Synthesis, biological activity and in silico study of alkyl eugenol derivatives as Mycobacterium tuberculosis inhibitors

Abstract

Since ancient times, tuberculosis (TB) has been a fatal infectious disease, made even more difficult to treat with the emergence of drug-resistant strains. The present work aimed to evaluate the antituberculosis activity of newly synthesized eugenol derivatives, and their iron chelation ability as well. The mycobacterium H37Rv strain was sensitive to all tested compounds. The compounds 2-methoxy-4-propenyl-1-propynyloxybenzene (1), 3,5-bis(trifluoromethyl) benzyloxy-2-methoxy-4-propenylbenzene (3) and ethyl 2-methoxy-4-propenylphenylcarbonate (5) showed the best growth inhibitory activity at a concentration of 10 µg/mL. Also, a considerable iron chelation activity for 1 and 5 translated by EC50 values of 0.94 and 0.33 µg/mL, respectively. Generally, the synthesized derivatives illustrated an encouraging in silico pharmacokinetic profile. The molecular docking study revealed that compound 3 exhibited the excellent binding affinity within the active sites of MabA and PanK targets, involving hydrogen bond interactions, fluorine interactions and hydrophobic interactions. Our results suggest that compound 3 could potentially act via the inhibition of MabA and PanK proteins. While, derivatives 1 and 5 could have a potential iron chelation mechanism against mycobacterial growth.