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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection
Journal of medicinal chemistry, v 55(13), pp 6061-6075
12 Jul 2012
PMID: 22712544
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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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Details
- Title
- Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection
- Creators
- Wenquan Yu - Hepatitis B FoundationTina Gill - Drexel UniversityLijuan Wang - Drexel UniversityYanming Du - Hepatitis B FoundationHong Ye - Hepatitis B FoundationXiaowang Qu - Drexel UniversityJu-Tao Guo - Drexel UniversityAndrea Cuconati - Hepatitis B FoundationKang Zhao - Tianjin UniversityTimothy M Block - Drexel UniversityXiaodong Xu - Hepatitis B FoundationJinhong Chang - Drexel University
- Publication Details
- Journal of medicinal chemistry, v 55(13), pp 6061-6075
- Publisher
- American Chemical Society; Washington, DC
- Grant note
- R43 AI084267 / NIAID NIH HHS U01 AI061441 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000306259400006
- Scopus ID
- 2-s2.0-84863852895
- Other Identifier
- 991019167665904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal