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

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 mu M. The CC50 of the most active substances was determined to be within 0.8-9.8 mu M. The conjugation between the pharmacophoric groups of sunitinib (indolinone) and imatinib through the formation of spirooxindoles produced a series of 25 derivatives. All of them had their inhibitory activities evaluated against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-ABL1 and against healthy cells. image