Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group

Rong Jian Lu, John A. Tucker, Tatiana Zinevitch, Olga Kirichenko, Vitalii Konoplev, Svetlana Kuznetsova, Sergey Sviridov, Jason Pickens, Sagun Tandel, Enugurthi Brahmachary, Yang Yang, Jian Wang, Stephanie Freel, Shelly Fisher, Alana Sullivan, Jiying Zhou, Sherry Stanfield-Oakley, Michael Greenberg, Dani Bolognesi, Brian BrayBarney Koszalka, Peter Jeffs, Alisher Khasanov, You An Ma, Cynthia Jeffries, Changhui Liu, Tatiana Proskurina, Tong Zhu, Alexander Chucholowski, Rongshi Li, Connie Sexton

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The crystal structures of many tertiary α-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the α-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.

Original languageEnglish (US)
Pages (from-to)6535-6544
Number of pages10
JournalJournal of Medicinal Chemistry
Volume50
Issue number26
DOIs
StatePublished - Dec 27 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Lu, R. J., Tucker, J. A., 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., ... Sexton, C. (2007). Design and synthesis of human immunodeficiency virus entry inhibitors: Sulfonamide as an isostere for the α-ketoamide group. Journal of Medicinal Chemistry, 50(26), 6535-6544. https://doi.org/10.1021/jm070650e