, B.; KUMAR, B. S.; HUNNUR, R. K. Synthesis and biological property of some novel 1,3,4-oxadiazoles. Eur. J. Med. Chem. 45: 4587-4593, 2010. 242 RANE, R. A.; GUTTE, S. D.; SAHU, N. U. Synthesis and evaluation of novel 1,3,4- oxadiazole derivatives of marine bromopyrrole alkaloids as antimicrobial agent. Bioorg. Med. Chem. Lett. 22: 6429-6432, 2012. REEN, R. K.; JAMWAL, D. S.; TANEJA, S. C.; KOUL, J. L.; DUBEY, R. K.; WIEBEL, F. J.; SINGH, J. Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small-intestine of rat and guinea-pig in vivo by piperine. Biochem. Pharmacol. 46(2): 229-238, 1993. RIBEIRO, T. S.; FREIRE-DE-LIMA, L.; PREVIATO, J. O.; MENDONÇAPREVIATO, L.; HEISE, N.; LIMA, M. E. F. Toxic effects of natural piperine and it derivatives on epimastigota and amastigotes of Trypanosoma cruzi. Bioorg. Med. Chem. Lett. 14: 3555-3558, 2004. RODIG, O. R., BELL-JR, D. E., CLARK, A. K. Organic Chemystry Laboratory, Standard and Microscale Experiments. Saunders College Publishing. 215, 1990. RODRIGUES, M. L.; NIMRICHTER, L.; OLIVEIRA, D. L.; FRASES, S.; MIRANDA, K.; ZARAGOZA, O.; ALVAREZ, M.; NAKOUZI, A.; FELDMESSER, M.; CASADEVALL, A. Vesicular polysacharide export in Cryptococcus neofornmans is a eukariotic solution to the problem of fungal trans-cell wall transport. Eukaryot Cell. 6(1): 48-59, 2007. RUSSO, F and GHELARDONI, M. On various derivatives of 2-(o-ethoxy phenyl)- 1,3,4-oxadiazole 5- mercapto-substituted. Boll. Chim. Farm. 106(12): 826-836, 1967. SABO, J. A.; ABDEL-RAHMAN, S. M. Voriconazole: A new triazole antifungal. Ann. Pharmacother. 34: 1032-1043, 2000. SAHIN, G.; PALASKA, E.; EKIZOGLU, M.; OZALP, M. Synthesis and antimicrobial activity of some 1,3,4-oxadiazole derivatives. Il Farmaco. 57: 539-542, 2002. 243 SAITOH, M.; KUNITOMO, J.; KIMURA, E.; HAYASE, Y.; KOBAYASHI, H.; UCHIYAMA, N.; KAWAMOTO, T.; TANAKA, T.; MOL, C. D.; DOUGAN, D. R. Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3β. Bioorg. Med. Chem. 17: 2017-2029, 2009. SAVARIZ, F. C.; FORMAGIO, A. S. N.; BARBOSA, V. A.; FOGLIO, M. A.; CARVALHO, J. E.; DUARTE, M. C. T.; FILHO, B. P. D.; SARRAGIOTTO, M. H. Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3- alkylamino(methyl)-2-thioxo-1,3,4-oxadiazol-5-yl]β-carboline derivatives. J. Braz. Chem. Soc. 21(2): 288-298, 2010. SCHELMAN, W. R.; LIU, G.; WILDING, G.; MORRIS, T.; PHUNG, D.; DREICER, R. A phase I study of Zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest. New Drugs. 29(1): 118-125, 2011. SCHLECKER, R.; THIEME, P. C. The synthesis of antihypertensive 3-(1,3,4- oxadiazol-2-yl)-phenoxypropanolahines. Tetrahedron. 44: 3289-3294, 1988. SEMLER, U.; GROSS, G. G. Distribution of piperine in vegetative pert sod Piper nigrum. Phytochem. 27(5): 1566-1567, 1998. SHOBA, G.; JOY, D.; THANGAM, J.; MAJEED, M.; RAGENDRAN, R.; SRINIVAS, P. S. R. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Medica. 64(4): 353-356, 1998. SIEGER, G.M.; BARRINGER, W.C.; KRUEGER, J.E.; Mannich Derivatives of Medicinals: Derivatives of Some Carbonic Anhydrase Inhibitors. J. Med. Chem. 14(2): 458-460, 1971. SILVA, E. F.; CANTO-CAVALHEIRO, M. M.; BRAZ, V. R.; CYSNEFINKELSTEIN, L.; LEON, L. L.; ECHEVARRIA, A. Synthesis, and biological evaluation of new 1,3,4-thiadiazolium-2-phenylamine derivatives against Leishmania 244 amazonensis promastigotes and amastigotes. Eur. J. Med. Chem. 37(12): 979-984, 2002. SILVERSTEIN, R. M.; BASSLER, G. C.; MORRILL, T. C.; Identificação espectrométrica de compostos orgânicos. Guanabara Koogan. 5ºEd.: 3-39, 1994. SOUZA, W. Doenças negligenciadas. Academia Brasileira de Ciências. 2010. SRINIVASAN, K. Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit. Rev. Food Sci Nutr. 47(8): 735-48, 2007. STEENBERGEN, J. N.; CASADEVALL. A. The origin and maintenance for the human pathogenic fungus Cryptococcus neoformans. Microbes Infect. 5: 667-675, 2003. SUETH-SANTIAGO, V.; FRANKLIM. T. N.; DRUMOND, N. L.; LIMA, M. E. F. CYP51: Uma boa idéia? Rer. Virt. Quim. 2014 (aceito para publicação) TANOWITZ, H. B.; MONTGOMERY, S. P. Chagas disease has now gone global. PLoS Neglected Tropical Diseases. 5(4): e1136, 2011. TEMESGEN, Z. SIRAJ. D. S. Raltegravir: First in class HIV-integrase inhibitor. Therap. Clin. Risk Manag. 4: 493-500, 2008. TRAMONTINI, M. and ANGIOLINI, L. Further advances in the chemistry of mannich bases. Tetrahedron. 46(6): 1791-1837, 1990. URBINA, J. A. Chemotherapy of Chagas’ disease: the how and the why. J. Mol. Med. 77:332–338, 1999. URBINA, J. A.; DOCAMPO, R. Specific chemoteraphy of Chagas disease: controversies and advances. Trends in Parasitology. 19(11): 495-501, 2003. 245 VANDEPUTTE, P.; FERRARI, S.; COSTE, A. T. Antifungal resistance and new strategies to control fungal infections. Int. J. Microbiol. 2012: 1-26, 2012. VARDAN, S.; SMULYAN, H.; MOOKHERJEE, S.; EICH, R. Effects of tiodazosin, a new antihypertensive, hemodynamics and clinical variables. Clin. Pharmacol. Ther. 34 (3): 290-296, 1983. VEIGA-SANTOS, P.; BARRIAS, E. S.; SANTOS, J. F. C.; MOREIRA, T. L. B.; CARVALHO, T. M. U.; URBINA, J. A.; SOUZA W. Effects of aminodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int. J. Antimic. Agents. 40: 61-71, 2012. VENKATASAMY, R.; FAAS, L.; YOUNG, A. R.; RAMAN, A.; HIDER, R. C. Effects of piperine analogues on stimulation of piperine analogues on stimulation of melanocyte proliferation and melanocyte differentiation. Bioorg. Med. Chem. 12(8): 1905-1920, 2004. VIEGAS-JUNIOR, C.; DANUELLO, A.; BOLZANI, V. S.; BARREIRO, E. J.; FRAGA, C. A. Molecular hybridization: A useful tool in the design of new drug prototypes. Chem. Med. Chem. 14(17): 1829-1852, 2007. VILCHEZ, R. A.; FUNG, J.; KUSNE, S. Cryptococcosis in organ transplant recipients: an overview. Am. J. Transplant. 2: 575-580, 2002. VOSOOGHI, M.; AKBARZADEH, T.; FALLAH, A.; FAZELI, M. R.; JAMALIFAR, H.; SHAFIEE, A. Synthesis of substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4- triazole derivatives as potential antimicrobial agents. J. Sci. Islam. Repub. Iran. 16: 145- 151, 2005. XU, W.; HE, M.; HAN, F.; CHEN, X.; PAN, Z.; WANG, J.; TONG, M. Synthesis and antifungal activity of novel sulfone derivatives containing 1,3,4-oxadiazole moieties. Molecules. 