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.
Highlights
Among the zoonotic diseases with importance in human and veterinary medicine, sporotrichosis should be highlighted due to the increasing reports in both human and animals
Considering the repurposing strategy, the urgency of a novel therapeutic to sporotrichosis and the absence of literature information regarding the activity of pyrazinoic acid (POA) derivatives against fungi, the aim of this study was to evaluate the activity of different POA derivatives against Sporothrix brasiliensis
The compounds 3 and 4 can be highlighted due to fungistatic and fungicidal activities against 100% of S. brasiliensis isolated from cats (6/6) and S. schenckii standard strain from a human
Summary
Among the zoonotic diseases with importance in human and veterinary medicine, sporotrichosis should be highlighted due to the increasing reports in both human and animals This infection is clinically characterized by subcutaneous nodules, ulcers and crusts, which can spread to systemic organs (Madrid et al, 2012). The emergence of antifungal resistance has made the therapeutic control of the disease in animals more difficult (Rodrigues et al, 2014a; Borba-Santos et al, 2015; Waller et al, 2016), and has encouraged the search for new molecules with antifungal potential With this regard, drug repurposing (or called repositioning) is an approach that is frequently under consideration to find novel therapeutic options to diseases in the urgent state.
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