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

2-(Methylthio)--(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide was identified as an inhibitor against Chikungunya virus (CHIKV) with good antiviral activity [EC = 0.6 μM; EC = 0.93 μM and viral titer reduction (VTR) of 6.9 logs at 10 μM concentration] with no observed cytotoxicity (CC = 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 led to the discovery of a new potent inhibitor -(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide , which showed a VTR of 8.7 logs at 10 μM against CHIKV and an EC of 0.45 μM with considerably improved MLM stability ( = 74 min) as compared to . Mechanism of action studies show that inhibits alphavirus replication by blocking subgenomic viral RNA translation and structural protein synthesis. The efficacy studies of compound on CHIKV infection in mice are reported.