Optimization of Small-Molecule Inhibitors of Influenza Virus Polymerase: From Thiophene-3-Carboxamide to Polyamido Scaffolds

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• 作者：Susan Lepri ; Giulio Nannetti ; Giulia Muratore ; Gabriele Cruciani ; Renzo Ruzziconi ; Beatrice Mercorelli ; Giorgio Pal霉 ; Arianna Loregian ; Laura Goracci
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 22, 2014
• 年：2014
• 卷：57
• 期：10
• 页码：4337-4350
• 全文大小：516K
• 年卷期：v.57,no.10(May 22, 2014)
• ISSN：1520-4804

文摘

Influenza virus infections represent a serious concern to public health, being characterized by high morbidity and significant mortality. To date, compounds targeting the viral ion-channel M2 or the viral neuraminidase are the drugs available for treatment of influenza, but the emergence of drug-resistant viral mutants renders the search for novel targets and their possible inhibitors a major priority. Recently, we demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein鈥損rotein disruption by small molecules, with thiophene-3-carboxamide derivatives emerging as promising candidates for the development of new anti-influenza drugs with broad-spectrum activity. Here, we report a further dissection of the thiophene-3-carboxamide structure. By using a GRID molecular interaction field (MIF)-based scaffold-hopping approach, more potent and nontoxic polyamido derivatives were identified, highlighting a new space in the chemical variability of RdRP inhibitors. Finally, a possible pharmacophoric model highlighting the key features required for RdRP inhibition is proposed.