A series of triazolo-thiadiazepines 4a-k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a-k and not the enamine-tautomer 6a-k. The structures of the newly synthesized triazolo-thiadiazepines 4a-k and triazolo-thiadiazines 8a-b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a 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 IC50 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 (IC50 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.
Keywords: 4-Amino-1,2,4-triazolethione; Chalcone; EGFR; HEPG-2; MCF-7; PTSA; Thiadiazepine.