Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-10-11T22:26:01Z No. of bitstreams: 1 ValeskaSantanaDeSenaPereira_TESE.pdf: 4424545 bytes, checksum: 27d11137997bb962be78ddc99763e2fe (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-10-17T22:34:42Z (GMT) No. of bitstreams: 1 ValeskaSantanaDeSenaPereira_TESE.pdf: 4424545 bytes, checksum: 27d11137997bb962be78ddc99763e2fe (MD5) / Made available in DSpace on 2016-10-17T22:34:42Z (GMT). No. of bitstreams: 1 ValeskaSantanaDeSenaPereira_TESE.pdf: 4424545 bytes, checksum: 27d11137997bb962be78ddc99763e2fe (MD5) Previous issue date: 2016-05-18 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico (CNPq) / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / A resist?ncia aos antimal?ricos dispon?veis no mercado leva ? necessidade do desenvolvimento de novos compostos com novos alvos farmacol?gicos. Os derivados de naftoquinonas s?o descritos como compostos l?deres promissores para o desenvolvimento de f?rmacos antimal?ricos. Em vista disso, n?s avaliamos a atividade antiplasmodial in vitro de tr?s derivados de hidroxinaftoquinonas contra o est?gio intraeritroc?tico assexuado de Plasmodium falciparum, assim como par?metros toxicol?gicos in vitro e in vivo e investigamos um prov?vel mecanismo de a??o relacionado ? via dos isopren?ides atrav?s de marca??es metab?licas de precursores da via com tr?tio radioativo, complementado com estudos de docking com um template da octaprenil pirofosfato sintase. Os derivados de hidroxinaftoquinonas analisados tiveram boa atividade antiplasmodial, com IC50 menor que 20 ?M para a cepa 3D7 e menor que 50 ?M para a cepa Dd2. A janela terap?utica ? segura, com ?ndice de seletividade variando entre 36,7 e 143,0. Os compostos n?o causaram hem?lise nas doses testadas (10 e 50 vezes maiores que as respectivas IC50), e n?o desencadearam sinais de toxicidade no teste de toxicidade aguda in vivo apesar de o composto 4a ter promovido esteatose hep?tica e hemorragia no tecido renal. Considerando um prov?vel mecanismo de a??o, os derivados de hidroxinaftoquinonas parecem inibir a s?ntese dos precursores isopr?nicos, principalmente a menaquinona e o tocoferol e os estudos de docking revelaram nove poss?veis intera??es com alta energia em quatro s?tios de liga??o diferentes com um template da octaprenil pirofosfato sintase. Em nossos resultados, o composto 4c foi o mais promissor, visto que possuiu o menor IC50 no teste antiplasmodial in vitro, menor citotoxicidade in vitro e toxicidade aguda in vivo, al?m de ter inibido os tr?s produtos da via dos isopren?ides testados, podendo ser considerado um candidato padr?o para o processo de ?hit-to-lead. / The resistance to antimalarial drugs available on the market leads to the need for the development of new compounds with novel pharmacological targets. The naphthoquinone derivatives are described as promising compounds leading to the development of antimalarial drugs. That said, we evaluated the antiplasmodial in vitro activity of three derivatives of hydroxy-naphthoquinones against asexual intraeritrocitic stage of Plasmodium falciparum, as well as toxicological in vitro and in vivo parameters and investigate a possible mechanism of action related to the isoprenoid pathway through metabolic markers via the precursors of radioactive tritium, complete with docking studies with a template of octaprenil pyrophosphate synthase. Hydroxy-naphthoquinones derivatives analyzed had good antiplasmodial activity with IC50 less than 20 ?M for 3D7 strain and less than 50 ?M for Dd2 strain. The therapeutic window is safe with selectivity index ranging between 36.7 and 143.0. The compounds did not cause hemolysis at the doses tested (10 and 50 times greater than their IC50), and not triggered signs of toxicity in acute toxicity test in vivo even though the compound 4a have promoted hepatic steatosis and haemorrhage in kidney tissue. Whereas a likely mechanism of action, the hydroxy-naphthoquinones derivatives appear to inhibit the synthesis of isoprenic precursors, especially menaquinone and tocopherol and docking studies revealed nine possible interactions with high energy in four different binding sites with a template of octaprenil pyrophosphate synthase. In our results, the compound 4c was the most promising, since it possessed the lowest IC50 in antiplasmodial test in vitro, lower cytotoxicity in vitro and in vivo acute toxicity, and has inhibited the three via the tested isoprenoid products, might be considered a standard candidate for the process "hit-to-lead.

