1,2,3-Triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids: A switch for improvement of antibreast cancer activity targeting epidermal growth factor receptor

• Published in: Tetrahedron letters 2024-08, Vol.146, p.155180, Article 155180
• Main Authors: Telukuntla, Praveen, Chandrakanth, Munugala, Amrutha, P.G., Thomas, Neethu Mariam, Gondru, Ramesh, Valluru, Krishna Reddy, Banothu, Janardhan
• Format: Article
• Language: English
• Subjects: Anticancer; EGFR; Molecular docking; Thiadiazine; Triazole
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2024.155180

[Display omitted] •Synthesized a series of phenyl-linked 1,2,3-triazole–[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids via click reaction.•Hybrids 7f and 7h, exhibited superior in vitro anti-breast cancer activity compared to the standard drug Erlotinib.•Hybrids 7f and 7h demonstrated high efficacy in the in vitro EGFR inhibition assay when compared with Erlotinib.•Docking and ADMET studies suggest that compounds 7f and 7h hold promise as leads for further drug design and development. The development of anticancer agents targeting EGFR represents a promising strategy in the field of medicinal chemistry. Consequently, a novel series of 1,2,3-triazole – [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hybrids (7a-i &8a-f) were designed, synthesized, and screened for their in vitro anticancer activity against three human breast cancer cell lines, MCF-7, MDA-MB-231, and MDA-MB-415. Notably, hybrids 7f and 7h, featuring 4-fluorophenyl and 3,5-dichlorophenyl substitutions, respectively, exhibited superior activity against MCF-7 and MDA-MB-231 cell lines, and comparable activity against MDA-MB-415 cell line, compared to the standard drug Erlotinib. Toxicity studies on the noncancerous breast cell line MCF-10A indicate that these compounds are selective for cancer cell lines. Furthermore, these compounds demonstrated high efficacy in the in vitro EGFR inhibition assay, with IC50 values of 0.419 ± 0.05 μM and 0.312 ± 0.02 μM, respectively, in comparison to Erlotinib (IC50: 0.421 ± 0.03 μM). In silico experiments, including molecular docking studies to elucidate the interaction mode with the EGFR active site and ADMET analysis to verify drug-likeness properties, were also conducted for the potent compounds. Both experimental and in silico investigations suggest that compounds 7f and 7h hold promise as lead compounds for further drug design and development endeavors.