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

Abstract

Thymoquinone (<b>TQ</b>), a natural compound with antimicrobial and antitumor activity, was used as the starting molecule for the preparation of 3-aminothymoquinone (<b>ATQ</b>) 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 (<b>1a</b>) has been determined by X-ray diffraction. All compounds were tested for their antibacterial, antifungal and antitumor activities. <b>TQ</b> and <b>ATQ</b> showed better antibacterial activity against tested Gram-positive and Gram-negative bacterial strains than benzoxazoles. <b>ATQ</b> had the most potent antifungal effect against <i>Candida albicans</i>, <i>Saccharomyces cerevisiae</i> and <i>Aspergillus brasiliensis</i>. Three benzoxazole derivatives and <b>ATQ</b> showed the highest antitumor activities. The most potent was 2-(4-fluorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (<b>1f</b>). 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 <b>TQ</b>, was 2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazole-5-ol (<b>1e</b>). Docking studies indicated that <b>1e</b> and <b>1f</b> have significant effects against selected receptors playing important roles in tumour survival.