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

Abstract

AbstractThe synthesis of some new quinoline‐thiazolidine‐2,4‐dione coupled pyrazoles (7 a–7 n) via Knoevengal condensation, N‐alkynylation and tandem one‐pot Sonogashira coupling‐cyclocondensation 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‐(quinolin‐4‐ylmethylene) thiazolidine‐2,4‐dione (7 d) 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 IC50 (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‐4ylmethylene)thiazolidine‐2,4‐dione (7 e), (Z)‐3‐((3‐(4‐chlorophenyl)‐1H‐pyrazol‐5‐yl)methyl)‐5‐(quinolin‐4‐ylmethylene)thiazolidine‐2,4‐dione (7 h), (Z)‐4‐(5‐((2,4‐dioxo‐5‐(quinolin‐4‐ylmethylene)thiazolidin‐3‐yl)methyl)‐1H‐pyrazol‐3‐yl)benzonitrile (7 i) and (Z)‐3‐((3‐(4‐nitrophenyl)‐1H‐pyrazol‐5‐yl)methyl)‐5‐(quinolin‐4‐ylmethylene)thiazolidine‐2,4‐dione (7 j) showed most promising potency against MCF‐7 with IC50 values 5.97‐6.43 μg/mL. The ability of compounds 7 d, 7 e, 7 h, 7 i, 7 j and 7 m to inhibit EGFR tyrosine kinase was also studied and found that compounds 7 d and 7 m 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 7 d, 7 i, and 7 m and erlotinib on EGFR, and these compounds had encouraging binding energies and inhibition constants in comparison to erlotinib. Finally, compounds 7 d, 7 i and 7 m have high intestinal absorption with Caco‐2 permeability and followed Lipinski rules without any deviation.