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

Hydralazine (HZ) and dihydralazine (DHZ) are phtalazine derivatives substituted at position 1 (HZ) or 1 and 4 (DHZ) by a hydrazinyl substituent. These compounds are widely used for treatment of hypertension and/or heart failure, acting essentially as vasodilators on the arteries and arterioles. In this study, the antioxidant activity of HZ and DHZ in the gas phase as well as 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 N9H bond plays a deciding role in the HOO* radical scavenging of HZ1 and DHZ1, whereas the HOO* radical scavenging activities of HZ2 and DHZ2 are defined by the dissociation of N10H and N11H bonds, respectively. The rate constants of the HOO* radical scavenging of the HZ and DHZ in the gas phase are in the range of 9.64106 to 4.52108 M1s1, whereas they are in the range of 2.62104 to 5.13107 M1s1 and 5.75104 to 6.66106 M1s1 in the aqueous solution and lipid media, respectively. The HOO* radical scavenging of DHZ1 and DHZ2 is thus faster than that of the reference antioxidant compound Trolox in all of the studied environments. Consistently the DHZs are not only vasodilators but also potent antioxidants.