N-Alkoxyphenylhydroxynaphthalenecarboxamides and Their Antimycobacterial Activity

• Main Authors: Tomas Gonec, Sarka Pospisilova, Tereza Kauerova, Jiri Kos, Jana Dohanosova, Michal Oravec, Peter Kollar, Aidan Coffey, Tibor Liptaj, Alois Cizek, Josef Jampilek
• Format: Article
• Language: English
• Published: MDPI AG 2016-08-01
• Series: Molecules
• Subjects: hydroxynaphthalenecarboxamides; in vitro antimycobacterial activity; MTT assay; lipophilicity; structure-activity relationships
• Online Access: http://www.mdpi.com/1420-3049/21/8/1068

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.