Enterovirus 71 (EV-A71) is the main causative pathogen of childhood hand, foot and\nmouth disease. Effective medicine is currently unavailable for the treatment of this viral disease.\nUsing the fragment-hopping strategy, a series of 2-aryl-isoindolin-1-one compounds were designed,\nsynthesized and investigated for their in vitro antiviral activity towards multiple EV-A71 clinical\nisolates (H, BrCr, Shenzhen98, Jiangsu52) in Vero cell culture in this study. The structureâ??activity\nrelationship (SAR) studies identified 2-phenyl-isoindolin-1-ones as a new potent chemotype with\npotent antiviral activity against EV-A71. Ten out of the 24 tested compounds showed significant\nantiviral activity (EC50 < 10 microM) towards four EV-A71 strains. Compounds A3 and A4 exhibited\nbroad and potent antiviral activity with the 50% effective concentration (EC50) values in the range of\n1.23â??1.76 microM. Moreover, the selectivity indices of A3 and A4 were significantly higher than those of\nthe reference compound, pirodavir. The western blotting experiment indicated that the viral VP1 was\nsignificantly decreased at both the protein and RNA level in a dose-dependent manner following\ntreatment with compound A3. Moreover, compound A3 inhibited the viral replication by acting on\nthe virus entry stage. In summary, this study led to the discovery of 2-aryl-isoindolin-1-ones as a\npromising scaffold with potent anti-EV-A71 activities, which deserves further in-depth studies.
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