title: Antiparasitic lethality of sulfonamidebenzamides in kinetoplastids.
abstract: A sulfonamidebenzamide series was assessed for anti-kinetoplastid parasite activity based on structural similarity to the antiparasitic drug, nifurtimox. Through structure-activity optimization, derivatives with limited mammalian cell toxicity and increased potency toward African trypanosomes and Leishmania promastigotes were developed. Compound 22 had the best potency against the trypanosome (EC50=0.010μM) while several compounds showed ∼10-fold less potency against Leishmania promastigotes without impacting mammalian cells (EC50>25μM). While the chemotype originated from an unrelated optimization program aimed at selectively activating an apoptotic pathway in mammalian cancer cells, our preliminary results suggest that a distinct mechanism of action from that observed in mammalian cells is responsible for the promising activity observed in parasites.
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Hackler
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Patrick
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Kahney
authors.affiliation: KU Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Flaherty
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA; Fiske Drug Discovery Laboratory, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Sharlow
authors.affiliation: Eukaryotic Pathogens Innovation Center, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: KU Specialized Chemistry Center, University of Kansas, Lawrence, KS 66047, USA. Electronic address: jennifer.golden@wisc.edu.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Golden
mesh_terms: D000977:Antiparasitic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007891:Leishmania / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D000977:Antiparasitic Agents; D001549:Benzamides; D013449:Sulfonamides
keywords: African sleeping sickness; Antiparasitic; Leishmaniasis; Sulfonamide