article · Journal of Enzyme Inhibition and Medicinal Chemistry
A new series of 2-aminobenzothiazole hybrid molecules linked to distinct chemical groups has been synthesised and evaluated for anticancer activity. In laboratory evaluations across colon, liver, and breast cancer cell lines, the compound designated 4a proved the most effective inhibitor, closely followed by compounds 4e and 8a which exhibited notable potency against breast cancer cells. All three selected compounds demonstrated low toxicity toward normal human cells. Further cellular investigations in breast cancer models revealed that compounds 4a and 4c halt cell progression in the S phase, whereas compound 8a halts cells at the G1/S phase boundary. In target enzyme assays, compound 4a served as an active inhibitor of VEGFR-2, with potency approaching that of the reference drug Sorafenib, while computational modelling confirmed successful binding within the target active site.
Cancer therapies often suffer from high toxicity toward healthy cells and limited efficacy against aggressive tumours. Developing novel chemical compounds that selectively suppress cancer cell proliferation and inhibit key disease-driving enzymes such as VEGFR-2, whilst sparing non-cancerous cells, is essential for designing safer and more targeted future oncology treatments.
This work identifies early-stage lead compounds for small-molecule oncology drug development, particularly targeted at VEGFR-2 inhibition. The prospective users would be medicinal chemistry programmes, biotechnology companies, and pharmaceutical developers focused on cancer therapeutics. Because the findings are currently limited to chemical synthesis, computational modelling, and in vitro cellular assays, the technology remains at an early discovery stage requiring extensive in vivo evaluation and pharmacokinetic profiling before any therapeutic development.
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A new series of 2-aminobenzothiazole hybrids linked to thiazolidine-2,4-dione <b>4a-e</b>, 1,3,4-thiadiazole aryl urea <b>6a-d,</b> and cyanothiouracil moieties <b>8a-d</b> was synthesised. The in vitro antitumor effect of the new hybrids was assessed against three cancer cell lines, namely, HCT-116, HEPG-2, and MCF-7 using Sorafenib (SOR) as a standard drug. Among the tested compounds, <b>4a</b> was the most potent showing IC50 of 5.61, 7.92, and 3.84 µM, respectively. Furthermore, compounds <b>4e</b> and <b>8a</b> proved to have strong impact on breast cancer cell line with IC50 of 6.11 and 10.86 µM, respectively. The three compounds showed a good safety profile towards normal WI-38 cells. Flow cytometric analysis of the three compounds in MCF-7 cells revealed that compounds <b>4a</b> and <b>4c</b> inhibited cell population in the S phase, whereas <b>8a</b> inhibited the population in the G1/S phase. The most promising compounds were subjected to a VEGFR-2 inhibitory assay where <b>4a</b> emerged as the best active inhibitor of VEGFR-2 with IC50 91 nM, compared to 53 nM for SOR. In silico analysis showed that the three new hybrids succeeded to link to the active site like the co-crystallized inhibitor SOR.
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DOI: 10.1080/14756366.2023.2166036
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