16: 9129-9141, 2011. 246 YOSHIDA, Y.; AOYAMA, Y.; NOSHIRO, M.; GOTOH, O. Sterol 14α-Demethylase P450 (CYP51) provides a breakthrough for the discussion on the evolution of cytochrome P450 gene superfamily. Biochem. Biophys. Res. Commun. 273: 799-804, 2000. YOUNG, R. W.; WOOD, K. H. The cyclization of 3-acyldithiocarbazate Esters. J. Am. Chem. Soc. 77(2): 400-403, 1955. WANG, Y.; SAUER, D. R.; DJURIC, S. W. A simple and efficient one step synthesis of benzoxazoles and benzimidazoles from carboxylic acids. Tetrahedron Lett. 47: 105, 2006. WHO. http://www.who.int/mediacentre/factsheets/fs340/en/. Acessado em 05/08/2014. ZARAGOZA, O.; CASADEVALL, A. Experimental modulation of capsule size in Cryptococcus neoformans. Biol. Proced. Online. 6: 10-15, 2004. ZARAGOZA, O.; MIHU, C.; CASADEVALL, A.; NOSANCHUK, J. D. Effect of amphotericin B on capsule and cell size in Cryptococcus neoformans during murine infection. Antimicrob. Agents Chemother. 49: 4358-4361, 2005. ZARAGOZA, O.; MES-ARANGO, A. C.; GOMES-LOPES, A.; BERNALMERTINEZ, L.; RODRIGUES-TUDELA, J. L.; CUENCA-ESTRELLA, M. Process analysis of variables for standardization of antifungal susceptibility testing of nonfermentative yeasts. Antimicrob. Agents Chemother. 55(4): 1563-1570, 2011. ZHENG, Q. Z.; ZHANG, X. M.; XU, Y.; CHENG, K.; JIAO, Q. C. ZHU, H. L. Synthesis, biological evaluation, and molecular docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents. Bioorg. Med. Chem. 18(22): 7836-7841, 2010. ZUGER, A.; LOUIE, E.; HOLZMAN, R. S.; SIMBERKOFF, M. S.; RAHAL, J. J. Cryptococcal disease in patients with AIDS: Diagnostic feature and outcome of treatment. Ann. Int. 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dc.title.por.fl_str_mv Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
dc.title.alternative.eng.fl_str_mv Planning, synthesis and evaluation of the antifungal and trypanocidal activities of piperine and 1,3,4-Oxadiazol-2-Tione nucleus derivatives
title Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
spellingShingle Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
Ferreira, Welisson da Silva
Química Orgânica
Síntese Orgânica
Piperaceae
Fungicidas
Trypanossoma Cruzi
Cryptococcus neoformans
Organic Chemistry
Organic Synthesis
Fungicides
Química
title_short Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
title_full Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
title_fullStr Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
title_full_unstemmed Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
title_sort Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona
author Ferreira, Welisson da Silva
author_facet Ferreira, Welisson da Silva
author_role author
dc.contributor.author.fl_str_mv Ferreira, Welisson da Silva
dc.contributor.advisor1.fl_str_mv Lima, Marco Edilson Freire de
dc.contributor.advisor1ID.fl_str_mv 88020266704
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/8392420706762318
dc.contributor.referee1.fl_str_mv Coelho, Fernando Antônio Santos
dc.contributor.referee2.fl_str_mv Dias, Ayres Guimarães
dc.contributor.referee3.fl_str_mv Nimrichter, Leonardo
dc.contributor.referee4.fl_str_mv Graebin, Cedric Stephan
dc.contributor.authorID.fl_str_mv 08754329728
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/2399464111506427
contributor_str_mv Lima, Marco Edilson Freire de
Coelho, Fernando Antônio Santos
Dias, Ayres Guimarães
Nimrichter, Leonardo
Graebin, Cedric Stephan
dc.subject.por.fl_str_mv Química Orgânica
Síntese Orgânica
Piperaceae
Fungicidas
Trypanossoma Cruzi
Cryptococcus neoformans
topic Química Orgânica
Síntese Orgânica
Piperaceae
Fungicidas
Trypanossoma Cruzi
Cryptococcus neoformans
Organic Chemistry
Organic Synthesis
Fungicides
Química
dc.subject.eng.fl_str_mv Organic Chemistry
Organic Synthesis
Fungicides
dc.subject.cnpq.fl_str_mv Química
description O desenvolvimento deste trabalho faz parte de uma linha de pesquisa que visa utilizar produtos naturais abundantes e accessíveis, que já possuam atividades biológicas relevantes descritas, como matéria-prima e fonte inspiradora de estruturas na síntese de novos derivados e análogos com potencial antifúngico e antichagásico. A piperina, extraída da pimenta do reino, bem como alguns derivados e análogos, preparados pelo nosso grupo de pesquisa, demonstraram efeito tóxico sobre o Trypanosoma cruzi, agente etiológico da Doença de Chagas. Além da atividade tóxica frente a protozoários, também é descrita para este produto natural a atividade antifúngica, entre outras. Descrevemos aqui o planejamento, a síntese e a caracterização de 19 novos derivados e análogos da piperina, bem como a avaliação da atividade destes contra epimastigotas do T. cruzi, contra cepas do fungo Cryptococcus neoformans e a avaliação da citotoxicidade frente a células humanas. Para todos os compostos preparados foi homologado o heterociclo da classe 1,3,4-oxadiazol-2-tiona, descrito como unidade farmacofórica para a atividade antifúngica. Os resultados obtidos nas avaliações biológicas realizadas indicam que os derivados 89 e 90 apresentam as melhores atividades contra o T. cruzi. O derivado 90 apresenta o melhor perfil antifúngico, apresentando atividade comparável ao fármaco fluconazol nos ensaios realizados. Estudos sobre a interferência destes compostos no perfil lipídico da membrana do T. cruzi e do C. neoformans, sugerem que este possa ser um dos mecanismos de ação destes derivados. O conjunto de resultados descritos, indicam que os derivados 89 (insaturado) e 90 (saturado), ambos com 4 carbonos na cadeia espaçadora e com estruturas mais semelhantes à amida natural, apresentam as melhores atividades antiparasitária e antifúngica, respectivamente, validando o planejamento realizado neste trabalho.
publishDate 2014
dc.date.issued.fl_str_mv 2014-11-14
dc.date.accessioned.fl_str_mv 2023-12-21T18:58:27Z
dc.date.available.fl_str_mv 2023-12-21T18:58:27Z
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 Ferreira, Welisson da Silva. Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona. 2014. [251 f]. Tese( Programa de Pós-Graduação em Química) - Universidade Federal Rural do Rio de Janeiro, [Seropédica-RJ] .
dc.identifier.uri.fl_str_mv https://rima.ufrrj.br/jspui/handle/20.500.14407/10174
identifier_str_mv Ferreira, Welisson da Silva. Planejamento, síntese e avaliação das atividades antifúngica e tripanocida da piperina e derivados do núcleo 1,3,4-Oxadiazol-2-Tiona. 2014. [251 f]. Tese( Programa de Pós-Graduação em Química) - Universidade Federal Rural do Rio de Janeiro, [Seropédica-RJ] .
url https://rima.ufrrj.br/jspui/handle/20.500.14407/10174
dc.language.iso.fl_str_mv por
language por
dc.relation.references.por.fl_str_mv ABE, F.; NAGAFUJI, S.; OKAWA, M.; KINJO, J.; AKAHANE, H.; OGURA, T.; MARTINEZ-ALFARO, M. A.; REYES-CHILPA, R. Trypanocidal Constituents in Plants: Evaluation of some Mexican plants for their Trypanocidal activity and active constituents in the seeds of Persea Americana. Biol. Pharm. Bull. 28(7): 1314-1317, 2005. ABORAIA, A. S., ABDEL-RAHMAN, H. M. Novel 5-(2-hydroxyphenyl)-3- substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents. Bioorg. Med. Chem. 14: 1236-1246, 2005. ABORAIA, A. S.; ABDEL-RAHMAN, H. M.; MAHFOUZ, N. M.; EL-GENDY, M. A. Novel 5-(2-hydroxyphenyl)-3-substituted-2,3-dihydro-1,3,4-oxadiazole-2-thione derivatives: Promising anticancer agents. Bioorg. Med. Chem. 14: 1236-1246, 2006. AGGARWAL, N.; KUMAR, R.; DUREJA, P.; KHURANA, J. M. Synthesis of novel nalidixic acid-based derivatives as potent antibacterial agents. Chem. Biol. Drug. Des. 79: 384-397, 2012. ALMASIRAD, A.; SHAFIEE, A.; ABDOLLAHI, M.; NOEPARAST, A.; SHAHROKHINEJAD, N.; VOUSOOGHI, N.; TABATABAI, S. A.; KHORASAMI, R. Synthesis and analgesic activity of new 1,3,4-oxadiazoles and 1,2,4-triazoles. Med. Chem. Res. 20: 435-442, 2011. ALMAZIRAD, A.; VOUSOOGHI, N.; TABATABAI, S. A. KEBRIAEEZADEH, A.; SHAFIEE, A. Synthesis, anticonvulsivant and muscle relaxant activities of substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole. Acta. Chim. Slov. 54: 317-324, 2007. AMIR, M.; SHIKHA, K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino)phenyl]acetic acid derivatives. Eur. J. Med. Chem. 39: 535-545, 2004. 230 ANDERSON, T. M.; CLAY, M. C.; CIOFFI, A. G.; DIAZ, K. A.; HISAO, G. S.; TUTTLE, M. D.; NIEUWKOOP. A. J.; COMELLAS, G.; MARYUM, N.; WANG, S.; UNO, B. E.; WILDEMAN, E. L.; GONEN, T.; RIENSTRA, C. M.; BURKE, M. D. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nat. Chem. Biol. 10: 400-406, 2014. ATAL, C. K.; ZUTSHI, U.; RAO, P. G. Scientific evidence on the role of ayurvedic herbals on bioavailability of drugs. J. Ethnopharm. 4(2): 229-232, 1981. BANO, G.; RAINA, R. K.; ZUTSHI, U.; BEDI, K. L.; JOHRI, R. K.; SHARMA, S. C. Effect of piperine on bioavailability and pharmacokinetics of propanolol and theophylline in healthy-volunteers. Eur. J. Clin. Pharm. 41(6): 615-617, 1991. BARCHIESI, F.; SCHIMIZZI, A. M.; NAJVAR, L. K.; BOCANEGRA, R.; CASELLI, F.; DI-CESARE, S.; GIANNINI, D, DI-FRANCESCO, L. F.; GIACOMETTI, A.; CARLE, F.; SCALISE, G.; GRAYBILL, J. R. Interactions of posaconazole and flucytosine against Cryptococcus neoformans. Antimicrob. Agents. Chemother. 45(5): 1355-1359, 2001. BLICKE, F. F. The Mannich reactions. Organic Reactions. 1(10): 303-341, 1942. BRAMMER, K. W.; FARROW, P. R.; FAULKNER, J. K. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev. Infect. Dis. 12(S3): 318-326, 1990. BRENER, Z., ANDRADE, Z. A. Trypanosoma cruzi e a doença de Chagas. Guanabara Koogan, Rio de Janeiro, 1979. BUCHANAN, K. L.; MURPHY, J. W. What makes Cryptococcus neoformans a pathogen?. Emerg. Infect. Dis. 4(1): 71-83, 1998. BUSSE, O. Uber parasitare Zelleinschlusse und ihre Zuchtung. Zentralbl. Bakteriol. 16: 175-180, 1894. 231 CASADEVALL, A.; CLEARE, W.; FELDMESSER, M.; GLATMAN-FREEDMAN, A.; GOLDMAN, D. L.; KOZEL, T. R.; LENDVAI, N.; MUKHERJEE, J. PIROFSKI, L. A.; RIVERA, J.; ROSAS, A. L.; SCHARFF, M. D. Characterization of murine monoclonal antibody to Cryptococcus neoformans polysaccharide that is a candidate for human therapeutic studies. Antimicrob. Agents Chemother. 42: 1437-1446, 1998. CASADEVALL, A.; PERFECT, J. R. Cryptococcus Neoformans. ASM Press. 1998. CASALINUOVO, I. A.; DI-FRANCESCO, P.; GARACI, E. Fluconazole resistence in Candida albicans: A review of mecanisms. Eur. Rev. Med. Pharmacol. Sc. 8: 69-77, 2004. CHAGAS, C. Nova tripanozomiaze humana. “Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen. n. sp, ajente etiolójico de nova entidade mórbida do homem”. Mem. Inst. Oswaldo Cruz. 1: 159-218, 1909. CHIOU, C.; GROLL, A.; WALSH, T. New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist. 5: 120-135, 2000. CHOI, J. Y.; PODUST, L. M.; ROUSH, W. R. Drug strategies targenting CYP51 in neglected tropical diseases. Chem. Rev. 2014 (no prelo; doi:10.1021/cr5003134) COURA, J. R., VIÑAS, P. A. Chagas disease a new worldwide challenge. Nature. 