Síntese e avaliação antibacteriana de análogos simplificados da 4-hidroxiderricina
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Data
2022-02-01
Autores
Silva, Ana Luiza Moreira
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Universidade Estadual Paulista (Unesp)
Resumo
A descoberta de novos agentes antibacterianos se faz necessária devido ao elevado índice de mortalidade em decorrência de doenças bacterianas e ao aumento da incidência de microrganismos resistentes. O presente trabalho teve como objetivo a síntese, caracterização e avaliação da atividade antibacteriana de análogos simplificados da 4-hidroxiderricina (4-HD) contra espécies gram-positivas e gram-negativas, sendo determinados os valores de concentração inibitória mínima (CIM). Os compostos da série I foram sintetizados por meio da reação de condensação aldólica de Claisen-Schmidt sob catálise básica com rendimentos que variaram de 58 a 90%. Os 7 compostos dessa série foram testados, sendo 4 deles provenientes da quimioteca do Laboratório de Antibióticos e Quimioterápicos (LAQ). A estratégia sintética para a obtenção dos compostos da série II incluiu reações de iodação, condensações aldólicas e acoplamento de Suzuki-Miyaura, sendo que os dois análogos obtidos tiveram rendimento entre 10% e 70%. Os compostos foram caracterizados pela técnica de espectroscopia por Ressonância Magnética Nuclear de 1H e 13C. Os resultados biológicos indicaram perda de atividade com a retirada da prenila (série I) e com a substituição da 4-OH pela 4-OCH3 (série II), reafirmando a importância desses grupos na atividade antibacteriana. O ANA 9 se destacou por apresentar valores de CIM próximos aos valores determinados para a 4-HD, sendo duas vezes mais potente contra S. aureus e E. faecalis. Os análogos foram submetidos a ensaios antimicobacterianos e, em linhas gerais, os compostos da série I foram ativos, com ênfase no ANA 4* que foi tão potente quanto a 4-HD contra Mycobacterium tuberculosis, representando uma alternativa sinteticamente mais simples. Os compostos da série II não foram ativos, sugerindo que a metoxila originalmente presente na estrutura do protótipo seja relevante para a atividade.
The discovery of new antibacterial agents is necessary due to the high mortality rate caused by bacterial diseases and the incidence increase of resistant microorganisms. The aim of the present work was the synthesis, characterization and evaluation of the antibacterial activity of simplified 4-hydroxyderricin (4-HD) compounds against gram-positive and gram-negative species by the minimal inhibitory concentration (MIC). The series I compounds were synthesized through the Claisen-Schmidt aldol condensation reaction under basic catalysis with yields ranging from 58 to 90%. The 7 compounds of this series were tested, among which 4 of them came from the LAQ Chemical library. The synthetic strategy to obtain series II compounds included iodination reactions, aldol condensations and Suzuki-Miyaura coupling, with the two analogues obtained having yields between 10 and 70%. Structural confirmation was given by 1H and 13C Nuclear Magnetic Resonance spectroscopy. The biological results indicated loss of activity with the removal of prenyl in series I and also with the replacement of 4-OH by 4-OCH3 in series II, reaffirming the importance of these groups in antibacterial activity. ANA 9 was the highlight compound for presenting MIC values close to the ones determined for 4HD, being two times more potent against S. aureus e E. faecalis. These compounds were also submitted to antimycobaterial assays and, in general, the series I compounds were active, with emphasis on the ANA 4*, which was as potent as 4-HD against Mycobacterium tuberculosis, representing a synthetically simpler alternative. The series II compounds were not active, suggesting that the methoxyl group originally present in the prototype structure is relevant to the activity.
The discovery of new antibacterial agents is necessary due to the high mortality rate caused by bacterial diseases and the incidence increase of resistant microorganisms. The aim of the present work was the synthesis, characterization and evaluation of the antibacterial activity of simplified 4-hydroxyderricin (4-HD) compounds against gram-positive and gram-negative species by the minimal inhibitory concentration (MIC). The series I compounds were synthesized through the Claisen-Schmidt aldol condensation reaction under basic catalysis with yields ranging from 58 to 90%. The 7 compounds of this series were tested, among which 4 of them came from the LAQ Chemical library. The synthetic strategy to obtain series II compounds included iodination reactions, aldol condensations and Suzuki-Miyaura coupling, with the two analogues obtained having yields between 10 and 70%. Structural confirmation was given by 1H and 13C Nuclear Magnetic Resonance spectroscopy. The biological results indicated loss of activity with the removal of prenyl in series I and also with the replacement of 4-OH by 4-OCH3 in series II, reaffirming the importance of these groups in antibacterial activity. ANA 9 was the highlight compound for presenting MIC values close to the ones determined for 4HD, being two times more potent against S. aureus e E. faecalis. These compounds were also submitted to antimycobaterial assays and, in general, the series I compounds were active, with emphasis on the ANA 4*, which was as potent as 4-HD against Mycobacterium tuberculosis, representing a synthetically simpler alternative. The series II compounds were not active, suggesting that the methoxyl group originally present in the prototype structure is relevant to the activity.
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Palavras-chave
Chalcona, Síntese, Atividade antibacteriana, Chalcone, Synthesis, Antibacterial activity