Design, synthesis and cytotoxic evaluation of a selective serotonin reuptake inhibitor (SSRI) by virtual screening.

Depression is one of the most common mental illnesses, affecting almost 300 million people. According to the WHO, depression is one of the world's leading causes of disability and morbidity. People with this illness require both psychological and pharmaceutical treatment because severe depressive episodes often result in suicide. Selective serotonin reuptake inhibitors (SSRI) are widely used antidepressants that target the human serotonin transporter (hSERT). The crystallization of hSERT and the experimental data available allows cost and time-efficient computational tools like virtual screening (VS) to be utilized in the development of therapeutic agents. Here, we synthesized, characterized, and evaluated the biological activity of a novel SSRI analog of paroxetine, rationally designed by applying an artificial neural network-based QSAR model and a molecular docking analysis on hSERT. The analog N-substituted 18a showed higher affinity for the transporter (-10.2 kcal/mol), lower Ki value (1.19 nM) and a safer toxicological profile than paroxetine and was synthesized with a 71% yield. The in vitro cytotoxicity of the analog was evaluated using human glioblastoma (U87 MG), human neuroblastoma (SH SY5Y) and murine fibroblast (L929) cell lines. Also, the hemolytic ability of the compound was assessed on human erythrocytes. Results showed that analog 18a did not exhibit cytotoxic activity on the cell lines used and has no hemolytic activity at any of the concentrations tested, whereas with paroxetine, hemolysis was observed at 2.3, 1.29 y 0.67 mM. Based on these results, it is possible to suggest that analog 18a could be a promising new SSRI candidate for the treatment of this illness.

Design, Synthesis, and Development of 4-[(7-Chloroquinoline-4-yl)amino]phenol as a Potential SARS-CoV-2 Mpro Inhibitor.

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 IC50 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 IC50 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.