Nitroimidazole Derivatives. Relationship between Structure and Antitrichomonal Activity

Butler, Kyle V.; Howes, Harold L.; Lynch, Joseph E.; Pirie, D. K.

doi:10.1021/jm00317a030

Cited by 45 publications

(17 citation statements)

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“…1-Alkyl-5-nitroimidazoles 3 to 5 were prepared following methods described in the literature (2,13). Each product was completely characterized by 1 H and 13 C nuclear magnetic resonance and elemental analysis.…”

Section: Methodsmentioning

confidence: 99%

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Reactivity of Reduced [2Fe-2S] Ferredoxins Parallels Host Susceptibility to Nitroimidazoles

Vidakovic¹,

Crossnoe

Neidre

et al. 2003

Antimicrob Agents Chemother

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The kinetics of the electron transfer reaction between reduced [2Fe-2S] ferredoxins and select nitroimidazole antimicrobial agents is reported. The ferredoxins from the protozoan Trichomonas vaginalis and the cyanobacterium Anabaena sp. strain 7120 were studied because they are the proximal electron donors to nitroimidazoles in these two organisms with significantly different nitroimidazole susceptibilities. The rates of electron transfer from Anabaena ferredoxin to all nitroimidazoles were 1 to 2 orders of magnitude lower than for T. vaginalis ferredoxin. Quantitative structure-activity analysis of the kinetic data showed that the size of the alkyl substituent on the N-1 position of the imidazole ring strongly influenced the magnitude of the electron transfer rate constant. This implies that the distance between the iron-sulfur cluster and the nitro group of the imidazole is the critical variable in determining the rate of electron transfer. A correlation between the magnitude of the one-electron transfer rate constant with the susceptibility of the host organism to the cytotoxic effects of nitroimidazoles was also discovered. These results demonstrate that reductive activation is the most crucial step in determining the toxicity of nitroimidazoles. (2)] is a member of the nitroheterocycle class of antimicrobial compounds that also includes the nitroimidazole tinidazole and the nitrofuran nitrofurantoin. Metronidazole is a front-line antibiotic in use against a wide range of infectious species. For example, metronidazole is highly effective in treating trichomoniasis and is equally useful against other protozoal infections, including giardiasis and amebiasis (6). Further, metronidazole is the primary drug used to treat postoperative and other infections with anaerobic bacteria, including members of the genera Bacteroides, Fusobacterium, and Clostridium. In addition metronidazole is a component of the therapeutic regimen to eradicate Helicobacter pylori, which is responsible for the majority of cases of peptic ulcer disease and is a risk factor for gastric cancer (4).The importance of metronidazole in treating various infectious diseases and its unusually broad spectrum of activity have led to investigation of its mechanism of action. Most studies have focused on the activity of nitroimidazoles against the protozoan Trichomonas vaginalis, the causative organism of trichomoniasis in humans. Researchers initially believed that the drug inhibited hydrogenase, an enzyme involved in anaerobic carbohydrate metabolism (6). Further studies showed, however, that the ultimate target of the drug was DNA, and that nitroimidazoles not only inhibited DNA synthesis, but also degraded existing DNA (16). Labeling experiments implicated a radical intermediate as the agent responsible for DNA degradation. Within anaerobic cells nitroimidazoles were found to be reduced to radical anion species with the ability to initiate DNA degradation through abstraction of atoms of the nucleic acid backbone (5). The redox potential of nitroimid...

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Section: Methodsmentioning

confidence: 99%

“…Metronidazole [1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole (2)] is a member of the nitroheterocycle class of antimicrobial compounds that also includes the nitroimidazole tinidazole and the nitrofuran nitrofurantoin. Metronidazole is a front-line antibiotic in use against a wide range of infectious species.…”

mentioning

confidence: 99%

Reactivity of Reduced [2Fe-2S] Ferredoxins Parallels Host Susceptibility to Nitroimidazoles

Vidakovic¹,

Crossnoe

Neidre

et al. 2003

Antimicrob Agents Chemother

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“…1 would fit into one plot, indicating a standard biological effect (Hansch et al, 1968). However, the fact that a plateau is present in the curve shape clearly indicates that additional factors (primarily electronic) should be operating as well (Butler et al, 1967).…”

Section: Correlation Of Log P and Anti-parasitic Activitymentioning

confidence: 99%

Effect of the lipophilic parameter (log P) on the anti-parasitic activity of imidazo[1,2-a]pyridine derivatives

López‐Martínez¹,

Salgado-Zamora²,

Campos-Aldrete³

et al. 2011

Med Chem Res

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A number of imidazo[1,2-a]pyridine derivatives were selected and investigated in relation to antiparasitic (Trichomonas vaginalis) activity. After treatment with derivatives, biological activity was assessed by determination of the in vitro viability of cell cultures, using alamar blue as a metabolic indicator. A good correlation was found between the anti-parasitic activity and the partition coefficient log P determined experimentally on the tested compounds, which explained up to 84% of the measured activity. A favorable interval (0.9 ± 0.3 log P) was found for optimum biological response.

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“…THE antimicrobial nitroimidazole drugs, dimetridazole, metronidazole and tinidazole, are unusual in that they possess a wide spectrum of activity that has been reported to be limited to anaerobic bacteria and anaerobic protozoa (Prince et al, 1969;Edwards, Dye and Carne, 1973). Dimetridazole (1,2-dimethyl 5-nitroimidazole) was introduced to combat histomoniasis in poultry, but has been more recently used extensively in the prevention and treatment of swine dysentery (Griffin, 1972).…”

Section: T H E E F F E C T O F T H E N I T R O I M I D a Z O L E D R mentioning

confidence: 99%

The Effect of the Nitroimidazole Drug Dimetridazole on Microaerophilic Campylobacters

Fernie

Ware²,

Park

1977

Journal of Medical Microbiology

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Nitroimidazole Derivatives. Relationship between Structure and Antitrichomonal Activity

Cited by 45 publications

References 0 publications

Reactivity of Reduced [2Fe-2S] Ferredoxins Parallels Host Susceptibility to Nitroimidazoles

Reactivity of Reduced [2Fe-2S] Ferredoxins Parallels Host Susceptibility to Nitroimidazoles

Effect of the lipophilic parameter (log P) on the anti-parasitic activity of imidazo[1,2-a]pyridine derivatives

The Effect of the Nitroimidazole Drug Dimetridazole on Microaerophilic Campylobacters

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