| Congresso Brasileiro de Microbiologia 2023 | Resumo: 848-1 | ||||
Resumo:Antifungal resistance poses a global challenge that increasingly limits the available therapeutic options for treating these infections. This issue is particularly concerning in the case of Candida infections, especially those associated with healthcare settings, as they have been linked to a rise in morbidity and mortality rates, accompanied by a high level of resistance to clinically used antifungal agents. Given this scenario, it is imperative to explore novel therapeutic strategies, including the investigation of new natural or synthetic substances, as well as the exploration of synergistic effects among existing antifungal classes. Naphthoquinones, a subset of quinones, have garnered research attention due to their multifaceted mechanism of action. therefore, the objective of this work is to evaluate the antifungal potential of naphthoquinones, once data from the literature showed, the antifungal activity against strains that demonstrate resistance to commonly used clinical antifungals. This study aimed to evaluate the in vitro antifungal activity, as well as the in silico pharmacokinetic and toxicological profiles, of naphthoquinone compounds against Candida strains. The In silico analyses encompassed crucial absorption, distribution, metabolism, excretion, and toxicity (ADME-T) parameters using software such as SwissADME, admetSAR2, and pkCSM.As material for evaluation of in vitro tests employed six reference Candida strains: Candida albicans ATCC 10231, Candida glabrata ATCC 2001, Candida parapsilosis ATCC 22019, Candida dubliniensis ATCC 34135, Candida tropicalis ATCC 750 and Candida Krusei NCPF 3949. Four derivatives of naphthoquinone supplied by Professor Dr. Vitor Francisco Ferreira from the Department of Organic Chemistry at UFF. Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) techniques were employed to assess antifungal activity. The in silico ADME-T analyses revealed profiles that met desirable drug standards, as the series adhered to Lipinski's rule and Veber's filter, exhibited high intestinal absorption and oral bioavailability, and demonstrated low interaction with cytochrome P450 (CYP) enzymes. In terms of in silico toxicity, the compounds displayed low toxicity, with an LD50 classified as grade III, corresponding to slight toxicity. No inhibition of human ether-a-go-go-related gene (hERG) potassium channel genes was observed, and no corrosive or carcinogenic potential was identified. Of the four compounds, only one of the compounds showed hepatotoxic potential. Regarding in vitro antifungal activity evaluation, the series of naphthoquinone compounds demonstrated inhibitory activity against all Candida strains tested, with MICs ranging from 16 to 256 µg/ml, varying among species. The predominant characterization of activity was fungistatic based on the MFC. In conclusion, the naphthoquinone series exhibits promising potential as antifungal agents. Compound 6a emerges as the most noteworthy, displaying a MIC of 16 µg/ml against Candida albicans ATCC 10231 and Candida Krusei ATCC 34135, a CIM of 32 µg/ml against Candida glabrata ATCC 2001, and a MIC of 64 µg/ml against Candida parapsilosis ATCC 22019, Candida dubliniensis NCPF 3949, and Candida tropicalis ATCC 750. Palavras-chave: Antifungals, Candida, Naphthoquinones, Resistance Agência de fomento:Aperfeiçoamento de Pessoal de Nível Superior ( CAPES ) e Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) | |||||