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.