Multitargeted Anti‐Inflammatory Agents: Novel Pyrazole and Pyrazolo[1,5‐ <i>a</i> ]Pyrimidine Carbonic Anhydrase and COX‐2 Inhibitors With Optimal In Vivo Efficacy and Low Toxicity

ABSTRACT In this study, three series of pyrazole and pyrazolo[1,5‐ a ]pyrimidine derivatives 6a‐f , 8a‐f , and 10a‐f were designed and synthesized in response to the global need to safe and potent anti‐inflammatory agents. A rational design strategy was employed to synthesize compounds that inhibit inflammation‐related carbonic anhydrase isoforms (II, IX, and XII) alongside achieving selective inhibition of cyclooxygenase‐2 (COX‐2). Remarkably, the sulfonamide derivatives 6f, 8d, and 10e displayed high activity as carbonic anhydrase inhibitors against isoforms II, IX and XII in addition to their potent and selective COX‐2 inhibition effect (IC 50 = 57–87 nM; SI = 175–100). Among them, the multitargeted inhibitor 10e (COX‐2, IC 50 = 57 nM; CA II, K i = 49.9 nM; CA IX, K i = 67.5 nM; CA XII, K i = 54.6 nM) was further evaluated in vivo and demonstrated strong dual anti‐inflammatory and analgesic properties, with a rapid onset of action within the first hour and sustained efficacy over 5 h. Toxicological studies revealed that compound 10e possessed a favorable safety profile, showing no significant adverse effects on liver, kidney, or cardiac functions and minimal ulcerogenic potential. Molecular docking studies further supported these findings by confirming key binding interactions with CA II, IX, XII, and COX‐2 active sites.