In Silico and in Vitro Evaluation of Synthetic Chalcones against Paracoccidioides brasiliensis.

Abstract

Paracoccidioidomycosis (PCM) is an infectious disease caused by dimorphic fungi of the Paracoccidioides genus and causes a series of discomforts in affected patients. This work aimed to evaluate the antifungal potential of synthetic chalcones against Paracoccidioides brasiliensis (Pb) and to determine in silico possible therapeutic targets. An in silico evaluation of a database of 21 synthesized chalcones was carried out based on pharmacokinetic parameters, enzymatic inhibition, Tanimoto similarity, and the prediction of the spectrum of activity by PASS (prediction of activity spectra of substances). The most viable chalcones from the previous evaluation were selected for the measurement of minimum inhibitory concentration (MIC) against Pb and for cytotoxicity assays pre- and post-metabolization using HEPG2 cells. After in silico evaluation, the compounds 4, 11, 12, 20, and 21 were selected to carry out the molecular docking and in vitro tests. In the docking studies, multiple hydrophobic and polar intermolecular interactions were observed, such as hydrogen bonds, with emphasis on compound 20 in the active site of thioredoxin, where it made 4 hydrogen bonds with the residues Gln43, Ala36, and Thr38. In vitro testing revealed antifungal activity, with the MICs ranging from 32 to 128 μg/mL. In cytotoxicity assays, the 5 compounds exhibited reduced IC₅₀ values (5.51-14.85 μg/mL pre-metabolization and 10.48-35.4 μg/mL post-metabolization). The compounds 4, 11, 12, 20, and 21 have shown favorable predictions of pharmacokinetic characteristics and distinct actions compared to conventional medications, as well as antifungal activity with less toxicity after metabolization, making them the best candidates for further studies.