Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors

  • J Med Chem. 2012 Apr 12;55(7):3135-43. doi: 10.1021/jm2015952.
Bo Chao  1 ,  Xian-Kun Tong ,  Wei Tang ,  De-Wen Li ,  Pei-Lan He ,  Jean-Michel Garcia ,  Li-Min Zeng ,  An-Hui Gao ,  Li Yang ,  Jia Li ,  Fa-Jun Nan ,  Michael Jacobs ,  Ralf Altmeyer ,  Jian-Ping Zuo ,  You-Hong Hu
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
PMID: 22448770 DOI: 10.1021/jm2015952
Abstract

The results of a high-throughput screening assay using the DENV-2 replicon showed that the 2,4-diaminoquinazoline derivative 4a has a high Dengue Virus inhibitory activity (EC(50) = 0.15 μM). A series of 2,4-diaminoquinazoline derivatives based on 4a as a lead compound were synthesized and subjected to structure-antidengue activity relationship studies. Among the series of 2,4-diaminoquinazoline derivative probed, 4o was observed to display both the highest Antiviral potency (EC(50) = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.

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