Synthesis and Anti-HCV Activity of 4‑Hydroxyamino α‑Pyranone Carboxamide Analogues

High genetic variability in hepatitis C virus (HCV), emergence of drug resistant viruses and side effects demand the requirement for development of new scaffolds to show an alternate mechanism. Herein, we report discovery of new scaffold <b>I</b> based on 4-hydroxyamino α-pyranone carboxamide as promising anti-HCV agents. A comprehensive structure–activity relationship (SAR) was explored with several newly synthesized compounds. In all promising compounds (<b>17</b>–<b>19</b>, <b>21</b>–<b>22</b>, <b>24</b>–<b>25</b>, and <b>49</b>) with EC₅₀ ranging 0.15 to 0.40 μM, the aryl group at C-6 position of α-pyranone were unsubstituted. In particular, <b>25</b> demonstrated potential anti-HCV activity with EC₅₀ of 0.18 μM in cell based HCV replicon system with lower cytotoxicity (CC₅₀ > 20 μM) and provided a new scaffold for anti-HCV drug development. Further investigations, including biochemical characterization, are yet to be performed to elucidate its possible mode of action