N-Alkoxyphenylhydroxynaphthalenecarboxamides and Their Antimycobacterial Activity

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-carboxamidedemonstrated 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.

Chromatographic and Computational Study of Hydro-lipophilic Properties of <em>N</em>-Alkoxyphenylhydroxy-naphthalenecarboxamides

“…All these observations correspond to biological activities; e.g. series A and C, but also stronger antiproliferative effect against the human monocytic leukemia THP-1 cell line [10,13]. In addition, compounds of series B significantly affected photosystem II, which resulted in the inhibition of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts [14].…”

“…Reagents and conditions: (a) R-Br, NaH, acetonitrile, room temperature, 24 h; (b) PCl 3 , chlorobenzene, MW, 15 min. [10,13].…”

“…The discussed N-alkoxyphenylhydroxy-naphthalenecarboxamides 1a-7c were synthesized using microwave-assisted synthesis as described recently by Kos et al [9] and Gonec et al [10][11][12][13] The studied compounds are presented in Table 1.…”

“…Log k, calculated from the capacity factor k, is used as the lipophilicity index converted to log P scale [4]. N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1-hydroxynaphthalene-2-carboxanilides and N-alkoxy-2-hydroxynaphthalene-1-carboxanilides were recently synthesized and tested for their antibacterial and antimycobacterial activity as well as for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts [9][10][11][12][13][14]. Since it was found that the lipophilicity of these significantly biologically effective agents determined their activity, in this study hydrolipophilic properties of all three series are investigated.…”

Preparation and Hydro-Lipophilic Properties of Selected Novel Chlorinated and Brominated N-Arylcinnamamides

“…Ring-substituted N-arylcinnamanilides were recently synthesized and tested for their antibacterial, antimycobacterial, and antifungal activity as well as for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts [10,11]. These compounds were designed based on the excellent experience with naphthalenecarboxamides-simple molecules with a number of biological activities, and in fact, ring-substituted (2E)-N-aryl-3-phenylprop-2-enamides can be considered as open or radical analogues of described naphthalene-2-carboxanilides [12][13][14][15][16][17] characterized by high spatial flexibility and solubility, see Figure 1. Since N-phenylcinnamamide skeleton can be considered as a privileged scaffold providing multi-target agents, new anilide halogenated derivatives were prepared.…”