Structure based molecular design, synthesis and biological evaluation of α-pyrone analogs as anti-HSV agent

Several options for treating Herpes Simplex Virus type 1 and type 2 are available. However, non-specific inhibition and drug resistance warrants the discovery of new anti-herpetic compounds with better therapeutic profile or different mode of action. The non-nucleoside inhibitors of HSV DNA polymerase target the site that is less important for the binding of a natural nucleoside or nucleoside inhibitors. In the present study, we have explored the possibility to find a new lead molecule based on α-pyrone analogs as non-nucleoside inhibitors using structure based modeling approach. The designed molecules were synthesized and evaluated for anti-HSV activity using MTT assay. The compound 5h with EC<SUB>50</SUB> 7.4 μg/ml and CC<SUB>50</SUB> 52.5 μg/ml was moderately active against HSV when compared to acyclovir. A plaque reduction assay was also carried out and results reveal that 5h is more effective against HSV-1 with better selective index of 12.8 than against HSV-2 (SI = 3.6). The synthesized compounds were also evaluated for anti-HIV activity, but none were active

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