Inhibitors of HIV-1 attachment. Part 4: A study of the effect of piperazine substitution patterns on antiviral potency in the context of indole-based derivatives.
4-Fluoro- and 4-methoxy-1-(4-benzoylpiperazin-1-yl)-2-(1H-indol-3-yl)ethane-1,2-dione (2 and 3, respectively) have been characterized as potent inhibitors of HIV-1 attachment that interfere with the interaction of viral gp120 with the host cell receptor CD4. As part of an effort to understand fundamental aspects of this pharmacophore, discovered originally using a high throughput cell-based screen, modification and substitution of the piperazine ring was examined in the context of compounds 6a-ah. The piperazine ring was shown to be a critical element of the HIV-1 attachment inhibiting pharmacophore, acting as a scaffold to deploy the indole glyoxamide and benzamide in a topographical relationship that complements the binding site on gp120.
Wang
Tao
T
Department of Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Tao.Wang@bms.com
Kadow
John F
JF
Zhang
Zhongxing
Z
Yin
Zhiwei
Z
Gao
Qi
Q
Wu
Dedong
D
Parker
Dawn DiGiugno
DD
Yang
Zheng
Z
Zadjura
Lisa
L
Robinson
Brett A
BA
Gong
Yi-Fei
YF
Spicer
Timothy P
TP
Blair
Wade S
WS
Shi
Pei-Yong
PY
Yamanaka
Gregory
G
Lin
Pin-Fang
PF
Meanwell
Nicholas A
NA
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053585:Virus Attachment / Q000187:drug effects*
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D007211:Indoles; D010879:Piperazines; C514793:gp120 protein, Human immunodeficiency virus 1