Atividade antifúngica de uma beta-amino-cetona (base de Mannich) contra espécies patogênicas de Trichophyton

Abstract

The members of Trichophyton genus are important human pathogens that cause cutaneous mycoses, and the species T. rubrum is responsible for most cases. Currently, there is a great need to develop new antifungal drugs, since the available drugs has problems such as lack of effectiveness and high toxicity. In view of this, the aim of the work was to evaluate the activity of nine compounds of beta-amino ketones class against Trichophyton species. The antifungal activity was determined by the broth microdilution assay, from which the minimum inhibitory concentrations (MIC) of the compounds were defined. Among the compounds tested, 3-(morpholin-4-yl)-1-phenylpropan-1-one (AB1) was the most active, presenting MIC of 7.81 µg/ml against T. rubrum. This compound also demonstrated some selectivity for T. rubrum compared to another fungus (Candida albicans - MIC of 250 µg/ml) and bacteria [Staphylococcus aureus (MIC of 62.5 µg/ml) and Escherichia coli (MIC of 250 µg/ml)]. In addition, AB1 exhibited fungicidal activity and was equally active against conidia and hyphae of T. rubrum, being also active against clinical samples of Trichophyton spp. In these clinical samples, the MIC values of AB1 were often lower than those of the reference antifungal (fluconazole). AB1 toxicity in human cells (MRC-5) was also tested, using the MTT assay, by means of which the IC50 values (concentration that inhibits 50% of cell growth) and the selectivity index (SI) were determined, which were 37.75 µg/ml and 4.83, respectively. Its in vivo toxicity was also evaluated in Galleria mellonella, where the compound did not demonstrate toxicity until the highest concentration tested (160 mg/ml). Finally, a laser scanning confocal microscopy assay was performed, which revealed damage to the cell membrane and inhibition in the growth of T. rubrum hyphae after treatment with AB1. The data set indicates that the compound AB1 has the potential to be developed as a new antifungal agent directed to the treatment of mycoses caused by species of Trichophyton.