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

Laurène da Costa (1, 2) , Els Scheers (3) , Antonio Coluccia (4) , Alessia Rosetti (2) , Manon Roche (5, 2) , Carole Di Giorgio (6) , Johan Neyts (7) , Thierry Terme (2) , Roberto Cirilli (8) , Giuseppe La Regina (9) , Romano Silvestri (10) , Carmen Mirabelli , Patrice Vanelle (2)

1 UGA [2016-2019] - Université Grenoble Alpes [2016-2019]
2 ICR - Institut de Chimie Radicalaire
3 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
4 Dipartimento di Chimica e Tecnologie del Farmaco
5 APHM - Assistance Publique - Hôpitaux de Marseille
6 IMBE - Institut méditerranéen de biodiversité et d'écologie marine et continentale
7 Rega Institute for Medical Research [Leuven, België]
8 Dipartimento del Farmaco
9 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
10 Department of Drug Chemistry and Technologies = Dipartimento di Chimica et Tecnologie del Farmaco [Roma]

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 (EC 50 < 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.

Keywords: RV; VP1 protein; capsid binder; chiral inhibitors; heterocycles

Domains: Chemical Sciences; Life Sciences [q-bio]

Laurène da Costa, Els Scheers, Antonio Coluccia, Alessia Rosetti, Manon Roche, et al.. Structure-Based Drug Design of Potent Pyrazole Derivatives against Rhinovirus Replication. Journal of Medicinal Chemistry, 2018, 61 (18), pp.8402-8416. ⟨10.1021/acs.jmedchem.8b00931⟩. ⟨hal-02094656⟩