Synthesis of Quinoline-Thiazolidine-2,4-dione Coupled Pyrazoles as in vitro EGFR Targeting Anti-Breast Cancer Agents and Their in silico Studies

摘要

The synthesis of some new quinoline-thiazolidine-2,4-dione coupled pyrazoles (7a-7n) via Knoevengal condensation, N-alkynylation and tandem one-pot Sonogashira coupling-cyclo-condensation paths was described. All the compounds were further evaluated for their in vitro anti-breast cancer activity against MDA-MB-231 and MCF-7 and results were compared with standard drug erlotinib. Most of analogues were potent against MCF-7 than the MDA-MB-231. In specific, compounds (Z)-3-((3-(4-methoxyphenyl)-1H-pyrazol-5-yl)methyl)-5-(quino-lin-4-ylmethylene) thiazolidine-2,4-dione (7d) and (Z)-5-(5-((2,4-dioxo-5-(quinolin-4-ylmethylene)thiazolidin-3-yl)methyl)-1H-pyrazol-3-yl)isophthalonitrile (7 m) had superior potency against MCF-7 and MDA-MB-231 with IC_(50) (μg/mL) values ranging from 2.13 to 6.07. Besides, compounds (Z)-3-((3-(3,5-dimethoxyphenyl)-1H-pyrazol-5-yl)methyl)-5-(quinolin-4ylmeth-ylene)thiazolidine-2,4-dione (7e), (Z)-3-((3-(4-chlorophenyl)-1H-pyrazol-5-yl)methyl)-5-(quinolin-4-ylmethylene)thiazolidine-2,4- dione (7h), (Z)-4-(5-((2,4-dioxo-5-(quinolin-4-ylmeth- ylene)thiazolidin-3-yl)methyl)-1H-pyrazol-3-yl)benzonitrile (7i) and (Z)-3-((3-(4-nitrophenyl)-1H-pyrazol-5-yl)methyl)-5-(quino-lin-4-ylmethylene)thiazolidine-2,4-dione (7j) showed most promising potency against MCF-7 with IC_(50) values 5.97-6.43 μg/ mL. The ability of compounds 7d, 7e, 7h, 7i, 7j and 7m to inhibit EGFR tyrosine kinase was also studied and found that compounds 7d and 7m showed remarkable potency as compared to erlotinib with inhibition 87.6% and 91.4% respectively. Molecular docking studies were then carried out for most potent compounds 7d, 7i, and 7m and erlotinib on EGFR, and these compounds had encouraging binding energies and inhibition constants in comparison to erlotinib. Finally, compounds 7d, 7i and 7m have high intestinal absorption with Caco-2 permeability and followed Lipinski rules without any deviation.