Design, Synthesis And Virtual Screening Of Isatin Derivaties As SARS CoV 3CL^pro Inhibitors

Severe acute respiratory syndrome(SARS) , whose pathogen is positive-strand RNA coronavirus (Coronavirus, CoV), a new type of coronavirus, which is a serious hazard to human health and the lives infectious disease, outbreak between 2002 and 2003 in southern China. Although the anti-SARS drug research had become a focus, there is no drug against the SARS virus yet. In this paper, we designed and synthesized 12 isatin derivatives. These compounds were virtually screened by molecular docking in order to discover lead compounds with better anti-SARS virus activity.The biological activity of isatin derivatives have been reported in lots of literatures, especially anti-viral activity. Based on the previous studies, a series of 1-(substituted)alkyl-3-(substituted)aniline-isatin derivatives were designed and synthesized from isatin as a lead compound. These compounds were virtually screened by the software of AutoDock 4.0.Twelve 1-(substituted)alkyl-3-(substituted) aniline-isatin derivatives were synthesized. Their chemical structures were confirmed by elemental analysis, 1H-NMR and MS. Eleven of them have been unreported. Preliminary virtual screening results show that the activity of most compounds were better than compounds which have been reported. In these compounds, compound kl-Ⅱd exhibited the best activity with the Ki values 0.072μM.Docking results showed that it can't improve the activiety via substituting the N-hydrogen-1-isatin by alkyl. But their 3-position's schiff base have superior activitys. Among these isatin schiff base derivatives, electron-donating group can improve activity, while electron-withdrawing group reduce activity. The number of substituents on phenyl affect the preferred conformation of compounds. Further research about substitutions on 3-(substituted) aniline and 5-position or 6-position of isatin may find out better compound aginst SARS agent.