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

68 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

Access to Document

10.1016/j.bmcl.2009.02.040

Cite this

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

@article{ba481414aac04c14a2669fb997c88da6,

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

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.",

keywords = "HIV-1 attachment inhibitor, HIV-1 entry inhibitor, HIV-1 gp120 inhibitor, HIV-1 inhibitor",

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

year = "2009",

month = apr,

day = "1",

doi = "10.1016/j.bmcl.2009.02.040",

language = "English (US)",

volume = "19",

pages = "1977--1981",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "7",

}

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

C2 - 19251416

AN - SCOPUS:61849171237

SN - 0960-894X

VL - 19

SP - 1977

EP - 1981

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 7

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this