465(7301): S6-7, 2010. COURNIA, Z.; ULLMANN, G. M.; SMITH, J. C. Differential effects of cholesterol, ergosterol and lanosterol on a dipalmitoyl phosphatidylcholine membrane: a molecular dynamics simulation study. J. Phys. Chem. 111: 1786-1801, 2007. DABIRI, M.; SALEHI, P.; BAGHBANZADEH, M.; BAHRAMNEJAD, M. A facile procedure for the one-pot synthesis of unsymmetrical 2,5-disubstituted 1,3,4- oxadiazoles. Tetrah. Lett. 47(39): 6983-6986, 2006. 232 DASH, S.; KUMAR, B. A.; SINGH, J.; MAITY, B. C.; MAITY, T. K. Synthesis of some novel 3,5-disubstituted 1,3,4-oxadiazole derivatives and anticancer activity on EAC animal model. Med. Chem. Res. 20(8): 1206-1213, 2011. DE-SARRO, A.; LA-CAMERA, E.; FERA, M. T. New and investigational triazole agents for the treatment of invasive fungal infections. J. Chemother. 20: 661-671, 2008. DESAI, N. C.; DODIYA, A. M.; RAJPARA, K. M.; RUPALA, Y. M. Synthesis and antimicrobial screening of 1,3,4-oxadiazole and clubbed thiophene derivatives. J. Sau. Chem. Soc. 18: 255-261, 2014. DOCAMPO, R.; MORENO, S. N.; TURRENS, J. F.; KATZIN, A. M.; GONZALEZCAPPA, S. M.; STOPPANI, A. O. Biochemical and ultrastructural alterations produced by miconazole and econazole in Trypanosoma cruzi. Mol. Biochem. Parasitol. 3: 169- 180, 1981. DONNICI, C. L.; NOGUEIRA, L. J.; ARAUJO, M. H.; OLIVEIRA, S. R. MAGALHÃES, T. F. F.; LOPES, M. T. P.; ARAUJO, A. C.; STOIANOFF, M. A. R. In vitro studies of the activity of dithiocarbamate organoruthenium complexes against clinically relevant fungal pathogens. Molecules. 19: 5402-5420, 2014. DUSCHAK, V.G.; COUTO, A. S. An Insight on Targets and Patented Drugs for Chemotherapy of Chagas Disease. Recent Patents on Anti-Infective Drug Discovery, 2: 19-51, 2007. EL-EMAM, A.; AL-DEEB, O.A.; AL-OMAR, M.; LEHMAN, J., Synthesis, antimicrobial, and anti-HIV activity of certain 5-(1-adamantyl)-3-substituted aminomethyl-1,3,4-oxadiazoline-2-thiones, Bioorg. Med. Chem., 12, 5107-5113, 2004. ELOY, F.; LENAERS, R. Synthèse d’amino-oxadiazoles-1,2,4. Helv. Chim. Acta. 49(4): 1430-1432, 1966. 233 ESTRELA. J. L. V., GUEDES, R. N. C., MALTHA, C. R. A., FASOLIN, M. Toxicidade de amidas análogas à piperina a larvas de Ascia monuste orseis Godart e Spodoptera frugiperda. Neotrop. Entomol. 32, 343, 2003. FAO. Food and Agriculture of the United Nations. Statistical Databases. Disponível em: <http://faostat.fao.org/faostat > Acesso em: 9 de janeiro de 2014. FERREIRA, C.; SOARES, D. C.; BARRETO-JUNIOR, C. B.; NASCIMENTO, M. T.; FREIRE-DE-LIMA, L.; DELORENZI, J. C.; LIMA, M. E. F.; ATELLA, G. C.; FOLLY, E.; CARVALHO, T. M. Leishmanicidal effects of piperine, its derivatives, and analogues on Leishmania amazonensis. Phytochemistry. 72: 2155-2164, 2011. FERREIRA, W. S., FRANKLIM, T. N., LOPES, N. D., DE LIMA, M. E. F. Piperina, seus Análogos e Derivados: Potencial como Antiparasitários. Rev. Vir. Quim. 4(3): 208- 224, 2012. FERREIRA, W. S.; FREIRE-DE-LIMA, L.; SARAIVA, V. B.; ALISSON-SILVA, F.; MENDONÇA-PREVIATO, L.; PREVIATO, J. O.; ECHEVARRIA, A.; LIMA, M. E. Novel 1,3,4-thiadiazolium-2-phenylamine chlorides derived from natural piperine as trypanocidal agents: chemical and biological studies. Bioorg. Med. Chem. 16(6): 2984- 2991, 2008. FOLCH, J.; LEES, M.; SLOANE-STANLEY, G. H. A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226: 497-509, 1957. FRANKLIM, T. N.; FREIRE-DE-LIMA, L.; DINIZ, J. N. S.; PREVIATO, J. O.; CASTRO, R. N.; MENDONÇA-PREVIATO, L.; LIMA, M. E. F. Desing, synthesis and trypanocidal evaluation of novel 1,2,4-triazoles-3-thiones derived from natural piperine. Molecules. 18: 6366-6382, 2013. FRASER, J. A.; GILES, S. S.; WENINK, E. C.; GEUNES-BOYER, S. G.; WRIGHT, J. R.; DIEZMANN, S.; ALLEN, A.; STAJICH, J. E.; DIETRICH, F. E.; PERFECT, J. R.; HEITMAN, J. Same-sex mating and origin of the Vancouver Island Cryptococcus gattii outbreak. Nature. 437: 1360-1364, 2005. 234 FREITAS, J. J. R.; SILVA, E. E.; REGUEIRA, J. L. L. F.; DE-ALMEIDA, S. A.; CAVALCANTE, P. M. M.; OLIVEIRA, R. N.; FREITAS J. R. 1,2,4-oxadiazóis: Síntese e aplicações. Rev. Vir. Quim. 4(6): 670-691, 2012. FRIES, B. C.; GOLDMAN, D. L.; CHERNIAK, R.; JU, R.; CASADAVALL, A. Phenotypic Switching in Cryptococcus neoformans: Results in changes in cellular morphology and glucuronoxylomannan structure. Infect. Immun. 67(11): 6076-6083, 1999. GARCIA-HERMOSO, D.; JANBON, G.; DROMER, F. Epidemiological evidence for dormant Cryptococcus neoformans infection. J. Clin. MIcrobiol. 