Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia

Carlos A. Valdez, Jonathan C. Tripp, Yukiko Miyamoto, Jaroslaw Kalisiak, Petr Hruz, Yolanda S. Andersen, Sabrina E. Brown, Karina Kangas, Leo V. Arzu, Barbara J. Davids, Frances D. Gillin, Jacqueline A. Upcroft, Peter Upcroft, Valery V. Fokin, Diane K. Smith, K. Barry Sharpless, Lars Eckmann

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Infections with the diarrheagenic pathogen, Giardia lamblia, are commonly treated with the 5-nitroimidazole (5-NI) metronidazole (Mz), and yet treatment failures and Mz resistance occur. Using a panel of new 2-ethenyl and 2-ethanyl 5-NI derivatives, we found that compounds with a saturated bridge between the 5-NI core and a pendant ring system exhibited only modestly increased antigiardial activity and could not overcome Mz resistance. By contrast, olefins with a conjugated bridge connecting the core and a substituted phenyl or heterocyclic ring showed greatly increased antigiardial activity without toxicity, and several overcame Mz resistance and were more effective than Mz in a murine giardiasis model. Determination of the halfwave potential of the initial one-electron transfer by cyclic voltammetry revealed that easier redox activation correlated with greater antigiardial activity and capacity to overcome Mz resistance. These studies show the potential of combining systematic synthetic approaches with biological and electrochemical evaluations in developing improved 5-NI drugs.

Original languageEnglish
Pages (from-to)4038-4053
Number of pages16
JournalJournal of Medicinal Chemistry
Volume52
Issue number13
DOIs
Publication statusPublished - 9 Jul 2009
Externally publishedYes

Fingerprint

Electrochemistry
Giardia lamblia
Metronidazole
Giardiasis
Alkenes
Treatment Failure
Oxidation-Reduction
4-nitroimidazole
Electrons
Infection
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia. / Valdez, Carlos A.; Tripp, Jonathan C.; Miyamoto, Yukiko; Kalisiak, Jaroslaw; Hruz, Petr; Andersen, Yolanda S.; Brown, Sabrina E.; Kangas, Karina; Arzu, Leo V.; Davids, Barbara J.; Gillin, Frances D.; Upcroft, Jacqueline A.; Upcroft, Peter; Fokin, Valery V.; Smith, Diane K.; Sharpless, K. Barry; Eckmann, Lars.

In: Journal of Medicinal Chemistry, Vol. 52, No. 13, 09.07.2009, p. 4038-4053.

Research output: Contribution to journalArticle

Valdez, CA, Tripp, JC, Miyamoto, Y, Kalisiak, J, Hruz, P, Andersen, YS, Brown, SE, Kangas, K, Arzu, LV, Davids, BJ, Gillin, FD, Upcroft, JA, Upcroft, P, Fokin, VV, Smith, DK, Sharpless, KB & Eckmann, L 2009, 'Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia', Journal of Medicinal Chemistry, vol. 52, no. 13, pp. 4038-4053. https://doi.org/10.1021/jm900356n
Valdez, Carlos A. ; Tripp, Jonathan C. ; Miyamoto, Yukiko ; Kalisiak, Jaroslaw ; Hruz, Petr ; Andersen, Yolanda S. ; Brown, Sabrina E. ; Kangas, Karina ; Arzu, Leo V. ; Davids, Barbara J. ; Gillin, Frances D. ; Upcroft, Jacqueline A. ; Upcroft, Peter ; Fokin, Valery V. ; Smith, Diane K. ; Sharpless, K. Barry ; Eckmann, Lars. / Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia. In: Journal of Medicinal Chemistry. 2009 ; Vol. 52, No. 13. pp. 4038-4053.
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AU - Andersen, Yolanda S.

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AU - Upcroft, Jacqueline A.

AU - Upcroft, Peter

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