Síntese e avaliação biológica de 1H e 2H-1,2,3-triazóis

• Ano de defesa: 2013
• Autor(a) principal: Gonzaga, Daniel Tadeu Gomes
• Orientador(a): Silva, Fernando de Carvalho da
• Banca de defesa: Freitas, Rossimiriam Pereira de , Faria, Robson Xavier , Silva, Barbara Vasconcellos da , Jordâo, Alessandro Kappel , Martins, Daniela de Luna
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Programa de Pós-Graduação: Programa de Pós-graduação em Química
• Departamento: Química
• Palavras-chave em Português: Síntese orgânica; Triazol; Composição farmacológica; HIV
• Palavras-chave em Inglês: Organic synthesis; triazole; Pharmaceutical composition; HIV
• Área do conhecimento CNPq: CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA
• Link de acesso: https://app.uff.br/riuff/handle/1/20721

In this study the main objective was to synthesize a series of functionalized 1,2,3-triazoles in regioposições 1H and 2H and evaluate these triazoles against various biological targets: Mtb-glucosidase enzymes, HIV, Candida albicans, and lock P2X7 receptor. 101a-e-phenyl ester 101 type alcohols 1H-1,2,3-triazoles were synthesized by Huisgen cycloaddition between azides and aromatic alkyne catalyzed by Cu (I) (CuAAC). From the triazole alcohols 101a and some transformations such as esterification to generate compounds 184a-t, alkylation was performed to obtain ethers 185a-oe partial oxidation to produce aldehydes 102a-e. In the quest to find new analogs 1H-1,2,3-triazoles were prepared 186a and the oximes, hydrazones and acyl hydrazones 187a-187i1 by addition of hydroxylamine appropriately substituted phenyl hydrazines and aldehydes to isoniazid respectively obtained and 4-vinyl previously 1H-1,2,3-triazole (188) through a Wittig reaction. Likewise, the 5-amino-1-phenyl-1H-1,2,3-triazol-4-methyl carboxylate (189) was obtained using the method of enolate addition of aromatic azides. Regarding the number of 2H-1,2,3-triazole This was prepared by a sequence of reactions involving the synthesis of 41a and osazonas from the nucleophilic addition to D-glucose by phenyl substituted hydrazines. Then the osazonas suffered oxidative cyclization leading to osotriazóis 42a and which finally underwent oxidative cleavage of a reaction leading to the formation of aldehydes 2H-1,2,3-triazole 43ae. The 3-carboxaldehyde-2H-1,2,3-triazole derivatives 43a and were the key synthetic intermediates for obtaining of all other substances from the class of 2H-1,2,3-triazole. However, only the aldehyde 43a originating from the reaction with phenylhydrazine, was employed for the other derivatives, those containing substituents on the portion of phenylhydrazine (42b-e) presented insoluble in the solvents used. Thus, were synthesized oxime 191, hydrazones and acyl hydrazones 192a-h and alcohol 2H-1,2,3-triazole 193 through the reduction reaction of 43a and from this, the 2H-1,2,3-triazole esters 194a of the 2H-1,2,3-triazole ethers 195a-c were prepared. The compounds were evaluated in biological tests for tuberculosis by the Dra. Maria Cristina Lourenço (FioCruz / IOC), inhibition of glucosidase by Dr. Floriano Paes Silva Junior group (FioCruz / IOC), HIV virus by Dr.Thiago Moreno de Souza (FioCruz / IOC) and his research group of Prof. antifungal pelogrupo Emerson da Silva Lima (UFAM), by Prof. anticancer. Patricia Zancan (UFRJ) and the antagonism of the P2X7 receptor by Dr. Robson Xavier Faria (FioCruz / IOC) group. For testing against Mycobacterium tuberculosis, the etiological agent of tuberculosis, no sample showed active. IC50 values ​​between 25 and 100 / ml. Importantly, the WHO recommends that compounds having values ​​below 6.25 g / mL are considered active. The evaluation was performed glycosidase inhibition front of maltase and α-amylase enzymes. In the inhibition of maltase was obtained with the highest four substances having enzyme inhibition percent inhibition ranging from 60.3 to 99.4% and IC50 ranging from 53.9 to 92.8 uM. The reference drug is Acarbose which showed 48.1% inhibition and IC50 uM 108.8. Three compounds were promising inhibition against α-amylase having high degree of enzyme inhibition ranging from 60.1 to 88.6% (acarbose showed 99.6% inhibition). Biological test against HIV resulted in eleven substances AltoTripAdvisor inhibition of viral growth. Percent inhibition of HIV ranged from 80.8 to 98%. The evaluation against Candida albicans resulted in no active compound, not leading to no reduction in growth. In relation to the blockade of P2X7 receptor, four substances were greatly active possessing IC50 in nM range and are being considered for other experiments.