37: 3204-3209, 1999. GHANI, U.; ULLAH, N. New potent inhibitors of tyrosinase: Novel clues to binding of 1,3,4-oxadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2-(3H)-thiones, 4-amino-1,2,4- triazole-5(4H)-thiones and substituted hydrazides to the dicopper active site. Bioorg. Med. Chem. 18: 4042-4048, 2010. GIRI, S.; SINGH, H.; YADAV, L. D. S. Studies in oxadiazoles: Synthesis of some 2- mercapto-1,3,4-oxadiazoles and related compounds as potential fungicides. Agr. Biol. Chem. 40(1): 17-21, 1976. GRECCO, S. S.; REIMÃO, J. Q.; TEMPONE, A. G.; SARTORELLI, P.; ROMOFF, P.; FERREIRA, M. J. P.; FAVERO, O. A.; LAGO, J. H. G. Isolation of na antileishmanial and antitrypanosomal flavanone from leaves of Baccharis retusa. Prarasitol. Res. 106: 1245-1248, 2010. GUIMARAES, C. R. W; BOGER, D. L.; JORGENSEN, W. L. Elucidation of fatty acid amide hydrolase inhibition by potent α-ketoheterocycle derivatives from Monte Carlo simulations. J. Am. Chem. Soc. 127(49): 17377-17384, 2005. GUPTA, S. K.; BANSAL, P.; BHARDWAJ, R. K.; VELPANDIAN, T. Comparative anti-nociceptive, anti-inflamatory and toxicity profile of nimesulide vs nimesulide and piperine combination. Pharmacol. Res. 41(6): 657-662, 2000. 235 GURGEL-GONÇALVES, R., GALVÃO, C., COSTA, J., PETERSON, A. T. Geographic Distribution of Chagas Disease Vectors in Brazil Based on Ecological Niche Modeling. J. Trop. Med. 2012: 1-15, 2012. HAINES, T. H. Do sterols reduce proton and sodium leaks through lipid bilayers? Prog. Lipid Res. 40: 299-324, 2001. HARSANYI, K.; KISS, P.; KORBONITS, D.; MALYATA, I. R. The synthesis of an antitussive action derivative of 1,2,4-oxadiazole, 3-(2,2-diphenylethyl)-5-(2- piperidinoethyl)-1,2,4-oxadiazole. Arzneim. Forsch. 16 (5): 615-617, 1966. HULL, C. M.; HEITMAN, J. Genetics of Cryptococcus neoformans. Annu. Rev. Genet. 36: 557-615, 2002. IKAN, R. In: Natural Products: A Laboratory Guide, Academic Press, 2nd Edition: 233- 238, 1991. IZUMI, E.; UEDA-NAKAMURA, T.; DIAS-FILHO, B. P.; VEIGA-JUNIOR, V. F.; NAKAMURA, C. V. Natural products and Chagas’ disease: a review of plant compounds studied for activity against Trypanosoma cruzi. Nat. Prod. Rep. 28: 809- 823, 2011. JAMES, N. D.; GROWCOTT, J. W. Zibotentan. Drug. Fut. 34(8): 624, 2009. KAPLANCIKLI, Z. A. Synthesis of some oxadiazole derivatives as new anticandidal agents. Molecules. 16: 7662-7671, 2011. JAYAKANTHAN, M.; CHANDRASEKAR, S.; MUTHUKUMARAN, J.; MATHUR, P. P. Analysis of CYP3A4-HIV-1 protease drugs interactions by computational methods for Highly Active Antiretroviral Therapy in HIV/AIDS. J. Mol. Graphics Modell. 28(5): 455-463, 2010. 236 JOHRI, R. K.; THUSU, N.; KHAJURIA, A.; ZUTSHI, U. Piperine-mediated changes in the permeability of rat intestinal epithelial-cells the status of gamma-glutamyl transpeptidase activity, uptake of amino-acid and lipid-peroxidation. Biochem. Pharmacol. 43(7): 1401-1407, 1992. KANTHIAH, S.; KALUSALINGAM, A.; VELAYUTHAM, R.; VIMALA, A. T.; BEYATRICKS, J. 5-(2-aminophenyl)-1,3,4-oxadiazole-2(3H)-thione derivatives: synthesis, characterization and antimicrobial evaluation. Int. J. Pharm. Sc. Rev. Res. 6(1): 64-67, 2011. KAPIL, A. Piperine: a potent inhibitor of Leishmania donovani promastigotes in vitro, Planta Medica. 59: 474, 1993. KAPPE, C.O.; DALLINGER, D. Controlled microwave heating in modern organic synthesis: highlights from the 2004-2008 literature. Molecular Diversity, 13(2): 71-193, 2009. KATZ, R. L.; LUKEMAN, J. M. The comparative diagnostic accuracy of cancer-cell deterction obtained with Ficoll-Hypaque gradient separation and standard centrifugation technics on body-cavity fluids. Amer. J. Clin. Pathol. 74: 18-24, 1980. KOPARIR, M.; CETIN, A.; CANSIZ, A. 5-Furan-2yl[1,3,4]oxadiazole-2-thiol, 5-furan- 2yl-4H[1,2,4]triazole-3-thiol and their thiol-thione tautomerism. Molecules. 10: 475- 480, 2005. KOUL, S.; KOUL, J. L.; TANEJA, S. C.; DHAR, K. L.; JAMWAL, D. S.; SINGH, K.; REEN, R. R.; SINGH, J. Structure-activity relationship of piperine and its synthetic analogues for their inhibitory potentials of rat hepatic microsomal constitutive and inducible cytochrome P450 activities. J. Bioorg. Med. Chem. 8(1): 251-268, 2000. KUMAR, R.; KHOKARA, S. L. Chemistry and common synthetic route of 1,3,4- oxadiazole: Na important heterocyclic moiety in medicinal chemistry. Int. J. Inst. Pharm. Life Sc. 2(5): 126-143, 2012. 237 LEPESHEVA, G. I.; VILLALTA, F.; WATERMAN, M. R. Targeting Trypanosoma cruzi Sterol 14α-Demethylase (CYP51). Advances in Parasitology. 75: 65-87, 2011. LEPESHEVA, G. I.; WATERMAN, M. R. Sterol 14α-Demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochem. Biophys. Acta. 1770: 467-477, 2007. LEPESHEVA, G. I.; ZAITSEYA, N. G.; NES, W. D.; ZHOU, W.; ARASE, M.; LIU, J. CYP51 from Trymanosoma cruzi: A phyla-specific residue in the B’ helix defines substrate preferences of sterol 14-α-demethylase. J. Biol. Chem. 281: 3577-3585, 2006. LEUNG, D.; DU, W.; HARDOWIN, C.; CHENG, H.; HWANG, I.; CRAVATT, B. F.; BOGER, D. L. