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

• Published in: Chemical biology & drug design 2017-10, Vol.90 (4), p.489-495
• Main Authors: Korosh, Travis, Bujans, Emmanuel, Morada, Mary, Karaalioglu, Canan, Vanden Eynde, Jean Jacques, Mayence, Annie, Huang, Tien L., Yarlett, Nigel
• Format: Article
• Language: English
• Subjects: Animals; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Bisbenzimidazole - analogs & derivatives; Bisbenzimidazole - pharmacology; Bisbenzimidazole - therapeutic use; bisbenzimidazoles; Cell Line, Tumor; Drug Resistance; Female; Humans; Metronidazole - pharmacology; Mice; Microbial Sensitivity Tests; minimum inhibition concentration assay; pyruvate:ferredoxin oxidoreductase; subcutaneous assay; Trichomonas vaginalis; Trichomonas vaginalis - drug effects; Trichomonas vaginalis - growth & development; Trichomonas Vaginitis - drug therapy
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12972

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.