S??ntese e avalia????o da atividade antimal??rica in vitro e in vivo, citotoxicidade e toxicidade aguda de derivados Semissint??ticos de 4-nerolidilcatecol

Submitted by Divis??o de Documenta????o/BC Biblioteca Central (ddbc@ufam.edu.br) on 2017-05-23T20:00:00Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o - Karla L. Nogueira.pdf: 2581121 bytes, checksum: 51f4a19124d973da05a54ea9d7bc1132 (MD5) Approved for entry into archive by Divis??o de Documenta????o/BC Biblioteca Central (ddbc@ufam.edu.br) on 2017-05-23T20:04:15Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o - Karla L. Nogueira.pdf: 2581121 bytes, checksum: 51f4a19124d973da05a54ea9d7bc1132 (MD5) Approved for entry into archive by Divis??o de Documenta????o/BC Biblioteca Central (ddbc@ufam.edu.br) on 2017-05-23T20:04:36Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o - Karla L. Nogueira.pdf: 2581121 bytes, checksum: 51f4a19124d973da05a54ea9d7bc1132 (MD5) Made available in DSpace on 2017-05-23T20:04:36Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Disserta????o - Karla L. Nogueira.pdf: 2581121 bytes, checksum: 51f4a19124d973da05a54ea9d7bc1132 (MD5) Previous issue date: 2016-12-19 FAPEAM - Funda????o de Amparo ?? Pesquisa do Estado do Amazonas alaria is among the most important infectious diseases prevalent in the tropical and subtropical regions of the world that can lead to a serious and longstanding morbidity and is therefore considered a serious public health problem. The disease is possible to be transmitted by 5 species of the genus Plasmodium spp. Infecting humans that are inoculated into the human vertebrate host by biting the vector species of the genus Anopheles spp. Of each endemic region in the world. In South America, Brazil has an important representation in malaria indices also attributed to the endemic Amazon region. The search for new antimalarial drugs is an urgent necessity, as cases of resistance to most of the drugs used in restricted antimalarial therapy worldwide are increasing. Historically quinine and artemisinin have been used as classic antimalarial drugs whose isolation was from plants and which served as a model for the development of synthetic and / or semisynthetic antimalarials with improved physicochemical and pharmacological characteristics. The objective of this study was to reproduce by means of semisynthesis some derivatives of a larger mass scale of the natural substance 4-nerolidylcatechol (4-NC), isolated from Piper peltata, in order to evaluate them for their antimalarial activity in vitro, By inhibition of Plasmodium falciparum, cytotoxic activity in normal fibroblastic cell line (MRC-5) and to determine their selectivity indices (IS), in addition to the in vivo evaluation to verify the suppression of Plasmodium berghei (malaria transmitting species for murine model) and evaluation Of acute toxicity after oral administration of the derivatives to the healthy animal model. Nine 4-NC derivatives were synthesized, two of them unpublished, as well as two new derivatives of peltatol A, a substance also isolated from P. peltata. The chemical and reactional improvements led to the achievement of derivatives with higher yields, a reduction in reaction time in a day scale, and the possibility of substitution of chlorinated solvents by cleaner solvents, which lead to yields equivalent to those obtained with chlorinated solventes. Regarding the results obtained in vitro, only the new propionylated derivative of 4-NC was considered partially active against P. falciparum (IC50 = 10.5 ??M). In the in vivo analysis, the percentage of parasite suppression of the derivatives against the plasmodial species causing malaria in rodents and that is widely used for this type of evaluation, it was found that the new dipropionylated, dibutyrylated and dipentylated derivatives, as well as the mixture of the monomethylated and epoxidized derivatives and peltatol A, all at a dose of 200 mg / kg / day, showed suppression of parasitemia against P. berghei of 41, 33, 47, 36, 40 and 51%, respectively, compared to controls treated with the vehicle alone (blank). The derivatives were not considered to be toxic to the MRC-5 lineage nor did they stimulate any