Synthesis and in vitro antifungal activity of. isoniazid-derived hydrazones against Coccidioides posadasii

Coccidioidomycosis is a potentially severe infection caused by dimorphic fungi Coccidioides immitis and Coccidioides posadasii. Although guidelines are well established, refractory disease is a matter of concern in the clinical management of coccidioidomycosis. In the present study three isoniazid-derived hydra zones N'-[(E)-1-(4-methoxyphenypethylidenelpyridine-4-carbohydrazide, N'-[(E)-1-(4-methylphenyl) ethylidene]pyridine-4-carbohydrazide, and N'-[(E)-1-(phenyl)ethylidenelpyridine-4-carbohydrazide were synthesized and evaluated for antifungal activity against C. posadasii. Susceptibility assays were performed by macrodilution testing. Interactions between the hydrazones and amphotericin B or itraconazole were evaluated by the checkerboard method. We also investigated the impairment of such compounds on cell ergosterol and membrane integrity. The synthesized molecules were able to inhibit C posadasii in vitro with MIC values that ranged from 25 to 400 mu g/mL. Drug interactions between synthesized molecules and amphotericin B proved synergistic for the majority of tested isolates; regarding itraconazole, synergism was observed only when strains were tested against N'-[(E)-1-(phenyl) ethylidene]pyridine-4-carbohydrazide. Reduction of cellular ergosterol was observed when strains were challenged with the hydrazones alone or combined with antifungals. Only N'-[(E)-1-(4-methylphenyl) ethylidene]pyridine-4-carbohydrazide altered membrane permeability of C posadasii cells. Isoniazid-derived hydrazones were able to inhibit C posadasii cells causing reduction of ergosterol content and alterations in the permeability of cell membrane. This study confirms the antifungal potential of hydrazones against pathogenic fungi. (C) 2016 Elsevier Ltd. All rights reserved.