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

Bo Chao (1) , Xian-Kun Tong (1) , Wei Tang (1) , De-Wen Li (1) , Pei-Lan He (1) , Jean-Michel Garcia (2) , Li-Min Zeng (1) , An-Hui Gao (1) , Li Yang (1) , Jia Li (1) , Fa-Jun Nan (1) , Michael Jacobs (3, 4) , Ralf Altmeyer (2) , Jian-Ping Zuo (1) , You-Hong Hu (1)

1 State Key Laboratory of Drug Research
2 Centre de recherche Université de Hong-Kong-Pasteur
3 Royal Free
4 University College Medical School

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.

Domains: Virology

Bo Chao, Xian-Kun Tong, Wei Tang, De-Wen Li, Pei-Lan He, et al.. Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors.. Journal of Medicinal Chemistry, 2012, 55 (7), pp.3135-43. ⟨10.1021/jm2015952⟩. ⟨pasteur-00698608⟩