Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication

Laurène Da Costa, Els Scheers, Antonio Coluccia, Adriano Casulli, Manon Roche, Carole Di Giorgio, Johan Neyts, Thierry Terme, Roberto Cirilli, Giuseppe La Regina, Romano Silvestri, Carmen Mirabelli, Patrice Vanelle

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Abstract

Rhinoviruses (RVs) have been linked to exacerbations of many pulmonary diseases, thus increasing morbidity and/or mortality in subjects at risk. Unfortunately, the wide variety of RV genotypes constitutes a major hindrance for the development of Rhinovirus replication inhibitors. In the current investigation, we have developed a novel series of pyrazole derivatives that potently inhibit the Rhinovirus replication. Compounds 10e and 10h behave as early stage inhibitors of Rhinovirus infection with a broad-spectrum activity against RV-A and RV-B species (EC50 < 0.1 μM). We also evaluate the dynamics of the emerging resistance of these promising compounds and their in vitro genotoxicity. Molecular docking experiments shed light on the pharmacophoric elements interacting with residues of the drug-binding pocket.

Original languageEnglish
Pages (from-to)8402-8416
Number of pages15
JournalJournal of Medicinal Chemistry
Volume61
Issue number18
DOIs
Publication statusPublished - Sep 27 2018

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Da Costa, L., Scheers, E., Coluccia, A., Casulli, A., Roche, M., Di Giorgio, C., Neyts, J., Terme, T., Cirilli, R., La Regina, G., Silvestri, R., Mirabelli, C., & Vanelle, P. (2018). Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication. Journal of Medicinal Chemistry, 61(18), 8402-8416. https://doi.org/10.1021/acs.jmedchem.8b00931