Synthesis and in vitro antifungal activity of isoniazid-derived hydrazones against Coccidioides posadasii. (September 2016)

• Record Type: Journal Article
• Authors: Cordeiro, Rossana de Aguiar; de Melo, Charlline Vládia Silva; Marques, Francisca Jakelyne de Farias; Serpa, Rosana; Evangelista, Antônio José de Jesus; Caetano, Erica Pacheco; Mafezoli, Jair; de Oliveira, Maria da Conceição Ferreira; da Silva, Marcos Reinaldo; Bandeira, Tereza de Jesus Pinheiro Gomes; Moreira, José Luciano Bezerra; Brilhante, Raimunda Sâmia Nogueira; Rocha, Marcos Fábio Gadelha; Sidrim, José Júlio Costa
• Is Part Of: Microbial pathogenesis. Volume 98(2016)
• Page Start: 1
• Page End: 5
• Publication Date: 2016-09
• Subjects: Coccidioides -- Hydrazones -- Isoniazid -- Antifungal susceptibility -- Synergism; Pathogenic microorganisms -- Periodicals; Pathology, Molecular -- Periodicals; Communicable Diseases -- microbiology -- Periodicals; Communicable Diseases -- parasitology -- Periodicals; Micro-organismes pathogènes -- Périodiques; Pathologie moléculaire -- Périodiques; Electronic journals; 616.9041
• DOI: 10.1016/j.micpath.2016.06.022
• Languages: English
• ISSNs: 0882-4010

Abstract

Abstract: 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 hydrazones N ′-[( E )-1-(4-methoxyphenyl)ethylidene]pyridine-4-carbohydrazide, N ′-[( E )-1-(4-methylphenyl)ethylidene]pyridine-4-carbohydrazide, and N ′-[( E )-1-(phenyl)ethylidene]pyridine-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 μg/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. Graphical abstract: Highlights: Three isoniazid-derived hydrazones were synthetized. All compounds showed antifungal activity against Coccidioides posadasii. Synthetized hydrazones reduced fungal ergosterol content. Isoniazid-derived hydrazones altered permeability of fungal cell membrane.