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity. Bioorg. Med. Chem. Lett. 15(5): 1423-1428, 2005. LIAO, J.; YANG, F.; ZHANG, L.; CHAI, X.; ZHAO, Q.; YU, S.; ZOU, Y.; MENG, Q.; WU, Q. Synthesis and biological evalution of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents. Arch. Pharm. Res. 1-10, 2014. LIMA, L. M.; BARREIRO, E. J. Bioisosterism: A useful strategy for molecular modification and drug disign. Curr. Med. Chem. 12: 23-49, 2005. LIMA, J. S. S.; OLIVEIRA, R. B.; ROCHA, W.; OLIVEIRA, P. C.; UARTEZANI, W. Z. Análise espacial de atributos químicos do solo e da produção da cultura pimenta-doreino (Piper nigrum). Idesia (Chile). 28(2): 31-39, 2010. LIN, Z. X.; HOULT, J. R. S.; BENNET, D. C.; RAMAN, A. Stimulation of mouse melanocyte proliferation by Piper nigrum fruit extract and its main alkaloid, piperine. Planta Med. 65(7): 600-603, 1999. 238 LOURINHO, M. P.; COSTA, C. A. S.; SOUZA, L. C.; SOUZA, L. C.; NETOS, C. F. O. Conjuntura da pimenta do reino no mercado nacional e na região norte do Brasil. Enc. Biosf. 10(18): 1016-1031, 2014. LUIZE, P. S.; UEDA-NAKAMURA, T.; DIAS-FILHO, B. P.; CORTEZ, D. A. G.; NAKAMURA, C. V. Activity of Neolignans isolated from Piper regnellii (Miq.) C. DC. var. pallescens (C. DC.) YUNCK against Trypanosoma cruzi. Biol. Pharm. Bull. 29(10): 2126-2130, 2006. MA, H.; MAY, R. C. Virulence in Cryptococcus Species. Adv. Appl. Microbiol. 67: 131-190, 2009. MA, L.; XIAO, Y.; LI, C.; XIE, Z. L.; LI, D. D.; WANG, Y. T.; MA, H. T.; ZHU, H. L.; WANG, M. H.; YE, Y. H. Synthesis and antioxidant activity of novel Mannich base of 1,3,4-oxadiazole derivatives possessing 1,4-benzodioxan. Bioorg. Med. Chem. 21(21): 6763-6770, 2013. MACAEV, F.; RUSU, G.; POGREBNOI, S.; GUDIMA, A.; STINGACI, E.; VLAD, L.; SHVETS, N.; KANDEMIRLI, F.; DIMOGLO, A.; REYNOLDS, R. Synthesis of novel 5-aryl-2-thio-1,3,4-oxadiazoles and the study of their structure-anti mycobacterial activities. Bioorg. Med. Chem. 13: 4842-4850, 2005. MARCH, J. Advanced Organic Chemistry-Reactions, Mecanism and Structure. John Willey and Sons. 3ºed: 388, 437-8, 1099, 1100 e 1101, 1985. MAYEKAR, A. N.; YATHIRAJAN, H. S.; NARAYANA, B.; SAROJINI, B. K.; KUMARI, N. S. Synthesis and antimicrobial studies on new substituted 1,3,4- oxadiazole derivatives bearing 6-bromonaphthalene moiety. Int. J. Chem. 2(1): 38-54, 2010. MBWAMBO, Z. H.; KAPINGU, M. C.; MOSHI, M. J.; MACHUMI, F.; APERS, S.; COS, P.; FERREIRA, D.; MARAIS, J. P.; VANDEN-BERGHE, D.; MAES, L.; VLIETINCK, A.; PIETERS, L. A. Antiparasitic activity of some xanthones and 239 biflavonoids from the root bark of Garcinia livingstonei. J. Nat. Prod. 69(3): 369-372, 2006. MCFADDEN, D. C.; CASADEVALL, A. Capsule and melanin synthesis in Cryptococcus neoformans. Med. Mycol. 39: 19-30, 2001. MEANWELL, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54: 2529-2591, 2011. MEGHWAL, M.; GOSWAMI, T. K. Piper nigrum and Piperine: An update. Phytother. Res. 27(8): 1121-1130, 2013. MELO, J. L. R.; ECHEVARRIA, A. Sistemas enzimáticos de Tripanossomatídeos como Potenciais alvos quimioterápicos. Rer. Virt. Quim. 4(4): 374-392, 2012. MENDOZA, D. T.; URENA-GONZALEZ, L. D.; ORTEGA-BARRIA, E.; CAPSON, T. L.; RIOS, L. C. Five new cassane diterpenes from Myrospermum frutescens with activity against Trypanosoma cruzi. J. Nat. Prod. 66(7): 928-932, 2003. MITCHELL, T. G.; PERFECTS, J. R. Cryptococcosis in the era of AIDS-100 years after the discovery of Cryptococcus neoformans. Clin. Microbiol. Rev. 8(4): 515-548, 1995. MORETTI, C.; SAUVAIN, M.; LAVAUD, C.; MASSIOT, G.; BRAVO, J. A.; MUÑOZ, V. A novel antiprotozoal aminosteroid from Saracha punctata. J. Nat. Prod. 61: 1390-1393, 1998. MOSMANN, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J. Immun. Meth. 65(1): 55-63, 1983. NAVEENA, C. S.; BOJA, P.; KUMARI, N. S. Synthesis, characterization and antimicrobial activity of some disubstituted 1,3,4-oxadiazoles carrying 2- (aryloxymethyl)phenyl moiety. Eur. J. Med. Chem. 45: 4708-4719, 2010. 240 NOBREGA, A. A.; GARCIA, M. H.; TATTOO, E.; OBARA, M. T.; COSTA, E.; SOBEL, J.; ARAUJO, W. N. Oral transmission of Chagas disease by consumption of açaí palm fruit, Brazil. Emerging Infectious Diseases. 15(4): 653-655, 2009. OGATA, M.; ATOBE, H.; KUSHIDA, H.; YAMAOTO, K. In vitro sensitivity of mycoplasmas isolated from various animals and sewage to antibiotics and nitrofurans. J. Antibiot. 24: 443-451, 1971. OLIVEIRA, C. S.; LIRA, B. F.; BARBOSA-FILHO, J. M.; LORENZO, J. G. F.; ATHAYDE-FILHO, P. F. Synthetic approaches and pharmacological activity of 1,3,4- oxadiazoles: A review of the literature from 2000-2012. Molecules. 17: 10192-10231, 2012. OLIVEIRA, R. G.; ALENCAR-FILHO, E. B.; VASCONCELLOS, M. L. A. A. A influencia da piperina na biodisponibilidade de fármacos: Uma abordagem molecular. Quim. Nova. 37(1): 69-73, 2014. PARMAR, V. S., JAIN, S. C., BISHT, K. S., JAIN., TANEJA, P., JHA, A., TYAGI, O. D., PRASAD, A. K., WENGEL, J., OLSEN, C. E., BOLL, P. M. Phytochemistry of the genus Piper. Phytochem. 46(4): 597-673, 1997. PASSOS L. A. C.; GUARALDO, A. M. A.; BARBOSA, R. L.; DIAS, V. L.; PEREIRA, K. S.; SCHMIDT. F. L.; FRANCO, R. M. B.; ALVES, D. P. Sobrevivência e infectividade do Trypanosoma cruzi na polpa de açaí: estudo in vitro e in vivo. Epidemiol. Serv. Saúde. 