In recent years, drug discovery paradigm has been shifted from conventional single target inhibition toward multitarget design concept. In current research, we have reported synthesis, in-vitro, in-vivo and acute toxicity determination of N-substituted pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents. We synthesized cycloalkyl, alkyl and aryl carbonyl derivatives by the Michael addition of ketones to N-substituted maleimides using self-assembled three component system as an organocatalyst. Anti-inflammatory potential of the compounds was determined by using different in-vitro assays, like cyclooxygenase-1, cyclooxygenase-2 and 5-lipoxygenase, albumin denaturation and anti-protease assays. Amongst the synthesized compounds, 13a-e series of compounds showed inhibition in low micromolar to submicromolar ranges. These compounds also demonstrated COX-2 selectivity. Compound 13e with IC50 value 0.98 μM and SI of 31.5 emerged as the most potent inhibitor of COX-2. Based on in-vitro results, in-vivo anti-inflammatory investigations were performed on compounds 3b and 13evia carrageenan induced paw edema test. The possible mode of action of compounds 3b and 13e were ascertained with various mediators like histamine, bradykinin, prostaglandin and leukotriene. In-vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The selectivity of the compounds against cyclooxygenase isoforms was supported by docking simulations. Selective COX-2 inhibitors showed significant interactions with the amino acid residues present in additional secondary COX-2 enzyme pocket. Furthermore, in-silico pharmacokinetic predictions confer the drug-like characteristics.
Keywords: 5-Lipoxygenase; Albumin denaturation; Cyclooxygenase-1/2; Michael addition; Protease inhibition; Succinimides.
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