title: Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates.
abstract: A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2to C10H20) containing a meta- (m) or para (p)-benzimidazole linkage to the phenylene ring was tested for ability to inhibit the growth of metronidazole-susceptible (C1) and metronidazole-refractory (085) Trichomonas vaginalis isolates under aerobic and anaerobic conditions. Compound 3m, 2,2'-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, displayed a 5.5-fold lower minimum inhibitory concentration (MIC) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 μm compared to 145 μm). A dose of 25 mg/kg per day for four days of compound 3m cured a subcutaneous mouse model infection using T. vaginalis isolates 286 (metronidazole susceptible) and 085 (metronidazole refractory). Compound 3m was weakly reduced by pyruvate:ferredoxin oxidoreductase, but unlike metronidazole was not dependent upon added ferredoxin. It is concluded from structure-activity relationships that there was no obvious trend based on the length of the central aliphatic chain, or the steric position of the bisbenzimidazole enabling prediction of biological activity. The compounds generally fulfill Lipinski's rile of five, indicating their potential as drug leads.
authors.affiliation: Department of Chemistry and Physical Sciences, Pace University, New York, NY, USA.|Haskins Laboratories, Pace University, New York, NY, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Korosh
authors.affiliation: Department of Chemistry and Physical Sciences, Pace University, New York, NY, USA.|Haskins Laboratories, Pace University, New York, NY, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bujans
authors.affiliation: Haskins Laboratories, Pace University, New York, NY, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Morada
authors.affiliation: Department of Chemistry and Physical Sciences, Pace University, New York, NY, USA.
authors.forename: Canan
authors.initials: C
authors.lastname: Karaalioglu
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Vanden Eynde
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Mayence
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Tien L
authors.initials: TL
authors.lastname: Huang
authors.affiliation: Department of Chemistry and Physical Sciences, Pace University, New York, NY, USA.|Haskins Laboratories, Pace University, New York, NY, USA.
authors.forename: Nigel
authors.identifier: http://orcid.org/0000-0002-7493-4346
authors.initials: N
authors.lastname: Yarlett
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D006690:Bisbenzimidazole / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008795:Metronidazole / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D014247:Trichomonas Vaginitis / Q000188:drug therapy*; D014246:Trichomonas vaginalis / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000981:Antiprotozoal Agents; D008795:Metronidazole; D006690:Bisbenzimidazole
keywords: 
  Trichomonas vaginalis
  ; bisbenzimidazoles; minimum inhibition concentration assay; pyruvate:ferredoxin oxidoreductase; subcutaneous assay