Made available in DSpace on 2014-12-17T14:10:27Z (GMT). No. of bitstreams: 1 BrunoMSW_DISSERT.pdf: 2493064 bytes, checksum: 67d2a8f0addf9c48ec5976ed766a8e15 (MD5) Previous issue date: 2012-10-15 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Malaria is a disease of global distribution, recognized by governments around the world as a serious public health problem, affecting more than 109 countries and territories and endangering more than 3.3 billion people. The economic costs of this disease are also relevant: the African continent itself has malaria-related costs of about $ 12 billion annually. Nowadays, in addition to chloroquine, Plasmodium falciparum is resistant to many drugs used in the treatment of malaria, such as amodiaquine, mefloquine, quinine and sulfadoxine-pyrimethamine; resistance of Plasmodium vivax to treatments, although less studied, is also reported. Nature, in general, is responsible for the production of most known organic substances, and the plant kingdom is responsible for the most of the chemical diversity known and reported in the literature. Most medicinal plants commercialized in Brazil, however, are of exotic origin, which makes the search for endemic medicinal plants, besides a patent necessity, a fascinating subject of academic research and development. This study aimed to: (i) verify the antimalarial activity of ethanolic and hydroalcoholic extracts of Boerhavia paniculata Rich. And acetonic extract of Clethra scabra Pers. in Swiss albino mice infected by Plasmodium berghei NK65, (ii) observe possible combined effects between the course of infection by P. berghei NK65 and administration of these extracts in Swiss albino mice, and (iii) conduct a preliminary study of the acute toxicity of these extracts in Swiss albino mice. All extracts notable pharmacological activities - with parasite infections inhibitions ranging from 22% to 54%.These characteristics suggest that the activities are relevant, although comparatively lower than the activity displayed by the positive control group (always above 90%). The general framework of survival analysis demonstrates an overall reduction in survival times for all groups. Necroscopy has not pointed no change in color, shape, size and/or consistency in the evaluated organs - the only exception was the livers of rats submitted to treatment to hydroalcoholic extracts: these organs have been presented in a slightly congestive aspect with mass increasing roughly 28% higher than the other two groups and a p-value of 0.0365. The 250 mg/Kg ethanolic group has been pointed out by the Dunn s post test, as the only class with simultaneous inequalities (p<0.05) between positive and negative control groups. The extracts, notably ethanol extract, have, in fact, a vestigial antimalarial activity, although well below from the ones perceived to chloroquine-treated groups; nevertheless, the survival times of the animals fed with the extracts do not rise by presence of such therapy. Both the toxicopharmacological studies of the synergism between the clinical course of malaria and administration of extracts and the isolated evaluation of toxicity allow us to affirm the absence of toxicity of the extracts at the level of CNS and ANS, as well as their non-influence on food and water consumption patterns, until dosages of 500 mg/Kg. Necroscopic analysis leads us to deduct a possible hepatotoxic effect of hydroalcoholic extract at dosages of 500 mg/Kg, and an innocuous tissue activity of the ethanol extract, in the same dosage. We propose a continuation of the studies of these extracts, with protocol modifications capable of addressing more clearly and