Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns.
The effects of introducing simple halogen, alkyl, and alkoxy substituents to the 4, 5, 6 and 7 positions of 1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione, an inhibitor of the interaction between HIV gp120 and host cell CD4 receptors, on activity in an HIV entry assay was examined. Small substituents at C-4 generally resulted in increased potency whilst substitution at C-7 was readily tolerated and uniformly produced more potent HIV entry inhibitors. Substituents deployed at C-6 and, particularly, C-5 generally produced a modest to marked weakening of potency compared to the prototype. Small alkyl substituents at N-1 exerted minimal effect on activity whilst increasing the size of the alkyl moiety led to progressively reduced inhibitory properties. These studies establish a basic understanding of the indole element of the HIV attachment inhibitor pharmacophore.
Meanwell
Nicholas A
NA
Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. nicholas.meanwell@bms.com
Wallace
Owen B
OB
Fang
Haiquan
H
Wang
Henry
H
Deshpande
Milind
M
Wang
Tao
T
Yin
Zhiwei
Z
Zhang
Zhongxing
Z
Pearce
Bradley C
BC
James
Jennifer
J
Yeung
Kap-Sun
KS
Qiu
Zhilei
Z
Kim Wright
J J
JJ
Yang
Zheng
Z
Zadjura
Lisa
L
Tweedie
Donald L
DL
Yeola
Suresh
S
Zhao
Fang
F
Ranadive
Sunanda
S
Robinson
Brett A
BA
Gong
Yi-Fei
YF
Wang
Hwei-Gene Heidi
HG
Spicer
Timothy P
TP
Blair
Wade S
WS
Shi
Pei-Yong
PY
Colonno
Richard J
RJ
Lin
Pin-Fang
PF
D000818:Animals; D002460:Cell Line; D004285:Dogs; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D053585:Virus Attachment / Q000187:drug effects*
D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D007211:Indoles