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Design and Synthesis of Quinolizidine Derivatives as Influenza Virus and HIV-1 Inhibitors

[ Vol. 28 , Issue. 24 ]

Author(s):

Zhao Dang, Lei Zhu, Lan Xie, Kuo-Hsiung Lee, Faisal Malik, Zhijun Li, Li Huang* and Chin-Ho Chen*   Pages 4995 - 5003 ( 9 )

Abstract:


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.

Keywords:

Aloperine, privileged scaffold, influenza A virus, HIV-1, quinolizidine derivatives, HIV-1 inhibitors.

Affiliation:

Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 19104, Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 19104, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710



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