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Aplicação de QSPRs à modelação de compostos anti-tuberculares derivados da tiobenzanilida
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O trabalho apresentado nesta tese de mestrado foi realizado no Grupo de Estrutura e Reactividade do Centro de Química e Bioquímica da Faculdade de Ciências da Universidade de Lisboa no âmbito de um projecto mais vasto de concepção e síntese de novos compostos antituberculares derivados da isoniazida, do benzimidazole e da tiobenzanilida. Uma vez que a tuberculose é uma das doenças mais contagiosas da nossa sociedade e devido à falta de eficácia no combate contra a doença, tornou-se necessário e urgente a procura de novos e melhores fármacos que permitam controlar e diminuir o aparecimento de estirpes resistentes do Mycobacterium tuberculosis e a associação com o VIH/SIDA. Compostos como as tioamidas têm sido alvos de variados estudos e pensa-se que possam, a longo prazo, fazer parte do tratamento contra a tuberculose. É neste contexto que surge este trabalho com derivados de tiobenzanilidas. Foram purificados os compostos tiobenzanilida, 4'-metoxitiobenzanilida e 4'-bromo-4-metiltiobenzanilida,sintetizados anteriormente, avaliado o seu grau de pureza por CG e por pontos de fusão e efectuada a sua caracterização por RMN e IV. Determinou-se também experimentalmente o coeficiente de partição destes compostos juntamente com outros quatro (4'-bromotiobenzanilida, 4'-bromo-4-metoxitiobenzanilida, 4'-cloro-4-metoxitiobenzanilida e 3',4'-dicloro-4-metoxitiobenzanilida)através do método do Shake-Flask, após optimização do correspondente procedimento experimental. Os resultados obtidos concordam com os valores de clogP estimados com o programa ChemDraw©. Estabeleceram-se também para um conjunto alargado de compostos desta família duas relações quantitativas estrutura-propriedade (QSPR) tendo como variáveis dependentes clogP elog(1/MIC). As equações modelo obtidas foram validadas interna e externamente apresentando uma boa capacidade interpretativa e uma eficaz capacidade preditiva. A equação referente a clogP foi aplicada aos 4 compostos di-substituídos anteriormente referidos e os valores previstos pela equação encontram-se bastante próximos dos valores obtidos experimentalmente e dos valores teóricos. Com base nas equações modelo estabelecidas foram propostos o design e a síntese de 4 novos compostos desta família com actividade anti-tubercular prevista promissora, a saber a 3',5'- dinitrotiobenzanilida, a 2-trifluorometil-3',5'-dinitrobenzanilida, a 2-trifluorometil-4'- octiltiobenzanilida e a 4'-benzil-2-trifluorometiltiobenzanilida). Destes apenas se conseguiu realizar com sucesso a síntese total e a respectiva caracterização do composto 2-trifluorometil-4'- octiltiobenzanilida.
The work presented in this thesis was carried out in the Structure and Reactivity Group of the Centro de Química e Bioquímica of Faculdade de Ciências da Universidade de Lisboa, in the scope of a much wider project involving the design and synthesis of new anti-tubercular compounds such as isoniazid, benzimidazole and thiobenzanilide derivatives. Since tuberculosis is one of the most contagious diseases in our society and due to the unsuccessful combat against it, it's became necessary and urgent the search for new and better drugs that will allow us to sustain and diminish the appearance of Mycobacterium tuberculosis resistant strains as well as the association with HIV/AIDS. Compounds like thioamides have been used in many of these studies and it is believed that they can become potential drugs against tuberculosis. In this work 3 compounds (thiobenzanilide, 4'-methoxythiobenzanilide and 4'-bromo-4- methylthiobenzanilide), previously synthesized, were purified. Their purity was assessed through GC and melting points' determination and the characterization was done by NMR and IR. Partition coefficients were also experimentally determined for these and 4 other compounds (4'- bromothiobenzanilide, 4'-bromo-4-methoxythiobenzanilide, 4'-chloro-4-methoxythiobenzanilide, 3',4'-dichloro-4-methoxythiobenzanilide) by the Shake-Flask method, after experimental procedure optimization and the results are in good agreement with the values estimated by the ChemDraw© program. It was also established for a large set of thiobenzanilide derivatives two quantitative structure-properties relationships (QSPR) having as dependent variables clogP and log(1/MIC). The obtained equations were internally and externally validated and showed to have a good interpretive ability and an effective predictive power. The clogP equation was applied to 4 out of the 7 previously referred compounds (those with two substituents) and the results are very close to both experimental and theoretical values. Based on the model equations, it was proposed the design and synthesis of 4 new compounds of this family with anticipated promising anti-tubercular activity, namely 3',5'dinitrothiobenzanilide, 2-trifluoromethyl-3',5'-dinitrothiobenzanilide, 2 trifluoromethyl-4'- octylthiobenzanilide and 4'-benzyl-2 trifluoromethylthiobenzanilide. Of these only 2- trifluoromethyl-4'-octylthiobenzanilide was fully synthesized with success and duly characterized.
The work presented in this thesis was carried out in the Structure and Reactivity Group of the Centro de Química e Bioquímica of Faculdade de Ciências da Universidade de Lisboa, in the scope of a much wider project involving the design and synthesis of new anti-tubercular compounds such as isoniazid, benzimidazole and thiobenzanilide derivatives. Since tuberculosis is one of the most contagious diseases in our society and due to the unsuccessful combat against it, it's became necessary and urgent the search for new and better drugs that will allow us to sustain and diminish the appearance of Mycobacterium tuberculosis resistant strains as well as the association with HIV/AIDS. Compounds like thioamides have been used in many of these studies and it is believed that they can become potential drugs against tuberculosis. In this work 3 compounds (thiobenzanilide, 4'-methoxythiobenzanilide and 4'-bromo-4- methylthiobenzanilide), previously synthesized, were purified. Their purity was assessed through GC and melting points' determination and the characterization was done by NMR and IR. Partition coefficients were also experimentally determined for these and 4 other compounds (4'- bromothiobenzanilide, 4'-bromo-4-methoxythiobenzanilide, 4'-chloro-4-methoxythiobenzanilide, 3',4'-dichloro-4-methoxythiobenzanilide) by the Shake-Flask method, after experimental procedure optimization and the results are in good agreement with the values estimated by the ChemDraw© program. It was also established for a large set of thiobenzanilide derivatives two quantitative structure-properties relationships (QSPR) having as dependent variables clogP and log(1/MIC). The obtained equations were internally and externally validated and showed to have a good interpretive ability and an effective predictive power. The clogP equation was applied to 4 out of the 7 previously referred compounds (those with two substituents) and the results are very close to both experimental and theoretical values. Based on the model equations, it was proposed the design and synthesis of 4 new compounds of this family with anticipated promising anti-tubercular activity, namely 3',5'dinitrothiobenzanilide, 2-trifluoromethyl-3',5'-dinitrothiobenzanilide, 2 trifluoromethyl-4'- octylthiobenzanilide and 4'-benzyl-2 trifluoromethylthiobenzanilide. Of these only 2- trifluoromethyl-4'-octylthiobenzanilide was fully synthesized with success and duly characterized.
Descrição
Tese de mestrado em Química (Química, Saúde e Nutrição), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2008
Palavras-chave
Química Teses de mestrado