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

Una Glamočlija,Amar Osmanović,Marko Klobučar,Emira Kahrović,Irena Novaković,Iztok Turel,Anja Harej,Sandra Kraljević Pavelić,Selma Špirtović-Halilović,Davorka Završnik,Elma Veljović,Boris Mandić,Jakob Kljun,Snežana Trifunović,Sunčica Roca,Subhash Padhye

doi:10.3390/molecules23123297

Abstract

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.

Highlights

IntroductionTQ is a molecule withand numerous biological activities antimicrobial [8,9,10,11], antiepileptic, anti-inflammatory, antioxidant, anti-hypertensive [1], such as antitumor [3,4,5,6,7], antimicrobial [8,9,10,11], antiepileptic, anti-inflammatory, antioxidant, immunomodulatory and neuromodulatory [13]
ATQ was reacted with different aryl aldehydes to produce Schiff bases which underwent cyclization into corresponding benzoxazoles (Scheme 1)
The reaction itself has been well known for decades, reports are limited to the synthesis of benzobisoxazoles obtained by reacting two molar equivalents of aldehydes with 2,5-diaminoquinone [32,33], a reaction which was recently employed by the research group of

Summary

Introduction

TQ is a molecule withand numerous biological activities antimicrobial [8,9,10,11], antiepileptic, anti-inflammatory, antioxidant, anti-hypertensive [1], such as antitumor [3,4,5,6,7], antimicrobial [8,9,10,11], antiepileptic, anti-inflammatory, antioxidant, immunomodulatory and neuromodulatory [13]. There are examples of preparation of derivatives with improved disadvantage of TQ is its low aqueous solubility. There are examples of preparation of TQ derivatives solubility and biological effects [14,15,16,17,18].effects [14,15,16,17,18].

Methods

Results

Conclusion