Síntese e avaliação antibacteriana e antimicobacteriana de 4-hidroxiderricina e seus análogos
Carregando...
Data
2022-01-27
Autores
Theodoro, Reinaldo dos Santos
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
As infecções microbianas e a resistência aos antibióticos têm sido os desafios mais significativos que ameaçam a saúde pública atualmente. A 4-hidroxiderricina (4HD) é uma chalcona prenilada de ocorrência natural que foi isolada da Angelica keiskei (Ashitaba) e demonstra múltiplas atividades farmacológicas, principalmente antibacteriana. Neste contexto, 4HD e três séries de análogos foram planejados, sintetizados e investigados contra bactérias, micobactérias e fungos clinicamente importantes. Este trabalho utilizou a 4-hidroxiderricina como protótipo para o planejamento de análogos, os quais foram concebidos pela permutação da subunidade p-hidroxila por grupos eletrodoadores e eletro-atratores (Série I), além das modificações nas subunidades 2'-hidroxila, 3'-prenila e 4'-metoxila (Série II) e reduções da cetona α,β-insaturadas (Série III). Foram descritas a síntese de 111 substâncias, incluindo intermediários (68) e substâncias-alvo (45), sendo 26 novas e 8 produtos naturais. As substâncias-alvo (1 - 45) foram preparadas através de reações de Iodações Regiosseletivas, O-Metilações, Proteções, Condensações Aldólicas entre aldeídos e cetonas via catálise básica, Acoplamentos de Suzuki, Rearrajnos [1,3]-Sigmatrópicos, Desproteções e reações de Redução. Primeiramente, 4HD se mostrou fortemente ativo contra bactérias e micobactérias com valores de CIM de 1,56 - 400 μg.mL-1, principalmente contra bactérias gram-positivas. 4HD apresentou potente atividade inibitória contra biofilme de MSSA e MRSA com valores de CIMB50 de 1,56 e 0,78 μg.mL-1, respectivamente. Verificamos também que 4HD tem ação bactericida, por lesar a membrana citoplasmática de B. subtilis, com baixa citotoxicidade contra as células HaCaT. 4HD mostrou ser um potente agente antifúngico contra cepas de T. rubrum e T. mentagrophytes com valores de CIM de 0,9 - 31,2 μg.mL-1, e atividade moderada contra C. auris com valores de CIM de 31,2 μg.mL-1. 4HD agiu sinergicamente e potencializou a atividade da terbinafina em 5 a 10 vezes e do itraconazol em 2 a 4 vezes. Além disso, a membrana celular dos fungos dermatófitos foi o alvo do 4HD, pois o ergosterol exógeno diminuiu consideravelmente sua atividade antifúngica (CIM> 31,2 μg.mL-1). As atividades antibacterianas e antimicobacterianas dos derivados chalcônicos 2 - 38 foram de 1,56 a 400 μg.mL-1. Estudos de REA sugeriram que 3'-prenila, 2'-hidroxila e 4-hidroxila são pontos farmacofóricos fundamentais de 4HD para a atividade antibacteriana e antimicobacteriana. Além disso, a troca do grupo prenila em 4HD por um grupo benzila não alterou significativamente a atividade antibacteriana, proporcionando uma relação bioisostérica não-clássica entre essas duas subunidades. Derivados de chalconas reduzidas foram as classes de compostos mais ativos neste trabalho. A estratégia de redução da cetona α, β-insaturada causou aumento na atividade antibacteriana de algumas chalconas inicialmente inativas, como a 4'-O-metilbavachalcona (16). Além disso, a redução de 4HD formou as dihidrocalconas 29 e 30 e o 1,3-diarilpropano 35, que foram mais promissores que seu substrato, principalmente contra MSSA e MRSA. Portanto, a redução da cetona α, β-insaturada de 4HD não levou à perda da atividade antibacteriana. Os compostos 13, 29, 30 e 37 mostraram potente atividade na inibição do biofilme de MSSA e MRSA. O composto 29 (4-hidroxidihidroderricina) mostrou baixa citotoxicidade contra células HaCaT. Portanto, a 4-hidroxiderricina e seus análogos são promissores agentes antibacterianos e antifúngicos, podendo ser uma alternativa no tratamento e combate às diversas infecções causadas por essas bactérias, micobactérias e fungos. Assim, 4HD e 29 podem ser considerados compostos líderes promissores para a descoberta de novos fármacos.
