Background. Zinc-containing compounds are a promising basis for the development of new non-steroidal anti-inflammatory drugs (NSAIDs), which can raise the effectiveness and safety of pharmaceutical management of inflammation and pain.

Objective: To study the anti-inflammatory, ulcerogenic, etc., effects of zinc-imidazole complexes, such as allyl-2 (bis (N-allyl-2-methylimidazole) zinc diacetate), allim-2 (bis (N-allenyl-2-methylimidazole) zinc diacetate), and propargyl-2 (bis (N-propargyl-2-methylimidazole) zinc diacetate) in comparison with zinc complexes with known NSAIDs, such as diclofenac, nimesulide, and ketorolac.

Material and methods. In silico modeling of candidate molecules allyl-2, allim-2, propargyl-2, zinc-diclofenac, zinc-nimesulide, and zinc-ketorolac was performed using a toolkit of chemoinformatic analysis methods developed by scientific school of Yu.I. Zhuravlev and K.V. Rudakov through topological analysis of chemographs and numerical forecasting of distinguishing features of complex systems. These methods include the theory of chemograph analysis, methods for predicting numerical target variables, the combinatorial theory of solvability/regularity, and topological methods for data analysis. The pharmacological capabilities of molecules within the framework of chemoreactome methodology were evaluated by comparing the chemical structure of the query molecule with the structures of molecules whose molecular-pharmacological properties have been established and available in the PubChem, HMDB, STRING, and PharmGKB databases.

Results. The obtained chemoreactome evaluations revealed the capacity of zinc-imidazole complexes to inhibit of prostaglandin D2 binding to the prostaglandin D2 receptor on platelets (IC50 448–627 nM; zinc-NSAID: 588–997 nM) with comparable effects of zinc-imidazole complexes and zinc-NSAID on cyclooxygenase-2 (COX-2) inhibition in whole blood (IC50 295–428 nM). Zinc-imidazole complexes were characterized by a more pronounced inhibition of the proinflammatory signaling cascade of the NF-κB transcription factor (IC50 173–419 nM; zinc-NSAID 498–508 nM), alpha-1 adrenergic receptor (28 nM; zinc-NSAID: 235–411 nM), and angiotensin receptor-1 (IC50 16–22 nM; zinc-NSAID: 20–74 nM), indicating an antihypertensive effect. The antinociceptive activity of zinc-imidazole complexes (IC50 0.16 mg/kg) upon subcutaneous administration to mice in acetic acid-induced writhing was more pronounced than that of zinc-NSAIDs (0.9–1.0 mg/kg) with the exception of zinc-ketorolac (0.16 mg/kg). Compared to the zinc-NSAIDs, all zinc-imidazole complexes under study were characterized by similar and extremely low values ​​of antimicronutrient action scores (antivitamin score 0.38–0.61, antimicroelement score 0.37–0.88; compared to two- or three-fold higher scores for zinc-NSAIDs), which indicates the absence of adverse effects of zinc-imidazole complexes on micronutrient metabolism.

Conclusion. The studied candidate molecules (zinc-imidazole complexes), in addition to COX inhibition, may exhibit additional pharmacological properties to a greater extent than the studied zinc complexes with known NSAIDs.