4‑Substituted-2-Thiazole Amides as Viral Replication Inhibitors of Alphaviruses

2-(Methylthio)-N-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide 1 was identified as an inhibitor against Chikungunya virus
(CHIKV) with good antiviral activity [EC50 = 0.6 μM;
EC90 = 0.93 μM and viral titer reduction (VTR) of
6.9 logs at 10 μM concentration] with no observed cytotoxicity
(CC50 = 132 μM) in normal human dermal fibroblast
(NHDF) cells. Structure–activity relationship (SAR) studies
to further improve the potency, efficacy, and drug-like properties
of 1 led to the discovery of a new potent inhibitor N-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide 26, which showed a VTR of 8.7 logs at 10 μM against
CHIKV and an EC90 of 0.45 μM with considerably improved
MLM stability (t1/2 = 74 min) as compared
to 1. Mechanism of action studies show that 26 inhibits alphavirus replication by blocking subgenomic viral RNA
translation and structural protein synthesis. The in vivo efficacy studies of compound 26 on CHIKV infection
in mice are reported.