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Aim:  17 new 4-methoxynaphthalene- N -acylhydrazones were synthesized in order to evaluate their biological action against important pathogens. Methods:   In vitro susceptibility assays of compounds were performed against Paracoccidioides brasiliensis and Mycobacterium tuberculosis . Results: Compounds 4a , 4b and 4k were the most potent against P. brasiliensis , two with minimum inhibitory concentrations of ≤1 μg ml -1 and exhibited pharmacological synergy with amphotericin B. The compounds also showed activity against M. tuberculosis , with 4c and 4k being the more promising. Compound 4k showed good synergistic antimycobacterium activity with ethambutol. None of the compounds tested showed toxicity. Conclusion: We highlight the compound 4k , as a potential agent for the treatment of patients co-infected with paracoccidioidomycosis and tuberculosis.

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.