Abstract
A series of fifteen new N-alkoxyphenylanilides of 3-hydroxynaphthalene-2-carboxylic acid was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium tuberculosis H37Ra and M. avium subsp. paratuberculosis. Some of the tested compounds showed antibacterial and antimycobacterial activity against the tested strains comparable with or higher than that of the standards ampicillin or rifampicin. 3-Hydroxy-N-(2-propoxyphenyl)naphthalene-2-carboxamide and N-[2-(but-2-yloxy)-phenyl]-3-hydroxynaphthalene-2-carboxamide had MIC = 12 µM against all methicillin-resistant S. aureus strains; thus their activity is 4-fold higher than that of ampicillin. The second mentioned compound as well as 3-hydroxy-N-[3-(prop-2-yloxy)phenyl]-naphthalene-2-carboxamide had MICs = 23 µM and 24 µM against M. tuberculosis respectively. N-[2-(But-2-yloxy)phenyl]-3-hydroxynaphthalene-2-carboxamide demonstrated higher activity against M. avium subsp. paratuberculosis than rifampicin. Screening of the cytotoxicity of the most effective antimycobacterial compounds was performed using THP-1 cells, and no significant lethal effect was observed for the most potent compounds. The compounds were additionally tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. N-(3-Ethoxyphenyl)-3-hydroxynaphthalene-2-carboxamide (IC50 = 4.5 µM) was the most active PET inhibitor. The structure-activity relationships are discussed.
Highlights
Recent studies have shown that, despite antibacterial therapy, methicillin-resistantStaphylococcus aureus (MRSA) infections are still associated with serious clinical consequences, especially treatment failure, higher morbidity and mortality [1], prolonged hospitalization [2], increased health care costs [2], etc
Because of M. tuberculosis, the pathogenic role of non-tuberculous mycobacteria (NTM) in humans was overshadowed for a long time
Based on the fact that the change in the colour of Alamar Blue is caused by a decrease of mycobacterial cell metabolism, it may be hypothesized that the mechanism of action of these N-alkoxyphenylamides of 3-hydroxynaphthalene-2-carboxylic acid could be connected with an effect on mycobacterial energy metabolism [32], we cannot rule out the possibility that the studied compounds acted upon a salicylanilides-like site present in the mycobacteria, as mentioned above ([7,8] and refs. therein)
Summary
Recent studies have shown that, despite antibacterial therapy, methicillin-resistantStaphylococcus aureus (MRSA) infections are still associated with serious clinical consequences, especially treatment failure, higher morbidity and mortality [1], prolonged hospitalization [2], increased health care costs [2], etc. Activity against MRSA is of a great importance in the new generation of antibacterial agents because of the worldwide increasing prevalence of this pathogen [3], more frequent antibiotic resistance to available anti-MRSA drugs, their toxicity and general lack of oral agents [4]. NTM have become more prevalent human pathogens, causing difficult-to-treat or incurable diseases, potentially ending in death when the patient is immunocompromised. NTM can cause a broad spectrum of diseases, such as pulmonary disease, lymphadenitis, skin and soft tissue disease, gastrointestinal and skeletal infections. They are resistant to standard antimycobacterial therapy, but may be susceptible to some standard antibiotics. The resistance to these antibiotics develops quickly [6]
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