A survey of core replacements in indole-based HIV-1 attachment inhibitors

Tao Wang, Owen B. Wallace, Zhongxing Zhang, Haiquan Fang, Zhong Yang, Brett A. Robinson, Timothy P. Spicer, Yi Fei Gong, Wade S. Blair, Pei-Yong Shi, Pin Fang Lin, Milind Deshpande, Nicholas A. Meanwell, John F. Kadow

Research output: Contribution to journalArticle

Abstract

Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp 113 in gp120, the antiviral potency of several analogues met or exceeded that of 3, demonstrating that engaging Asp 113 is not a prerequisite for potent antiviral activity.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - Jan 1 2019

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Antiviral Agents
HIV-1
CD4 Antigens
Capsid Proteins
Amides
Topography
Derivatives
Surveys and Questionnaires
indole

Keywords

  • Attachment Inhibitor
  • Azaindole
  • Bicyclic
  • Heteroaryl
  • Heterocycle
  • HIV-1
  • Indole
  • Replacement
  • Tricyclic

ASJC Scopus subject areas

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

Cite this

A survey of core replacements in indole-based HIV-1 attachment inhibitors. / Wang, Tao; Wallace, Owen B.; Zhang, Zhongxing; Fang, Haiquan; Yang, Zhong; Robinson, Brett A.; Spicer, Timothy P.; Gong, Yi Fei; Blair, Wade S.; Shi, Pei-Yong; Lin, Pin Fang; Deshpande, Milind; Meanwell, Nicholas A.; Kadow, John F.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.

Research output: Contribution to journalArticle

Wang, T, Wallace, OB, Zhang, Z, Fang, H, Yang, Z, Robinson, BA, Spicer, TP, Gong, YF, Blair, WS, Shi, P-Y, Lin, PF, Deshpande, M, Meanwell, NA & Kadow, JF 2019, 'A survey of core replacements in indole-based HIV-1 attachment inhibitors' Bioorganic and Medicinal Chemistry Letters. https://doi.org/10.1016/j.bmcl.2019.03.018
Wang, Tao ; Wallace, Owen B. ; Zhang, Zhongxing ; Fang, Haiquan ; Yang, Zhong ; Robinson, Brett A. ; Spicer, Timothy P. ; Gong, Yi Fei ; Blair, Wade S. ; Shi, Pei-Yong ; Lin, Pin Fang ; Deshpande, Milind ; Meanwell, Nicholas A. ; Kadow, John F. / A survey of core replacements in indole-based HIV-1 attachment inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2019.
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