Synthesis and Antifungal Activity In Vitro of Isoniazid Derivatives against Histoplasma capsulatum var. capsulatum

Abstract

f Histoplasmosis is a severe infection that affects millions of patients worldwide and is endemic in the Americas. Amphotericin B (AMB) and itraconazole are highly effective for the treatment of severe and milder forms of the disease, but AMB is toxic, and the bioavailability of itraconazole is erratic. Therefore, it is important to investigate new classes of drugs for histoplasmosis treatment. In this study, a series of nine isoniazid hydrazone derivatives were synthesized and evaluated for their antifungal activities in vitro against the dimorphic fungus Histoplasma capsulatum var. capsulatum. The drugs were tested by microdilution in accordance with CLSI guidelines. The compound N=-(1-phenylethylidene)isonicotinohydrazide had the lowest MIC range of all the compounds for the yeast and filamentous forms of H. capsulatum. The in vitro synergy of this compound with AMB against the planktonic and biofilm forms of H. capsulatum cells was assessed by the checkerboard method. The effects of this hydrazone on cellular ergosterol content and membrane integrity were also investigated. The study showed that the compound alone is able to reduce the ergosterol content of planktonic cells and can alter the membrane permeability of the fungus. Furthermore, the compound alone or in combination with AMB showed inhibitory effects against mature biofilms of H. capsulatum. N=-(1-Phenylethylidene)isonicotinohydrazide alone or combined with AMB might be of interest in the management of histoplasmosis.

Antifungal therapeutics for dimorphic fungal pathogens

“…However, using isoniazid as the core, chemical structure modification improved its antifungal potential; 3 of 9 isoniazid derivatives had significantly lower MICs against Histoplasma yeasts with one having inhibitory activity at concentrations as low as 7.8 mg/mL. 62 Extending the in vitro tests of the isoniazid-hydrazone derivative to Coccidioides demonstrated it had an MIC of 50 mg/mL against mycelia of this dimorphic fungal pathogen. 87 Although Coccidioides spherules were not tested, there is a reasonable possibility that the MIC will be lower since Histoplasma yeasts were 8-16X more sensitive to the isoniazid-hydrazone than were mycelia.…”

“…87 Although Coccidioides spherules were not tested, there is a reasonable possibility that the MIC will be lower since Histoplasma yeasts were 8-16X more sensitive to the isoniazid-hydrazone than were mycelia. 62 Antiretroviral protease inhibitors have inhibitory activity against Histoplasma. Saquinavir is active against both filamentous and yeast forms with an MIC around 0.4 mg/mL.…”

“…This is not an insignificant question as the yeast and hyphal forms of the dimorphic fungi can have dramatically different susceptibilities. [62][63][64][65][66][67][68][69] For example, early studies with echinocandins showed antifungal effects on the hyphal form of Histoplasma. 67 However, subsequent tests against the yeast form indicated that caspofungin was anywhere from 20-to 1000-fold less effective.…”

Quantitative Microplate-Based Growth Assay for Determination of Antifungal Susceptibility of Histoplasma capsulatum Yeasts

“…However, some of these early reports were based on tests with the filamentous form, and subsequent in vitro susceptibility tests employing the yeast form demonstrated that the Histoplasma yeasts are comparatively resistant to the echinocandins (16,17,20). This morphology-based discrepancy in antifungal susceptibility is not limited to echinocandins and highlights the need to use the most appropriate cell type during antifungal testing (21). With the increasing importance of monitoring antifungal drug resistance and the acceleration of new an-tifungal drug discovery efforts, optimized methods for highthroughput antifungal tests on Histoplasma yeasts are essential.…”

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

“…capsulatum [10]. In the present study we have developed isoniazid-derived hydrazones and evaluated their antifungal activity against another dimorphic fungal species, C. posadasii.…”