Síntese e avaliação de dimetoxichalconas halogenadas como agentes antidermatofíticos
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Data
2023-03-06
Autores
Avesani, João Gabriel Giaretta
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Universidade Estadual Paulista (Unesp)
Resumo
As dermatofitoses são infecções causadas por fungos queratinofílicos que acometem pele, pelos e unha. São as infecções prevalentes dentre as dermatomicoses, podendo atingir 15 a 32 % da população mundial. Dentre os fatores que corroboram o surgimento e manutenção das dermatofitoses, incluem-se idade, clima, classe socioeconômica e ocupação. Possuem um tratamento medicamentoso longo e de alto custo econômico, o qual promove alto índice de abandono, provocando recidivas e cronicidade. As chalconas são substâncias de plantas e que possuem inúmeros efeitos bioativos, principalmente antifúngico. Em trabalhos anteriores realizados pela equipe do Laboratório de Antibióticos e Quimioterápicos – LAQ, observou atividade antifúngica de dimetoxichalconas contra Candida spp. No presente trabalho, buscou-se a síntese e avaliação antifúngica de 12 análogos halogenados da 2’,5’-dimetoxichalcona. Em uma primeira etapa avaliou-se a atividade antifúngica por meio dos valores de concentração inibitória mínima (CIM). Os compostos 3F e 4F apresentaram valores de CIM de 7,8 µg/mL contra cepas de Trichophyton rubrum e Trichophyton mentagrophytes. A substância 4Cl exibiu valores de CIM de 15,6 µg/mL contra cepas de T. rubrum, T. mentagrophytes e Microsporum canis. Esses três compostos foram selecionados para avaliações de bioatividade adicionais (como...). O experimento de checkerboard indicou uma ação aditiva dos três compostos com os fármacos terbinafina, itraconazol e fluconazol, exceto 4F que apresentou ação indiferente com o fluconazol. Para elucidar uma possível ação contra a membrana e parede celular fúngicas, foi conduzido ensaios com ergosterol e sorbitol adicionados no meio de cultura. Observou-se uma ação em membrana citoplasmática, com um aumento de 16 vezes na CIM com o meio suplementado com ergosterol. Pelo ensaio de tempo de morte foi possível verificar que 3F e 4F apresentaram ação fungicida, inibindo em 100% o crescimento de T. rubrum em 24 e 8 horas respectivamente. O composto 4Cl exibiu ação fungistática. O ensaio de toxicidade in vitro foi realizado contra queratinócitos humanos (HaCaT), onde observou uma alta toxicidade e um índice de seletividade (IS) menor que 0,5. No ensaio de toxicidade in vivo contra larvas de Tenebrio molitor, as mesmas apresentaram uma taxa de 30 a 60% de sobrevivência frente as chalconas. Os resultados obtidos demonstram uma alta probabilidade no desenvolvimento de novos agentes antidermatofíticos, auxiliando assim o tratamento dessas infecções.
Dermatophytoses are infections caused by keratinophilic fungi that affect the skin, hair and nails. They are the most prevalent infections among dermatomycoses, affecting 15 to 32% of the world's population. Among the factors that corroborate the emergence and maintenance of dermatophytosis, include age, climate, socioeconomic class and occupation. They have a long drug treatment and high economic cost, which promotes a high rate of abandonment, causing relapses and chronicity. Chalcones are plant substances that have numerous bioactive effects, mainly antifungal. In previous works carried out by the team of the Laboratory of Antibiotics and Chemotherapeutics - LAQ, observed antifungal activity of dimethoxyhalcones against Candida spp. In the present work, we sought the synthesis and antifungal evaluation of 12 halogenated analogues of 2',5'-dimethoxyhalcone. In a first step, the antifungal activity was evaluated using the minimum inhibitory concentration (MIC) values. Compounds 3F and 4F showed MIC values of 7.8 µg/mL against strains of Trichophyton rubrum and Trichophyton mentagrophytes. The 4Cl substance exhibited MIC values of 15.6 µg/mL against strains of T. rubrum, T. mentagrophytes and Microsporum canis. These three compounds were selected for further bioactivity evaluations (how...). The checkerboard experiment indicated an additive action of the three compounds with the drugs terbinafine, itraconazole and fluconazole, except 4F which showed indifferent action with fluconazole. To elucidate a possible action against the fungal membrane and cell wall, tests were conducted with ergosterol and sorbitol added to the culture medium. An action on the cytoplasmic membrane was observed, with a 16-fold increase in MIC with the medium supplemented with ergosterol. By the time of death assay, it was possible to verify that 3F and 4F had a fungicidal action, inhibiting the growth of T. rubrum by 100% in 24 and 8 hours, respectively. Compound 4Cl exhibited fungistatic action. The in vitro toxicity assay was carried out against human keratinocytes (HaCaT), where a high toxicity and a selectivity index (IS) lower than 0.5 were observed. In the in vivo toxicity test against Tenebrio molitor larvae, they showed a 30 to 60% survival rate against chalcones. The results obtained demonstrate a high probability in the development of new antidermatophytic agents, thus helping the treatment of these infections.
Dermatophytoses are infections caused by keratinophilic fungi that affect the skin, hair and nails. They are the most prevalent infections among dermatomycoses, affecting 15 to 32% of the world's population. Among the factors that corroborate the emergence and maintenance of dermatophytosis, include age, climate, socioeconomic class and occupation. They have a long drug treatment and high economic cost, which promotes a high rate of abandonment, causing relapses and chronicity. Chalcones are plant substances that have numerous bioactive effects, mainly antifungal. In previous works carried out by the team of the Laboratory of Antibiotics and Chemotherapeutics - LAQ, observed antifungal activity of dimethoxyhalcones against Candida spp. In the present work, we sought the synthesis and antifungal evaluation of 12 halogenated analogues of 2',5'-dimethoxyhalcone. In a first step, the antifungal activity was evaluated using the minimum inhibitory concentration (MIC) values. Compounds 3F and 4F showed MIC values of 7.8 µg/mL against strains of Trichophyton rubrum and Trichophyton mentagrophytes. The 4Cl substance exhibited MIC values of 15.6 µg/mL against strains of T. rubrum, T. mentagrophytes and Microsporum canis. These three compounds were selected for further bioactivity evaluations (how...). The checkerboard experiment indicated an additive action of the three compounds with the drugs terbinafine, itraconazole and fluconazole, except 4F which showed indifferent action with fluconazole. To elucidate a possible action against the fungal membrane and cell wall, tests were conducted with ergosterol and sorbitol added to the culture medium. An action on the cytoplasmic membrane was observed, with a 16-fold increase in MIC with the medium supplemented with ergosterol. By the time of death assay, it was possible to verify that 3F and 4F had a fungicidal action, inhibiting the growth of T. rubrum by 100% in 24 and 8 hours, respectively. Compound 4Cl exhibited fungistatic action. The in vitro toxicity assay was carried out against human keratinocytes (HaCaT), where a high toxicity and a selectivity index (IS) lower than 0.5 were observed. In the in vivo toxicity test against Tenebrio molitor larvae, they showed a 30 to 60% survival rate against chalcones. The results obtained demonstrate a high probability in the development of new antidermatophytic agents, thus helping the treatment of these infections.
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Palavras-chave
Dermatófitos, Chalconas, Metoxichalconas, Dermatophytes, Chalcone, Methoxychalcone