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Open AccessArticle

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

Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
Pharmaceutical Chemistry Department, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 32241, Saudi Arabia
Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh, 11451, Saudi Arabia
Authors to whom correspondence should be addressed.
Molecules 2019, 24(24), 4471;
Received: 6 November 2019 / Revised: 29 November 2019 / Accepted: 4 December 2019 / Published: 6 December 2019
(This article belongs to the Section Organic Chemistry)
A series of triazolo-thiadiazepines 4ak 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 4ak and not the enamine-tautomer 6ak. The structures of the newly synthesized triazolo-thiadiazepines 4ak and triazolo-thiadiazines 8ab 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. View Full-Text
Keywords: 4-Amino-1,2,4-triazolethione; Chalcone; PTSA; Thiadiazepine; HEPG-2; MCF-7; EGFR 4-Amino-1,2,4-triazolethione; Chalcone; PTSA; Thiadiazepine; HEPG-2; MCF-7; EGFR
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Boraei, A.T.A.; Ghabbour, H.A.; Gomaa, M.S.; El Ashry, E.S.H.; Barakat, A. Synthesis and Anti-Proliferative Assessment of Triazolo-Thiadiazepine and Triazolo-Thiadiazine Scaffolds. Molecules 2019, 24, 4471.

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