title: Discovery and optimization of 2,4-diaminoquinazoline derivatives as a new class of potent dengue virus inhibitors.
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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chao
authors.forename: Xian-Kun
authors.initials: XK
authors.lastname: Tong
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: De-Wen
authors.initials: DW
authors.lastname: Li
authors.forename: Pei-Lan
authors.initials: PL
authors.lastname: He
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Garcia
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Zeng
authors.forename: An-Hui
authors.initials: AH
authors.lastname: Gao
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
authors.forename: Michael
authors.initials: M
authors.lastname: Jacobs
authors.forename: Ralf
authors.initials: R
authors.lastname: Altmeyer
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Zuo
authors.forename: You-Hong
authors.initials: YH
authors.lastname: Hu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D057166:High-Throughput Screening Assays; D006801:Humans; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012093:Replicon / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C574639:5-tert-butoxyquinazoline-2,4-diamine; D000998:Antiviral Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D011799:Quinazolines