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 (nu<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 nu, 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 approximately 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.
Cavalcanti
J C M
JC
Departamento de Química, CCEN, UFAL, Cidade Universitária-Tabuleiro do Martins, Maceió, Alagoas 57072-970, Brazil.
de Abreu
F C
FC
Oliveira
N V
NV
de Moura
M A B F
MA
Chaves
J G
JG
Alves
R J
RJ
Bertinaria
M
M
Fruttero
R
R
Goulart
M O F
MO
D000900:Anti-Bacterial Agents / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004563:Electrochemistry / Q000379:methods*; D004566:Electrodes; D016480:Helicobacter pylori / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D008795:Metronidazole / Q000031:analogs & derivatives / Q000032:analysis* / Q000737:chemistry*; D010084:Oxidation-Reduction; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000644:Quaternary Ammonium Compounds; D008795:Metronidazole; C009405:tetrabutylammonium; D004121:Dimethyl Sulfoxide