Thermodynamic and Kinetic Studies of the Radical Scavenging Behavior of Hydralazine and Dihydralazine: Theoretical Insights

Abstract

Hydralazine (HZ) and dihydralazine (DHZ) are phthalazine derivatives substituted at position 1 (HZ) or positions 1 and 4 (DHZ) by a hydrazinyl substituent. These compounds are widely used for treating hypertension and heart failure, essentially acting as vasodilators on the arteries and arterioles. In this study, the antioxidant activity of HZ and DHZ in the gas phase and in physiological environments was investigated by thermodynamic and kinetic calculations. It was found that the HOO^• radical scavenging activity of these compounds follows the formal hydrogen transfer (FHT) mechanism. The H abstraction of the N9-H bond plays a deciding role in the HOO^• radical scavenging of HZ-1 and DHZ-1, whereas the HOO^• radical scavenging activities of HZ-2 and DHZ-2 are defined by the dissociation of the N10-H and N11-H bonds, respectively. The rate constants for the HOO^• radical scavenging of the HZ and DHZ in the gas phase are in the range of 9.64 × 10⁶ to 4.52 × 10⁸ M^-1 s^-1, whereas in aqueous solutions and the lipid medium they are in the range of 2.62 × 10⁴ to 5.13 × 10⁷ M^-1 s^-1 and 5.75 × 10⁴ to 6.66 × 10⁶ M^-1 s^-1, respectively. The HOO^• radical scavenging of DHZ-1 and DHZ-2 is thus faster than that of the reference antioxidant compound Trolox in all the studied environments. Consistently, DHZs are not only vasodilators but also potent antioxidants.