Synthesis and electrochemistry of 2-ethenyl and 2-ethanyl derivatives of 5-nitroimidazole and antimicrobial activity against Giardia lamblia.
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.
Valdez
Carlos A
CA
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Tripp
Jonathan C
JC
Miyamoto
Yukiko
Y
Kalisiak
Jaroslaw
J
Hruz
Petr
P
Andersen
Yolanda S
YS
Brown
Sabrina E
SE
Kangas
Karina
K
Arzu
Leo V
LV
Davids
Barbara J
BJ
Gillin
Frances D
FD
Upcroft
Jacqueline A
JA
Upcroft
Peter
P
Fokin
Valery V
VV
Smith
Diane K
DK
Sharpless
K Barry
KB
Eckmann
Lars
L
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
D000981:Antiprotozoal Agents; D009593:Nitroimidazoles; D008795:Metronidazole; C052587:4-nitroimidazole