title: Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents.
abstract: New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50 <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate.
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Suryadevara
authors.forename: Kishore Kumar
authors.initials: KK
authors.lastname: Racherla
authors.forename: Srinivas
authors.initials: S
authors.lastname: Olepu
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.forename: Hari Babu
authors.initials: HB
authors.lastname: Tatipaka
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Arif
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Planer
authors.forename: Galina I
authors.initials: GI
authors.lastname: Lepesheva
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Buckner
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D007093:Imidazoles / Q000494:pharmacology*; D008958:Models, Molecular; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D058888:14-alpha Demethylase Inhibitors; D007093:Imidazoles
keywords: CYP51; Chagas disease; Dialkylimidazole; Sterol 14-alpha demethylase; Trypanosoma cruzi