Inventi Rapid: Med Chem

Inventi:prmc/114838/26

In-Vivo Analgesic, Anti-Inflammatory Activities and Molecular Docking Analysis of Novel Bi-Pyridines Derivatives

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....