Aix-Marseille Univ, Institut de Chimie Radicalaire , Laboratoire de Pharmacochimie Radicalaire , UMR 7273 CNRS, 27 Boulevard Jean Moulin , 13385 Marseille , Cedex 05 , France.
KU Leuven-University of Leuven , Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy , B-3000 Leuven , Belgium.
J Med Chem. 2018 Sep 27;61(18):8402-8416. doi: 10.1021/acs.jmedchem.8b00931. Epub 2018 Sep 7.
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 < 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.
鼻病毒（RV）与许多肺部疾病的恶化有关，从而增加了高危人群的发病率和/或死亡率。不幸的是，RV 基因型的多样性是开发鼻病毒复制抑制剂的主要障碍。在目前的研究中，我们开发了一系列新型吡唑衍生物，它们能够有效抑制鼻病毒的复制。化合物 10e 和 10h 作为鼻病毒感染的早期抑制剂，对 RV-A 和 RV-B 种具有广谱活性（EC<0.1 μM）。我们还评估了这些有前途的化合物出现耐药性的动态及其体外遗传毒性。分子对接实验阐明了与药物结合口袋残基相互作用的药效团元素。
