Cyclic voltammetric determination of free radical species from nitroimidazopyran: a new antituberculosis agent

Abstract

PA-824 (2-nitro-6-(4-trifluoromethoxy-benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine) is being tested as antituberculosis drug. Little is known on the action mechanism of PA-824; however the reduction of the nitro group seems to be a key step in the metabolic activation, as is observed for the well-known bactericidal metronidazole. Consequently, this paper is focused on the cyclic voltammetric behavior of PA-824 with the aim of revealing the formation and stability of the corresponding nitro radical anion and its comparison with the metronidazole behavior. Both compounds PA-824 and metronidazole reveal, in aprotic medium (DMSO+0.1 tetrabutylammonium hexafluorophosphate), a similar reduction pattern showing a well-resolved couple due to nitro reduction to form the corresponding nitro radical anion. The electrode reaction obeys an EC2 mechanism with a dimerization reaction as the chemical step in aprotic medium. Using cyclic voltammetry theory for a dimerization reaction we have calculated the second-order decay constants, k(2,dim) and the half-life time, t(1)/(2), for the nitro radical anions formed from PA-824 and metronidazole. We have obtained k(2,dim) values of 2.22 x 10(2) and 2.58 x 10(4) M(-1)s(-1) for metronidazole and PA-824, respectively. Our voltammetric results show that the PA-824 nitro radical anion requires more energy for formation (about 200 mV) and it is approximately 100 times less stable than the metronidazole radical anion.