*2.2.9 Cardioprotective properties*

Cardioprotective activity was studied in isolated atrial rhythm disturbances induced by hydrogen peroxide oxidation [53], in postischemic reperfusion fibrillations of the heart ventricles [54], in the technique of rhythm disturbances caused by calcium chloride and adrenaline intoxication [55], and in the myocardial ischemia provoked by coronary occlusion [31] and the experimental myocardial infarction method [56]. As a result it was found that enoxifol exerted an antiarrhythmic effect, increasing the resistance of cardiomyocyte membranes to LPO products. The compound increased the stability of the myocardium of animals having a non-antioxidant diet to calcium chloride cardiac arrhythmias and increased myocardial tolerance to ischemia. Enoxifol completely prevented ventricular fibrillation of the heart in postischemic myocardial reperfusion. It reduced the extrasystole severity and ventricular fibrillation and reduced the death of animals in the model of coronary artery occlusion and systemic peroxidation syndrome. The novel compound limited area of necrosis in experimental myocardial infarction. It showed activity in doses 7.9, 14, and 20.5 mg/kg [39, 55].

### *2.2.10 Antithrombotic and antiaggregant effects*

Enoxifol had a pronounced antithrombotic effect in arterial thrombosis models induced by application of ferric chloride and electric current on the rat carotid artery and blocked platelet aggregation caused by ADP, collagen, adrenaline, arachidonic acid, thrombin, and an agonist of thromboxane receptors U46619 [24]. The antioxidant compound reduced levels of proaggregant and vasoconstrictor ТХА2, which was confirmed by a decreased level of MDA in the ex vivo pathology caused by thrombin, and decreased the level of total and membrane-bound calcium in platelets, inhibiting calmodulin-dependent PDE cAMP.

### *2.2.11 Action on hemorheology*

The study of the enoxifol action on hemorheology was carried out in the model of "increased viscosity syndrome" according to the method [57]. An improvement in blood flow, membrane plasticity, and inhibition of erythrocyte aggregation under the influence of enoxifol administration in dose 5 mg/kg was found [18]. An increase in the rate of local cerebral blood flow and a direct effect on the tone of cerebral vessels in a similar dose were determined in the method of tissue microcirculation [58]. The study of the enoxifol effect on hemorheology in models of severe forms of streptozotocin diabetes was also performed. Antioxidant compound corrected hemobiological parameters (aggregation, deformability, mechanical properties of erythrocytes), almost normalized indicators of lipid peroxidation, reducing the products of peroxidation, and increased the activity of antioxidant enzymes. The effective dose was 5 mg/kg for the course of the 3-day administration preliminary to diabetes modeling [58].

## *2.2.12 Pharmacokinetic profile*

In the study of the pharmacokinetic properties of enoxifol [27], determination was carried out for 12 hours in the blood and internal organs and in the

**253**

*Condensed Benzimidazoles Are a Novel Scaffold for Antioxidant Agents' Search and Development*

urine and feces within 48 hours. It was found that the absolute bioavailability of unchanged enoxifol was 30% and for the total amount of enoxifol and its active metabolites, 99%. When administered orally, enoxifol was well absorbed from the gastrointestinal tract, the maximum concentration in the blood was observed after 1 hour, and after 7 hours the compound was not detected. The excretion of the compound occurs mainly through the intestines, and only one-fifth is excreted unchanged; a small amount of enoxifol is excreted through the kidneys. The half-life for enoxifol was 1.43 hours. After the intravenous administration, the maximum concentration of the compound in the blood is determined in 10 minutes; after 7 hours the antioxidant in the blood was not recorded. The excretion of the infusion form of enoxifol occurs mainly through the kidneys in the unchanged form. In a much smaller amount, enoxifol was eliminated with

A study of the drug safety of enoxifol [59] found that the antioxidant compound can be attributed to low-toxic substances. The acute toxicity of enoxifol after oral administration was 1792.56 mg/kg for male and 2260.28 mg/kg for female rats. When administered intravenously, the LD50 was determined for male in dose 109.20 mg/kg and for female rats in dose 126.04 mg/kg. Chronic administration in therapeutic doses (5–25 mg/kg) showed that toxic effects in the central nervous system, liver function, kidney function, and the generative system were not observed. In the high dose (200 mg/kg), slight deviations in the behavioral responses of animals and a slight decrease in the detoxification function of the liver were observed.

Summarizing the data obtained, we can conclude that condensed benzimidazole derivatives with π-electron redundancy are a new scaffold for searching antioxidant substances. The highest amount of compounds with high antioxidant activity was found in derivatives of 2-(hetaryl)-aroylmethyl-, and 9-dialkylaminoethyl-IMBI,

The revealed compound enoxifol from the 9-dialkylaminoethyl-IMBI series exhibits pronounced antioxidant, hepatoprotective, antihypoxic, cerebroprotective, nootropic, stress-protective, neuropsychotropic, actoprotective, cardioprotective, antithrombogenic and hemorheological properties. Pharmacokinetic parameters of enoxifol were established, and general and specific toxicities were studied. All mentioned above allows us to consider enoxifol to be the basis of a new

*DOI: http://dx.doi.org/10.5772/intechopen.82817*

feces. The half-life was 0.78 hours [27].

