Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.
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.
Lu
Rong-Jian
RJ
Trimeris, Inc., 3500 Paramount Parkway, Morrisville, North Carolina 27560, USA. rongjian.lu@sequoiapharma.com
Tucker
John A
JA
Zinevitch
Tatiana
T
Kirichenko
Olga
O
Konoplev
Vitalii
V
Kuznetsova
Svetlana
S
Sviridov
Sergey
S
Pickens
Jason
J
Tandel
Sagun
S
Brahmachary
Enugurthi
E
Yang
Yang
Y
Wang
Jian
J
Freel
Stephanie
S
Fisher
Shelly
S
Sullivan
Alana
A
Zhou
Jiying
J
Stanfield-Oakley
Sherry
S
Greenberg
Michael
M
Bolognesi
Dani
D
Bray
Brian
B
Koszalka
Barney
B
Jeffs
Peter
P
Khasanov
Alisher
A
Ma
You-An
YA
Jeffries
Cynthia
C
Liu
Changhui
C
Proskurina
Tatiana
T
Zhu
Tong
T
Chucholowski
Alexander
A
Li
Rongshi
R
Sexton
Connie
C
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; C451732:BMS 806; D010879:Piperazines