Abstract
A series of nineteen N-(alkoxyphenyl)-2-hydroxynaphthalene-1-carboxamides and a series of their nineteen positional isomers N-(alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides were prepared and characterized. Primary in vitro screening of all the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, M. kansasii and M. smegmatis. Screening of the cytotoxicity of the compounds was performed using human monocytic leukemia THP-1 cells. Some of the tested compounds showed antimycobacterial activity comparable with or higher than that of rifampicin. For example, 2-hydroxy-N-(4-propoxyphenyl)-naphthalene-1-carboxamide showed the highest activity (MIC = 12 µM) against M. tuberculosis with insignificant cytotoxicity. N-[3-(But-2-yloxy)phenyl]- and N-[4-(but-2-yloxy)phenyl]-2-hydroxy-naphthalene-1-carboxamide demonstrated high activity against all tested mycobacterial strains and insignificant cytotoxicity. N-(Alkoxyphenyl)-1-hydroxynaphthalene-2-carboxamides demonstrated rather high effect against M. smegmatis and M. kansasii and strong antiproliferative effect against the human THP-1 cell line. Lipophilicity was found as the main physicochemical parameter influencing the activity. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Structure-activity relationships are discussed.
Highlights
In spite of the approval of some new antituberculosis drugs, such as bedaquillin or delamanid [1], tuberculosis (TB) ranks alongside human immunodeficiency virus as a leading cause of deaths worldwide [2]
More frequent occurrences of lethal complications associated with immunocompromised populations include systemic infections caused by common, initially non-pathogenic mycobacterial strains (e.g., M. kansasii, M. avium, M. smegmatis, etc.), which cause difficult-to-treat or incurable diseases due to suppressed immunity
The condensation of 2-hyroxynaphthalene-1-carboxylic acid or 1-hydroxynaphthalene-2-carboxylic acid with appropriate alkoxy-substituted anilines using phosphorus trichloride in dry chlorobenzene under microwave conditions yielded a series of nineteen N-substituted-2-hydroxy-naphthalene-1carboxamides 1–7c and nineteen N-substituted-1-hydroxynaphthalene-2-carboxamides
Summary
In spite of the approval of some new antituberculosis drugs, such as bedaquillin or delamanid [1], tuberculosis (TB) ranks alongside human immunodeficiency virus as a leading cause of deaths worldwide [2]. More frequent occurrences of lethal complications associated with immunocompromised populations include systemic infections caused by common, initially non-pathogenic mycobacterial strains (e.g., M. kansasii, M. avium, M. smegmatis, etc.), which cause difficult-to-treat or incurable diseases due to suppressed immunity. These non-tuberculous mycobacteria (NTM) are recognized as significant human pathogens and cause diseases (such as pulmonary disease, lymphadenitis, skin and soft tissue disease, gastrointestinal and skeletal infections) that result in significant morbidity. The emergence of MDR-TB and NTM makes the discovery of new molecular scaffolds a priority to achieve effective control of both TB and NTM [3]
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