3D-QSAR Studies of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones Derivatives as RSV Fusion Inhibitors

Background: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory- tract infections (ALRI) in young children, elderly and high-risk adults and results in considerable hospitalizations. The fusions of RSV were proved to be a potent target in combating virus. Methods: A series of newly reported isoindol-5-ones derivatives as RSV fusion inhibitors was studied via in silico methodologies 3D-QSAR (CoMFA and CoMSIA) to explore compounds with better activity. Internal and external cross-validation techniques were investigated. Results: Satisfactory CoMFA model (q2=0.542, r2=0.908) and CoMSIA model (q2=0.563, r2=0.874) were obtained. The external validation indicated that CoMFA and CoMSIA models possessed high predictive powers with Q2 F2 values of 0.734 and 0.701, respectively. The contour maps shows the bulky, and hydrogen bond acceptor groups at R2 position are essential to improve the antivirus activity. The minor and hydrophobic groups such as ether bond at para-position or metaposition of substituent group R1 may increase their activities. Conclusion: The plots of CoMFA and CoMISA provided information of the structure–activity relationship and revealed the chemical features affecting the antivirus activity. These results expand our understanding of RSV fusion inhibitors and could be helpful in rationally designing of new analogs with more potent inhibitory activities.