title: Synthesis and in vitro antifungal activity of isoniazid-derived hydrazones against Coccidioides posadasii.
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.
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil. Electronic address: rossanacordeiro@ufc.br.
authors.forename: Rossana de Aguiar
authors.initials: Rde A
authors.lastname: Cordeiro
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Charlline Vládia Silva
authors.initials: CV
authors.lastname: de Melo
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Francisca Jakelyne de Farias
authors.initials: FJ
authors.lastname: Marques
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Rosana
authors.initials: R
authors.lastname: Serpa
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Antônio José de Jesus
authors.initials: AJ
authors.lastname: Evangelista
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Erica Pacheco
authors.initials: EP
authors.lastname: Caetano
authors.affiliation: Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Jair
authors.initials: J
authors.lastname: Mafezoli
authors.affiliation: Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Maria da Conceição Ferreira
authors.initials: Mda C
authors.lastname: de Oliveira
authors.affiliation: Department of Organic and Inorganic Chemistry, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Marcos Reinaldo
authors.initials: MR
authors.lastname: da Silva
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil; Christus College, School of Medicine, Fortaleza, Ceará, Brazil.
authors.forename: Tereza de Jesus Pinheiro Gomes
authors.initials: Tde J
authors.lastname: Bandeira
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: José Luciano Bezerra
authors.initials: JL
authors.lastname: Moreira
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Raimunda Sâmia Nogueira
authors.initials: RS
authors.lastname: Brilhante
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil; Graduate Program in Veterinary Science, State University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Marcos Fábio Gadelha
authors.initials: MF
authors.lastname: Rocha
authors.affiliation: Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors.forename: José Júlio Costa
authors.initials: JJ
authors.lastname: Sidrim
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D053898:Biosynthetic Pathways / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D003045:Coccidioides / Q000187:drug effects*; D004357:Drug Synergism; D004875:Ergosterol / Q000096:biosynthesis; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010539:Permeability / Q000187:drug effects
chemical_list: D000935:Antifungal Agents; D006835:Hydrazones; D017964:Itraconazole; D000666:Amphotericin B; D004875:Ergosterol
keywords: Antifungal susceptibility; Coccidioides; Hydrazones; Isoniazid; Synergism