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Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection
Journal article   Open access   Peer reviewed

Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection

Wenquan Yu, Tina Gill, Lijuan Wang, Yanming Du, Hong Ye, Xiaowang Qu, Ju-Tao Guo, Andrea Cuconati, Kang Zhao, Timothy M Block, …
Journal of medicinal chemistry, v 55(13), pp 6061-6075
12 Jul 2012
DOI: https://doi.org/10.1021/jm300171v
PMID: 22712544
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc3395807View
Accepted (AM) Open Open Access (License Unspecified)

Abstract

1-Deoxynojirimycin - analogs & derivatives alpha-Glucosidases Animals Antiviral Agents - chemical synthesis Antiviral Agents - chemistry Antiviral Agents - pharmacology Biological Availability Cattle Cell Line Cricetinae Dengue - drug therapy Dengue - virology Dengue Virus - drug effects Diarrhea Viruses, Bovine Viral - drug effects Glycoside Hydrolase Inhibitors Humans Male Microbial Sensitivity Tests Rats Rats, Sprague-Dawley Structure-Activity Relationship Viral Envelope Proteins - analysis Viral Envelope Proteins - immunology Virus Replication - drug effects
We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Chemistry, Medicinal
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