Abstract
A series of chloroquine analogs were designed to search for a less toxic chloroquine derivative as a potential SARS-CoV-2 Mpro inhibitor. Herein, an ANN-based QSAR model was built to predict the IC(50) values of each analog using the experimental values of other 4-aminoquinolines as the training set. Subsequently, molecular docking was used to evaluate each analog's binding affinity to Mpro. The analog that showed the greatest affinity and lowest IC(50) values was synthesized and characterized for its posterior incorporation into a polycaprolactone-based nanoparticulate system. After characterizing the loaded nanoparticles, an in vitro drug release assay was carried out, and the cytotoxicity of the analog and loaded nanoparticles was evaluated using murine fibroblast (L929) and human lung adenocarcinoma (A549) cell lines. Results show that the synthesized analog is much less toxic than chloroquine and that the nanoparticulate system allowed for the prolonged release of the analog without evidence of adverse effects on the cell lines used; therefore, suggesting that the analog could be a potential therapeutic option for COVID-19.