期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 10, 页码 4337-4350出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500300r
关键词
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资金
- Italian Ministry of Health
- Istituto Superiore Sanita, Progetto Finalizzato
- ESCMID Research Grant
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 I I demonstrated that the viral RNA-dependent RNA polymerase (RdRP) complex can be an optimal target of protein protein 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.
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