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Open AccessArticle

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

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Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
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Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Pharmaceutical Chemistry Department, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 32241, Saudi Arabia
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Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
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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; https://doi.org/10.3390/molecules24244471
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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MDPI and ACS Style

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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