signs of acute toxicity in healthy mice after oral administration and still showed satisfactory selectivity indices. Finally, although the inhibition levels of the derivatives studied were not considered significant at a dose of 200 mg / kg / day, their mechanism of antimalarial action - inhibition of isoprenoid biosynthesis and inhibition of hemozoin formation - still makes them competitive and which may be better investigated for their exploitation as antimalarials and / or other biological activities A mal??ria est?? entre as mais importantes doen??as infecciosas prevalentes nas regi??es tropicais e subtropicais no mundo que pode conduzir a um grave e duradouro estado de morbidade, sendo portanto considerada um grave problema de sa??de p??blica. A doen??a ?? poss??vel de ser transmitida por 5 esp??cies do g??nero Plasmodium spp. infectantes de humano que s??o inoculadas no hospedeiro vertebrado humano mediante a picada das esp??cies vetoras do g??nero Anopheles spp. pr??prias de cada regi??o end??mica no mundo. Na Am??rica do Sul, o Brasil tem importante representa????o nos ??ndices de mal??ria tamb??m atribu??da ?? end??mica regi??o amaz??nica. A busca por novas drogas antimal??ricas ?? uma necessidade urgente visto que em todo o mundo s??o crescentes os casos de resist??ncia ?? maioria das drogas utilizadas na restrita terapia antimal??rica. Historicamente tem-se quinina e artemisinina como antimal??ricos cl??ssicos cujo isolamento deu-se a partir de plantas e os quais serviram como modelo para o desenvolvimento de antimal??ricos sint??ticos e/ou semissint??ticos com caracter??sticas f??sico-qu??micas e farmacol??gicas mais aprimoradas. Este estudo teve como objetivo reproduzir por meio de semiss??ntese alguns derivados, em maior escala maior de massa, da subst??ncia natural 4-nerolidilcatecol (4-NC), isolado de Piper peltata, afim de avali??-los quanto a sua atividade antimal??rica in vitro, mediante inibi????o de Plasmodium falciparum, atividade citot??xica em linhagem celular fibrobl??stica normal (MRC-5) e determinar seus ??ndices de seletividade (IS) al??m da avalia????o in vivo para verifica????o da supress??o de Plasmodium berghei (esp??cie transmissora de mal??ria para modelo murino) e avalia????o da toxicidade aguda ap??s administra????o oral dos derivados ao modelo animal sadio. Foram sintetizados nove derivados de 4-NC, sendo dois deles in??ditos, bem como dois novos derivados de peltatol A, subst??ncia tamb??m isolada de P. peltata. Os melhoramentos qu??micos e reacionais conduziram a obten????o de derivados com maiores rendimentos, diminui????o de tempo reacional em escala de dias al??m da confirmada possibilidade da substitui????o de solventes clorados por solventes mais limpos que conduzem a obten????o de rendimentos equivalentes aos obtidos por meio de solventes clorados. Em rela????o aos resultados obtidos in vitro, apenas o novo derivado propanoilado de 4-NC foi considerado parcialmente ativo contra P. falciparum (CI50 = 10,5 ??M). J?? na an??lise in vivo, o percentual de supress??o parasit??ria dos derivados contra a esp??cie plasmodial causadora de mal??ria em roedores e que ?? amplamente utilizada para este tipo de avalia????o, constatou-se que os novos derivados dipropanoilado, dibutirilado e dipentanoilado, e ainda a mistura dos derivados monometilados e epoxidados e peltatol A, todos ?? dose de 200 mg/kg/dia, exibiram supress??o da parasitemia contra P. berghei de 41, 33, 47, 36, 40 e 51%, respectivamente, em compara????o aos controles tratados apenas com o ve??culo (branco). Os derivados n??o foram considerados t??xicos para a linhagem MRC-5, tampouco estimularam quaisquer sinais de toxicidade aguda em camundongos sadios ap??s administra????o oral e ainda apresentaram satisfat??rios ??ndices de seletividade. Por fim, ainda que os n??veis de inibi????o dos derivados estudados n??o tenham sido considerados significativos ?? dose de 200 mg/kg/dia, seu mecanismo de a????o antimal??rica ??? inibi????o da bioss??ntese de isopren??ides e inibi????o da forma????o de hemozo??na ??? ainda os torna competitivos e pass??veis de melhores estudos acerca de sua explora????o como antimal??ricos e/ou outras atividades biol??gicas.