A rationale approach in developing proline based small peptide as U-shaped analogues of arachidonic acid: Dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for developing anti-inflammatory agents

Guided by the molecular modelling studies, here, we report the development of small molecules containing Pro-Pro, Gly-Pro-Pro ester motifs as dual inhibitors of COX-2 and 5-LOX enzymes. The synthesized compounds exhibited potent inhibitory activities against COX-2 and 5-LOX, with IC₅₀ values in nanomolar range. Lineweaver-Burk plot analysis revealed that these molecules act as competitive inhibitors of COX-2 and 5-LOX. In vivo studies using the HET-CAM assay indicated that the compounds exhibit moderate to good anti-inflammatory effects. Hence, taking into account the physicochemical properties, including aqueous solubility, binding affinity to HSA and stability in blood plasma and liver microsomes, anti-inflammatory agents targeting dual pathways of arachidonic acid metabolism are identified.