Optimization of pyrrolizine-based Schiff bases with 4-thiazolidinone motif: Design, synthesis and investigation of cytotoxicity and anti-inflammatory potency.

Two new series of pyrrolizine-5-carboxamides were synthesized and evaluated for their anticancer and anti-inflammatory activities. The new compounds exhibited potent cytotoxicity (IC 50 = 0.10–22.96 μM) against three cancer (MCF-7, A2780 and HT29) cell lines with selectivity index in the range of 1–258. Moreover, these compounds also exhibited significant anti-inflammatory activity (18.13–44.51% inhibition of inflammation) mediated by inhibition of COX-1/2 with preferential inhibition of COX-2. The study of SAR revealed favorable cytotoxic outcomes of the aliphatic side chain and 4-thiazolidinone moiety at C6 of the pyrrolizine nucleus, while anti-inflammatory activities was improved with the (hetero)aromatic substituents. The IC 50 values which inhibit COX-2 were higher than those needed to inhibit the growth of cancer cell lines. Mechanistic studies also revealed inhibition of multiple kinases by compounds 12 , 19 and 22. Moreover, compounds 12 , 14 , 16 and 22 induced cell cycle arrest and apoptosis in MCF-7 cells. Docking studies revealed nice fitting of the new compounds into COX-1/2. Additionally, compounds 12 , 19 and 22 also exhibited higher affinity for CDK2 than CAN508. To sum up, the above-mentioned data highlight these compounds as promising anti-inflammatory and anticancer agents. Image 1 • Two new series of pyrrolizines bearing Schiff bases or 4-thiazolidinone moiety were synthesized and evaluated for their cytotoxic activity. • Compound 22 induced G1 cell cycle arrest and apoptosis in MCF-7 cells. • Compounds 12 , 19 and 22 displayed inhibitory activity against CDK2 (IC 50 = 0.58–1.27 μM). • Compounds 14 exhibited potent in vivo anti-inflammatory activity mediated by COX-2 inhibition (IC 50 = 0.64 μM). • Binding modes of the new compounds into COXs, CDK2, Aurora A, BRAF and EGFR enzymes were investigated. [ABSTRACT FROM AUTHOR]