21(2): 223-232, 2012. PENA-DIAZ, J.; MONTALVETTI, A.; FLORES, C. L.; CONSTAN, A.; HURTADOGUERRO, R.; DE SOLZA, W. Mitochondrial localization of the mevalonate pathway enzyme 3-Hydroxy-3-methyl-glutaryl-CoA redutase in the Trypanosomatidae. Mol. Biol. Cell. 15: 1356-1363, 2004. 241 PERES, L. A. B.; DELFINO, V. D. A.; MOCELIN, A. J.; TUTIDA, L. A.; FAVERO, M. E.; MATSUO, T. Padronização do teste do MTT em modelo de preservação a frio como instrumento de avaliação da viabilidade celular renal. J. Bras. Nefrol. 30(1): 48- 53, 2008. PETRIKKOS, G.; SKIADA, A. Recent advances in anti-fungal chemotherapy. Int. J. Anti-microb. Agents. 30: 108-117, 2007. PINAZO, M. J.; ESPINOSA, G.; GALLEGO, M.; LOPES-CHEJADE, P. L.; URBINA, J. A.; GASCON, J. Successful treatment with posaconazol of a patient with chronic Chagas disease and systemic lupus erythematosus. Am. J. Trop. Med. Hyg. 82: 583-587, 2010. PINTO, E.; AFONSO, C.; DUARTE, S.; VALE-SILVA, L.; COSTA, E.; SOUSA, E.; PINTO, M. Antifungal activity of xanthones: evaluation of their effect on ergosterol biosynthesis by high-performance liquid chromatography. Chem. Biol. Drug. Des. 77(3): 212-222, 2011. PLATEL, K.; SRINIVASAN, K. Influence of dietary spices or their active principles on pancreatic digestive enzymes in albino rats. Nahrung. 44(1): 42-46, 2000. RAAY, B.; MEDDA, S.; MUKHOPADHYAY, S. BASU, M. K. Targetin of piperine intercalated in mannose-coated liposomes in experimental leishmaniasis. Indian J. Biochem. Biopharmacol. 36(4): 248-251, 1999. RAJAPAKNE, H. A.; ZHU, H.; YOUNG, M. B.; MOTT, B. T. A mild and efficient one pot synthesis of 1,3,4-oxadiazoles from carboxylic acids and acyl hidrazides. Tetrahedron Lett. 47: 4827-4830, 2006. RAMAPRASAD, G. C.; KALLURAYA, B.; KUMAR, B. S.; HUNNUR, R. K. Synthesis and biological property of some novel 1,3,4-oxadiazoles. Eur. J. Med. Chem. 45: 4587-4593, 2010. 242 RANE, R. A.; GUTTE, S. D.; SAHU, N. U. Synthesis and evaluation of novel 1,3,4- oxadiazole derivatives of marine bromopyrrole alkaloids as antimicrobial agent. Bioorg. Med. Chem. Lett. 22: 6429-6432, 2012. REEN, R. K.; JAMWAL, D. S.; TANEJA, S. C.; KOUL, J. L.; DUBEY, R. K.; WIEBEL, F. J.; SINGH, J. Impairment of UDP-glucose dehydrogenase and glucuronidation activities in liver and small-intestine of rat and guinea-pig in vivo by piperine. Biochem. Pharmacol. 46(2): 229-238, 1993. RIBEIRO, T. S.; FREIRE-DE-LIMA, L.; PREVIATO, J. O.; MENDONÇAPREVIATO, L.; HEISE, N.; LIMA, M. E. F. Toxic effects of natural piperine and it derivatives on epimastigota and amastigotes of Trypanosoma cruzi. Bioorg. Med. Chem. Lett. 14: 3555-3558, 2004. RODIG, O. R., BELL-JR, D. E., CLARK, A. K. Organic Chemystry Laboratory, Standard and Microscale Experiments. Saunders College Publishing. 215, 1990. RODRIGUES, M. L.; NIMRICHTER, L.; OLIVEIRA, D. L.; FRASES, S.; MIRANDA, K.; ZARAGOZA, O.; ALVAREZ, M.; NAKOUZI, A.; FELDMESSER, M.; CASADEVALL, A. Vesicular polysacharide export in Cryptococcus neofornmans is a eukariotic solution to the problem of fungal trans-cell wall transport. Eukaryot Cell. 6(1): 48-59, 2007. RUSSO, F and GHELARDONI, M. On various derivatives of 2-(o-ethoxy phenyl)- 1,3,4-oxadiazole 5- mercapto-substituted. Boll. Chim. Farm. 106(12): 826-836, 1967. SABO, J. A.; ABDEL-RAHMAN, S. M. Voriconazole: A new triazole antifungal. Ann. Pharmacother. 34: 1032-1043, 2000. SAHIN, G.; PALASKA, E.; EKIZOGLU, M.; OZALP, M. Synthesis and antimicrobial activity of some 1,3,4-oxadiazole derivatives. Il Farmaco. 57: 539-542, 2002. 243 SAITOH, M.; KUNITOMO, J.; KIMURA, E.; HAYASE, Y.; KOBAYASHI, H.; UCHIYAMA, N.; KAWAMOTO, T.; TANAKA, T.; MOL, C. D.; DOUGAN, D. R. Design, synthesis and structure-activity relationships of 1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3β. Bioorg. Med. Chem. 17: 2017-2029, 2009. SAVARIZ, F. C.; FORMAGIO, A. S. N.; BARBOSA, V. A.; FOGLIO, M. A.; CARVALHO, J. E.; DUARTE, M. C. T.; FILHO, B. P. D.; SARRAGIOTTO, M. H. Synthesis, antitumor and antimicrobial activity of novel 1-substituted phenyl-3-[3- alkylamino(methyl)-2-thioxo-1,3,4-oxadiazol-5-yl]β-carboline derivatives. J. Braz. Chem. Soc. 21(2): 288-298, 2010. SCHELMAN, W. R.; LIU, G.; WILDING, G.; MORRIS, T.; PHUNG, D.; DREICER, R. A phase I study of Zibotentan (ZD4054) in patients with metastatic, castrate-resistant prostate cancer. Invest. New Drugs. 29(1): 118-125, 2011. SCHLECKER, R.; THIEME, P. C. The synthesis of antihypertensive 3-(1,3,4- oxadiazol-2-yl)-phenoxypropanolahines. Tetrahedron. 44: 3289-3294, 1988. SEMLER, U.; GROSS, G. G. Distribution of piperine in vegetative pert sod Piper nigrum. Phytochem. 27(5): 1566-1567, 1998. SHOBA, G.; JOY, D.; THANGAM, J.; MAJEED, M.; RAGENDRAN, R.; SRINIVAS, P. S. R. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Medica. 