Design, Synthesis, Molecular Docking, and Anti-Inflammatory Potential of Amide Coupling Carboxylate Derivatives

Eight new amide-based carboxylate derivatives were synthesized and evaluated for anti-inflammatory potentials using in-vitro, in-vivo and in silico studies. In cyclooxygenase-2 assay, maximum percent antagonist potential was exhibited by sodium 4-((4-fluorophenyl) amino)-4-oxobutanoate (93.91 %), bis ((4-((4-methoxy-2-nitrophenyl)amino)-4-oxobutanoyl)oxy) zinc (93.04 %), and bis ((4-((4-bromo-2-fluorophenyl) amino)-4-oxobutanoyl)oxy)zincio (2-bromopyridine) (92.64 %) with IC50 values of 1.65, 2.08, and 0.288 mu M/ml respectively. Celecoxib demonstrated 98.60 % effect with an IC50 value of 0.041 mu M/ml. In LOX assay, 4-((4-methoxy-2-nitrophenyl)amino)-4-oxobutanoic acid (97.03 %), bis ((4-((4-methoxy-2-nitrophenyl)amino)-4-oxobutanoyl)oxy)zinc (95.45 %), and (92.53 %) demonstrated maximum percent effect with IC50 values 3.48, 0.45, and 0.83 mu M/ml respectively. The standard 5-lipoxygenase inhibitor (montelukast) resulted from a 98.39 % inhibitory effect with an IC50 value of 0.194 mu M/ml. In in-vivo analysis, the potent tested compounds (5, 10, and, 20 mg/kg) significantly (p<0.001) reversed the induced edema by carrageenan. The standard drug aspirin displayed significant results (74-83 %). The standard drugs in these phlogestic agents displayed excellent results like cetirizine (67.9 %), celecoxib (81.61 %), icatibant (82.22 %) and nemesulide (87.17 %) at 5th h. The compounds displayed the inhibitory potential against targeted proteins. 4-((4-methoxy-2-nitrophenyl)amino)-4-oxobutanoic acid, 4-((4-fluorophenyl)amino)-4-oxobutanoic acid and sodium 4-((4-bromo-2-fluorophenyl)amino)-4-oxobutanoate shown excellent behavior by giving negative binding energies close of standard drugs montelukast (5F1A: -7.9 kcal/mol) and diclofenac (3O8Y: -8.5 Kcal/mol). The tested compounds were proven significant anti-inflammatory potentials.