Enteroviruses are small, non-enveloped RNA viruses responsible for poliomyelitis, encephalitis, acute heart failure or severe hepatitis in newborns. In the United States recent outbreaks of coxsackievirus B1 (CVB1) infections and coxsackievirus A6 served as reminders of the ongoing threat raised by these pathogens. No antiviral agents are currently approved to treat enterovirus infections. Extensive studies in pursuit of candidate antiviral agents have targeted the viral capsid, the virus-encoded RNA polymerase and proteases, and other viral proteins involved in replication. By applying a rapid, live virus assay to identify enterovirus inhibitors from nearly 86,000 compounds, a novel group of antienteroviral compounds: 1H-pyrazolo[3,4-b]pyridine-4-carboxamides were identified. The target of these compounds was identified as the viral 2C protein, which plays a role in RNA replication. In order to establish a good structure−activity relationship (SAR) and identify the most ‘druglike’ members of this pharmacophore, a series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the SAR was obtained by utilizing the variation of four positions, namely, N1, C6, C4, and linker unit. From the screened analogues, the inhibitors with the highest selectivity indices at 50% inhibition of viral replication (SI50) were those with isopropyl at the N1 position and thiophenyl-2-yl unit at C6 position. Furthermore, the C4 position offered the greatest potential for improvement because many different N-aryl groups had better antiviral activities and compatibilities than the lead compound JX001. For example, JX040 with a 2-pyridyl group was the analogue with the most potent activity against non-polio enteroviruses, and JX025, possessing a 3-sulfamoylphenyl moiety, had the best activity against polioviruses. In addition, analogue JX037, possessing a novel pyrazolopyridine heterocycle, was also shown to have good antienteroviral activity, which further enlarges the compound space for antienteroviral drug design.

Synthesis and structure−activity relationship (SAR) studies of novel pyrazolopyridine derivatives as inhibitors of enterovirus replication

2019 Fall National Meeting

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