In vitro antitrichomonal activity of water-soluble prodrug esters of metronidazole

Vermeersch, Hans; Remon, Jean Paul; Permentier, Dirk; Schacht, Etienne

doi:10.1016/0378-5173(90)90079-j

Cited by 9 publications

(3 citation statements)

References 15 publications

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“…The authors maintained that the phenylalanine (37) and leucine (39) prodrugs presented a higher intrinsic antitrichomonal activity Fig. (13) [57]. Fig.…”

Section: Metronidazole Prodrugsmentioning

confidence: 93%

A Prodrug Approach to Improve the Physico-Chemical Properties and Decrease the Genotoxicity of Nitro Compounds

Chin¹,

Bosquesi²,

Santos

2011

CPD

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In therapeutics research, the nitro compounds are part of an important group of drugs with multiple pharmacological activities. However, in drug design, the inclusion of a nitro group in a molecule changes the physico-chemical and electronic properties and is associated with increased mutagenicity and carcinogenicity. In addition, several studies have related the relationship between the antimicrobial and/or anti-protozoal activity and the mutagenic effect to reduction of the nitro group. This work reviews the toxicity of nitro compounds and shows how the use of prodrugs can increase the biological activity and decrease the genotoxicity of nitro compounds, without any modification in nitro reduction behavior, but rather by physico-chemical improvement. Examples are given of metronidazole and nitrofurazone prodrugs.

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“…The authors maintained that the phenylalanine (37) and leucine (39) prodrugs presented a higher intrinsic antitrichomonal activity Fig. (13) [57]. Fig.…”

Section: Metronidazole Prodrugsmentioning

confidence: 93%

A Prodrug Approach to Improve the Physico-Chemical Properties and Decrease the Genotoxicity of Nitro Compounds

Chin¹,

Bosquesi²,

Santos

2011

CPD

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“…hemisuccinate, hemiglutarate and hemimaleate was studied. However, those prodrugs showed limited stability in aqueous solution and were slowly and incompletely converted in-vivo to metronidazole (Larsen et al 1988 ;Vermeersch et al 1990). Alternatively, a water-soluble metronidazole phosphate ester prodrug with adequate chemical stability was reported by Cho et al (1982), but it was found that it was not rapidly or quantitatively converted to the parent drug in-vivo.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

Mahfouz

Hassan

2001

Journal of Pharmacy and Pharmacology

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A series of amino acid esters (3a-e) have been synthesized and evaluated as potential prodrugs of metronidazole with the aim of improving aqueous solubility and therapeutic efficacy. The aqueous solubility and the lipophilicity (expressed as the log P value) of metronidazole and its esters were investigated. In general the prodrugs revealed enhanced water solubility compared with metronidazole. N,N-diethylglycinate hydrochloride (3a) and 4-ethylpiperazinoacetate (3e) derivatives displayed higher aqueous solubility, which exceeded that of the parent drug by factors of approximately 140 and 100, respectively. All the esters revealed lower log P values than metronidazole except for the 4-phenylpiperazinoacetate derivative (3f), which was 6.5-times more lipophilic than metronidazole. The hydrolysis kinetics of the esters were studied in aqueous phosphate buffer (pH 7.4) and 80% human plasma at 37 degrees C. In all cases the hydrolysis followed pseudo-first-order kinetics and resulted in a quantitative reversion to metronidazole as evidenced by HPLC analysis. The prodrugs exhibited adequate chemical stability (half-life, t1/2, 4-16 h) in aqueous phosphate solution of pH 7.4. In 80% human plasma they were hydrolysed within a few minutesto metronidazole. The esters 3d (methylpiperazinoacetate derivative) and 3f were exempted since their t1/2 values were approximately 2.5 and 8.5 h, respectively. A comparative pH-rate profile study of N,N-diethylglycinate hydrochloride (3a) and 4-ethyl-piperazinoacetate (3e) derivatives in aqueous buffer solution over the pH range 2.2-10 was investigated. The results indicated that 3a showed marked stability at pH 2-6 followed by accelerated hydrolysis at pH 7.4. The basic ester 3e was found to be less stable at lower pH values but exhibited comparative stability at physiological pH. Moreover, in-vivo experiments in rabbits revealed a higher metronidazole plasma level with sustained release characteristics within the prodrug-treated animals (10- and 2.5-fold) as compared with the parent drug-treated group. In conclusion, the designed amino acid esters 3a and 3c-e might be considered as good candidates for water-soluble prodrug forms of metronidazole.

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“…It is advantageous to combine the antiprotozoal and anaerobic antibacterial action of metronidazole with antibacterial action of ciprofloxacin to form a broad spectrum chemotherapeutic agent (Werk et al, 1988;Mimura et al, 2002) by synthesizing a mutual prodrug. The alcoholic functional group in metronidazole is readily esterifiable and therefore, it appeared to be possible to obtain ester derivatives providing the desired improvement in water solubility (Vermeersch et al, 1990) and at the same time possessing a high susceptibility to undergo enzymatic hydrolysis in the body (Yang et al, 2001;Mahtouz et al,1998;Johnansen et al, 1984;Johnansen et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Degradation kinetics of metronidazole and its mutual prodrug with ciprofloxacin: a calorimetric analysis

Chadha¹,

Aggarwal²,

Jain³

et al. 2008

International Journal of Biological and Chemical Sciences

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Calorimetric technique has aroused considerable interest as a versatile tool in pharmaceutical industry and academia to provide useful information about thermodynamic and kinetic aspects of drug molecules. The present paper utilizes this technique to monitor the hydrolytic degradation of metronidazole and its prodrug with ciprofloxacin, i.e. 2-(2-methyl-5-nitroimidazol-1-yl)ethyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-quinoline-3-carboxylate. The synthesis of the present mutual prodrug was envisaged to combine the antiprotozoal and anaerobic antibacterial effects of metronidazole with antibacterial effects of ciprofloxacin. Heat flux microcalorimeter was used to determine the rate of heat evolved during the degradation of the drug and prodrug as a function of concentration, pH and temperature. In terms of enthalpy of hydrolysis the response is exothermic both for drug and prodrug. However, the absolute value of the enthalpy of reaction (∆ r H 0) is low for the prodrug. The degradation followed pseudo first order kinetics, showed marked stability at pH 3-7 followed by accelerated hydrolysis at higher pH, characteristic of general acid-base catalysis. The catalytic rate constant for hydrogen ion (k H) and hydroxyl ion (k OH) were found to be 0.413 and 526.1 M-1 h-1, respectively, at 318.15 K. The hydrolysis of the prodrug was found to be approximately 50-60 times faster than that of the drug. This may be attributed to the fact that hydrolysis of ester group in prodrug is assisted by keto group on the ciprofloxacin. However, there is no effect of protonation of nitrogen in piperazine ring in ciprofloxacin on the hydrolysis due to the distance from the ester moiety.

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In vitro antitrichomonal activity of water-soluble prodrug esters of metronidazole

Cited by 9 publications

References 15 publications

A Prodrug Approach to Improve the Physico-Chemical Properties and Decrease the Genotoxicity of Nitro Compounds

A Prodrug Approach to Improve the Physico-Chemical Properties and Decrease the Genotoxicity of Nitro Compounds

Synthesis, chemical and enzymatic hydrolysis, and bioavailability evaluation in rabbits of metronidazole amino acid ester prodrugs with enhanced water solubility

Degradation kinetics of metronidazole and its mutual prodrug with ciprofloxacin: a calorimetric analysis

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