objectively their pharmacological and toxicological aspects / A mal?ria ? uma doen?a de distribui??o global, reconhecida por governos de todo o mundo como grave problema de sa?de p?blica, ocorrendo em mais de 109 pa?ses e territ?rios e pondo em risco mais de 3,3 bilh?es de pessoas. Os custos econ?micos da doen?a s?o tamb?m relevantes: apenas o continente africano tem um ?nus de cerca de US$12 bilh?es anuais. Hodiernamente, al?m da cloroquina, o Plasmodium falciparum apresenta resist?ncia aos diversos medicamentos usados na rotina, como amodiaquina, mefloquina, quinina e sulfadoxina-pirimetamina; a resist?ncia de Plasmodium vivax, apesar de menos estudada, tamb?m ? relatada. A natureza, de um modo geral, ? a respons?vel pela produ??o da maioria das subst?ncias org?nicas conhecidas, sendo o reino vegetal respons?vel pela maior parcela da diversidade qu?mica conhecida e registrada na literatura. A maioria das plantas medicinais comercializadas no Brasil, contudo, ? de origem ex?tica, o que torna a busca por plantas medicinais end?micas, al?m de uma patente necessidade, um fascinante assunto de pesquisa acad?mica e de desenvolvimento. Este trabalho teve por objetivo: (i) verificar a atividade antimal?rica dos extratos etan?lico e hidroalco?lico de Boerhavia paniculata Rich. e acet?nico de Clethra scabra Pers. em camundongos albinos Swiss infectados por Plasmodium berghei NK65; (ii) observar poss?veis efeitos combinados entre o curso da infec??o por P. berghei NK65 e a administra??o destes extratos em camundongos albinos Swiss; e (iii) realizar um estudo da toxicidade aguda destes extratos em camundongos albinos Swiss. Notam-se, em todos os extratos, atividades farmacol?gicas not?rias com inibi??es da parasitemia variando de 22% a 54% - caracter?sticas estas que sugerem atividades relevantes, apesar de comparativamente inferior ? atividade apresentada pelo grupo controle positivo (sempre superior a 90%). O quadro geral da an?lise de sobreviv?ncia demonstra uma redu??o global dos tempos de sobrevida para todos os grupos testados. A necroscopia n?o apontou, em um quadro geral, qualquer altera??o de cor, forma, tamanho e/ou consist?ncia nos ?rg?os avaliados nos estudos a ?nica exce??o recaiu sobre os f?gados dos animais submetidos ao extrato hidroalco?lico: estes se apresentaram sob um aspecto levemente congestivo, com aumento de massa cerca de 28% superior aos outros dois grupos e um p-valor de 0,0365. O grupo etan?lico 250 mg/Kg foi apontado, pelo p?s-teste de Dunn, como a ?nica classe com desigualdades simult?neas (p< 0,05) entre os grupos controles positivo e negativo. Os extratos analisados, notadamente o extrato etan?lico, apresentam, de fato, uma atividade antiplasm?dica resquicial, embora muito abaixo da percebida para grupos tratados com cloroquina; n?o obstante, os tempos de sobrevida dos animais submetidos aos tratamentos com os extratos n?o se elevam mediante a presen?a de tal terap?utica. Tanto o estudo t?xico-farmacol?gico do sinergismo entre a evolu??o cl?nica da mal?ria e a administra??o dos extratos quanto a avalia??o isolada de toxicidade nos permitem afirmar a aus?ncia de toxicidade dos extratos em n?vel de SNC e SNA, bem como a n?o influ?ncia destes nos padr?es de consumo h?drico e alimentar, at? as doses de 500 mg/Kg. A an?lise necrosc?pica nos leva ? dedu??o de um poss?vel efeito hepatot?xico do extrato hidroalco?lico, em doses de 500 mg/Kg, e uma atividade tecidual in?cua do extrato etan?lico, em mesma dosagem. Propomos uma continua??o dos estudos destes extratos, com modifica??es protocolares capazes de abordar, de forma mais clara e objetiva, seus aspectos farmacol?gicos e toxicol?gicos