1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights

Abstract

Human health is experiencing several obstacles in the modern medical era, particularly cancer. As a result, the cancer therapeutic arsenal should be continually expanded with innovative small molecules that preferentially target tumour cells. In this study, we describe the development of two small molecule series (7a–d and 12a–e) based on the 1-benzyl-5-bromoindolin-2-one scaffold that connected through a hydrazone linker to a 4-arylthiazole (7a–d) or 4-methyl-5-(aryldiazenyl)thiazole (12a–e) moiety. The anticancer activity of all the reported indolin-2-one derivatives was assessed against breast (MCF-7) and lung (A-549) cancer cell lines. The 4-arylthiazole-bearing derivatives 7c and 7d revealed the best anticancer activity toward MCF-7 cells (IC50 = 7.17 ± 0.94 and 2.93 ± 0.47, respectively). Furthermore, the VEGFR-2 inhibitory activity for 7c and 7d was evaluated. Both molecules disclosed good inhibitory activity, and their IC50 values were equal to 0.728 µM and 0.503 µM, respectively. Additionally, the impacts of 7d on the cell cycle phases as well as on the levels of different apoptotic markers (caspase-3, caspase-9, Bax, and Bcl-2) were assessed. Molecular docking and dynamic simulations are carried out to explore the binding mode of 7d within the VEGFR-2 active site.

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

“…In first, the intermediate building blocks pyrazoline carbothioamide intermediates 1a, b were accomplished by the reaction of precursor chalcone derivatives with thiosemicarbazide [48,53] (Scheme 1). The latter carbothioamides 1a, b were refluxed with hydrazonoyl chloride derivatives (2a-d) [42] in absolute ethanol to form the S-alkylated non-isolable intermediate 3a-h, which could undergo cyclization via nucleophilic addition followed by the loss of water, in case of 2a, b; R 1 = Me, or the loss of ethanol, in case of 2c, d; R 1 = OEt, to furnish the 5-(aryldiazenyl)4-methylthiazoles 4a-d and 2-(arylhydrazineylidene)thiazol-4(5H)-ones 5a-d, respectively (Scheme 1).…”

“…Furthermore, phenylthiazolyl-pyrazoline IV [41] and compound V exhibited potent cytotoxicity for MCF-7 with EGFR inhibition (IC 50 = 9 and 31 nM, respectively) [27]. For compound VI, it displayed antiproliferative activity for the breast cancer T-47D cell line with inhibition activity toward EGFR (IC 50 = 83 nM) [42] (Figure 1). According to the above data and in continuation of our scholarly interest in the chemistry of thiazolyl-pyrazolines and their biological activities [43][44][45], especially as possible anticancer agents [27,46,47], our objective was to enhance and modify a novel series of innovative thiazolyl-pyrazoline derivatives (4a-d, 5a-d, 6a, b, 7a-d, 8a, b, and 10a, b) as According to the above data and in continuation of our scholarly interest in the chemistry of thiazolyl-pyrazolines and their biological activities [43][44][45], especially as possible anticancer agents [27,46,47], our objective was to enhance and modify a novel series of innovative thiazolyl-pyrazoline derivatives (4a-d, 5a-d, 6a, b, 7a-d, 8a, b, and 10a, b) as potential dual-inhibitors against EGFR/HER2 with possible enhancement of their antiproliferative activities depending on introducing bioactive fragments like aryl-diazinyl, arylidene, isatin, or coumarin substitutions into the thiazole-pyrazoline combination as the core center (Figure 1).…”