Abstract
Infections caused by drug-resistant bacteria are a serious threat to human and global public health. Moreover, in recent years, very few antibiotics have been discovered and developed by pharmaceutical companies. Therefore, there is an urgent need to discover and develop new antibacterial agents to combat multidrug-resistant bacteria. In this study, two novel series of juglone/naphthazarin derivatives (43 compounds) were synthesized and evaluated for their antibacterial properties against various clinical and reference Gram-positive MSSA, clinical Gram-positive MRSA, and clinical and reference Gram-negative bacteria E. coli and P. aeruginosa. These strains are of clinical importance because they belong to ESKAPE pathogens. Compounds 3al, 5ag, and 3bg showed promising activity against clinical and reference MSSA (MIC: 1–8 µg/ml) and good efficacy against clinical MRSA (MIC: 2–8 µg/ml) strains. 5am and 3bm demonstrated better activity on both MSSA (MIC: 0.5 µg/ml) and MRSA (MIC: 2 µg/ml) strains. Their MICs were similar to those of cloxacillin against clinical MRSA strains. The synergistic effects of active compounds 3al, 5ag, 5am, 3bg, and 3bm were evaluated with reference antibiotics, and it was found that the antibiotic combination with 3bm efficiently enhanced the antimicrobial activity. Compound 3bm was found to restore the sensitivity of clinical MRSA to cloxacillin and enhanced the antibacterial activity of vancomycin when they were added together. In the presence of 3bm, the MIC values of vancomycin and cloxacillin were lowered up to 1/16th of the original MIC with an FIC index of 0.313. Moreover, compounds 3al, 5ag, 5am, 3bg, and 3bm did not present hemolytic activity on sheep red blood cells. In silico prediction of ADME profile parameter results for 3bm is promising and encouraging for further development.
Highlights
The introduction of antibiotics into clinical use was the major therapeutic advance of the 20th century (Trémolières, 2010)
With the aim of seeking further antibacterial active substances, we report the synthesis of two classes of 1,4naphthoquinone derivatives and the X-ray structural determination of two compounds
The final compounds were fully characterized by 1H nuclear magnetic resonance (NMR), 13C NMR, heteronuclear multiple bond correlation (HMBC), and infrared (IR) spectroscopy; high-performance liquid chromatography (HPLC); and high-resolution mass spectrometry (HRMS)
Summary
The introduction of antibiotics into clinical use was the major therapeutic advance of the 20th century (Trémolières, 2010). Increasing resistance to conventional drugs by strains such as methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa (P. aeruginosa), and Escherichia coli (E. coli) is pushing us to find new classes of antibiotics to circumvent multidrug-resistant infections These pathogens belonging to the ESKAPE group are a priority for the development of new compounds with antibacterial properties (Mulani et al, 2019). Evaluation of the adjuvant effect of the synthesized molecules on clinical resistant bacteria revealed potential restoration of activity between newly synthesized compounds and reference antibiotics. These evaluations against resistant bacteria, known to cause therapeutic problems in hospitals, are less reported in the literature. We determined the in vitro hemolytic activity of the most active compounds and the in silico ADME parameters of all compounds
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