Síntese e avaliação de xinjiachalcona A e seus análogos como potenciais agentes antibacterianos de amplo espectro
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2023-04-27
Autores
Lima, Kevin Henrique Souza
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Universidade Estadual Paulista (Unesp)
Resumo
A resistência microbiana tem se mostrado uma iminente ameaça à saúde pública, onde cerca de 4,95 milhões de mortes foram associadas a este fenômeno em 2019. Em 2017 a Organização Mundial da Saúde (OMS) elaborou uma lista de prioridade para desenvolvimento de novos antibióticos contra certos patógenos, alguns destes que se mostram resistentes aos métodos convencionais de tratamento. Nesse sentido, a descoberta por agentes antibacterianos inovadores se torna premente. A xinjiachalcona A (XCA) é uma retrochalcona O-isoprenilada de Glycyrrhiza inflata que apresentou atividade contra Helicobacter pylori, com concentração inibitória mínima (CIM) contra cepas padrão e isolados clínicos variando de 12,5 a 50,0 µM. Este trabalho tem como objetivo a síntese de XCA e de análogos simplificados com modificações no anel B, a fim de analisar a relação estrutura-atividade e a obtenção de análogos com amplo espectro de atividades antibacteriana e antimicobacteriana potencializadas. A estratégia sintética incluiu reações de O-alquilação (prenilação e metilação), bem como proteção/desproteção com/de tetraidropirano (THP) e condensações aldólicas de Claisen-Schmidt. XCA, equinatina (ECH) e Di-OMe apresentaram valores de concentração inibitória mínima de 147,7 μM, 115,6 μM e 175,8 μM, respectivamente contra H. pylori, o composto As2 apresentou concentração inibitória mínima de 162,1 μM contra E. faecium. O protótipo (XCA) e Di-OMe se mostraram ativas contra M. tuberculosis com valores de concentração inibitória mínima de 46,15 μM e 55 μM, respectivamente.
Microbial resistance has proven to be an imminent threat to public health, with around 4.95 million deaths associated with this phenomenon in 2019. In 2017, the World Health Organization (WHO) prepared a priority list for the development of new antibiotics against certain pathogens, some of which are resistant to conventional treatment methods. In this sense, the discovery of innovative antibacterial agents becomes urgent. Xinjiachalcone A (XCA) is an O-isoprenylated retrochalcone from Glycyrrhiza inflata that showed activity against Helicobacter pylori, with minimal inhibitory concentration (MIC) against standard strains and clinical isolates ranging from 12.5 to 50.0 µM. This work aimed at the synthesis of XCA and simplified analogs with modifications in the B ring, in order to analyze the structure-activity relationship and obtain analogues with a broad spectrum of potentiated antibacterial and antimycobacterial activities. The synthetic strategy included O-alkylation reactions (prenylation and methylation), as well as protection/deprotection with/from tetrahydropyran (THP) and Claisen-Schmidt aldol condensations. XCA, echinatin (ECH) and Di-OMe presented minimum inhibitory concentration values of 147.7 μM, 115.6 μM and 175.8 μM, respectively against H. pylori, the compound As2 presented minimum inhibitory concentration of 162.1 μM against E. faecium. The prototype (XCA) and Di-OMe are found to be active against M. tuberculosis with minimum inhibitory concentration values of 46.15 μM and 55 μM, respectively.
Microbial resistance has proven to be an imminent threat to public health, with around 4.95 million deaths associated with this phenomenon in 2019. In 2017, the World Health Organization (WHO) prepared a priority list for the development of new antibiotics against certain pathogens, some of which are resistant to conventional treatment methods. In this sense, the discovery of innovative antibacterial agents becomes urgent. Xinjiachalcone A (XCA) is an O-isoprenylated retrochalcone from Glycyrrhiza inflata that showed activity against Helicobacter pylori, with minimal inhibitory concentration (MIC) against standard strains and clinical isolates ranging from 12.5 to 50.0 µM. This work aimed at the synthesis of XCA and simplified analogs with modifications in the B ring, in order to analyze the structure-activity relationship and obtain analogues with a broad spectrum of potentiated antibacterial and antimycobacterial activities. The synthetic strategy included O-alkylation reactions (prenylation and methylation), as well as protection/deprotection with/from tetrahydropyran (THP) and Claisen-Schmidt aldol condensations. XCA, echinatin (ECH) and Di-OMe presented minimum inhibitory concentration values of 147.7 μM, 115.6 μM and 175.8 μM, respectively against H. pylori, the compound As2 presented minimum inhibitory concentration of 162.1 μM against E. faecium. The prototype (XCA) and Di-OMe are found to be active against M. tuberculosis with minimum inhibitory concentration values of 46.15 μM and 55 μM, respectively.
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Palavras-chave
Xinjiachalcona A, O-alquilação, Condensação de Claisen-Schmidt, Tetraidropirano, Bactérias, Microbactérias, Xinjiachalcone A, O-alkylation, Claisen-Schmidt Condensations, Tetrahydropyran, Bacterium, Mycobacterium