Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors

A benzo[6]­annulene,
4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)
benzamide (1a), was identified as an inhibitor against
Chikungunya virus (CHIKV)
with antiviral activity EC90 = 1.45 μM and viral
titer reduction (VTR) of 2.5 log at 10 μM with no observed cytotoxicity
(CC50 = 169 μM) in normal human dermal fibroblast
cells. Chemistry efforts to improve potency, efficacy, and drug-like
properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity
(EC90 = 270 nM and VTR of 4.5 log at 10 μM) and improved
liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the
nsP3 macrodomain. Further mechanism of action studies showed compounds
working through inhibition of human dihydroorotate dehydrogenase in
addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed
in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage
pathway.