Synthesis and Anti-Proliferative Assessment of Triazolo-Thiadiazepine and Triazolo-Thiadiazine Scaffolds

摘要

A series of triazolo-thiadiazepines – were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of . The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form – and not the enamine-tautomer – . The structures of the newly synthesized triazolo-thiadiazepines – and triazolo-thiadiazines – were elucidated using NMR ( H, and C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the tested cancer cell lines respectively, compared to doxorubicin (IC 4.0 µg/mL). Docking studies revealed that the thiadiazepine scaffold presented a suitable anchor, allowing good interaction of the various binding groups with the enzyme binding regions and sub-pockets.