Darbo tikslas. Susintetinti naujus 2,5-pakeistus-4-tiazolinono junginius ir ištirti jų antimikrobinį aktyvumą. Darbo uždaviniai: 1. Susintetinti 2,5-pakeistus-4-tiazolinono junginius. 2. Ištirti gautų junginių poveikį tyrimais in silico ir in vitro. 3. Susieti gautų junginių struktūros ryšį su jų aktyvumu. Metodai. Junginiai buvo sintezuoti mikrobangų metodu. Junginių aktyvumas buvo tiriamas in silico. Atliktas pirminis mikrobiologinis tyrimas in vitro užnuodytos lekštelės metodu. Rezultatai. Buvo susintetinti 8-uoni 2,5-pakeisti-4-tiazolinono dariniai. Atlikus tyrimus in silico, buvo nustatytas preliminarus poveikis S. aureus esančiam baltymui fabI. Atlikus pirminius tyrimus in vitro buvo pastebėtas trijų junginių su 5-nitrofurano pakaitu (VIP-41), 5-para-brombenzaldehido pakaitu (VIP-42), 5-dimetilamino (VIP-47) galimas priešmikrobinis poveikis prieš tirtus mikroorganizmus. Išvados. Atlikus tyrimus in vitro nustatyta, jog aktyviausi junginiai yra: VIP-41 ir VIP-47. Rodanino darinių propilo pakaitu 2-oje padėtyje priešmikrobinis aktyvumas mažesnis nei su alilo pakaitu. Taip pat nustatyta, kad rodanino darinių, su nitrofurolo pakaitu didesniam antimikrobiniam veikimui reikalinga nitro grupė. Pats alilo pakaitas junginiams reikšmingo aktyvumo nesuteikia, o svarbesnis aktyvumui aldehido pakaitas 5-oje padėtyje. / The aim of research. Synthesize new 2,5-substituted-4-thiazolinone derivatives and evaluate their antimicrobial activity. Tasks of research: 1. Synthesize new 2,5-substituted-4-thiazolinone derivatives. 2. Evaluate antimicrobial activity of newly synthesized 2,5-substituted-4-thiazolinone derivatives. 3. Evaluate compounds structure-activity relationship. Methods. Compounds were synthesized with microwave method. Their activity was evaluated in silico. Synoptic research in vivo was accomplished by a poisoned plate technique. Results. 8 2,5-substituted-4-thiazolinone derivatives were synthesized. After in silico research was evaluated preliminary bactericidic compounds activity against S. aureus, acting on fabI protein. Synoptic research in vitro has shown antimicrobial activity of three compounds: 5-nitrofuran substituted (VIP-41), 5-para-brombenzaldehyde substituted (VIP-42), 5-dimethylaminebenzaldehyde substituted (VIP-47). Conclusions. Research in vitro has shown that the most active compounds are: VIP-41 and VIP-47. Evaluated, that 4-thiazolinone derivatives with propyl substituent in a 2-nd position antimicrobial activity is less than with allyl substituent. For better anctimicrobial activity nitro group is necessary in 4-thiazolinone derivatives with nitrofurfural substituent. Allyl substituent does not provide significant antimicrobial activity itself, more important is aldehyde substituent in 5-th position.