64(4): 353-356, 1998. SIEGER, G.M.; BARRINGER, W.C.; KRUEGER, J.E.; Mannich Derivatives of Medicinals: Derivatives of Some Carbonic Anhydrase Inhibitors. J. Med. Chem. 14(2): 458-460, 1971. SILVA, E. F.; CANTO-CAVALHEIRO, M. M.; BRAZ, V. R.; CYSNEFINKELSTEIN, L.; LEON, L. L.; ECHEVARRIA, A. Synthesis, and biological evaluation of new 1,3,4-thiadiazolium-2-phenylamine derivatives against Leishmania 244 amazonensis promastigotes and amastigotes. Eur. J. Med. Chem. 37(12): 979-984, 2002. SILVERSTEIN, R. M.; BASSLER, G. C.; MORRILL, T. C.; Identificação espectrométrica de compostos orgânicos. Guanabara Koogan. 5ºEd.: 3-39, 1994. SOUZA, W. Doenças negligenciadas. Academia Brasileira de Ciências. 2010. SRINIVASAN, K. Black pepper and its pungent principle-piperine: a review of diverse physiological effects. Crit. Rev. Food Sci Nutr. 47(8): 735-48, 2007. STEENBERGEN, J. N.; CASADEVALL. A. The origin and maintenance for the human pathogenic fungus Cryptococcus neoformans. Microbes Infect. 5: 667-675, 2003. SUETH-SANTIAGO, V.; FRANKLIM. T. N.; DRUMOND, N. L.; LIMA, M. E. F. CYP51: Uma boa idéia? Rer. Virt. Quim. 2014 (aceito para publicação) TANOWITZ, H. B.; MONTGOMERY, S. P. Chagas disease has now gone global. PLoS Neglected Tropical Diseases. 5(4): e1136, 2011. TEMESGEN, Z. SIRAJ. D. S. Raltegravir: First in class HIV-integrase inhibitor. Therap. Clin. Risk Manag. 4: 493-500, 2008. TRAMONTINI, M. and ANGIOLINI, L. Further advances in the chemistry of mannich bases. Tetrahedron. 46(6): 1791-1837, 1990. URBINA, J. A. Chemotherapy of Chagas’ disease: the how and the why. J. Mol. Med. 77:332–338, 1999. URBINA, J. A.; DOCAMPO, R. Specific chemoteraphy of Chagas disease: controversies and advances. Trends in Parasitology. 19(11): 495-501, 2003. 245 VANDEPUTTE, P.; FERRARI, S.; COSTE, A. T. Antifungal resistance and new strategies to control fungal infections. Int. J. Microbiol. 2012: 1-26, 2012. VARDAN, S.; SMULYAN, H.; MOOKHERJEE, S.; EICH, R. Effects of tiodazosin, a new antihypertensive, hemodynamics and clinical variables. Clin. Pharmacol. Ther. 34 (3): 290-296, 1983. VEIGA-SANTOS, P.; BARRIAS, E. S.; SANTOS, J. F. C.; MOREIRA, T. L. B.; CARVALHO, T. M. U.; URBINA, J. A.; SOUZA W. Effects of aminodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int. J. Antimic. Agents. 40: 61-71, 2012. VENKATASAMY, R.; FAAS, L.; YOUNG, A. R.; RAMAN, A.; HIDER, R. C. Effects of piperine analogues on stimulation of piperine analogues on stimulation of melanocyte proliferation and melanocyte differentiation. Bioorg. Med. Chem. 12(8): 1905-1920, 2004. VIEGAS-JUNIOR, C.; DANUELLO, A.; BOLZANI, V. S.; BARREIRO, E. J.; FRAGA, C. A. Molecular hybridization: A useful tool in the design of new drug prototypes. Chem. Med. Chem. 14(17): 1829-1852, 2007. VILCHEZ, R. A.; FUNG, J.; KUSNE, S. Cryptococcosis in organ transplant recipients: an overview. Am. J. Transplant. 2: 575-580, 2002. VOSOOGHI, M.; AKBARZADEH, T.; FALLAH, A.; FAZELI, M. R.; JAMALIFAR, H.; SHAFIEE, A. Synthesis of substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4- triazole derivatives as potential antimicrobial agents. J. Sci. Islam. Repub. Iran. 16: 145- 151, 2005. XU, W.; HE, M.; HAN, F.; CHEN, X.; PAN, Z.; WANG, J.; TONG, M. Synthesis and antifungal activity of novel sulfone derivatives containing 1,3,4-oxadiazole moieties. Molecules. 16: 9129-9141, 2011. 246 YOSHIDA, Y.; AOYAMA, Y.; NOSHIRO, M.; GOTOH, O. Sterol 14α-Demethylase P450 (CYP51) provides a breakthrough for the discussion on the evolution of cytochrome P450 gene superfamily. Biochem. Biophys. Res. Commun. 273: 799-804, 2000. YOUNG, R. W.; WOOD, K. H. The cyclization of 3-acyldithiocarbazate Esters. J. Am. Chem. Soc. 77(2): 400-403, 1955. WANG, Y.; SAUER, D. R.; DJURIC, S. W. A simple and efficient one step synthesis of benzoxazoles and benzimidazoles from carboxylic acids. Tetrahedron Lett. 47: 105, 2006. WHO. http://www.who.int/mediacentre/factsheets/fs340/en/. Acessado em 05/08/2014. ZARAGOZA, O.; CASADEVALL, A. Experimental modulation of capsule size in Cryptococcus neoformans. Biol. Proced. Online. 6: 10-15, 2004. ZARAGOZA, O.; MIHU, C.; CASADEVALL, A.; NOSANCHUK, J. D. Effect of amphotericin B on capsule and cell size in Cryptococcus neoformans during murine infection. Antimicrob. Agents Chemother. 49: 4358-4361, 2005. ZARAGOZA, O.; MES-ARANGO, A. C.; GOMES-LOPES, A.; BERNALMERTINEZ, L.; RODRIGUES-TUDELA, J. L.; CUENCA-ESTRELLA, M. Process analysis of variables for standardization of antifungal susceptibility testing of nonfermentative yeasts. Antimicrob. Agents Chemother. 55(4): 1563-1570, 2011. ZHENG, Q. Z.; ZHANG, X. M.; XU, Y.; CHENG, K.; JIAO, Q. C. ZHU, H. L. Synthesis, biological evaluation, and molecular docking studies of 2-chloropyridine derivatives possessing 1,3,4-oxadiazole moiety as potential antitumor agents. Bioorg. Med. Chem. 18(22): 7836-7841, 2010. ZUGER, A.; LOUIE, E.; HOLZMAN, R. S.; SIMBERKOFF, M. S.; RAHAL, J. J. Cryptococcal disease in patients with AIDS: Diagnostic feature and outcome of treatment. Ann. Int. Med. 104: 240-244, 1986.
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