title: Synthesis and antifungal activity in vitro of isoniazid derivatives against histoplasma capsulatum var. capsulatum.
abstract: 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.
authors: Postgraduate Program in Medical Microbiology, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: Rossana
authors: R
authors: de Aguiar Cordeiro
authors: Francisca Jakelyne
authors: FJ
authors: de Farias Marques
authors: Rebecca
authors: R
authors: de Aguiar Cordeiro
authors: Marcos Reinaldo
authors: MR
authors: da Silva
authors: Angela
authors: A
authors: Donato Maia Malaquias
authors: Charlline Vládia
authors: CV
authors: Silva de Melo
authors: Jair
authors: J
authors: Mafezoli
authors: Maria da Conceição
authors: Mda C
authors: Ferreira de Oliveira
authors: Raimunda Sâmia
authors: RS
authors: Nogueira Brilhante
authors: Marcos Fábio
authors: MF
authors: Gadelha Rocha
authors: Tereza de Jesus
authors: Tde J
authors: Pinheiro Gomes Bandeira
authors: José Júlio
authors: JJ
authors: Costa Sidrim
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D006658:Histoplasma / Q000187:drug effects*; D007538:Isoniazid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests
chemical_list: D000935:Antifungal Agents; D007538:Isoniazid