Bipyridine scaffolds are important structural motifs in medicinal chemistry because minor variations in nitrogen substitution or halogenation can significantly influence polarity, receptor binding and pharmacological activity. In the present study, a series of bipyridine derivatives (Ia–Ih) was synthesized, evaluated for analgesic and anti-inflammatory activities and subjected to molecular docking analysis. A PMB-protected bipyridyl amine was prepared through Buchwald–Hartwig amination and subsequently deprotected to obtain the key amino intermediate Ia. Structural modification of this intermediate afforded the N-methyl (Ic), N,N-dimethyl (Ib) and N-formyl (Ih) derivatives, while diazotization followed by Sandmeyer-type substitution produced the bromo (Ie), fluoro (If) and iodo (Ig) analogues. Analgesic activity was assessed in mice using Eddy’s hot-plate method at oral doses of 100 and 200 mg/kg, with indomethacin as the reference drug. Anti-inflammatory activity was evaluated in rats using the carrageenan-induced paw-edema model at the same dose levels. Molecular docking was performed using Molegro Virtual Docker against PDB ID 3CFL and the binding poses were ranked using MolDock and re-rank scores. Compounds Ia, Ib, Ic and Ih showed marked and dose-dependent analgesic activity. At 200 mg/kg, the highest increases in reaction latency at 60 min were observed for Ia (88.60%), Ib (86.20%), Ih (85.52%) and Ic (82.76%). In the paw-edema model, Ia, Ic and If exhibited notable late-phase anti-inflammatory activity. At 6 h and 200 mg/kg, Ia produced the highest edema inhibition (85.83%), followed by Ic (78.83%) and If (77.53%). Docking analysis revealed favourable binding of several derivatives within the 3CFL active cavity. Compound Ih showed the best predicted binding affinity, with a MolDock score of −124.138 and a re-rank score of −85.0291, followed by Ib and Ic. A conserved hydrogen-bond interaction with Asn594 was observed among the principal docked ligands, suggesting a shared anchoring mode. Overall, the synthesized bipyridine derivatives demonstrated promising analgesic and anti-inflammatory effects. Compound Ia emerged as the most consistent dual-activity candidate, whereas Ih, Ib and Ic showed superior predicted binding affinities. These findings support further mechanistic, target-confirmation, toxicity and structural-optimization studies.
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