Design and Synthesis of Quinolizidine Derivatives as Influenza Virus and HIV-1 Inhibitors.
BACKGROUND: We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low μM concentrations. OBJECTIVE: The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. METHODS: Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti- influenza virus infection of MDCK cell assay, respectively. RESULTS: Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti-influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost anti-HIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 μM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. CONCLUSION: The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.
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Related Subject Headings
- Quinolizidines
- Orthomyxoviridae
- Medicinal & Biomolecular Chemistry
- Madin Darby Canine Kidney Cells
- HIV-1
- Dogs
- Antiviral Agents
- Animals
- 3404 Medicinal and biomolecular chemistry
- 3214 Pharmacology and pharmaceutical sciences
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Quinolizidines
- Orthomyxoviridae
- Medicinal & Biomolecular Chemistry
- Madin Darby Canine Kidney Cells
- HIV-1
- Dogs
- Antiviral Agents
- Animals
- 3404 Medicinal and biomolecular chemistry
- 3214 Pharmacology and pharmaceutical sciences