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

被引：37

作者：

Da Costa, Laurene ^{[1
]}

Scheers, Els ^{[2
]}

Coluccia, Antonio ^{[3
]}

Casulli, Adriano ^{[4
]}

Roche, Manon ^{[1
]}

Di Giorgio, Carole ^{[6
]}

Neyts, Johan ^{[2
]}

Terme, Thierry ^{[1
]}

Cirilli, Roberto ^{[5
]}

La Regina, Giuseppe ^{[3
]}

Silyestri, Romano ^{[3
]}

Mirabelli, Carmen ^{[2
]}

Vanelle, Patrice ^{[1
]}

机构：

[1] Aix Marseille Univ, Inst Chim Radicalaire, Lab Pharmacochim Radicalaire, UMR CNRS 7273, 27 Blvd Jean Moulin, F-13385 Marseille 05, France

[2] KU Leuven Univ Leuven, Dept Microbiol & Immunol, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Leuven, Belgium

[3] Sapienza Univ Rome, Dept Drug Chem & Technol, Lab Affiliated Ist Pasteur Italia Fdn Cenci Bolog, Piazzale Aldo Moro 5, I-00185 Rome, Italy

[4] Ist Super Sanita, Dept Infect Dis, European Reference Lab Parasites, WHO Collaborating Ctr Epidemiol Detect & Control, Viale Regina Elena 299, I-00161 Rome, Italy

[5] Ist Super Sanita, Ctr Nazl Controllo & Valutaz Farmaci, Viale Regina Elena 299, I-00161 Rome, Italy

[6] Aix Marseille Univ, CNRS, IRD, Avignon Univ,IMBE UMR 7263,Lab Mutagenese Environ, 27 Blvd Jean Moulin, F-13385 Marseille 05, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 18期

关键词：

OBSTRUCTIVE PULMONARY-DISEASE; ANTIVIRAL AGENTS; OTITIS-MEDIA; INHIBITORS; INFECTIONS; RECEPTOR; SUSCEPTIBILITY; EXACERBATIONS; OPTIMIZATION; ENTEROVIRUS;

D O I：

10.1021/acs.jmedchem.8b00931

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M). 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.

引用

页码：8402 / 8416

页数：15

共 51 条

[1]

[Anonymous], 2017, SMALL MOL DRUG DISC

[2] Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication [J].