title: Identification and Structure-Activity Relationships of Diarylhydrazides as Novel Potent and Selective Human Enterovirus Inhibitors.
abstract: Enterovirus 71 (EV71) plays an important role in hand-foot-and-mouth disease. In this study, a series of diarylhydrazide analogues was synthesized, and the systematic exploration of SAR led to potent enterovirus inhibitors, of which compound 15 exhibits significant improvements in inhibition potency with an EC50 value of 0.02 μM against EV71. It is very interesting that this class of diarylhydrazides exhibits activities against a series of human enteroviruses at the picomolar level, including EV71 and Coxsackieviruses B1 (CVB1), CVB2, CVB3, CVB4, CVB5, and CVB6 (EC50 as low as 0.5 nM). Compared with the reference antienterovirus drug 1 (enviroxime) and known inhibitor 5 (WIN 51711), the four highly selective compounds 15, 27, 41 and 47 inhibited EV71 replication with EC50 values of 0.17-0.02 μM and SI values in a range of 978.4-12338. A preliminary mechanistic study indicated that VP1 might be the target site for this type of compound.
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences , Wuhan 430071, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.affiliation: College of Life Sciences, Wuhan University , Wuhan 430072, China.
authors.forename: Ningyuan
authors.initials: N
authors.lastname: Sun
authors.affiliation: College of Life Sciences, Wuhan University , Wuhan 430072, China.
authors.forename: Haoming
authors.initials: H
authors.lastname: Wu
authors.affiliation: College of Life Sciences, Wuhan University , Wuhan 430072, China.
authors.forename: Deyin
authors.initials: D
authors.lastname: Guo
authors.affiliation: College of Life Sciences, Wuhan University , Wuhan 430072, China.
authors.forename: Po
authors.initials: P
authors.lastname: Tien
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences , Wuhan 430071, China.
authors.forename: Chune
authors.initials: C
authors.lastname: Dong
authors.affiliation: College of Life Sciences, Wuhan University , Wuhan 430072, China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology, Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, Wuhan University School of Pharmaceutical Sciences , Wuhan 430071, China.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004770:Enterovirus / Q000737:chemistry / Q000187:drug effects*; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014709:Vero Cells; D015678:Viral Structural Proteins / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; D006834:Hydrazines; D015678:Viral Structural Proteins