Abstract
Enterovirus 71 (EV-A71) is the main causative pathogen of childhood hand, foot and mouth disease. Effective medicine is currently unavailable for the treatment of this viral disease. Using the fragment-hopping strategy, a series of 2-aryl-isoindolin-1-one compounds were designed, synthesized and investigated for their in vitro antiviral activity towards multiple EV-A71 clinical isolates (H, BrCr, Shenzhen98, Jiangsu52) in Vero cell culture in this study. The structure–activity relationship (SAR) studies identified 2-phenyl-isoindolin-1-ones as a new potent chemotype with potent antiviral activity against EV-A71. Ten out of the 24 tested compounds showed significant antiviral activity (EC50 < 10 µM) towards four EV-A71 strains. Compounds A3 and A4 exhibited broad and potent antiviral activity with the 50% effective concentration (EC50) values in the range of 1.23–1.76 μM. Moreover, the selectivity indices of A3 and A4 were significantly higher than those of the reference compound, pirodavir. The western blotting experiment indicated that the viral VP1 was significantly decreased at both the protein and RNA level in a dose-dependent manner following treatment with compound A3. Moreover, compound A3 inhibited the viral replication by acting on the virus entry stage. In summary, this study led to the discovery of 2-aryl-isoindolin-1-ones as a promising scaffold with potent anti-EV-A71 activities, which deserves further in-depth studies.
Highlights
Hand, foot and mouth disease (HFMD) is a seasonal epidemic infectious disease that mainly affects children under five years old [1,2]
Anti-EV-A71 activity was evaluated in Vero cell cultures infected by different EV-A71 clinical isolates
Preliminary structure–activity relationship (SAR) studies suggested that 2-substitutedphenyl-isoindolin-1-one is an important pharmacophore for anti-EV-A71 activity
Summary
Foot and mouth disease (HFMD) is a seasonal epidemic infectious disease that mainly affects children under five years old [1,2]. Its common features include symptoms of pyrexia, vomiting, papulovesicular rash on the palms and soles, and oral ulcers in infected children. (EV-A71), which was first isolated in 1969, is an enterovirus belonging to the Picornaradae family and is considered to be the main pathogen involved in HFMD [3,4]. EV-A71 infection can cause severe nervous system diseases including encephalitis, myoclonic jerks, neurogenic pulmonary edema and even death [2,5]. EV-A71 infection has been a public health problem in China since the domestic outbreak in 2008, which led to nearly 490,000 reported cases [6].
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