Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro.
Human cryptococcosis can occur as a primary or opportunistic infection and develop as an acute, subacute, or chronic, systemic infection involving different host organs. We evaluated the antifungal activity of thirteen compounds against Cryptococcus gattii and Cryptococcus neoformans in vitro, by assessing the toxicity of the compounds showing the greatest antifungal activity in VERO cells and murine macrophages. From these results, four compounds were considered promising for further studies because they displayed low cytotoxicity and significant antifungal activity. The heterocyclic compounds 1b, 1c, 1d, and 1m have antifungal activity levels between that of amphotericin B and fluconazole in vitro. The death curve of Cryptococcus spp. treated with these four compounds was similar to the curve obtained for amphotericin B, in that we observed a significant reduction in cell viability within the first 24 h of treatment. Additionally, we found that there was no effect when these compounds were combined with amphotericin and fluconazole, except for 1c, which antagonized the effect of amphotericin B against C. gattii, also reflected in the reduction of the post-antifungal effect (PAFE); however, this interaction did not alter the ergosterol content. The results shown in this paper reveal the discovery of novel thiazole compounds, which are easy to synthesize, and with potentially exhibit antifungal activity, and display low cytotoxicity in normal mammalian cells. These compounds can be used as prototypes for the design of new antifungal drugs against C. gattii and C. neoformans.
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Nívea
N
Pereira de Sá
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia da UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Cleudiomar Inácio
CI
Lino
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia da UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Nayara Cristina
NC
Fonseca
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Beatriz Martins
BM
Borelli
Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Jonas Pereira
JP
Ramos
Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Elaine Maria
EM
Souza-Fagundes
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Carlos Augusto
CA
Rosa
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Daniel Assis
DA
Santos
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia da UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Renata
R
Barbosa de Oliveira
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address: sjohann@icb.ufmg.br.
Susana
S
Johann
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D056285:Cryptococcus gattii / Q000187:drug effects*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014709:Vero Cells
D000935:Antifungal Agents; D013844:Thiazoles
Antifungal; Cryptococcus; Cytotoxicity; Thiazole