Discovery of new benzothiazole-1,2,3-triazole hybrid-based hydrazone/thiosemicarbazone derivatives as potent EGFR inhibitors with cytotoxicity against cancer.

Considering the widespread availability of certain medicines, there is still a critical need for potent anti-cancer agents. It is owing to numerous negative impacts and non-functionality of current drugs, particularly during the late stages of illness. To accomplish this, the new array of 1,2,3-triazole-benzothiazole molecular conjugates tethering hydrazone/thiosemicarbazone linkage 8a-l have been successfully synthesized via the efficient copper-catalyzed 1,3-dipolar cycloaddition of the appropriate un/substituted benzothiazole azides 4a-c with several O-propargylated benzylidene derivatives 7a-d. The newly established 1,2,3-triazole structural hybrids were thoroughly characterized using appropriate spectroscopic techniques (IR, 1H, 13C-NMR & CHN analysis). The cytotoxic features of the investigated triazole hybrids were assessed against three human cancer cell lines, A549, T47-D, and HCT-116 cancer cells, using the MTT assay. Based on the findings, the breast cancer cell line T47D displayed promising results with IC50 values of 13, 17, and 19 μM for the synthesized molecules 8a-c, respectively. Furthermore, the safety assessment of these compounds on normal cell lines revealed a relatively low risk to normal cells, as indicated by their IC50 values exceeding 500 μM, suggesting a reasonable safety margin. Interestingly, the most relevant derivatives 8a, 8b, and 8c, exhibited IC50 values of 0.69, 1.16, and 4.82 μM, respectively, causing inhibition of 98.5%, 96.8%, and 92.3%, compared to Erlotinib (IC50 = 1.3 μM, 98.2% inhibition). Molecular docking results exhibited a good binding affinity of compounds 8a and 8b towards the EGFR active site. Accordingly, these compounds can be further developed as target-oriented EGFR chemotherapeutics against cancer.