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. 2012 Oct 25;55(20):8582-7.
doi: 10.1021/jm300612z. Epub 2012 Oct 16.

(S)-N-(2,5-Dimethylphenyl)-1-(quinoline-8-ylsulfonyl)pyrrolidine-2-carboxamide as a small molecule inhibitor probe for the study of respiratory syncytial virus infection

Blake P Moore  1 , Dong Hoon Chung, Daljit S Matharu, Jennifer E Golden, Clinton Maddox, Lynn Rasmussen, James W Noah, Melinda I Sosa, Subramaniam Ananthan, Nichole A Tower, E Lucile White, Fuli Jia, Thomas E Prisinzano, Jeffrey Aubé, Colleen B Jonsson, William E Severson
Affiliations

(S)-N-(2,5-Dimethylphenyl)-1-(quinoline-8-ylsulfonyl)pyrrolidine-2-carboxamide as a small molecule inhibitor probe for the study of respiratory syncytial virus infection

Blake P Moore et al. J Med Chem. .

Abstract

A high-throughput, cell-based screen was used to identify chemotypes as inhibitors for human respiratory syncytial virus (hRSV). Optimization of a sulfonylpyrrolidine scaffold resulted in compound 5o that inhibited a virus-induced cytopathic effect in the entry stage of infection (EC₅₀ = 2.3 ± 0.8 μM) with marginal cytotoxicity (CC₅₀ = 30.9 ± 1.1 μM) and reduced viral titer by 100-fold. Compared to ribavirin, sulfonylpyrrolidine 5o demonstrated an improved in vitro potency and selectivity index.

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Figures

Figure 1
Figure 1
Structure of ribavirin 1
Figure 2
Figure 2
Shaded regions of hit compound 2 optimized by structure-activity relationships.
Figure 3
Figure 3
Comparison of ribavirin with analogs 5b, 5o and 5t in a time of addition assay.
Scheme 1
Scheme 1. Chemical Synthesis of Sulfonylpyrrolidine Analogs
Reagents and conditions: (a) L-proline, 10% aq. K2CO3, THF, 50 °C, 5 h, then 3N HCl; (b) DIPEA, HATU, substituted aniline, DMF, rt, 2 h.
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