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Discovery and Optimization of 2,4-Diaminoquinazoline Derivatives as a New Class of Potent Dengue Virus Inhibitors

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journal contribution
posted on 12.04.2012, 00:00 by Bo Chao, 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
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 (EC50 = 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 (EC50 = 2.8 nM, SI > 1000) and an excellent pharmacokinetic profile.