Design, Synthesis, Molecular Docking, Structure Activity Relationship, and In Vivo Evaluation of Pyrazole–Pyrimidines for Discovering New Nonsteroidal Anti‐Inflammatory Drugs

Nonsteroidal anti-inflammatory drugs are among the most prescribed worldwide to treat pain, fever, and inflammation. However, they can cause severe adverse effects such as gastric, duodenal, hepatic, and renal injuries. Thus, the search for effective and new drugs is of high priority. Herein, the synthesis of a new series 4-((5-substituted-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl) pyrimidin-2-substituted (pyrazole-pyrimidines) obtained through the cyclocondensation reaction of pyrazole-enaminones with amidines under mild conditions is reported. The chemical structures are confirmed by ¹H and ¹³C NMR, mass spectrometry, and single-crystal X-ray analysis for compounds 4c and 4g. Molecular docking studies are conducted to identify selective cyclooxygenase-2 (COX-2) inhibitors, revealing that compounds 4d, 4j, and 4k display higher binding affinity. ADMET predictions (absorption, distribution, metabolism, excretion, and toxicity) corroborate to the docking results, suggesting favorable pharmacokinetic and toxicological properties. The in vivo antinociceptive activity is investigated in mice using the capsaicin-induced nociception model. Oral administration of compounds 4d, 4e, 4f, 4j, and 4k significantly reduces nociceptive responses, achieving effects comparable or superior to celecoxib, without altering locomotor activity. Altogether, the findings demonstrate that pyrazole-pyrimidine derivatives, especially 4d and 4k, are promising candidates for the development of selective COX-2 analgesics, combining antinociceptive efficacy with a favorable toxicological profile.