Rotenone enhances antifungal activity of novel pyrazoles against Candida spp.

Mycoses annually affect about 2 million individuals worldwide, especially in tropical countries. Candida spp., one of the main etiologic agents of these mycoses, and in particular Candida albicans has been the most isolated pathogen in patients with severe clinical cases of invasive candidiasis and candidemia, causing frequent infections or opportunistic and chronic systemic forms. However, the emergence of non-albicans infections has become a public health concern worldwide. In discovering har.mless molecules, the pyrazoles have attracted many scientists because their great synthetic versatility and extensive therapeutic properties such as antibacterials, antivirals, antimalarials, and anti-inflammatories, anti-leishmaniasis, and antifungals. They are part of Azole compounds used for decades for antifungal treatment. The azole action mechanism is related to ergosterol synthesis inhibition by blocking the target enzymes, known as Erg11p, leading to fungistatic action. We evaluated the antifungal potential of 12 pyrazole derivatives. Compound 1d caused prominent action against Candida glabrata. Thus, we employed Rotenone as a mitochondrial complex I inhibitor. Rotenone helped to enhance the effect of the novel pyrazole derivatives tested against Candida spp, decreasing MICs value from a range of 250-500 to <3.1 mu g/mL. Pyrazoles had a reduced cytotoxicity effect on in vivo cell culture than ketoconazole. Although ROS production might be a possible mechanism, it remained unclear. Thus, new studies must elucidate this synergistic action.