title: 2,3,4-Trihydroxybenzyl-hydrazide analogues as novel potent coxsackievirus B3 3C protease inhibitors.
abstract: Human coxsackievirus B3 (CVB3) 3C protease plays an essential role in the viral replication of CVB3, which is a non-enveloped and positive single-stranded RNA virus belonging to Picornaviridae family, causing acute viral myocarditis mainly in children. During optimization based on SAR studies of benserazide (3), which was reported as a novel anti-CVB3 3C(pro) agent from a screening of compound libraries, the 2,3,4-trihydroxybenzyl moiety of 3 was identified as a key pharmacophore for inhibitory activity against CVB3 3C(pro). Further optimization was performed by the introduction of various aryl-alkyl substituted hydrazide moieties instead of the serine moiety of 3. Among the optimized compounds, 11Q, a 4-hydroxyphenylpentanehydrazide derivative, showed the most potent inhibitory activity (IC50 = 0.07 μM). Enzyme kinetics studies indicated that 11Q exhibited a mixed inhibitory mechanism of action. The antiviral activity against CVB3 was confirmed using the further derived analogue (14b) with more cell permeable valeryl ester group at the 2,3,4-trihydroxy moiety.
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju, 500-712, Republic of Korea.
authors.forename: Bo-Kyoung
authors.initials: BK
authors.lastname: Kim
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju, 500-712, Republic of Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.affiliation: Division of Cardiology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, Republic of Korea.
authors.forename: Eun-Seok
authors.initials: ES
authors.lastname: Jeon
authors.affiliation: Division of Cardiology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, Republic of Korea.
authors.forename: Eun-Seon
authors.initials: ES
authors.lastname: Ju
authors.affiliation: The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Republic of Korea. Electronic address: lakjeong@snu.ac.kr.
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology (GIST), 123, Cheomdangwagi-ro, Buk-gu, Gwangju, 500-712, Republic of Korea; Department of Biomedical Science and Engineering (BMSE), Gwangju Institute of Science and Technology (GIST), 123 Cheomdangwagi-ro, Buk-gu, Gwangju, 500-712, Republic of Korea. Electronic address: yongchul@gist.ac.kr.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology; D002648:Child; D003546:Cysteine Endopeptidases; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology*; D010539:Permeability; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000998:Antiviral Agents; D001555:Benzene Derivatives; D006834:Hydrazines; D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D014764:Viral Proteins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases
keywords: Benserazide; Cosxackievirus B3; CosxackievirusB3 3C protease inhibitor; Picornavirus family