Microbial infections and antibiotic resistance have been the most significant challenges threatening the health of society today. 4-hydroxyderricin (4HD) is a naturally occurring prenylated chalcone that has been isolated from Angelica keiskei (Ashitaba) and demonstrates multiple pharmacological activities, mainly antibacterial. In this context, 4HD and three series of analogs were designed, synthesized, and investigated against clinically important bacteria, mycobacteria, and fungi. This work used 4-hydroxyderricin as a prototype for the planning of analogs, which were designed by the permutation of the p-hydroxyl subunit by electron donor and electro-attracting groups (Series I), changing the 2'-hydroxyl, 3'-prenyl and 4'-methoxyl subunits (Series II) and α,β-unsaturated ketone reductions (Series III). The synthesized 111 substances were described, including intermediates (68) and target substances (45), 26 of which were new and 8 were natural products. The target substances (1 – 45) were prepared through Regioselective Iodations, O-Methylations, Protections, Aldol Condensations between aldehydes and ketones on basic catalysis, Suzuki couplings, [1,3]-Sigmatropic Rearrangements, Deprotections, and reactions of Reduction. First, 4HD showed to be strongly active against bacteria and mycobacteria with MIC values of 1.56 – 400 µg.mL-1, mainly against gram-positive bacteria. 4HD showed potent inhibitory activity against S. aureus MSSA and MRSA biofilm with MICB50 values of 1.56 and 0.78 µg.mL-1, respectively. We also found that 4HD has a bactericidal action by damaging the cytoplasmatic membrane of B. subtilis, with low cytotoxicity against HaCaT cells. 4HD was shown to be a potent antifungal agent against T. rubrum, and T. mentagrophytes strains with MIC values of 0.9 – 31.2 µg.mL-1 and moderate activity against C. auris with MIC values of 31.2 µg.mL-1. 4HD acted synergistically and potentiated the activity of terbinafine 5- to 10-fold and itraconazole 2- to 4-fold. The cell membrane of dermatophyte fungi was the target of 4HD since exogenous ergosterol considerably decreased the antifungal activity (MIC>31.2 µg.mL-1). The antibacterial and antimycobacterial activities of the chalcones derivatives 2 – 38 ranged from 1.56 to 400 µg.mL-1. SAR studies have suggested that 3'-prenyl, 2'-hydroxyl, and 4-hydroxyl are fundamental pharmacophoric points of 4HD for antibacterial and antimycobacterial activity. Furthermore, exchanging the prenyl group in 4HD for a benzyl group did not significantly alter the antibacterial activity, providing a non-classical bioisosteric relationship between these two subunits. Reduced chalcones derivatives were the most active compounds classes in this work. The α,β-unsaturated ketone reduction strategy caused an increase in the antibacterial activity of some chalcones that were initially not active, such as 4'-O-methylbavachalcone (16). Furthermore, 4HD reduction formed dihydrochalcones 29 and 30 and 1,3-diarylpropane 35, which were more promising than their substrate, mainly against MSSA and MRSA. Therefore, reduction of α,β-unsaturated ketone from 4HD did not lead to loss of antibacterial activity. Compounds 13, 29, 30, and 37 showed potent activity in inhibiting the biofilm of MSSA and MRSA. Compound 29 (4-hydroxydihydroderricin) showed low cytotoxicity against HaCaT cells. Therefore, 4-hydroxyderricin and its analogs are promising antibacterial and antifungal agents and may be an alternative in treating and combating various infections caused by these bacteria, mycobacteria, and fungi. Thus, 4HD and 29 can be considered promising lead compounds to discover new drugs.
