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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1977-1981
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number7
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

Fingerprint

HIV Fusion Inhibitors
HIV Envelope Protein gp120
CD4 Antigens
Halogens
Ethane
HIV-1
Assays
Substitution reactions
HIV
indole
alkoxyl radical
Surveys and Questionnaires

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

Meanwell, N. A., Wallace, O. B., Fang, H., Wang, H., Deshpande, M., Wang, T., ... 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

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 journalArticle

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, P-Y, 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
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. / Inhibitors of HIV-1 attachment. Part 2 : An initial survey of indole substitution patterns. In: Bioorganic and Medicinal Chemistry Letters. 2009 ; Vol. 19, No. 7. pp. 1977-1981.
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