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.
Trimeris, Inc., 3500 Paramount Parkway, Morrisville, North Carolina 27560, USA. rongjian.lu@sequoiapharma.com
Rong-Jian
RJ
Lu
John A
JA
Tucker
Tatiana
T
Zinevitch
Olga
O
Kirichenko
Vitalii
V
Konoplev
Svetlana
S
Kuznetsova
Sergey
S
Sviridov
Jason
J
Pickens
Sagun
S
Tandel
Enugurthi
E
Brahmachary
Yang
Y
Yang
Jian
J
Wang
Stephanie
S
Freel
Shelly
S
Fisher
Alana
A
Sullivan
Jiying
J
Zhou
Sherry
S
Stanfield-Oakley
Michael
M
Greenberg
Dani
D
Bolognesi
Brian
B
Bray
Barney
B
Koszalka
Peter
P
Jeffs
Alisher
A
Khasanov
You-An
YA
Ma
Cynthia
C
Jeffries
Changhui
C
Liu
Tatiana
T
Proskurina
Tong
T
Zhu
Alexander
A
Chucholowski
Rongshi
R
Li
Connie
C
Sexton
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