Bioisosteric-replacement-driven optimization of 4-methoxynaphthalene-N-acylhydrazones with anti-Paracoccidioides activity

Paracoccidioidomycosis (PCM) is a serious system fungal infection that causes significant death and suffering, particularly in Latin America. The treatment of PCM is limited by a few pharmacological options that require long-term administration protocols. Considering the few classes of drugs available for the treatment of PCM and the long time of the treatment, developing new anti-PCM compounds is relevant. With the purpose to develop new 4-methoxynaphthalene-N-acylhydrazone bioisosteres with anti-Paracoccidioides activity, a series of 4-methoxynaphthalene-N-acylhydrazones, which had already been tested against P. brasiliensis, was used to develop shape-based models. The models underwent statistical validation and were used to filter a library of compounds, which were ranked using scoring functions. Molecular docking analysis was used to select 6 compounds that were synthesized and evaluated biologically using minimum inhibitory concentration, minimum fungicidal concentration tests, and cytotoxicity. Using this protocol, we prioritized 6 compounds for synthesis and in vitro biological evaluation. Among them, two compounds (AOS2 and AOS3) were found to exhibit nanomolar activity against two P. brasiliensis isolates and low cytotoxicity for BalbC/3T3 cells (selectivity indexes >2048). The designed and synthesized 4-methoxynaphthalene-N-acylhydrazones could serve as a promising starting point for the development of anti-PCM agents.