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Desenvolvimento de fármacos para o tratamento da tuberculose através do alvo DprE1 : ésteres e amidas derivados de ácidos nitrocinâmicos e nitrosalicílicos como potenciais fármacos antituberculosos
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Orientador(es)
Resumo(s)
A tuberculose humana (TB) é causada pela bactéria Mycobacterium tuberculosis (Mtb). A TB ativa
ultrapassou o VIH/SIDA como causa de morte. A coinfecção com VIH acelera o progresso destas
doenças, porque não há mitigação de patogénicos em indivíduos imunocomprometidos. Os
microrganismos criam mutações, tornam-se mais resistentes e a eficácia dos medicamentos diminui.
Portanto, são necessários novos agentes antimicobacterianos com novos mecanismos de ação para
mitigar o aumento de casos de infeções por Mtb resistente.
Em trabalhos prévios, ácidos fracos como o ácido benzóico demonstraram atividade antituberculosa. Os
ésteres derivados desses compostos mostraram-se mais ativos do que os correspondentes ácidos. As
amidas correspondentes não apresentaram atividade relevante, mas os derivados cujo anel aromático
contêm grupos nitro (especialmente 3,5-dinitro) mostraram-se significativamente mais ativos, o que
levou à hipótese que pudessem ter um mecanismo de atuação distinto.
Nitrocompostos como as benzotiazinonas ou N-(2-(4-metoxifenoxi)etil)-3,5-dinitrobenzamida (DNB1)
atuam sobre o decaprenilfosforil-β‐D‐ribose oxidase (DprE1), um enzima essencial para a biossíntese
da parede celular.
Os objetivos deste trabalho consistiram na síntese de ésteres e amidas de ácidos fracos e dos
correspondentes nitrocompostos; e na determinação das atividades antituberculosas, para verificar um
possível aumento da atividade dos compostos.
Sintetizaram-se pela primeira vez, pelos métodos A, B e C: três 3-nitro-5-(trifluorometil) benzotioatos
(T1-T3); quatro cinamatos e oito N-cinamamidas dos ácidos cinâmico, 3-nitro e 4-nitro cinâmicos (EC1-
EC4; AC1-AC8); e dez salicilatos e dez N-salicilamidas dos ácidos salicílico, 3-nitro, 4-nitro, 5-nitro e
3,5-dinitro salicílicos (ES1-ES10; AS1-AS10). Obtiveram-se rendimentos entre os 8% e os 95%.
Realizaram-se caracterizações por espectroscopia de NMR e FTIR; e ensaios de atividade
antimicobacteriana, para avaliar os efeitos dos grupos substituintes; das funções amida, éster e tioéster;
e do comprimento do grupo alcóxilo (4, 6, 8, 10 e 12 átomos de carbono). Os derivados salicílicos foram
os mais promissores; a 4-nitro-octil-N-salicilamida (composto AS3) apresentou maior atividade (CIM
<0,5 mg/L).
Human tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb). Active TB has surpassed HIV/AIDS as cause of death. Co-infection with HIV accelerates the progress of these diseases because there is no pathogen mitigation in immunocompromised individuals. Microorganisms create mutations, become more resistant, and the effectiveness of drugs decreases. Therefore, new antimycobacterial agents with novel mechanisms of action are needed to mitigate the increase in cases of resistant Mtb infections. In previous work, weak acids such as benzoic acid have demonstrated antitubercular activity. The esters derived from these compounds were more active than the corresponding acids. The corresponding amides did not show relevant activity. Still, the derivatives whose aromatic ring contained nitro groups (especially 3,5-dinitro) were significantly more active, which led to the hypothesis that they could have a distinct mechanism of action. Nitrocompounds such as benzothiazinones or N-(2-(4-methoxyphenoxy)ethyl)-3,5-dinitrobenzamide (DNB1) act on decaprenylphosphoryl-β‐D‐ribose oxidase (DprE1), an essential enzyme for cell wall biosynthesis. The objectives of this work consisted in synthesizing esters and amides of weak acids and their corresponding nitrocompounds; and in determining the antitubercular activities, to verify a possible increase in the activity of the compounds. The following were synthesized for the first time by methods A, B and C: three 3-nitro-5- (trifluoromethyl) benzothioates (T1-T3); four cinnamates and eight N-cinnamamides of cinnamic, 3- nitro and 4-nitro cinnamic acids (EC1-EC4; AC1-AC8); and ten salicylates and ten N-salicylamides of salicylic, 3-nitro, 4-nitro, 5-nitro and 3,5-dinitro salicylic acids (ES1-ES10; AS1-AS10). Yields between 8% and 95% were obtained. Characterizations were performed by NMR and IV spectroscopy; and antimycobacterial activity assays, to evaluate the effects of the substituent groups; of the amide, ester, and thioester functions; and of the length of the alkoxyl group (4, 6, 8, 10 and 12 carbon atoms). Salicylic derivatives were the most promising; 2-hydroxy-4-nitro-N-octylbenzamide (AS3 compound) showed higher activity (MIC <0.5 mg/L).
Human tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb). Active TB has surpassed HIV/AIDS as cause of death. Co-infection with HIV accelerates the progress of these diseases because there is no pathogen mitigation in immunocompromised individuals. Microorganisms create mutations, become more resistant, and the effectiveness of drugs decreases. Therefore, new antimycobacterial agents with novel mechanisms of action are needed to mitigate the increase in cases of resistant Mtb infections. In previous work, weak acids such as benzoic acid have demonstrated antitubercular activity. The esters derived from these compounds were more active than the corresponding acids. The corresponding amides did not show relevant activity. Still, the derivatives whose aromatic ring contained nitro groups (especially 3,5-dinitro) were significantly more active, which led to the hypothesis that they could have a distinct mechanism of action. Nitrocompounds such as benzothiazinones or N-(2-(4-methoxyphenoxy)ethyl)-3,5-dinitrobenzamide (DNB1) act on decaprenylphosphoryl-β‐D‐ribose oxidase (DprE1), an essential enzyme for cell wall biosynthesis. The objectives of this work consisted in synthesizing esters and amides of weak acids and their corresponding nitrocompounds; and in determining the antitubercular activities, to verify a possible increase in the activity of the compounds. The following were synthesized for the first time by methods A, B and C: three 3-nitro-5- (trifluoromethyl) benzothioates (T1-T3); four cinnamates and eight N-cinnamamides of cinnamic, 3- nitro and 4-nitro cinnamic acids (EC1-EC4; AC1-AC8); and ten salicylates and ten N-salicylamides of salicylic, 3-nitro, 4-nitro, 5-nitro and 3,5-dinitro salicylic acids (ES1-ES10; AS1-AS10). Yields between 8% and 95% were obtained. Characterizations were performed by NMR and IV spectroscopy; and antimycobacterial activity assays, to evaluate the effects of the substituent groups; of the amide, ester, and thioester functions; and of the length of the alkoxyl group (4, 6, 8, 10 and 12 carbon atoms). Salicylic derivatives were the most promising; 2-hydroxy-4-nitro-N-octylbenzamide (AS3 compound) showed higher activity (MIC <0.5 mg/L).
Descrição
Tese de Mestrado, Química, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Tuberculose Mycobacterium tuberculosis Derivados de ácidos fracos Nitrocompostos Atividade antimicobacteriana Teses de mestrado - 2023