Synthesis and anticancer activity evaluation of new linked/fused bioisosteric pyrazole-thiazole-bearing hybrid molecules

Molecular hybridization is a rational strategy for the design of new heterocyclic molecules with potential anticancer activity. Two series of linked and fused bioisosteric pyrazole-thiazole-bearing hybrid molecules were synthesized as promising anticancer agents. Synthetic approaches based on aminolysis and Knoevenagel condensation were used for the creation of target 5-ene-4-((5-methyl-1H-pyrazol-3-yl)amino)thiazol-2(5H)-ones 3a–d and their fused analogs - pyrazolo[3,4-b]thiazolo[5,4-e]pyridines 4a–f. The structure of these hybrids was confirmed by means of NMR/LC-MS spectra and X-ray analysis. Novel pyrazole-thiazole hybrid molecules were screened on “60 lines screening” (DTP NCI) and a panel of human cancer cell lines. The derivative 3b was identified as the most active molecule against leukemic cell line CCRF-CEM (GI₅₀ = 1.01 μM), while the compound 3c demonstrated the highest toxicity towards human leukemia Jurkat T-cells (IC₅₀ = 5.66 ± 0.61 μM) and induced apoptotic DNA fragmentation in these cells (40.90 ± 1.07 %). It was also highly toxic for MCF-7 breast adenocarcinoma cells (IC₅₀ = 2.17 ± 0.36 μM). At the same time, the compound 3c exhibited low toxicity towards pseudo-normal cells of HaCaT (IC₅₀ = 68.23 ± 0.54 μM), BALB/3T3 (IC50 = 56.03 ± 0.54 μM), and Mv1Lu (IC₅₀ = 50.05 ± 0.44 μM) lines. A significant difference in the anticancer activity in vitro was detected between synthesized derivatives and linked hybrids which showed higher activity compared to fused analogs. Pharmacokinetic analysis of the developed molecules 3a–c predicts their potential as promising anticancer agents with further need in investigation of the mechanisms of their action.