Abstract
In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a–n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds 8e and 8n were found to be the most active congeners against MCF-7 cells (IC50 = 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC50 = 1.93 µM). Moreover, eight selected pyridines 8b, 8d, 8e, 8i, 8j and 8l–n were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines 8b and 8e proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both 8b and 8e exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for 8b; 12–78%, GI for 8e; 15–91%). Pyridines 8b and 8e were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC50 values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study.
Highlights
Cancer represents one of the most important health problems worldwide because it is deemed to be the second major cause of mortality throughout the world after cardiovascular diseases
We report the synthesis of a novel series of pyridine-ureas 8a–n
All the prepared pyridines were evaluated for their anti-proliferative activity towards the breast cancer
Summary
Cancer represents one of the most important health problems worldwide because it is deemed to be the second major cause of mortality throughout the world after cardiovascular diseases. The high mortality rate that occurs in cancer patients is due to the late diagnosis, and the delayed initiation of the medical treatment of the disease. There are a large number of chemotherapeutic drugs available, the medical need is still largely unmet. GLOBOCAN statistics, about 14.1 million newly diagnosed cancer cases were recorded. Among the newly diagnosed cases in females, breast cancer ranked in the first position worldwide and was regarded as the main cause of deaths attributed to cancer [1,2].
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