Synthesis and Structure–Activity Relationship (SAR) Studies of Novel Pyrazolopyridine Derivatives as Inhibitors of Enterovirus Replication

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 structure–activity
relationship 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.