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Synthesis, Biological Evaluation and Docking Studies of Benzoxazoles Derived from Thymoquinone

Scientific Research Department, Bosnalijek JSC, Jukićeva 53, 71000 Sarajevo, Bosnia and Herzegovina
School of Medicine, University of Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina
Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne 8, 71000 Sarajevo, Bosnia and Herzegovina
Interdisciplinary Science and Technology Research Academy, University of Pune, 2390-B, Hidayatullah Road, 411001 Pune, India
NMR Centre, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
ICTM, Center for Chemistry, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia
Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
Department of Chemistry, Faculty of Science, University of Sarajevo, Zmaja od Bosne 35, 71000 Sarajevo, Bosnia and Herzegovina
Centre for High-throughput Technologies, Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia
Author to whom correspondence should be addressed.
Molecules 2018, 23(12), 3297;
Received: 15 November 2018 / Revised: 30 November 2018 / Accepted: 2 December 2018 / Published: 12 December 2018
(This article belongs to the Section Medicinal Chemistry)
Thymoquinone (TQ), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (ATQ) from which ten novel benzoxazole derivatives were prepared and characterized by elemental analysis, IR spectroscopy, mass spectrometry and NMR (1H, 13C) spectroscopy in solution. The crystal structure of 4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazole-5-ol (1a) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. TQ and ATQ showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. ATQ had the most potent antifungal effect against Candida albicans, Saccharomyces cerevisiae and Aspergillus brasiliensis. Three benzoxazole derivatives and ATQ showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1f). Western blot analyses have shown that this compound inhibited phosphorylation of protein kinase B (Akt) and Insulin-like Growth Factor-1 Receptor (IGF1R β) in HeLa and HepG2 cells. The least toxic compound against normal fibroblast cells, which maintains similar antitumor activities as TQ, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (1e). Docking studies indicated that 1e and 1f have significant effects against selected receptors playing important roles in tumour survival. View Full-Text
Keywords: thymoquinone; benzoxazoles; anticancer activity; antimicrobial activity; western blotting; molecular docking thymoquinone; benzoxazoles; anticancer activity; antimicrobial activity; western blotting; molecular docking
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Glamočlija, U.; Padhye, S.; Špirtović-Halilović, S.; Osmanović, A.; Veljović, E.; Roca, S.; Novaković, I.; Mandić, B.; Turel, I.; Kljun, J.; Trifunović, S.; Kahrović, E.; Kraljević Pavelić, S.; Harej, A.; Klobučar, M.; Završnik, D. Synthesis, Biological Evaluation and Docking Studies of Benzoxazoles Derived from Thymoquinone. Molecules 2018, 23, 3297.

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