4‑Substituted-2-Thiazole\nAmides as Viral Replication\nInhibitors of Alphaviruses

2-(Methylthio)-<i>N</i>-(4-(naphthalen-2-yl)thiazol-2-yl)nicotinamide <b>1</b> was identified as an inhibitor against Chikungunya virus\n(CHIKV) with good antiviral activity [EC<sub>50</sub> = 0.6 μM;\nEC<sub>90</sub> = 0.93 μM and viral titer reduction (VTR) of\n6.9 logs at 10 μM concentration] with no observed cytotoxicity\n(CC<sub>50</sub> = 132 μM) in normal human dermal fibroblast\n(NHDF) cells. Structure–activity relationship (SAR) studies\nto further improve the potency, efficacy, and drug-like properties\nof <b>1</b> led to the discovery of a new potent inhibitor <i>N</i>-(4-(3-((4-cyanophenyl)amino)phenyl)thiazol-2-yl)-2-(methylthio)nicotinamide <b>26</b>, which showed a VTR of 8.7 logs at 10 μM against\nCHIKV and an EC<sub>90</sub> of 0.45 μM with considerably improved\nMLM stability (<i>t</i><sub>1/2</sub> = 74 min) as compared\nto <b>1</b>. Mechanism of action studies show that <b>26</b> inhibits alphavirus replication by blocking subgenomic viral RNA\ntranslation and structural protein synthesis. The <i>in vivo</i> efficacy studies of compound <b>26</b> on CHIKV infection\nin mice are reported.