Synthesis and anticancer activity studies of new pyrazoline derivatives

In the current work, new thiazolyl-pyrazoline derivatives (3a-v) were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma and MCF-7 human breast adenocarcinoma cell lines. 1-(4-(4-Fluorophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3c), 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-morpholinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3f) and 1-(4-(4-cyanophenyl)thiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-chlorophenyl)-2-pyrazoline (3q) showed potent anticancer activity against A549 and MCF-7 cell lines as compared to erlotinib. Besides, these compounds exhibited selective cytotoxicity between Jurkat human leukemic T-cell line and PBMC. Compounds 3c, 3f and 3q were also searched for their apoptotic effects on A549 and MCF-7 cell lines and inhibitory potencies against eight different receptor tyrosine kinases (RTKs). The results indicated that compounds 3f and 3q induced apoptosis in both cell lines significantly and showed promising epidermal growth factor receptor (EGFR) inhibitory activity with IC50 values of 4.34±0.66 and 4.71±0.84 μM, respectively when compared with erlotinib (0.05±0.01 μM). Furthermore, compound 3f also inhibited HER2 and HER4 with IC50 values of 2.28±0.53 μM and 4.68±1.12 μM, respectively. According to molecular docking studies, compound 3f demonstrated high affinity into the binding sites of EGFR and HER2 forming important interactions. In vitro and in silico studies pointed out that compound 3f exhibited multi-targeted RTK inhibition and apoptosis induction.