Aim: Novel 4-methoxy-naphthalene derivatives were synthesized based on hits structures in order to evaluate the antifungal activity against Paracoccidioides spp.
Methods: Antifungal activity of compounds was evaluated against P. brasiliensis and most promising compounds 2 and 3 were tested against eight clinically important fungal species.
Results: Compound 3 was the more active compound with MIC 8 to 32 μg.ml-1 for Paracoccidioides spp without toxicity monkey kidney and murine macrophagecells. Carbohydrazide 3 showed good synergistic antifungal activity with amphotericin B against P. brasiliensis specie. Titration assay of carbohydrazide 3 with PbHSD enzyme demonstrates the binding ligand-protein. Molecular dynamics simulations show that ligand 3 let the PbHSD protein more stable.
Conclusion: New carbohydrazide 3 is an attractive lead for drug development to treat paracoccidioidomycoses.
Keywords: antifungal activity; carbohydrazide; homoserine dehydrogenase; molecular modeling.