Synthesis, Antibacterial Activity and Insilco Studies of 1-(2- ethyl acetate)-2-styryl 5-nitroimidazole Derivatives.
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Date
2023-05
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Addia Ababa University
Abstract
The proliferation of drug-resistant microorganisms that have acquired new resistance
mechanisms contributes to the development of antimicrobial resistance. For more than
60 years, metronidazole (2) has served as an antibacterial and antiprotozoal agent.
However, its prolonged usage has resulted in drug-resistance and associated with
adverse effects. Metronidazole is usually not effective on Gram-negative and Gram-
positive facultative anaerobic bacteria, which are considered as the most life-
threatening pathogens. However, there are reports of metronidazole analogues with
potent activity against the facultative anaerobic bacteria indicate that there is a different
mode of action of metronidazole. As a result, it is important to synthesize new
metronidazole analogs with unique mode of action in order to enhance the antibacterial
efficacy of metronidazole while reducing toxicity. Recent studies have shown that the
enzyme FabH (β-ketoacyl-acyl carrier protein synthase III), responsible for the first
step of fatty acid biosynthesis (FAB), is a promising target for nitroimidazole
derivatives that can be used as an effective anti-infective. In this study, we synthesized
four 2-styryl 5-nitroimidazoles derivatives, via condensation of metronidazole with
respective benzaldehydes and subsequent acetylation reactions. The chemical
structures of the synthesized compounds were determined through 1H and 13C-NMR
spectroscopy. We evaluated the antimicrobial activity of the synthesized compounds
against six bacterial strains, three Gram- positive bacterial strains (S. aureus, S.
epidermidus and S. agalactiae) and three Gram-negative bacterial strains (E. coli, P.
aeruginosa and K. pneumoniae) using a two-fold serial dilution MTT assay. Of all the
synthesized compounds, compound 33, ((E)-2-(5-nitro-2-styryl-1H-imidazol-1-
yl)ethyl acetate) and 36, ((E)-2-(2-(4-(dimethylamino)styryl)-5-nitro-1H-imidazol-1-
yl)ethyl acetate) equally demonstrated the most potent antibacterial activity against S.
agalactiae (MIC = 1.56 μg/mL), P. aeruginosa (3.13 μg/mL), respectively.
Additionally, compound 33 and 36 also exhibited potent activity against K. pneumonia,
with an MIC value of 6.25 μg/mL and 12.5 μg/mL, respectively. Molecular docking
studies revealed that both compounds have favorable hydrophobic and electrostatic
interactions with conserved residues in the binding site of E. coli FabH -CoA complex
(1HNJ.pdb). Overall acetylation of 2-styryl-5-nitroimidazoles improved both their
biological activity and binding interaction with the target protein.
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Keywords
Antibacterial activity, 2-styryl 5-nitroimidazoles, β-Ketoacyl-acyl carrier protein synthase III (FabH)