Synthesis and Study Anti-Inflammatory Activity of Nicotinic Acid Hydrazones

Objective: The aim of this study is to produce novel of the new functionally substituted nicotinohydrazones, analyze their anti-inflammatory activity, and assess their toxicity. A promising avenue for the advancement of novel bioactive compounds is the pursuit of “hybrid molecules” that contain pharmacophore fragments within their structural composition, with a particular focus on the examination of these molecules for the discovery of novel biological activities. Methods: The synthesis of nicotinic acid hydrazones (II–VI) was performed by condensation of nicotinic acid hydrazide with various aldehydes in ethanol when refluxing the reaction mixture at 60–70°C. The anti-inflammatory activity was studied using the formalin paw edema method in non-linear white rats. The acute inflammatory reaction was reproduced by subplantar (i.e., underplantar or plantar aponeurosis) injection of 0.1 mL of a 2% formalin solution into the right paw using a conventional insulin syringe. Results and Discussion: The structure of the new functionally substituted nicotinohydrazones has been confirmed by a combination of the ¹H and ¹³C NMR methods, and COSY (¹H-¹H), HMQC (¹H–¹³C), and HMBC (¹H–¹³C) two-dimensional NMR spectroscopy methods.¹H, and ¹³C NMR spectroscopy were used to investigate all the prepared derivatives. The acute toxicity of the aforementioned compounds was preliminarily evaluated using a specially developed Toxicity Assessment Software Tool within the United States Environmental Protection Agency. The LD₅₀ values for rats following oral administration of the compounds tested by the QSAR method. According to the projected toxicological effects, compounds (II), (III) can be classified into Class 4 in terms of toxicity. Compounds (IV), (V) and (VI) have low toxicity and very low toxicity, respectively. Conclusions: The anti-inflammatory activity of the synthesized hydrazones has been evaluated and it has been demonstrated that these compounds were ineffective in comparison with ibuprofen at a dosage of 100 mg/kg (p² < 0.05). The low toxicity level of all the tested compounds was predicted by the computer modeling. The LD₅₀ values of the compounds range from 445.461 to 1491.991 mg/kg. The studies on the model of formalin paw edema in nonlinear white rats indicate the absence of an anti-inflammatory effect of the tested compounds.