Benzophenone derivatives: a novel series of potent and selective inhibitors of human immunodeficiency virus type 1 reverse transcriptase.
A series of benzophenone derivatives has been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (RT) and the growth of HIV-1 in MT-4 cells. Through the use of the structure-activity relationships within this series of compounds and computational chemistry techniques, a binding conformation is proposed. The SAR also indicated that the major interactions of 1h with the RT enzyme are through hydrogen bonding of the amide and benzophenone carbonyls and pi-orbital interactions with the benzophenone nucleus and an aromatic function separated from the benzophenone by a suitable spacer group. The crystal structure of compound 1h has been determined. A number of compounds with potent inhibitory activity against HIV-1 RT and HIV in cellular assays at levels comparable with AZT and our efforts to identify a metabolically stable analogue are described.
Wyatt
P G
PG
Medicinal Chemistry Department, Glaxo Research and Development Limited, Glaxo Medicines Research Centre, Stevenage, Herts, U.K.
Bethell
R C
RC
Cammack
N
N
Charon
D
D
Dodic
N
N
Dumaitre
B
B
Evans
D N
DN
Green
D V
DV
Hopewell
P L
PL
Humber
D C
DC
D001577:Benzophenones / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
D001577:Benzophenones; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase