Molecular structure and relative proton and electron affinities of isomeric nitroimidazoles

Abstract

. Can. J. Chem. 67, 1666 (1989).The isomeric 2-nitro, 4-nitro, and 5-nitroimidazoles have been studied in their planar ground state, C-NO2 rotational transition state, 3-H protonated conjugate acid and radical anion forms, with ab initio computations at the split-valence 3-21G basis set level. The stabilities of the parent compounds follow the order 5-NO2 -4-NO2 > 2-NO2. In solution 4-nitro is more stable than 5-nitro; the calculations suggest that this is a solvation effect, since the 4-nitro isomer has a considerably higher dipole moment. Barriers for nitro group rotation range from 10 to 16 kcal/mol. However, the relative change in dipole moment during the rotation is small, suggesting that dipole moments of nitroimidazoles are determined mainly by inductive effects, with resonance interactions being relatively unimportant. This conclusion is supported by calculations of molecular electrostatic potentials of the planar and rotated forms. Electron affinities follow the order 2-NO2 > 5-N02 >> 4-NO2, closely matching the order of biological effectiveness of nitroimidazole radiosensitizers. This is consistent with suggestions that the "nitro:nitro radical anion" redox cycle is an important determinant of biological activity.Key words: nitroimidazole, ab initio computation, rotational barrier, proton affinity, electron affinity. Optrant au niveau de l'ensemble de base 3-21G, on a effectuk des calculs ab initio sur les 2-nitro, 4-nitro et 5-nitroimidazoles dans leur ttat fondamental pla, dans leur Ctat de transition de rotation du C-NO2 ainsi que sous les formes acide conjuguC et radical anionique de la forme protonee en 3-H. Les stabilitts relatives des composks de base suivent l'ordre suivant : 5-NO2 -4-NO2 > 2-NO2. En solution, le 4-nitro est plus stable que le 5-NO2; les calculs indiquent que cette situation est le rtsultat d'un effet de solvatation dk au moment dipolaire beaucoup plus tlevt du 4-nitro. Les barribres i la rotation du groupement nitro varient de 10 i 16 kcal/mol. Toutefois, le changement relatif du moment dipolaire au cours de la rotation est faible; ce rtsultat suggkre que les moments dipolaires des nitroimidazoles sont principalement dtterminCs par des effets inductifs alors que les interactions de rtsonance ne sont pas trbs importantes. dette conclusion est s u p p o~t e par des calculs de potentiels tlectrostatiques moltculaires des formes planes et celles ayant subi une rotation. Les affinitts tlectroniques sont dans l'ordre 2-NO2 > 5-NO2 >> 4-NO2; cet ordre resemble beaucoup l'ordre observC pour l'efficacitt biologique des nitroimidazoles comme radiosensibilisateurs. Cette conclusion est en accord avec les suggestions suivant lesquelles le cycle rtdox de 1' <<anion radical nitro:nitro)> est un dtterminant important de l'activitt biologique.Mots cl6s : nitroimidazole, calcul ab initio, barribre ri. la rotation, affinitt protonique, affinitt tlectronique. [Traduit par la revue]A class of drugs which has seen active investigation over the In this case, the radical anion species is produced in...

Imidazole and Benzimidazole Derivatives as Chemotherapeutic Agents

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