Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1977-1981 |
| Number of pages | 5 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 19 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2009 |
| Externally published | Yes |
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Keywords
- HIV-1 attachment inhibitor
- HIV-1 entry inhibitor
- HIV-1 gp120 inhibitor
- HIV-1 inhibitor
ASJC Scopus subject areas
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry
- Biochemistry
Cite this
Inhibitors of HIV-1 attachment. Part 2 : An initial survey of indole substitution patterns. / Meanwell, Nicholas A.; Wallace, Owen B.; Fang, Haiquan; Wang, Henry; Deshpande, Milind; Wang, Tao; Yin, Zhiwei; Zhang, Zhongxing; Pearce, Bradley C.; James, Jennifer; Yeung, Kap Sun; Qiu, Zhilei; Kim Wright, J. J.; Yang, Zheng; Zadjura, Lisa; Tweedie, Donald L.; Yeola, Suresh; Zhao, Fang; Ranadive, Sunanda; Robinson, Brett A.; Gong, Yi Fei; Wang, Hwei Gene Heidi; Blair, Wade S.; Shi, Pei-Yong; Colonno, Richard J.; Lin, Pin fang.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 7, 01.04.2009, p. 1977-1981.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Inhibitors of HIV-1 attachment. Part 2
T2 - An initial survey of indole substitution patterns
AU - Meanwell, Nicholas A.
AU - Wallace, Owen B.
AU - Fang, Haiquan
AU - Wang, Henry
AU - Deshpande, Milind
AU - Wang, Tao
AU - Yin, Zhiwei
AU - Zhang, Zhongxing
AU - Pearce, Bradley C.
AU - James, Jennifer
AU - Yeung, Kap Sun
AU - Qiu, Zhilei
AU - Kim Wright, J. J.
AU - Yang, Zheng
AU - Zadjura, Lisa
AU - Tweedie, Donald L.
AU - Yeola, Suresh
AU - Zhao, Fang
AU - Ranadive, Sunanda
AU - Robinson, Brett A.
AU - Gong, Yi Fei
AU - Wang, Hwei Gene Heidi
AU - Blair, Wade S.
AU - Shi, Pei-Yong
AU - Colonno, Richard J.
AU - Lin, Pin fang
PY - 2009/4/1
Y1 - 2009/4/1
N2 - 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.
AB - 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.
KW - HIV-1 attachment inhibitor
KW - HIV-1 entry inhibitor
KW - HIV-1 gp120 inhibitor
KW - HIV-1 inhibitor
UR - http://www.scopus.com/inward/record.url?scp=61849171237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=61849171237&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2009.02.040
DO - 10.1016/j.bmcl.2009.02.040
M3 - Article
VL - 19
SP - 1977
EP - 1981
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 7
ER -