title: Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia.
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 half-wave 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.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Valdez
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Tripp
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Kalisiak
authors.forename: Petr
authors.initials: P
authors.lastname: Hruz
authors.forename: Yolanda S
authors.initials: YS
authors.lastname: Andersen
authors.forename: Sabrina E
authors.initials: SE
authors.lastname: Brown
authors.forename: Karina
authors.initials: K
authors.lastname: Kangas
authors.forename: Leo V
authors.initials: LV
authors.lastname: Arzu
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Davids
authors.forename: Frances D
authors.initials: FD
authors.lastname: Gillin
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Upcroft
authors.forename: Peter
authors.initials: P
authors.lastname: Upcroft
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.forename: Diane K
authors.initials: DK
authors.lastname: Smith
authors.forename: K Barry
authors.initials: KB
authors.lastname: Sharpless
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D004351:Drug Resistance; D055664:Electrochemical Techniques / Q000379:methods*; D016829:Giardia lamblia / Q000187:drug effects*; D005873:Giardiasis / Q000188:drug therapy; D008795:Metronidazole / Q000494:pharmacology; D009593:Nitroimidazoles / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction
chemical_list: D000981:Antiprotozoal Agents; D009593:Nitroimidazoles; D008795:Metronidazole; C052587:4-nitroimidazole