RESUMO
Ebselen (EB, compound 1) is an investigational organoselenium compound that reduces fungal growth, in part, through inhibition of the fungal plasma membrane H+ -ATPase (Pma1p). In the present study, the growth inhibitory activity of EB and of five structural analogs was assessed in a fluconazole (FLU)-resistant strain of Candida albicans (S2). While none of the compounds were more effective than EB at inhibiting fungal growth (IC50 â¼ 18 µM), two compounds, compounds 5 and 6, were similar in potency. Medium acidification assays performed with S2 yeast cells revealed that compounds 4 and 6, but not compounds 2, 3, or 5, exerted an inhibitory activity comparable to EB (IC50 â¼ 14 µM). Using a partially purified Pma1p preparation obtained from S2 yeast cells, EB and all the analogs demonstrated a similar inhibitory activity. Taken together, these results indicate that EB analogs are worth exploring further for use as growth inhibitors of FLU-resistant fungi.
Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida albicans/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Fúngicas/antagonistas & inibidores , Compostos Organosselênicos/farmacologia , ATPases Translocadoras de Prótons/antagonistas & inibidores , Antifúngicos/química , Azóis/química , Candida albicans/enzimologia , Candida albicans/crescimento & desenvolvimento , Membrana Celular/enzimologia , Meios de Cultivo Condicionados/química , Farmacorresistência Fúngica , Drogas em Investigação/química , Drogas em Investigação/farmacologia , Inibidores Enzimáticos/química , Fluconazol/farmacologia , Proteínas Fúngicas/metabolismo , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Concentração de Íons de Hidrogênio , Isoindóis , Cinética , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Estrutura Molecular , Compostos Organosselênicos/química , ATPases Translocadoras de Prótons/metabolismo , Tiazóis/química , Tiazóis/farmacologiaRESUMO
In an effort to find inhibitors that are effective against both Candida and Aspergillus spp., a series of 5(6)-(un)substituted benzotriazole analogs, represented by compounds 3a-3h and 3b'-3f', were prepared using a crystalline oxirane intermediate 1 previously synthesized in our laboratory. All the compounds were evaluated for inhibitory activity against various species of Candida and Aspergillus. Compounds 3b' (5,6-dimethylbenzotriazol-2-yl derivative), 3d (5-chlorobenzotriazol-1-yl derivative) and 3e' (6-methylbenzotriazol-1-yl derivative) exhibited potent antifungal activity, with the MICs for Candida spp. and Aspergillus niger, ranging from 1.6 microg/mL to 25 microg/mL and 12.5 microg/mL to 25 microg/mL, respectively. The present work describes the design, synthesis, regioisomer characterization (through COSY and NOESY 2D-NMR spectroscopy and single molecule X-ray crystallography), antifungal evaluation, molecular docking, and structure-activity relationships of the various 5(6)-(un)substituted benzotriazole analogs.
