Quinazolinone Compounds Have Potent Antiviral Activity against Zika and Dengue Virus

Dengue (DENV) and Zika (ZIKV) viruses are important human
pathogens,
causing ∼100 million symptomatic infections each year. These
infections carry a 20-fold increased incidence of serious neurological
diseases, such as microcephaly in newborns (for ZIKV) and Guillain-Barré
syndrome. Moreover, DENV can develop serious and possibly life-threatening
dengue hemorrhagic fever in certain patients. Patients recovered from
one of the four serotypes of DENV are still susceptible to other serotypes
with a higher likelihood of serious disease because of antibody-dependent
enhancement. Except for mosquito control, there have been no antiviral
drugs to prevent and treat ZIKV/DENV infections. Phenotypic screening
found that 2,3,6-trisubstituted quinazolinone compounds are novel
inhibitors of ZIKV replication. Fifty-four analogues were synthesized,
and their structure–activity relationships are discussed. Additional
testing shows that compounds 22, 27, and 47 exhibited broad and potent activities against ZIKV and
DENV with EC50 values as low as 86 nM with no significant
cytotoxicity to mammalian cells.