Acute Toxicity Evaluation of Pyridine Derivatives of 3,4-Dihydroquinoxalin-2-one and 3,4-Dihydro-2H-1,4-benzoxazin-2-one

Abstract

Objective: Compounds containing the quinoxaline and oxazine core have a diverse spectrum of biological activity, including antibacterial, antiviral, antitumor, antituberculosis, anti-inflammatory, and others. The introduction of a new pharmacophoric pyridine component into these derivatives can enhance the biochemical activity and metabolic stability of the resulting substance, increase cell permeability, and improve pharmacokinetic and pharmacodynamic properties. Previously, a number of pyridine derivatives of quinoxaline and oxazine were found to have pronounced and moderate antituberculosis, antibacterial, antifungal, and analgesic properties in vitro. In this regard, the aim of this study is to evaluate the acute toxicity of bis(3,4-dihydroquinoxalin-2-one) and bis(3,4-dihydro-2H-1,4-benzoxazin-2-one) derivatives upon intraperitoneal administration to guinea pigs. Methods: The acute toxicity of the bis-derivatives synthesized on the basis of 3,5-diacetyl-2,6-dimethylpyridine was studied after a single intraperitoneal administration to guinea pigs (6 groups of 6 individuals) at doses of 100, 200, and 400 mg/kg. The control group was group 7, which received 1.0 mL of physiological solution. Observation was carried out for 14 days. In the next stage, on the 15th day of the experiment, blood was collected for hematological and biochemical studies from the guinea pigs that were intraperitoneally administered with the test compounds, as well as from the guinea pigs of the control group. Results and Discussion: It was established that, according to K.K. Sidorov’s classification, pyridine derivative (3Z,3′Z)-3,3′-[(2,6-dimethylpyridin-3,5-diyl)bis(2-oxoethane-2-yl-1-ylidene)]bis(3,4-dihydroquinoxalin-2(1H)-one) had low toxicity, as evidenced by the absence of lethal outcomes from its administration to animals in the range of 100–400 μg/kg, which, however, was accompanied by signs of nervous disorder regardless of the dose of the compound, which disappeared within 24 h. When the guinea pigs were inoculated with another pyridine derivative, (3Z,3′Z)-3,3′-[(2,6-dimethylpyridin-3,5-diyl)bis(2-oxoethane-2-yl-1-ylidene)]bis(3,4-dihydro-2H-1,4-benzoxazin-2-one), more pronounced and prolonged signs of intoxication were observed as manifested by convulsive twitching of the hind limbs, decreased mobility, and a slow reaction to environmental stimuli, followed by the death of 33% of animals, when the compound was administered at a dose of 100 mg/kg, 66% at a dose of 200 mg/kg, and 100% at a dose of 400 mg/kg. The hematological and biochemical studies conducted on the 15th day after the administration of the test compounds showed the absence of significant deviations from normal physiological values, despite the presence of a reliable difference in individual indicators compared to the control group. Conclusions: Thus, the acute toxicity parameters of the test compounds were of different nature and were more pronounced in the pyridine derivative (3Z,3′Z)-3,3′-[(2,6-dimethylpyridin-3,5-diyl)bis(2-oxoethane-2-yl-1-ylidene)]bis(3,4-dihydro-2H-1,4-benzoxazin-2-one), however, both compounds can be recommended for subsequent study of the antibacterial and antiviral activity in guinea pigs.