Metronidazole Derivatives Research Articles

Effect of the leaving group on the electrodic reduction mechanism of anti- Helicobacter pylori metronidazole derivatives, in aprotic and protic media

Because redox properties are central to bioreductive drug activity and selectivity, six 2-methyl-5-nitroimidazole, substituted at the N1-ethyl side chain with I, Br, Cl, OAc, OMs and NH 3 + were synthesized and submitted to cyclic voltammetry and electrolyses, in order to define their electrodic reduction mechanism, in aprotic [dimethylsulphoxide (DMSO)+0.1 mol l −1 tetrabuthylammonium perchlorate (TBAP)] and phosphate-buffered media, on glassy carbon electrode, in comparison with metronidazole. Three of these compounds, namely, the iodo, bromo and ammonium salt derivatives showed significant anti- Helicobacter pylori (strain resistant to metronidazole) activity. All the cyclic voltammograms (CV), in aprotic medium, are similar to the one for metronidazole, except for −I, -Br and -NH 3 + derivatives. The CV of the N1-ethylhalide (-I, -Br) 5-nitroimidazole showed more intense and irreversible first waves, even at faster sweep rates ( ν<2 V s −1). The absence of the first wave anodic counterpart, along with analysis of the dependence of E p, I p and other parameters with ν, and results from electrolysis (consumption of two electrons) showed the process to be an ECE system, with halide release, after uptake of two electrons. This behaviour represents a case of dissociative electron transfer (ET). For the ammonium salt, self-protonation mechanism was evident. The facility of reduction represented by the first wave potential and concerning the substituents is NH 3 +>Br>I>Cl>OMs>OH>OAc. In aqueous phosphate-buffered medium, the electrochemical behaviour of all the compounds is similar to the one of metronidazole, represented by a unique and irreversible 4e −/4H + wave. The order of reduction ease is NH 3 +>Br∼OMs>I>OH>OAc. Aprotic medium allows a better discrimination between the substituents. Concerning biological activity, despite the impossibility of establishing a correlation, it has been observed that the more electrophilic compounds showed better anti- H. pylori activity.

Multifunctional derivatives of metronidazole

The design and synthesis of a series of multifunctional metronidazole derivatives are described. The main series are multi-esters having two or more metronidazole groups linked together by aryl or alkyl systems. A second system is two nitro-2-methylimidazole groups joined by a dimethylene link. The third is polymeric 2-(2-methyl-5-nitroimidazol-1-yl)ethyl acrylate. The triester, metronidazole trimesate, is exceptionally active as an antibacterial compound, which appears to be associated with a rigid, three-point attachment.

Kinetics of killing or growth of Trichomonas vaginalis in the presence of aminoglycosides, neomycin and geneticin (G418)

Few therapeutic drugs, other than metronidazole and close derivatives, are currently available to treat trichomoniasis. Trichomonas vaginalis is known to have a primitive ribosome based on small subunit ribosomal DNA sequence comparisons. Targeting ribosomal subunits, the aminoglycosides neomycin and geneticin (G418, distinct from gentamycin) were tested for activity against T. vaginalis. While neomycin had no effect, G418 was effective in killing cultured T. vaginalis cells at doses intermediate between those previously effective against prokaryotes and eukaryotes. G418 cytotoxicity requires further study before recommending this agent as topically applied therapy in refractory patients.

Evidence for the direct interaction of reduced metronidazole derivatives with DNA bases

The electrochemical behaviour of the bioreductive redox active nitroimidazole drug metronidazole has been examined in the presence and absence of the DNA bases using three electrochemical techniques, all of which indicate the capacity for interaction between reduced products and DNA bases. The 4-electron metronidazole (RNO 2) metronidazole-hydroxylainine (RNHOH) couple in an aqueous medium shows a positive shift in reduction potential upon addition of thynune, adenine and guanine, but a negative shift for cytosine. Interpretation of these results for an irreversible process is, however, inconclusive. In dimethylformamide/H 2O the presence of DNA base on the one-electron addition product, the nitro radical anion, was examined by cyclic voltammetry. All except guanine resulted in interaction with the metronidazole nitro radical anion (RNO 2 ⨪), as measured by the decrease in the retum-to-forward peak current ratio, in the following order of increasing reactivity: cytosine, adenine and thymine (at a metronidazole : base ratio of 1:1). The increase in the stability of the radical anion by increasing the pH of the dimethylformamide/H 2O medium resulted in a decreased reaction with thymine.

Single Dose Treatment with Tiberal of Giardia Lamblia Infection in Children

A new metronidazole derivative, Tiberal (Ro-07-0207, Roche Laboratories), was evaluated in 22 children with Giardia lamblia infection. Seven patients received an oral dose of 1 g twice daily for one day; the remaining 15 patients received a single dose of 50 mg/kg. Parasitological cure was noted in all 22 patients. Significant side effects were observed only in those children who received the drug at the higher dosage regime. The present study also confirms the findings of other authors that a mucosal imprint method is more reliable than examination of stools, duodenal juice or jejunal biopsy material for the detection of G. lamblia infection.

Secnidazole. A 5-nitroimidazole derivative with a long half-life.

The therapeutic activity of a single 2 g dose of secnidazole was studied in patients with urogenital trichomoniasis. In 140 patients, 97% were cured and the drug was well tolerated. In the laboratory, tests on sensitivity were made and the minimal inhibitory concentration (MIC) and the minimal trichomonacidal concentration (MTC) were determined on cultures that had recently been isolated at the clinic, and the pharmacokinetic properties of secnidazole in man were compared with those of tinidazole. The therapeutic efficacy of all the metronidazole derivatives was reviewed and a single-dose treatment is recommended. Therapeutic and prophylactic treatment is achieved by products with a long half-life. Secnidazole, with a half-life of 14.3 +/- 1.3 h (women) and 20.2 +/- 3.1 h (men), is particularly suitable for this type of treatment.