| Congresso Brasileiro de Microbiologia 2023 | Resumo: 211-1 | ||||
Resumo: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. There are currently nine genera of dermatophytes: Trichophyton, Epidermophyton, Nannizzia, Paraphyton, Lophophyton, Microsporum, Ctenomyces, Guarromyces and Arthroderma. Undoubtedly, Trichophyton rubrum is one of the most prevalent etiologic agents of dermatophytosis, ranging from 50% to 80%. Chalconic compounds have a common chemical skeleton of 1,3-diaryl-2-propen-1-one, which are two aromatic rings joined by an α,β-unsaturated ketone. Chalcones are widely distributed in nature in vegetables, fruits and other plants. In the present work, we sought the synthesis and antidermatophytic 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, 4F and 4Cl showed MIC values ranging from 7.8 to 15.6 µg ml-1 against strains of Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis and Epidermophyton floccosum. These three compounds were then selected for further bioactivity assessments. 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 the mechanism of action of these compounds, sorbitol and ergosterol assays were performed. An action on the cytoplasmic membrane was observed, with a 16-fold increase in MIC. Assay with sorbitol-supplemented medium did not result in an increase in MIC. Using the Time-kill assay, it was possible to verify that 3F and 4F had a fungicidal action, inhibiting the growth of T. rubrum by 100% in up to 24 hours. 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. However, in the in vivo toxicity test against Tenebrio molitor larvae, it showed acceptable toxicity, with a survival rate of 30 to 60% against chalcones. Results similar to terbinafine at 125 µg ml-1 (50%) and DMSO (60%). The results obtained demonstrate that these compounds are possible antifungal agents for the treatment of dermatophytoses. Palavras-chave: antifungal, chalcones, dermatophytes, methoxyhalcones Agência de fomento:Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) | |||||