Microbial infections and antibiotic resistance have been the most significant challenges threatening the health of society today. 4-hydroxyderricin (4HD) is a naturally occurring prenylated chalcone that has been isolated from Angelica keiskei (Ashitaba) and demonstrates multiple pharmacological activities, mainly antibacterial. In this context, 4HD and three series of analogs were designed, synthesized, and investigated against clinically important bacteria, mycobacteria, and fungi. This work used 4-hydroxyderricin as a prototype for the planning of analogs, which were designed by the permutation of the p-hydroxyl subunit by electron donor and electro-attracting groups (Series I), changing the 2'-hydroxyl, 3'-prenyl and 4'-methoxyl subunits (Series II) and α,β-unsaturated ketone reductions (Series III). The synthesized 111 substances were described, including intermediates (68) and target substances (45), 26 of which were new and 8 were natural products. The target substances (1 – 45) were prepared through Regioselective Iodations, O-Methylations, Protections, Aldol Condensations between aldehydes and ketones on basic catalysis, Suzuki couplings, [1,3]-Sigmatropic Rearrangements, Deprotections, and reactions of Reduction. First, 4HD showed to be strongly active against bacteria and mycobacteria with MIC values of 1.56 – 400 µg.mL-1, mainly against gram-positive bacteria. 4HD showed potent inhibitory activity against S. aureus MSSA and MRSA biofilm with MICB50 values of 1.56 and 0.78 µg.mL-1, respectively. We also found that 4HD has a bactericidal action by damaging the cytoplasmatic membrane of B. subtilis, with low cytotoxicity against HaCaT cells. 4HD was shown to be a potent antifungal agent against T. rubrum, and T. mentagrophytes strains with MIC values of 0.9 – 31.2 µg.mL-1 and moderate activity against C. auris with MIC values of 31.2 µg.mL-1. 4HD acted synergistically and potentiated the activity of terbinafine 5- to 10-fold and itraconazole 2- to 4-fold. The cell membrane of dermatophyte fungi was the target of 4HD since exogenous ergosterol considerably decreased the antifungal activity (MIC>31.2 µg.mL-1). The antibacterial and antimycobacterial activities of the chalcones derivatives 2 – 38 ranged from 1.56 to 400 µg.mL-1. SAR studies have suggested that 3'-prenyl, 2'-hydroxyl, and 4-hydroxyl are fundamental pharmacophoric points of 4HD for antibacterial and antimycobacterial activity. Furthermore, exchanging the prenyl group in 4HD for a benzyl group did not significantly alter the antibacterial activity, providing a non-classical bioisosteric relationship between these two subunits. Reduced chalcones derivatives were the most active compounds classes in this work. The α,β-unsaturated ketone reduction strategy caused an increase in the antibacterial activity of some chalcones that were initially not active, such as 4'-O-methylbavachalcone (16). Furthermore, 4HD reduction formed dihydrochalcones 29 and 30 and 1,3-diarylpropane 35, which were more promising than their substrate, mainly against MSSA and MRSA. Therefore, reduction of α,β-unsaturated ketone from 4HD did not lead to loss of antibacterial activity. Compounds 13, 29, 30, and 37 showed potent activity in inhibiting the biofilm of MSSA and MRSA. Compound 29 (4-hydroxydihydroderricin) showed low cytotoxicity against HaCaT cells. Therefore, 4-hydroxyderricin and its analogs are promising antibacterial and antifungal agents and may be an alternative in treating and combating various infections caused by these bacteria, mycobacteria, and fungi. Thus, 4HD and 29 can be considered promising lead compounds to discover new drugs.
Descrição
Palavras-chave
4-hidroxiderricina, Chalconas preniladas, Acoplamento de Suzuki, Rearranjo sigmatrópico, Redução, Bactérias, Micobactérias, Fungos, Bioisosterismo, Biofilme, 4-hydroxyderricin, Prenylated chalcones, Suzuki coupling, Sigmatropic rearrangement, Reduction, Bacteria, Mycobacteria, Fungi, Bioisosterism, Biofilm