Compound 5(University of Malakand)

This study explores the synthesis of new acyl hydrazide derivatives of mefenamic acid as potent analgesics with enhanced safety profiles. Thirteen compounds were synthesized via hydrazide intermediate functionalization and characterized spectroscopically (¹H/¹³C NMR, and HRESI-MS). In vivo evaluation (acetic acid writhing, formalin paw licking, and tail immersion tests) revealed significant peripheral and central analgesic activity, with compounds 5 (N'-(4-chlorobenzoyl)) and 11 (N'-(2,4-dichlorophenyl)) outperforming mefenamic acid (81.98 % vs. 80.71 % writhing inhibition at 30 mg/kg). Molecular docking (COX-2 PDB:5IKR) demonstrated strong binding affinity (-7.987 kcal/mol for 5) via halogen bonds with Val523/Tyr355. Density functional theory (B3PW91-D3/6-31G++**) identified optimal reactivity indices (Eg: 3.8-4.3 eV, ω: 2.8-3.0 eV, σ: > 0.52 eV^-1) correlating with bioactivity. Chlorinated derivatives exhibited balanced lipophilicity and target specificity, while aliphatic chains reduced efficacy. This work establishes halogenated acyl hydrazides as promising candidates for inflammation pain management with reduced gastrointestinal toxicity.