Avaliação antimicrobiana de 3-nitrobenzamidas sintéticas sobre espécies de Candida e estudos de docking molecular

• Ano de defesa: 2021
• Autor(a) principal: Ferreira Neto, Severino
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal da Paraíba; Brasil; Farmacologia; Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos; UFPB
• Palavras-chave em Português: Atividade antifúngica; Amidas; Imida; Nitrocompost; Antifungal activity; Amides; Imide; Nitro compound; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA
• Link de acesso: https://repositorio.ufpb.br/jspui/handle/123456789/22118

Fungal infections affect a significant part of the population. It is estimated that around 1 billion people around the world have been affected by some type of fungus. The Candida genus is responsible for several infectious diseases, especially in individuals with compromised immunity. In addition, the emergence of strains resistant to available drugs is worrying, which results in greater difficulties for treatment and association with cases of death. Therefore, the search for new pharmacotherapeutic alternatives is urgent. Nitrobenzene derivatives have several antimicrobial properties, including antifungal action. Thus, in the present study, the antifungal potential of fourteen 3- nitrobenzamide derivatives against Candida species (C. albicans, C. krusei and C. glabrata) was investigated and a structure-activity relationship of the substances evaluated was established. The 3-nitrobenzamide derivatives were prepared using the Schotten-Baumann reaction and were structurally characterized by the techniques of Infrared Spectroscopy and Nuclear Magnetic Resonance of 1H and 13C. The products obtained had yields of 25.2-72.7% and three derivatives from the collection are unprecedented (6, 8 and 10). In antifungal tests, the Minimum Inhibitory Concentration (MIC) was determined using the microdilution technique in 96-well plates and the Minimum Fungicidal Concentration (MFC) in solid culture medium. The possible mode of action was also investigated using the sorbitol and ergosterol assays. Nine compounds showed antifungal activity with MIC values ranging from 39.06 to 1250 µg/mL. Considering the analysis of the CFM/CIM ratio, which presented values in a range of 1 to 3, it can be seen that the derivatives have fungicidal action. Imide 14 showed the best fungicidal effect in the collection against strains of C. albicans, C. krusei and C. glabrata, with MIC and CFM values of 39.06 µg/mL. The data suggest that this compound does not act directly on the fungal cell membrane or through mechanisms that involve cell wall functions. Regarding the structure and antifungal activity relationship, the presence of the dicarbonyl system linked to nitrogen or methylenedioxide potentiates the inhibitory action against fungal species. The molecular docking study shows that seven out of ten targets that share higher docking scores belonging to the ergosterol biosynthetic pathway, with predicted binding to targets: GTP RHO1 binding protein, diphosphomevalonate decarboxylase, squalene monooxygenase, 24-C-sterol methyltransferase and squalene synthase; the small size of the molecule and the carbonyl groups, mainly, were ideal for stabilizing the molecule in the receptors. The analysis, formula made for C. albicans, was also done for C. krusei and C. glabrata species targets, in which there is a small mutation in C. krusei target residues, but which does not alter the compound binding in this target. Given these results, it is concluded that 3-nitrobenzamides are promising compounds for the development of new antifungal drugs against Candida spp.