Antifungal activity of two oxadiazole compounds for the paracoccidioidomycosis treatment

Paracoccidioidomycosis (PCM) is a neglected disease present in Latin America with difficulty in treatment and occurrence of serious sequelae. Thus, the development of alternative therapies is imperative. In the current work, two oxadiazole compounds (LMM5 and LMM11) presented fungicidal activity against Paracoccidioides spp. The minimum inhibitory and fungicidal concentration values ranged from 1 to 32 mu g/mL, and a synergic effect was observed for both compounds when combined with Amphotericin B. LMM5 and LMM11 were able to reduce CFU counts (>= 2 log(10)) on the 5(th) and 7(th) days of time-kill curve, respectively. The fungicide effect was confirmed by fluorescence microscopy (FUN-1/FUN-2). The hippocratic screening and biochemical analysis were performed in Balb/c male mice that received a high dose of each compound, and the compounds showed no in vivo toxicity. The treatment of experimental PCM with the new oxadiazoles led to significant reduction in CFU (>= 1 log(10)). Histopathological analysis of the groups treated exhibited control of inflammation, as well as preserved lung areas. These findings suggest that LMM5 and LMM11 are promising hits structures, opening the door for implementing new PCM therapies. Author summary Paracoccidioidomycosis (PCM) is a granulomatous fungal infection with clinically severe forms and serious pulmonary sequelae. The current limited arsenal and prolonged treatment regimen demonstrate the need for new antifungals. This study reveals two fungicidal oxadiazole compounds for PCM treatment. The in vitro assay showed the antifungal activity and the synergic effect with Amphotericin B. The high doses administration in mice showed absence of toxicity, which allowed to demonstrate the in vivo antifungal activity.