The radical scavenging activity of 1-methyl-1,4-dihydronicotinamide: theoretical insights into the mechanism, kinetics and solvent effects.

Abstract

1,4-Dihydronicotinamide derivatives, including 1-methyl-1,4-dihydronicotinamide (MNAH), are derivatives of the active center of nicotinamide coenzyme (NADH) and are therefore potent radical scavengers. MNAH serves as a useful model of NADH that allows for modeling studies to address the activity of this important biomolecule. In this work, MNAH activity was evaluated against typical free radicals using quantum chemical calculations in physiological environments, with a secondary aim of comparing activity against two physiologically relevant radicals of markedly different stability, HO˙, and HOO˙, to establish which of these is a better model for assessing antioxidant capacity in physiological environments. The HO˙ + MNAH reaction exhibited diffusion-limited overall rate constants in all media, including the gas phase. The HOO˙ antiradical activity of MNAH was also good, with overall rate constants of 2.00 × 104 and 2.44 × 106 M-1 s-1, in lipid and aqueous media, respectively. The calculated rate constant in water (k overall(MNAH + HOO˙) = 3.84 × 105 M-1 s-1, pH = 5.6) is in good agreement with the experimental data (k exp(NADH + HOO˙) = (1.8 ± 0.2)×105 M-1 s-1). In terms of mechanism, the H-abstraction of the C4-H bond characterized the HOO˙ radical scavenging activity of MNAH, whereas HO˙ could react with MNAH at several sites and following either of SET (in polar media), RAF, and FHT reactions, which could be ascribed to the high reactivity of HO˙. For this reason the results suggest that activity against HOO˙ is a better basis for comparison of anti-radical potential. In the broader context, the HOO˙ scavanging activity of MNAH is better than that of reference antioxidants such as trans-resveratrol and ascorbic acid in the nonpolar environment, and Trolox in the aqueous physiological environment. Therefore, in the physiological environment, MNAH functions as a highly effective radical scavenger.