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

作者：Lu Rong Jian^*; Tucker John A; Zinevitch Tatiana; Kirichenko Olga; Konoplev Vitalii; Kuznetsova Svetlana; Sviridov Sergey; Pickens Jason; Tandel Sagun; Brahmachary Enugurthi; Yang Yang; Wang Jian; Freel Stephanie; Fisher Shelly; Sullivan Alana; Zhou Jiying; Stanfield Oakley Sherry; Greenberg Michael; Bolognesi Dani; Bray Brian; Koszalka Barney; Jeffs Peter; Khasanov Alisher; Ma You An; Jeffries Cynthia; Liu Changhui; Proskurina Tatiana; Zhu Tong

来源：Journal of Medicinal Chemistry, 2007, 50(26): 6535-6544.

DOI：10.1021/jm070650e

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.

• 出版日期2007-12-27