The accumulation ability of enoxifol wasn't found [59].

with oxy- and dioxyphenyl substitutes especially.

*2.2.13 Toxicological properties*

**3. Conclusion**

effective drug.

*Condensed Benzimidazoles Are a Novel Scaffold for Antioxidant Agents' Search and Development DOI: http://dx.doi.org/10.5772/intechopen.82817*

urine and feces within 48 hours. It was found that the absolute bioavailability of unchanged enoxifol was 30% and for the total amount of enoxifol and its active metabolites, 99%. When administered orally, enoxifol was well absorbed from the gastrointestinal tract, the maximum concentration in the blood was observed after 1 hour, and after 7 hours the compound was not detected. The excretion of the compound occurs mainly through the intestines, and only one-fifth is excreted unchanged; a small amount of enoxifol is excreted through the kidneys. The half-life for enoxifol was 1.43 hours. After the intravenous administration, the maximum concentration of the compound in the blood is determined in 10 minutes; after 7 hours the antioxidant in the blood was not recorded. The excretion of the infusion form of enoxifol occurs mainly through the kidneys in the unchanged form. In a much smaller amount, enoxifol was eliminated with feces. The half-life was 0.78 hours [27].

#### *2.2.13 Toxicological properties*

*Antioxidants*

in various physical activity tests [52].

*2.2.10 Antithrombotic and antiaggregant effects*

*2.2.11 Action on hemorheology*

*2.2.12 Pharmacokinetic profile*

in platelets, inhibiting calmodulin-dependent PDE cAMP.

*2.2.9 Cardioprotective properties*

of energy metabolism (the level of lactate, glycogen, tryptophan, the ratio of pyruvate and lactate), normalized indicators of lipid peroxidation, and had a protective effect on the myocardium of animals during the period of exhaustive physical activity. A number of effective doses amounted to 1, 3, 5, 10, 20, 25, and 50 mg/kg

Cardioprotective activity was studied in isolated atrial rhythm disturbances induced by hydrogen peroxide oxidation [53], in postischemic reperfusion fibrillations of the heart ventricles [54], in the technique of rhythm disturbances caused by calcium chloride and adrenaline intoxication [55], and in the myocardial ischemia provoked by coronary occlusion [31] and the experimental myocardial infarction method [56]. As a result it was found that enoxifol exerted an antiarrhythmic effect, increasing the resistance of cardiomyocyte membranes to LPO products. The compound increased the stability of the myocardium of animals having a non-antioxidant diet to calcium chloride cardiac arrhythmias and increased myocardial tolerance to ischemia. Enoxifol completely prevented ventricular fibrillation of the heart in postischemic myocardial reperfusion. It reduced the extrasystole severity and ventricular fibrillation and reduced the death of animals in the model of coronary artery occlusion and systemic peroxidation syndrome. The novel compound limited area of necrosis in experimental myocardial infarction. It showed activity in doses 7.9, 14, and 20.5 mg/kg [39, 55].

Enoxifol had a pronounced antithrombotic effect in arterial thrombosis models induced by application of ferric chloride and electric current on the rat carotid artery and blocked platelet aggregation caused by ADP, collagen, adrenaline, arachidonic acid, thrombin, and an agonist of thromboxane receptors U46619 [24]. The antioxidant compound reduced levels of proaggregant and vasoconstrictor ТХА2, which was confirmed by a decreased level of MDA in the ex vivo pathology caused by thrombin, and decreased the level of total and membrane-bound calcium

The study of the enoxifol action on hemorheology was carried out in the model of "increased viscosity syndrome" according to the method [57]. An improvement in blood flow, membrane plasticity, and inhibition of erythrocyte aggregation under the influence of enoxifol administration in dose 5 mg/kg was found [18]. An increase in the rate of local cerebral blood flow and a direct effect on the tone of cerebral vessels in a similar dose were determined in the method of tissue microcirculation [58]. The study of the enoxifol effect on hemorheology in models of severe forms of streptozotocin diabetes was also performed. Antioxidant compound corrected hemobiological parameters (aggregation, deformability, mechanical properties of erythrocytes), almost normalized indicators of lipid peroxidation, reducing the products of peroxidation, and increased the activity of antioxidant enzymes. The effective dose was 5 mg/kg for the course of the 3-day administration preliminary to diabetes modeling [58].

In the study of the pharmacokinetic properties of enoxifol [27], determination was carried out for 12 hours in the blood and internal organs and in the

**252**

A study of the drug safety of enoxifol [59] found that the antioxidant compound can be attributed to low-toxic substances. The acute toxicity of enoxifol after oral administration was 1792.56 mg/kg for male and 2260.28 mg/kg for female rats. When administered intravenously, the LD50 was determined for male in dose 109.20 mg/kg and for female rats in dose 126.04 mg/kg. Chronic administration in therapeutic doses (5–25 mg/kg) showed that toxic effects in the central nervous system, liver function, kidney function, and the generative system were not observed. In the high dose (200 mg/kg), slight deviations in the behavioral responses of animals and a slight decrease in the detoxification function of the liver were observed. The accumulation ability of enoxifol wasn't found [59].
