Anti-Sporothrix brasiliensis activity of different pyrazinoic acid prodrugs: a repurposing evaluation

  • Stefanie Bressan Waller Universidade Federal de Pelotas, Faculdade de Veterinária, Departamento de Veterinária Preventiva, Centro de Diagnóstico e Pesquisa em Micologia Veterinária
  • Ceres Nakasu Universidade Federal de Pelotas, Faculdade de Veterinária, Departamento de Clínicas Veterinárias
  • Renata Osório de Faria Universidade Federal de Pelotas, Faculdade de Veterinária, Departamento de Veterinária Preventiva, Centro de Diagnóstico e Pesquisa em Micologia Veterinária
  • João Paulo dos Santos Fernandes Universidade Federal de São Paulo, Departamento de Ciências Farmacêuticas
  • Marlete Brum Cleff Universidade Federal de Pelotas, Faculdade de Veterinária, Departamento de Clínicas Veterinárias
Keywords: Sporotrichosis, Sporothrix schenckii complex, Itraconazole, Antifungal resistance, Prodrugs, Pyrazinoic acid derivatives

Abstract

From drug repurposing studies, this work aimed to evaluate the activity of different pyrazinoic acid (POA) derivatives against Sporothrix brasiliensis. The POA esters were prepared and characterized as previously reported by classical esterification reactions, with good to excellent yields. Sporothrix brasiliensis isolates from cats (n=6) and standard strains of S. brasiliensis and S. schenckii were used to assess the antifungal activity of the POA derivatives through broth microdilution assay (CLSI M38-A2). Among the tested compounds, molecules 3 and 4 showed fungistatic and fungicidal activities against all Sporothrix spp. strains, and the obtained MIC and MFC values ranged from 2.12 to 4.24 mg/mL and from 1.29 to 5.15 mg/mL, respectively. Compound 2 and 5 were active as in vitro inhibitors of fungal growth, but showed weak fungicidal activity, while molecules 1 and POA itself were inactive. The results suggest the activity of POA derivatives against Sporothrix spp. may be dependent on the lipophilicity. In addition, the antifungal susceptibility of the isolates to itraconazole was performed, showing that two Sporothrix isolates from cats were itraconazole-resistant. Compounds 3 and 4 were also active against these itraconazole-resistant isolates, indicating a possible alternative route to the standard mode of action of itraconazole.

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Published
2018-12-20
How to Cite
Waller, S., Nakasu, C., Faria, R., Fernandes, J. P., & Cleff, M. (2018). Anti-Sporothrix brasiliensis activity of different pyrazinoic acid prodrugs: a repurposing evaluation. Brazilian Journal of Pharmaceutical Sciences, 54(4), e17858. https://doi.org/10.1590/s2175-97902018000417858
Section
Articles