Spirooxadiazoline‐oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells

Abstract

Imatinib mesylate was the first representative BCR‐ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR‐ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR‐ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS‐1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino‐pyrimidine‐pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro‐oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8–9.8 µM.