Identification and Structure-Activity Relationships of Diarylhydrazides as Novel Potent and Selective Human Enterovirus Inhibitors

Journal of Medicinal Chemistry
Xin HanHai-Bing Zhou

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.

References

Mar 1, 1974·The Journal of Infectious Diseases·N J SchmidtH H Ho
May 1, 1983·Antimicrobial Agents and Chemotherapy·R J PhillpottsV B Tagart
May 9, 1997·Journal of Medicinal Chemistry·F VictorW A Spitzer
Mar 31, 2000·Bioorganic & Medicinal Chemistry Letters·Z SuiD C Argentieri
May 14, 2005·Journal of Virology·George A BelovEllie Ehrenfeld
May 6, 2006·Antiviral Research·Amy K Patick
Jun 28, 2008·Bioorganic & Medicinal Chemistry·Chih-Jung KuoPo-Huang Liang
Feb 25, 2009·Antimicrobial Agents and Chemotherapy·Armando M De PalmaJohan Neyts
Jun 23, 2009·Nature Medicine·Seiya YamayoshiSatoshi Koike
Jun 23, 2009·Nature Medicine·Yorihiro NishimuraHiroyuki Shimizu
Jul 15, 2009·Experimental Biology and Medicine·Yu-Wen LinShun-Hua Chen
Sep 25, 2009·Journal of Clinical Microbiology·Sheng-Wen HuangJen-Ren Wang
Nov 21, 2009·Journal of Medicinal Chemistry·Leire AguadoMaría-Jesús Pérez-Pérez
Nov 21, 2009·Journal of Biomedical Science·Jing-Yi LinShin-Ru Shih
Jul 6, 2010·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Edmond MaShuk Kwan Chuang
Oct 19, 2010·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Yan WuVincent T K Chow
Nov 5, 2010·Chemical & Pharmaceutical Bulletin·Xing-yue JiZhuo-rong Li
Apr 29, 2011·Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi·Chien-Hui HsuLi-Min Huang
Feb 7, 2012·European Journal of Medicinal Chemistry·Leire AguadoMaría-Jesús Pérez-Pérez
Mar 3, 2012·Science·Pavel PlevkaMichael G Rossmann
Jun 2, 2012·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Hongxia NiGuangwen Cao
Dec 25, 2012·Antiviral Research·Luqing ShangZheng Yin
Jan 22, 2013·Antimicrobial Agents and Chemotherapy·Rachel UlfertsFrank J M van Kuppeveld
Mar 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Pavel PlevkaMichael G Rossmann
Apr 9, 2013·Environmental Science & Technology·Min JinJunwen Li
Jun 29, 2013·Journal of Medicinal Chemistry·Kai SeehaferChristian D Klein
Jul 31, 2013·Antimicrobial Agents and Chemotherapy·Hilde M van der SchaarFrank J M van Kuppeveld
Jan 1, 2014·Antiviral Research·Yaxin WangZihe Rao
Jan 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Pavel PlevkaMichael G Rossmann
Feb 11, 2014·Nature Structural & Molecular Biology·Luigi De ColibusDavid I Stuart
Feb 1, 2011·Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi·Lieh-Bang Liou, Wan-Ju Chao
Feb 3, 2015·Cell Reports·Jeroen R P M StratingFrank J M van Kuppeveld
Feb 19, 2015·Antimicrobial Agents and Chemotherapy·Yaxin WangZihe Rao

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Citations

Aug 28, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jih Ru HwuJohan Neyts
Aug 5, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yu-Ting LiaoShun-Hua Chen
Sep 23, 2021·Chemical Biology & Drug Design·Shivali Sharma, Divya Utreja

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