Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates

Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates
Canan Karaalioglu, Mary Morada, Travis Korosh, Emmanuel Bujans, Jean Jacques Vanden Eynde, Nigel Yarlett, Tien L. Huang, Annie Mayence
A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to 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. A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to 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. Compound 3m, 2,2′-[α,ω-propanediylbis(oxy-1,3-phenylene)]bis-1H-benzimidazole, had good in vitro (9 μm) and in vivo (25 mg/kg per day for 4 days) activity. Compound 3m was reduced by pyruvate:ferredoxin oxidoreductase by a ferredoxin independent mechanism.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12972

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