article · Molecules
A novel series of pyridine-urea compounds, designated 8a to 8n, has been synthesised and tested in laboratory models as potential anticancer candidates. When evaluated against the MCF-7 breast cancer cell line, two variants, 8e and 8n, demonstrated higher inhibitory potency than the standard chemotherapy drug doxorubicin. Further testing across a broader panel of cancer cell lines through the United States National Cancer Institute protocol confirmed that compounds 8b and 8e possessed the strongest antiproliferative effects, inhibiting growth across all tested cancer types. In enzyme assays, both 8b and 8e also demonstrated inhibitory activity against VEGFR-2, a target linked to tumour blood vessel formation. Computational screening confirmed that the most active compounds met standard drug-likeness rules, and theoretical kinetic studies provided initial predictions of their absorption, distribution, metabolism, and excretion properties.
Cancer treatments often face limitations due to drug resistance and adverse side effects, driving the need for new therapeutic options. Identifying synthetic small molecules that halt cancer cell division and inhibit enzymes responsible for tumour progression offers potential starting points for developing targeted therapies that may eventually outperform existing clinical drugs.
This research provides early-stage chemical leads for pharmaceutical developers and oncology drug discovery programmes. Because the work is limited to laboratory cell assays, enzyme inhibition tests, and computational drug-likeness evaluations, these pyridine-urea compounds remain at the early discovery phase and require extensive preclinical validation, animal toxicity studies, and pharmacokinetic testing before entering clinical translation.
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In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas <b>8a</b>⁻<b>n</b> 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 <b>8e</b> and <b>8n</b> were found to be the most active congeners against MCF-7 cells (IC<sub>50</sub> = 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 (IC<sub>50</sub> = 1.93 µM). Moreover, eight selected pyridines <b>8b</b>, <b>8d</b>, <b>8e</b>, <b>8i</b>, <b>8j</b> and <b>8l</b>⁻<b>n</b> were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines <b>8b</b> and <b>8e</b> proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both <b>8b</b> and <b>8e</b> exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for <b>8b</b>; 12⁻78%, GI for <b>8e</b>; 15⁻91%). Pyridines <b>8b</b> and <b>8e</b> were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC<sub>50</sub> 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.
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DOI: 10.3390/molecules23061459
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