|173-1||Hydroxyaldimines as potent in vitro anticryptococcal agents|
|Autores:||Thaís Furtado Ferreira Magalhães (UFMG - Universidade Federal de Minas Gerais) ; Cleiton Moreira da Silva (UFMG - Universidade Federal de Minas Gerais) ; Maria Aparecida de Resende-stoianoff (UFMG - Universidade Federal de Minas Gerais) ; Danielle Letícia da Silva (UFMG - Universidade Federal de Minas Gerais) ; Luzia Valentina Modolo (UFMG - Universidade Federal de Minas Gerais) ; Cleide Viviane Buzanello Martins (UNIOESTE - Universidade Estadual do Oeste do Paraná) ; Rosemeire Brondi Alves (UFMG - Universidade Federal de Minas Gerais) ; Ana Lúcia Tasca Gois Ruiz (UNICAMP - Universidade Estadual de Campinas) ; Giovanna Barbarini Longato (UNICAMP - Universidade Estadual de Campinas) ; João Ernesto de Carvalho (UNICAMP - Universidade Estadual de Campinas) ; Ângelo de Fátima (UFMG - Universidade Federal de Minas Gerais) |
Cryptococcosis is a fungal infection that mainly affects immunocompromised and immunocompetent individuals, which contributes for increasing indices of mortality and morbidity. Treatment of cryptococcosis is challenging due to the development of microbial resistance and the limited number of commercial antifungal drugs, most of them exhibiting various side effects. The in vitro anticryptococcal activity of nine hydroxyaldimines was evaluated against 24 strains of Cryptococcus spp. Minimum inhibitory and fungicidal concentrations (MIC and MFC, respectively) of compounds were determined through the broth microdilution assay following the Clinical and Laboratory Standards Institute guideline. The selectivity index (SI) of hydroxyaldimines and fluconazole was verified from experiments done with monkey kidney (VERO) healthy cells exposed to compounds test for 48 h. Among the hydroxyaldimines evaluated, 2-(3-hydroxybenzylideneamino)phenol (3A9) (MIC = 6.7 and 3.6 mg/L) and 2-(2,3-dihydroxybenzylideneamino)phenol (3B7) (MIC = 5.2 and 3.6 mg/L) were, respectively, found the most potent compounds against C. gatti and C. neoformans as observed for the geometric mean MIC values. The MFC values for compounds 3A9 and 3B7 against C. gattii were 1.4 to 4.0-fold lower than that of fluconazole (MFC = 38.0 mg/L). Based on MFC values, compounds 3A9 and 3B7 were at least twice as potent as fluconazole (MFC = 24.0 mg/L) against C. neoformans. Analysis of selectivity index revealed that 3B7 was found more selective to Cryptococcus spp. than did 3A9. Notably, TGI values for 3A9 and 3B7 were about 2-fold higher that for amphotericin B, the drug currently most used to treat systemic fungal infections. The hydroxyaldimines 2-(2,3,4-trihydroxybenzylideneamino)phenol (3B10), 2-(benzo[d][1,3]dioxol-5-ylmethyleneamino)phenol (3C3), 2-(4-fluorobenzylideneamino)phenol (3D3) and 2-(4-nitrobenzylideneamino)phenol (3D9) showed to be slightly less potent than fluconazole. However, the high selectivity of such compounds toward fungal cells makes them good candidates for in vivo investigation of anti-Cryptococcus activity. The in vitro anticryptococcal activity of hydroxyaldimines against C. gattii and C. neoformans strains point out this class of molecules as lead for the development of selective and efficient anticryptococcal agents.
Palavras-chave: Cryptococcus species, Anticryptococcal activity, Antifungal activity, Schiff bases, Aldimines