Abstract
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•New analogs of pyrrolidine-2,5-dione were designed and synthesized.•The synthesized derivatives were evaluated against COX-1/2 and 5LOX.•The sulfonamide derivative 67 displayed preferential COX-2 affinity in nanomolar range.•Mechanism of inflammation was determined.•Docking studies were carried out.
Dual inhibition of the enzymatic pathways of cyclooxygenases (COX-1/COX-2) and lipoxygenase (LOX) is a rational approach for developing more efficient and safe anti-inflammatory agents. Herein, dual inhibitors of COX and LOX for the management of inflammation are reported. The structural modifications of starting pyrrolidine-2,5-dione aldehyde derivatives resulted in two structurally diverse families (Family A &B). Synthesized derivatives from both Families displayed preferential COX-2 affinity in submicromolar to nanomolar ranges. Disubstitution pattern of the most active series of compounds having N-(benzyl(4-methoxyphenyl)amino moiety presents a new template that is mimic to the diaryl pattern of traditional COX-2 inhibitors. Compound 78 with IC50 value of 0.051 ± 0.001 μM emerged as the most active compound. Highly potent COX-2/5-LOX inhibitors have also demonstrated appreciable in-vivo anti-inflammatory activity through carrageenan induced paw edema test. Moreover, the involvement of histamine, bradykinin, prostaglandin, and leukotriene mediators to adjust the inflammatory response were also studied. Apart from COX inhibition, sulfonamide is considered an important template for carbonic anhydrase inhibition. Hence, we also evaluated six sulfonamide derivatives for off-target in-vitro bovine carbonic anhydrase-II inhibition. Biological results were finally rationalized by docking simulations. Typically, most active COX-2 inhibitors interact with the amino acid residues responsible for the COX-2 selectivity.