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Optimization of small-molecule inhibitors of influenza virus polymerase: From thiophene-3-carboxamide to polyamido scaffolds

Lepri, Susan, Nannetti, Giulio, Muratore, Giulia, Cruciani, Gabriele, Ruzziconi, Renzo, Mercorelli, Beatrice, Palù, Giorgio, Loregian, Arianna and Goracci, Laura 2014. Optimization of small-molecule inhibitors of influenza virus polymerase: From thiophene-3-carboxamide to polyamido scaffolds. Journal of Medicinal Chemistry 57 (10) , p. 4337. 10.1021/jm500300r

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 16 October 2018
Last Modified: 17 Oct 2018 16:42
URI: http://orca.cf.ac.uk/id/eprint/115330

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