Síntese e avaliação de metoxichalconas como agentes antidermatofíticos
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Data
2022-08-18
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Universidade Estadual Paulista (Unesp)
Resumo
As chalconas são substâncias de plantas que apresentam inúmeras bioatividades, dentre elas atividade antifúngica, sendo de síntese concisa. Estudos realizados por este grupo de pesquisa demonstraram a ação da 2´,4´-dimetoxichalcona (JA-0) contra espécies de Candida, exibindo Concentração Inibitória Mínima (CIM) entre 15,6 µg/mL e 61,2 µg/mL. Com o objetivo de otimizar a atividade antifúngica dessas dimetoxichalconas, foi proposta uma série de análogos de JA-0 com modificações no anel B, por meio de substituintes eletrodoadores e eletroatratores. A síntese desses análogos, foi realizada por meio da reação aldólica de Claisen-Schmidt. A avaliação antidermatofítica foi realizada contra Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis e Epidermophyton floccosum incluindo cepas de referência da American Type Culture Collection (ATCC) e isolados oriundos de micoses superficiais. A partir dos valores da CIM, foram selecionados os três compostos mais ativos para avaliação da sua combinação com diferentes fármacos antifúngicos, a avaliação do tempo de morte e a avaliação da toxicidade contra queratinócitos humanos e larvas de Galleria mellonella. Foram obtidos trinta e um compostos com rendimentos globais entre 15 e 96%, e pureza entre 90 e 98%. Cinco substâncias são inéditas na literatura, JA-2F, JA-3Br, JA-3OMe, JA-2OH3F e JA-4-terc. Os ensaios de susceptibilidade fúngica in vitro indicaram os valores de CIM e da Concentração Fungicida Mínima (CFM). Os análogos mais ativos contra os dermatófitos exibiram valores de CIM entre 0,9 µg/mL e 31,2 µg/mL. Os compostos JA-0 e JA-2F apresentaram atividade antidermatofítica mais pronunciada sendo selecionadas para estudos mais aprofundados. O composto JA-4OMe, é um fármaco chalcônico já em comercialização, nos motivando a continuar com sua avaliação contra os dermatófitos. Os compostos JA-0, JA-2F JA-4OMe provocaram danos a membrana plasmática e na parede celular da célula fúngica, o que pode ser sugestivo para um mecanismo de ação. Ao combinar os análogos metoxilados com os antifúngicos anfotericina B, caspofungina, fluconazol, terbinafina e voriconazol, esses evidenciaram efeito sinérgico em combinação com a maior parte dos fármacos testados. Quanto a toxicidade contra G. mellonella, os três análogos não apresentaram toxicidade a 500 µg/mL. Os resultados obtidos indicam uma potencialidade das metoxichalconas para o desenvolvimento de novos agentes antifúngicos, demonstrando potencial aplicabilidade para o tratamento de dermatofitoses.
Chalcones are plant substances that have numerous bioactivities, including antifungal activity, being concise synthesis. Studies carried out by this research group demonstrated the action of 2´,4´-dimethoxyhalcone (JA-0) against Candida species, exhibiting Minimum Inhibitory Concentration (MIC) between 15.6 µg/mL and 61.2 µg/mL. With the objective of optimizing the antifungal activity of these dimethoxyhalcones, a series of JA-0 analogues with modifications in the B ring was proposed, through electrodes and electroattractors substituents. The synthesis of these analogues was performed using the Claisen-Schmidt aldol reaction. The antidermatophytic evaluation was performed against Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis and Epidermophyton floccosum, including reference strains from the American Type Culture Collection (ATCC) and isolates from superficial mycoses. From the MIC values, the three most active compounds were selected for the evaluation of their combination with different antifungal drugs, the evaluation of the time of death and the evaluation of toxicity against human keratinocytes and larvae of Galleria mellonella. Thirty-one compounds were obtained with overall yields between 15 and 96%, and purity between 90 and 98%. Five substances are unpublished in the literature, JA-2F, JA-3Br, JA-3OMe, JA-2OH3F and JA-4-terc. In vitro fungal susceptibility assays indicated MIC and Minimum Fungicide Concentration (MFC) values. The most active analogues against dermatophytes exhibited MIC values between 0.9 µg/mL and 31.2 µg/mL. Compounds JA-0 and JA-2F showed more pronounced antidermatophytic activity and were selected for further studies. The compound JA-4OMe, is a chalconic drug already in commercialization, motivating us to continue with its evaluation against dermatophytes. Compounds JA-0, JA-2F JA-4OMe caused damage to the plasma membrane and cell wall of the fungal cell, which may be suggestive of a mechanism of action. When combining the methoxylated analogues with the antifungals amphotericin B, caspofungin, fluconazole, terbinafine and voriconazole, these showed a synergistic effect in combination with most of the drugs tested. As for toxicity against G. mellonella, the three analogues did not show toxicity at 500 µg/mL. The results obtained indicate the potential of methoxyhalcones for the development of new antifungal agents, demonstrating potential applicability for the treatment of dermatophytosis.
Chalcones are plant substances that have numerous bioactivities, including antifungal activity, being concise synthesis. Studies carried out by this research group demonstrated the action of 2´,4´-dimethoxyhalcone (JA-0) against Candida species, exhibiting Minimum Inhibitory Concentration (MIC) between 15.6 µg/mL and 61.2 µg/mL. With the objective of optimizing the antifungal activity of these dimethoxyhalcones, a series of JA-0 analogues with modifications in the B ring was proposed, through electrodes and electroattractors substituents. The synthesis of these analogues was performed using the Claisen-Schmidt aldol reaction. The antidermatophytic evaluation was performed against Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis and Epidermophyton floccosum, including reference strains from the American Type Culture Collection (ATCC) and isolates from superficial mycoses. From the MIC values, the three most active compounds were selected for the evaluation of their combination with different antifungal drugs, the evaluation of the time of death and the evaluation of toxicity against human keratinocytes and larvae of Galleria mellonella. Thirty-one compounds were obtained with overall yields between 15 and 96%, and purity between 90 and 98%. Five substances are unpublished in the literature, JA-2F, JA-3Br, JA-3OMe, JA-2OH3F and JA-4-terc. In vitro fungal susceptibility assays indicated MIC and Minimum Fungicide Concentration (MFC) values. The most active analogues against dermatophytes exhibited MIC values between 0.9 µg/mL and 31.2 µg/mL. Compounds JA-0 and JA-2F showed more pronounced antidermatophytic activity and were selected for further studies. The compound JA-4OMe, is a chalconic drug already in commercialization, motivating us to continue with its evaluation against dermatophytes. Compounds JA-0, JA-2F JA-4OMe caused damage to the plasma membrane and cell wall of the fungal cell, which may be suggestive of a mechanism of action. When combining the methoxylated analogues with the antifungals amphotericin B, caspofungin, fluconazole, terbinafine and voriconazole, these showed a synergistic effect in combination with most of the drugs tested. As for toxicity against G. mellonella, the three analogues did not show toxicity at 500 µg/mL. The results obtained indicate the potential of methoxyhalcones for the development of new antifungal agents, demonstrating potential applicability for the treatment of dermatophytosis.
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Palavras-chave
Micoses superficiais, Chalconas, Metoxichalconas, Dermatófitos, Superficial mycoses, Chalcones, Methoxyhalcones, Dermatophytes