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Design and Synthesis of Human Immunodeficiency Virus Entry Inhibitors: Sulfonamide as an Isostere for the α-Ketoamide Group

2007; American Chemical Society; Volume: 50; Issue: 26 Linguagem: Inglês

10.1021/jm070650e

1520-4804

Rong-Jian Lu, John A. Tucker, Tatiana Zinevitch, Olga G. Kirichenko, Vitalii E. Konoplev, Svetlana Kuznetsova, С. И. Свиридов, Jason C. Pickens, Sagun Tandel, Enugurthi Brahmachary, Yang Yang, Jian Wang, Stephanie A. Freel, Shelly Fisher, Alana Sullivan, Jiying Zhou, Sherry Stanfield‐Oakley, Michael Greenberg, Dani P. Bolognesi, Brian L. Bray, Barney Koszalka, Peter W. Jeffs, Alisher Khasanov, You-An Ma, Cynthia Jeffries, Changhui Liu, Tatiana Proskurina, Tong Zhu, Alexander Chucholowski, Rongshi Li, Connie J. Sexton,

Pneumocystis jirovecii pneumonia detection and treatment

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.