While recent clinical trial results using posaconazole for the treatment of Chagas disease were disappointing [58], the enhanced potency we observed in L. donovani for 4-aminopyridyl-based non-azole inhibitors of CYP51 compared to ketoconazole and voriconazole supports the development of novel inhibitor scaffolds, potentially using our 4-aminopyridyl inhibitor series as a starting point. Here, CYP51A1 is linked to Chagas disease.