Produção Nacional
Revisado por pares
Evaluation of Coumarin and Neoflavone Derivatives as HCV NS 5 B Polymerase Inhibitors
2013; Wiley; Volume: 81; Issue: 5 Linguagem: Inglês
10.1111/cbdd.12105
ISSN1747-0285
AutoresDaniel Brian Nichols, Raquel A. C. Leão, Amartya Basu, Maksim Chudayeu, Paula de F. de Moraes, Tanaji T. Talele, Paulo R. R. Costa, Neerja Kaushik‐Basu,
Tópico(s)Fungal Plant Pathogen Control
ResumoCoumarins and coumestans represent an important family of compounds with diverse pharmacological properties. We recently identified coumestans as novel inhibitors of hepatitis C virus NS 5 B polymerase and predicted their binding in thumb pocket‐1 ( TP ‐1) of NS 5 B . As the coumarins are structurally related to coumestans by virtue of their common A ‐ and B ‐rings, we postulated them to also exhibit similar binding interaction with NS 5 B and inhibit its polymerase function. We therefore investigated 24 coumarin and neoflavone derivatives as candidate NS 5 B inhibitors and identified 14 compounds inhibiting NS 5 B polymerase activity with IC 50 values between 17 and 63 μ m . Of these, the newly synthesized 6,8‐diallyl‐5,7‐dihydroxycoumarin ( 8a ) was produced in three steps in high chemical yield from floroglucinol and found to be the most potent of this series, exhibiting activity similar to the reference coumestan LQB ‐ 34 . The binding site of 8a was mapped to TP ‐1 of NS 5 B by counter screening against P 495 L NS 5 B mutant, employed as a screen for TP ‐1 site binders. NS 5 B ‐ TP ‐1‐ 8a interaction map provided insight into 8a binding and offered clues for future SAR optimization.
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