Rationale design and multimodal evaluation of curcumin-derived analogues as next generation analgesic agents

Aim The study was aimed to synthesize curcumin analogues and evaluate their analgesic potential. The analogues, designated as K1–K4, were strategically modified with specific substitutions to optimize stability, increase bioavailability, and enhance their biological activity.Material and methods Four curcumin analogues (K1–K4) were successfully synthesized, characterized, and assessed for their analgesic efficacy via both in vitro cyclooxygenase-2 inhibition assay and in vivo experimental pain models.Results All the analogues exhibited prominent analgesic activities. Among them, K1 possessed optimal COX-2 inhibitory potential relative to the standard celecoxib. Similarly, in various pain‑mouse models, the K1 analogue demonstrated significant (p < 0.05) analgesic activity at a dose of 20 mg/kg body weight when compared with the control groups. Specifically, it exhibited 78.20% analgesic inhibition in the acetic acid-induced writhing test, 62.44% (Phase I) and 68.73% (Phase II) inhibition in the formalin-induced pain model, a 62.27% analgesic response in the tail immersion test, and a 71.07% response in the hot plate assay. Naloxone administration reversed the analgesic effects in all treated groups, indicating the involvement of opioid receptors.Conclusions Overall, compound K1 elicited the prominent analgesic responses, followed by K4, which could be attributed to the inhibition of the COX-2 pathway and could be considered as potent drug candidates.