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Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.

Publication ,  Journal Article
Lu, R-J; Tucker, JA; Zinevitch, T; Kirichenko, O; Konoplev, V; Kuznetsova, S; Sviridov, S; Pickens, J; Tandel, S; Brahmachary, E; Yang, Y ...
Published in: J Med Chem
December 27, 2007

The crystal structures of many tertiary alpha-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the alpha-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.

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Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

December 27, 2007

Volume

50

Issue

26

Start / End Page

6535 / 6544

Location

United States

Related Subject Headings

  • Virus Replication
  • Virus Internalization
  • Structure-Activity Relationship
  • Stereoisomerism
  • Piperazines
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • HIV-1
  • Drug Design
 

Citation

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Lu, R.-J., Tucker, J. A., Zinevitch, T., Kirichenko, O., Konoplev, V., Kuznetsova, S., … Sexton, C. (2007). Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group. J Med Chem, 50(26), 6535–6544. https://doi.org/10.1021/jm070650e
Lu, Rong-Jian, John A. Tucker, Tatiana Zinevitch, Olga Kirichenko, Vitalii Konoplev, Svetlana Kuznetsova, Sergey Sviridov, et al. “Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.J Med Chem 50, no. 26 (December 27, 2007): 6535–44. https://doi.org/10.1021/jm070650e.
Lu R-J, Tucker JA, Zinevitch T, Kirichenko O, Konoplev V, Kuznetsova S, et al. Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group. J Med Chem. 2007 Dec 27;50(26):6535–44.
Lu, Rong-Jian, et al. “Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.J Med Chem, vol. 50, no. 26, Dec. 2007, pp. 6535–44. Pubmed, doi:10.1021/jm070650e.
Lu R-J, Tucker JA, Zinevitch T, Kirichenko O, Konoplev V, Kuznetsova S, Sviridov S, Pickens J, Tandel S, Brahmachary E, Yang Y, Wang J, Freel S, Fisher S, Sullivan A, Zhou J, Stanfield-Oakley S, Greenberg M, Bolognesi D, Bray B, Koszalka B, Jeffs P, Khasanov A, Ma Y-A, Jeffries C, Liu C, Proskurina T, Zhu T, Chucholowski A, Li R, Sexton C. Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group. J Med Chem. 2007 Dec 27;50(26):6535–6544.
Journal cover image

Published In

J Med Chem

DOI

ISSN

0022-2623

Publication Date

December 27, 2007

Volume

50

Issue

26

Start / End Page

6535 / 6544

Location

United States

Related Subject Headings

  • Virus Replication
  • Virus Internalization
  • Structure-Activity Relationship
  • Stereoisomerism
  • Piperazines
  • Molecular Conformation
  • Models, Molecular
  • Medicinal & Biomolecular Chemistry
  • HIV-1
  • Drug Design