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Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors.

Publication ,  Journal Article
Zhao, Y; Chen, C-H; Morris-Natschke, SL; Lee, K-H
Published in: Eur J Med Chem
April 5, 2021

Prior modification of betulinic acid (1), a natural product lead with promising anti-HIV activity, produced 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat, 3), the first-in-class HIV maturation inhibitor. After 3-resistant variants were found during Phase I and IIa clinical trials, further modification of 3 produced 4 with improved activity against wild-type and 3-resistant HIV-1. In continued efforts to optimize 1, 63 final products have now been designed, synthesized, and evaluated for anti-HIV-1 replication activity against HIV-1NL4-3 infected MT-4 cell lines. Five known and 21 new derivatives were as or more potent than 3 (EC50 0.065 μM), while eight new derivatives were as or more potent than 4 (EC50 0.019 μM). These derivatives feature expanded structural diversity and chemical space that may improve the antiviral activity and address the growing resistance crisis. Structure-Activity Relationship (SAR) correlations were thoroughly analyzed, and a 3D Quantitative SAR model with high predictability was constructed to facilitate further rational design and development of new potent derivatives.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

April 5, 2021

Volume

215

Start / End Page

113287

Location

France

Related Subject Headings

  • Small Molecule Libraries
  • Quantitative Structure-Activity Relationship
  • Pentacyclic Triterpenes
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV-1
  • Drug Design
  • Cell Line
  • Betulinic Acid
 

Citation

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Zhao, Y., Chen, C.-H., Morris-Natschke, S. L., & Lee, K.-H. (2021). Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors. Eur J Med Chem, 215, 113287. https://doi.org/10.1016/j.ejmech.2021.113287
Zhao, Yu, Chin-Ho Chen, Susan L. Morris-Natschke, and Kuo-Hsiung Lee. “Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors.Eur J Med Chem 215 (April 5, 2021): 113287. https://doi.org/10.1016/j.ejmech.2021.113287.
Zhao Y, Chen C-H, Morris-Natschke SL, Lee K-H. Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors. Eur J Med Chem. 2021 Apr 5;215:113287.
Zhao, Yu, et al. “Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors.Eur J Med Chem, vol. 215, Apr. 2021, p. 113287. Pubmed, doi:10.1016/j.ejmech.2021.113287.
Zhao Y, Chen C-H, Morris-Natschke SL, Lee K-H. Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors. Eur J Med Chem. 2021 Apr 5;215:113287.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

April 5, 2021

Volume

215

Start / End Page

113287

Location

France

Related Subject Headings

  • Small Molecule Libraries
  • Quantitative Structure-Activity Relationship
  • Pentacyclic Triterpenes
  • Molecular Structure
  • Medicinal & Biomolecular Chemistry
  • Humans
  • HIV-1
  • Drug Design
  • Cell Line
  • Betulinic Acid