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Potential of bisbenzimidazole‐analogs toward metronidazole‐resistant Trichomonas vaginalis isolates
Author(s) -
Korosh Travis,
Bujans Emmanuel,
Morada Mary,
Karaalioglu Canan,
Vanden Eynde Jean Jacques,
Mayence Annie,
Huang Tien L.,
Yarlett Nigel
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12972
Subject(s) - metronidazole , trichomonas vaginalis , benzimidazole , chemistry , ferredoxin , microbiology and biotechnology , stereochemistry , antibiotics , biology , biochemistry , organic chemistry , enzyme
A bisoxyphenylene‐bisbenzimidazole series with increasing aliphatic chain length ( CH 2 to C 10 H 20 ) 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‐1 H ‐benzimidazole, displayed a 5.5‐fold lower minimum inhibitory concentration ( MIC ) toward T. vaginalis isolate 085 than metronidazole under aerobic growth conditions, (26 μ m compared to 145 μ m ). 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.