Optimization of small-molecule inhibitors of influenza virus polymerase: from thiophene-3-carboxamide to polyamido scaffolds.
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-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.
Department of Chemistry, Biology and Biotechnology, University of Perugia , 06123 Perugia, Italy.
Susan
S
Lepri
Giulio
G
Nannetti
Giulia
G
Muratore
Gabriele
G
Cruciani
Renzo
R
Ruzziconi
Beatrice
B
Mercorelli
Giorgio
G
Palù
Arianna
A
Loregian
Laura
L
Goracci
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology
D000998:Antiviral Agents; D013876:Thiophenes; D012324:RNA-Dependent RNA Polymerase