Design and synthesis of lipophilic phospharamidate d4T-MP prodrugs expressing high potency against HIV in cell culture

Structural determinants for in vitro activity and QSAR

A Q Siddiqui, C McGuigan, C Ballatore, F Zuccotto, I H Gilbert, E De Clercq, J Balzarini

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives, All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to-the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.

Original languageEnglish
Pages (from-to)4122-4128
Number of pages7
JournalJournal of Medicinal Chemistry
Volume42
Issue number20
DOIs
Publication statusPublished - 7 Oct 1999

Keywords

  • Amides
  • Anti-HIV Agents
  • Cell Line
  • Dideoxynucleotides
  • HIV-1
  • HIV-2
  • Phosphoric Acids
  • Prodrugs
  • Stavudine
  • Structure-Activity Relationship
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

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title = "Design and synthesis of lipophilic phospharamidate d4T-MP prodrugs expressing high potency against HIV in cell culture: Structural determinants for in vitro activity and QSAR",
abstract = "A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives, All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to-the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.",
keywords = "Amides, Anti-HIV Agents, Cell Line, Dideoxynucleotides, HIV-1, HIV-2, Phosphoric Acids, Prodrugs, Stavudine, Structure-Activity Relationship, Journal Article, Research Support, Non-U.S. Gov't",
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year = "1999",
month = "10",
day = "7",
doi = "10.1021/jm9807104",
language = "English",
volume = "42",
pages = "4122--4128",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
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Design and synthesis of lipophilic phospharamidate d4T-MP prodrugs expressing high potency against HIV in cell culture : Structural determinants for in vitro activity and QSAR. / Siddiqui, A Q; McGuigan, C; Ballatore, C; Zuccotto, F; Gilbert, I H; De Clercq, E; Balzarini, J.

In: Journal of Medicinal Chemistry, Vol. 42, No. 20, 07.10.1999, p. 4122-4128.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Design and synthesis of lipophilic phospharamidate d4T-MP prodrugs expressing high potency against HIV in cell culture

T2 - Structural determinants for in vitro activity and QSAR

AU - Siddiqui, A Q

AU - McGuigan, C

AU - Ballatore, C

AU - Zuccotto, F

AU - Gilbert, I H

AU - De Clercq, E

AU - Balzarini, J

PY - 1999/10/7

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N2 - A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives, All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to-the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.

AB - A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives, All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to-the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.

KW - Amides

KW - Anti-HIV Agents

KW - Cell Line

KW - Dideoxynucleotides

KW - HIV-1

KW - HIV-2

KW - Phosphoric Acids

KW - Prodrugs

KW - Stavudine

KW - Structure-Activity Relationship

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1021/jm9807104

M3 - Article

VL - 42

SP - 4122

EP - 4128

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -