Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M(pro)) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M(pro) significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M(pro). These novel compounds displayed excellent IC(50) data in the range of 0.516–5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures.