New Thiazolyl-Pyrazoline Derivatives as Potential Dual EGFR/HER2 Inhibitors: Design, Synthesis, Anticancer Activity Evaluation and In Silico Study

Abstract

A new series of thiazolyl-pyrazoline derivatives (4a–d, 5a–d 6a, b, 7a–d, 8a, b, and 10a, b) have been designed and synthesized through the combination of thiazole and pyrazoline moieties, starting from the key building blocks pyrazoline carbothioamides (1a–b). These eighteen derivatives have been designed as anticipated EGFR/HER2 dual inhibitors. The efficacy of the developed compounds in inhibiting cell proliferation was assessed using the breast cancer MCF-7 cell line. Among the new synthesized thiazolyl-pyrazolines, compounds 6a, 6b, 10a, and 10b displayed potent anticancer activity toward MCF-7 with IC50 = 4.08, 5.64, 3.37, and 3.54 µM, respectively, when compared with lapatinib (IC50 = 5.88 µM). In addition, enzymatic assays were also run for the most cytotoxic compounds (6a and 6b) toward EGFR and HER2 to demonstrate their dual inhibitory activity. They revealed promising inhibition potency against EGFR with IC50 = 0.024, and 0.005 µM, respectively, whereas their IC50 = 0.047 and 0.022 µM toward HER2, respectively, compared with lapatinib (IC50 = 0.007 and 0.018 µM). Both compounds 6a and 10a induced apoptosis by arresting the cell cycle of the MCF-7 cell line at the G1 and G1/S phases, respectively. Molecular modeling studies for the promising candidates 6a and 10a showed that they formed the essential binding with the crucial amino acids for EGFR and HER2 inhibition, supporting the in vitro assay results. Furthermore, ADMET study predictions were carried out for the compounds in the study.

Identification of dual-target isoxazolidine-isatin hybrids with antidiabetic potential: Design, synthesis, in vitro and multiscale molecular modeling approaches

“…Computer-aided ADMET (absorption, distribution, metabolism, excretion, and toxicity) screening was performed for the most potent analogue 5d to differentiate between drug-like and non-drug-like and to improve the quality control of drugs at the earliest stages in their development, using different computational approaches [ [78] , [79] , [80] , [81] , [82] ]. In the present work, ADMET properties of 5d were computed using swissADME, pre-ADMET and pKCSM tools.…”

Design, Synthesis and Biological Assessment of N′-(2-Oxoindolin-3-ylidene)-6-methylimidazo[2,1-b]thiazole-5-carbohydrazides as Potential Anti-Proliferative Agents toward MCF-7 Breast Cancer

“…In continuation to our research, which deals with the discovery of novel potent anticancer agents [ 23 , 24 , 25 , 26 , 27 , 28 ], herein we utilized the fragment linking strategy to construct novel anti-proliferative agents for MCF-7 breast cancer therapy and evaluated their effectiveness on VEGFR enzyme inhibition.…”