Journal
CHEMMEDCHEM
Volume 9, Issue 7, Pages 1522-1533Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201300505
Keywords
alkaloids; antiviral agents; dengue virus; lycorine; structure-activity relationships
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Funding
- Novartis Institute for Tropical Diseases (NITD), Singapore
- National Natural Science Foundation of China [21202087]
- National Basic Research Program of China (973 program) [2013CB911104]
- Fundamental Research Funds for the Central Universities [65124002]
- Specialized Research Fund for the Doctoral Program of Higher Education from the Ministry of Education of China [20120031120049]
- Tianjin Science and Technology Program [13JCYBJC24300, 13JCQNJC13100]
- Scientific Research Starting Foundation of Returned Overseas Chinese Scholars from the Ministry of Education of China
- 111 Project of the Ministry of Education of China [B06005]
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Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1-acetyllycorine exhibited the most potent anti-DENV activity (EC50=0.4 mu m) with a reduced cytotoxicity (CC50>300 mu m), which resulted in a selectivity index (CC50/EC50) of more than 750. The ketones 1-acetyl-2-oxolycorine (EC50=1.8 mu m) and 2-oxolycorine (EC50=0.5 mu m) also exhibited excellent antiviral activities with low cytotoxicity. Structure-activity relationships for the lycorine derivatives against DENV are discussed. A three-dimensional quantitative structure-activity relationship model was established by using a comparative molecular-field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties.
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