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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • December 27, 2007

Published In

Volume / Issue

  • 50 / 26

Start / End Page

  • 6535 - 6544

PubMed ID

  • 18052117

Pubmed Central ID

  • 18052117

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm070650e

Language

  • eng

Conference Location

  • United States