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-08-12T12:09:18Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Mestrado Lucianna PPGIT (Biblioteca).pdf: 1648880 bytes, checksum: 302834b98cb331c5e4d57aefa0fd3ce9 (MD5) / Made available in DSpace on 2016-08-12T12:09:18Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação Mestrado Lucianna PPGIT (Biblioteca).pdf: 1648880 bytes, checksum: 302834b98cb331c5e4d57aefa0fd3ce9 (MD5) Previous issue date: 2015-02-26 / FACEPE / A doença de Chagas, causada pelo protozoário Trypanosoma cruzi, é uma infecção parasitária sistêmica, que afeta cerca de 10 milhões de pessoas e causa, em média, cerca de 14.000 mortes por ano, além da estimativa de que 25 milhões de pessoas estão em risco de adquirir a doença. No Brasil, o Benznidazol (BZD) é o único fármaco utilizado para o tratamento durante a fase aguda, enquanto que, durante a fase crônica da doença, o mesmo mostra-se com atividade limitada. Dessa forma, o desenvolvimento de fármacos para o tratamento da doença de Chagas se faz necessário. Sabendo-se que o T. cruzi é susceptível às tiossemicarbazonas e seus bioisósteros, essas classes de compostos têm se mostrado promissoras para o desenvolvimento de drogas tripanocidas. Baseado em relatos na literatura de potentes tiossemicarbazonas tripanocidas, elegeu-se o composto protótipo (Composto 1i - página 21) deste trabalho, onde planejou-se por meio da estratégia de bioisosterismo, a síntese de inéditas aril-4-tiazolinonas, no intuito de obter compostos mais potentes e menos tóxicos. Além disso, de estabelecer a relação estrutura-atividade anti-T. cruzi, através da inserção de substituintes diversos nas posições N3 e C5 do anel heterociclo. Os compostos foram obtidos em duas etapas, sendo a primeira a obtenção das tiossemicarbazonas (Int 1-3), com rendimentos que variaram de 68% a 81%, e a segunda etapa, a reação destas (Int 1-3) com ésteres e ácidos halogenados para obtenção dos compostos cíclicos (LR 01-18) os quais apresentaram rendimentos de 23% a 97%. Todas as moléculas foram caracterizadas quimicamente por Ressonância Magnética Nuclear de Prótons (¹H-RMN) e Carbono (¹³CRMN) e Infravermelho (IV). A atividade tripanocida foi determinada em amastigostas e tripomastigotas da cepa Tulahuen e a toxicidade foi estimada em fibroblastos L929. Após realização dos ensaios biológicos, foi possível identificar os compostos LR-05, LR-07 e LR- 08 como agentes tripanocidas com potência superior ao BZD (21.90 μM), com valores de 13.27 μM, 12.20 μM e 2.46 μM, respectivamente. O composto LR-08 foi cerca de nove vezes mais potente que o BZD e possui como característica estrutural uma metila em N3 e outra metila em C5. Constatou-se que a funcionalização da tiossemicarbazona em tiazolinona foi benéfica, resultando em três compostos mais ativos (LR-07, LR-08 e LR-16) que os seus intermediários (Int 2-3). De maneira geral, foi possível identificar tiazolinonas mais ativas, para às formas evolutivas tripomastigota e amastigota, quando comparado ao BZD. / Chagas disease, caused by Trypanosoma cruzi protozoan, is a systemic parasitic infection that affects about 10 million people and causes on average about 14,000 deaths for year in addition to the estimated 25 million people are at risk acquiring the disease. In Brazil, Benznidazole (BZD) is the only drug used for the treatment during the acute phase, whereas during the chronic phase of the disease, shows the same with limited activity. Thus, the development of drugs for the treatment of Chagas disease is required. Knowing that the Trypanosoma cruzi is susceptible to thiosemicarbazone and its bioisosters, these classes of compounds have shown promise for the development of trypanocidal drugs. Based on reports in the powerful thiosemicarbazones trypanocides literature, was elected the prototype compound (Compound 1i - page 21) of this work, which was planned by bioisosterism strategy, the synthesis of aryl-4-thiazolinones unpublished, in order to more potent and less toxic compounds. Furthermore, to establish the relation structure-anti-T activity. cruzi, by inserting in the various substituents N3 and C5 positions of the heterocycle ring. The compounds were obtained in two steps, the first being the obtaining of thiosemicarbazone (Int 1-3), with yields ranging from 68% to 81% and the second step, the reaction of these (Int 1-3) with esters and halogenated acids to obtain the cyclic compound (LR 01-18) showed that yields of 23% to 97%. All molecules were chemically characterized by Proton Nuclear Magnetic Resonance (¹H-NMR) and carbon (¹³C-NMR) and Infrared (IR). The trypanocidal activity was determined in amastigostas and trypomastigotes of the Tulahuen strain and toxicity was estimated in L929 fibroblasts. After performing biological assays it was possible to identify compounds LR-05, LR-07 and LR-08 as trypanocidal agents with superior power to BZD (21.90 mM), with values of 13.27 uM, 12.20 uM and 2.46 uM, respectively. The LR- 08 compound was about nine times more potent than the BZD and has as structural feature in one methyl and one methyl N3 C5. It was found that functionalization of thiosemicarbazone was beneficial in thiazolinone, resulting in three more active compounds (LR-07, LR-08 and LR-16) their intermediaries (Int 2-3). In general, it was possible to identify more active thiazolinones to the amastigote and trypomastigote forms evolutionary compared to the BZD.