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

Abstract

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 <i>via</i> the efficient copper-catalyzed 1,3-dipolar cycloaddition of the appropriate un/substituted benzothiazole azides 4a-c with several <i>O</i>-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.