Potential of bisbenzimidazole-analogs toward metronidazole-resistant Trichomonas vaginalis isolates
© 2017 John Wiley & Sons A/S..
A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to C10 H20 ) 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:90 |
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| Enthalten in: |
Chemical biology & drug design - 90(2017), 4 vom: 10. Okt., Seite 489-495 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Korosh, Travis [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.09.2017 Date Revised 25.09.2017 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/cbdd.12972 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM269865756 |
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| 520 | |a © 2017 John Wiley & Sons A/S. | ||
| 520 | |a A bisoxyphenylene-bisbenzimidazole series with increasing aliphatic chain length (CH2 to C10 H20 ) 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 | ||
| 650 | 4 | |a Editorial | |
| 650 | 4 | |a Trichomonas vaginalis | |
| 650 | 4 | |a bisbenzimidazoles | |
| 650 | 4 | |a minimum inhibition concentration assay | |
| 650 | 4 | |a pyruvate:ferredoxin oxidoreductase | |
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| 700 | 1 | |a Bujans, Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Morada, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Karaalioglu, Canan |e verfasserin |4 aut | |
| 700 | 1 | |a Vanden Eynde, Jean Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Mayence, Annie |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Tien L |e verfasserin |4 aut | |
| 700 | 1 | |a Yarlett, Nigel |e verfasserin |4 aut | |
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