5-Aryl-1-Arylideneamino-1H-Imidazole-2(3H)-Thiones: Synthesis and In Vitro Anticancer Evaluation.

A novel series of N-1 arylidene amino imidazole-2-thiones were synthesized, identified using IR, 1H-NMR, and 13C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines; MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative 5 was the most potent of all against three cell lines. DNA flow cytometric analysis showed that, imidazoles 4d and 5 exhibit pre-G1 apoptosis and cell cycle arrest at G2/M phase. The results of the VEGFR-2 and B-Raf kinase inhibition assay revealed that compounds 4d and 5 displayed good inhibitory activity compared with reference drug erlotinib.

EGFR/VEGFR-2 dual inhibitor and apoptotic inducer: Design, synthesis, anticancer activity and docking study of new 2-thioxoimidazolidin-4one derivatives.

AIMS: EGFR and VEGFR-2 have emerged as promising targets for cancer management as they play a crucial role in tumor growth, angiogenesis and metastasis. A novel series of 2-thioxoimidazolidin-4-one derivatives were synthesized and evaluated as apoptotic inducers and EGFR/VEGFR-2 dual inhibitors. MAIN METHODS: The cytotoxic activities of all synthesized compounds were tested against MCF-7, HepG2 and A549 cell lines. The molecular mechanism of the most promising cytotoxic compounds was investigated via a series of assays including in vitro EGFR and VEGFR-2 inhibitory activity in MCF-7 cell line. Additionally, levels of p53, Bax, Bcl-2, caspase 7, 9 as well as cell cycle analysis were assessed in MCF-7 cell line to gain better understanding of their apoptotic activity. Molecular docking study was carried out to predict binding pattern of these compounds with EGFR and VEGFR-2 active sites. Finally, in silico ADME and drug-likeness profiling were calculated. KEY FINDINGS: Compounds 6 and 8a exhibited superior cytotoxic activity compared to sorafenib and erlotinib, against the three tested cell lines. In the same context, 6 and 8a showed better EGFR and VEGFR-2 inhibitory activity compared to the reference compounds. The later effect was further supported by the docking study. Furthermore, these compounds displayed potent apoptotic activity as evident by cell accumulation at pre-G1 phase and cell cycle arrest at G2/M phase together with increased p53, caspae-7 and caspase-9 levels and Bax/Bcl-2 ratio. Finally, synthesized compounds have acceptable drug likeness. SIGNIFICANCE: Compounds 6 and 8a act as potent dual EGFR/VEGFR-2 inhibitors with evident apoptotic activity.

Design, synthesis, and cytotoxicity screening of new synthesized imidazolidine-2-thiones as VEGFR-2 enzyme inhibitors.

A series of imidazolin-2-thione derivatives was synthesized and structurally confirmed through the use of different spectroscopic techniques such as infrared, nuclear magnetic resonance, and mass spectrometry along with elemental analyses. The breast cancer cell line MCF-7 was utilized in the evaluation of the cytotoxic activity of the prepared molecules. The tested molecules 3 and 7 exhibited the best results on MCF-7 cells, with mean IC50 values of 3.26 and 4.31 µM, respectively. The results of the VEGFR-2 assay indicated that compounds 3 and 7 displayed a good inhibition of the VEGFR-2 kinase enzyme. Additionally, DNA flow cytometry of compounds 3 and 7 showed cell cycle arrest at the G0/G1 phase, cell apoptosis, and marked DNA fragmentation in MCF-7 cells. Finally, compounds 3 and 7 were proved to upregulate the activation of effector caspase-3/7, as presented by the caspase-3/7 green flow cytometry assay.