Antihypoxic properties of 2-ethylthiobenzimidazole succinate

Background: 2-ethylthiobenzimidazole succinate (I) is a novel compound synthesized by analogy with Metaprot® (bemitil), a Russian-produced hydrobromide salt of 2-ethylthiobenzimidazole (II).

Aim: The work aimed to compare the antihypoxic effects of Compounds I and II in two models of normobaric hypoxia in mice.

Methods: Mice were randomized into eight groups (n = 8–12 per group) and exposed to normobaric hypoxia under two conditions: (1) in a jar test and (2) in a hypoxic chamber with a controlled gas composition, in which oxygen concentration was gradually reduced from 21% to 2% by nitrogen displacement. Compounds I and II were administered intraperitoneally once, 1 hour before hypoxia, at doses of 50 mg/kg and 100 mg/kg.

Results: In the jar test (hypercapnic hypoxia), both compounds significantly increased survival time by 13%–21%, with the 50 mg/kg dose being more effective. Under normobaric hypoxia with a variable gas composition, survival time at critical oxygen concentrations decreasing from 6% to 2% increased by 108% (from 8.2 to 17.0 min, p < 0.05) with Compound I and by 135% (to 19.3 min, p < 0.01) with Compound II. The threshold oxygen concentration tolerated by mice decreased from 4.56% in the control group to 3.23% after Compound I and to 2.97% after Compound II, corresponding to 71% and 65% of baseline values, respectively. The hypoxia-resistance score increased from 4.0 in controls to 8.8, corresponding to 220% (p < 0.01), and 9.5, corresponding to 238% (p < 0.001), after administration of Compounds I and II, respectively.

Conclusion: Compounds I and II at doses of 50 and 100 mg/kg exhibit a pronounced antihypoxic effect in two models of normobaric hypoxia in mice. The antihypoxic activity is comparable in magnitude for both compounds. The mechanism of the antihypoxic action of Compounds I and II appears to be similar and associated with the 2-ethylthiobenzimidazole moiety rather than with the anionic part of the molecule.