title: Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia.
abstract: Giardia lambliais an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstratedin vivoandin vitroPrior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representativeG. lambliastrains showed a wide spectrum ofin vitroactivities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing >100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasisin vivoThese findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Wan Jung
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Korthals
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Suhua
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Le
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Kalisiak
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: K Barry
authors.initials: KB
authors.lastname: Sharpless
authors.affiliation: Department of Chemistry, Dana and David Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, California, USA.
authors.forename: Valery V
authors.initials: VV
authors.lastname: Fokin
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California, USA leckmann@ucsd.edu.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D057930:Click Chemistry / Q000379:methods*; D016829:Giardia lamblia / Q000187:drug effects*; D009581:Nitrofurans / Q000737:chemistry* / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D000981:Antiprotozoal Agents; D009581:Nitrofurans; D011758:Pyrroles; D013844:Thiazoles
keywords: antimicrobial agents; drug screening