Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns

Nicholas A. Meanwell; Owen B. Wallace; Haiquan Fang; Henry Wang; Milind Deshpande; Tao Wang; Zhiwei Yin; Zhongxing Zhang; Bradley C. Pearce; Jennifer James; Kap Sun Yeung; Zhilei Qiu; J. J. Kim Wright; Zheng Yang; Lisa Zadjura; Donald L. Tweedie; Suresh Yeola; Fang Zhao; Sunanda Ranadive; Brett A. Robinson; Yi Fei Gong; Hwei Gene Heidi Wang; Wade S. Blair; Pei Yong Shi; Richard J. Colonno; Pin fang Lin

doi:10.1016/j.bmcl.2009.02.040

Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns

Nicholas A. Meanwell, Owen B. Wallace, Haiquan Fang, Henry Wang, Milind Deshpande, Tao Wang, Zhiwei Yin, Zhongxing Zhang, Bradley C. Pearce, Jennifer James, Kap Sun Yeung, Zhilei Qiu, J. J. Kim Wright, Zheng Yang, Lisa Zadjura, Donald L. Tweedie, Suresh Yeola, Fang Zhao, Sunanda Ranadive, Brett A. RobinsonYi Fei Gong, Hwei Gene Heidi Wang, Wade S. Blair, Pei Yong Shi, Richard J. Colonno, Pin fang Lin

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

60 Scopus citations

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	https://doi.org/10.1016/j.bmcl.2009.02.040
State	Published - Apr 1 2009

Keywords

HIV-1 attachment inhibitor
HIV-1 entry inhibitor
HIV-1 gp120 inhibitor
HIV-1 inhibitor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2009.02.040

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Meanwell, N. A., Wallace, O. B., Fang, H., Wang, H., Deshpande, M., Wang, T., Yin, Z., Zhang, Z., Pearce, B. C., James, J., Yeung, K. S., Qiu, Z., Kim Wright, J. J., Yang, Z., Zadjura, L., Tweedie, D. L., Yeola, S., Zhao, F., Ranadive, S., ... Lin, P. F. (2009). Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns. Bioorganic and Medicinal Chemistry Letters, 19(7), 1977-1981. https://doi.org/10.1016/j.bmcl.2009.02.040

Meanwell, NA, Wallace, OB, Fang, H, Wang, H, Deshpande, M, Wang, T, Yin, Z, Zhang, Z, Pearce, BC, James, J, Yeung, KS, Qiu, Z, Kim Wright, JJ, Yang, Z, Zadjura, L, Tweedie, DL, Yeola, S, Zhao, F, Ranadive, S, Robinson, BA, Gong, YF, Wang, HGH, Blair, WS, Shi, PY, Colonno, RJ & Lin, PF 2009, 'Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 7, pp. 1977-1981. https://doi.org/10.1016/j.bmcl.2009.02.040

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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.",

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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.

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Inhibitors of HIV-1 attachment. Part 2: An initial survey of indole substitution patterns

Abstract

Keywords

ASJC Scopus subject areas

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