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Research ArticleArticle

Acetylenic Linkers in Lead Compounds: A Study of the Stability of the Propargyl-Linked Antifolates

Wangda Zhou, Kishore Viswanathan, Dennis Hill, Amy C. Anderson and Dennis L. Wright
Drug Metabolism and Disposition October 2012, 40 (10) 2002-2008; DOI: https://doi.org/10.1124/dmd.112.046870
Wangda Zhou
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Kishore Viswanathan
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Dennis Hill
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Amy C. Anderson
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Dennis L. Wright
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
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Abstract

Propargyl-linked antifolates that target dihydrofolate reductase are potent inhibitors of several species of pathogenic bacteria and fungi. This novel class of antifolates possesses a relatively uncommon acetylenic linker designed to span a narrow passage in the enzyme active site and join two larger functional domains. Because the use of alkyne functionality in drug molecules is limited, it was important to evaluate some key physicochemical properties of these molecules and specifically to assess the overall stability of the acetylene. Herein, we report studies on four compounds from our lead series that vary specifically in the environment of the alkyne. We show that the compounds are soluble, chemically stable in water, as well as simulated gastric and intestinal fluids with half-lives of approximately 30 min after incubation with mouse liver microsomes. Their primary in vitro route of metabolism involves oxidative transformations of pendant functionality with little direct alteration of the alkyne. Identification of several major metabolites indicated the formation of N-oxides; the rate of formation of these oxides was highly influenced by branching substitutions around the propargyl linker. On the basis of the lessons of these metabolic studies, a more advanced inhibitor was designed, synthesized, and shown to have increased (t1/2 = 65 min) metabolic stability while maintaining potent enzyme inhibition.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Allergy and Infectious Diseases Extramural Activities [Grants AI073375, AI065143]; and the National Institutes of Health National Institute of General Medical Sciences [Grant GM067542].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.046870.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    DHFR
    dihydrofolate reductase
    MIC
    minimal inhibition concentration
    HPLC
    high-performance liquid chromatography
    DMSO
    dimethyl sulfoxide
    ACN
    acetonitrile
    HPMC
    hydroxypropylmethylcellulose
    AUC
    area under the curve
    MLM
    mouse liver microsomes
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    CID
    collision-induced dissociation
    THF
    tetrahydrofuran.

  • Received May 22, 2012.
  • Accepted July 18, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

STABILITY AND THE PROPARGYL-LINKED ANTIFOLATES

Wangda Zhou, Kishore Viswanathan, Dennis Hill, Amy C. Anderson and Dennis L. Wright
Drug Metabolism and Disposition October 1, 2012, 40 (10) 2002-2008; DOI: https://doi.org/10.1124/dmd.112.046870

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Research ArticleArticle

STABILITY AND THE PROPARGYL-LINKED ANTIFOLATES

Wangda Zhou, Kishore Viswanathan, Dennis Hill, Amy C. Anderson and Dennis L. Wright
Drug Metabolism and Disposition October 1, 2012, 40 (10) 2002-2008; DOI: https://doi.org/10.1124/dmd.112.046870
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