Design and synthesis of anticancer 1-hydroxynaphthalene-2-carboxanilides with a p53 independent mechanism of action

Spaczynska, Ewelina; Mrozek-Wilczkiewicz, Anna; Malarz, Katarzyna; Kos, Jiří; Goněc, Tomáš; Oravec, Michal; Gawecki, Robert; Bąk, Andrzej; Doháňošová, Jana; Kapustíková, Iva; Liptaj, Tibor; Jampílek, Josef; Musioł, Robert

doi:10.1038/s41598-019-42595-y

Cited by 39 publications

(19 citation statements)

References 91 publications

(87 reference statements)

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“…It can be stated that even the treatment with 30 μM did not lead to any significant toxic affect, i.e., LD 50 > 30 µM. This observation is in a good agreement with the previous result of antiproliferative assay published recently by Spaczynska et al [10].…”

Section: Resultssupporting

confidence: 91%

“…The reaction of 1-hydroxynaphthalene-2-carboxylic acid and an appropriate substituted aniline with phosphorus trichloride in dry chlorobenzene under microwave conditions gave a series of methoxylated and methylated N -aryl-1-hydroxynaphthalene-2-carboxanilides 1 – 26 , see Scheme 1 and Table 1. Compounds 1 – 4 , 8 – 10 [1], 5 – 7 , 11 – 19 , 21 , 22 , and 24 – 26 [10] were published recently.…”

Section: Resultsmentioning

confidence: 99%

“…Hydroxynaphthalenecarboxanilides demonstrated a spectrum of anti-infectious [1,2,3,4,5,6,7,8] and/or anti-proliferative properties [9,10], as was described recently. These structurally simple compounds, regarded as ring analogues of salicylanilides (e.g., niclosamide [11,12,13]), can be considered a part of the group of privileged structures.…”

Section: Introductionmentioning

confidence: 91%

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Bioactivity of Methoxylated and Methylated 1-Hydroxynaphthalene-2-Carboxanilides: Comparative Molecular Surface Analysis

et al. 2019

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A series of twenty-six methoxylated and methylated N-aryl-1-hydroxynaphthalene- 2-carboxanilides was prepared and characterized as potential anti-invasive agents. The molecular structure of N-(2,5-dimethylphenyl)-1-hydroxynaphthalene-2-carboxamide as a model compound was determined by single-crystal X-ray diffraction. All the analysed compounds were tested against the reference strain Staphylococcus aureus and three clinical isolates of methicillin-resistant S. aureus as well as against Mycobacterium tuberculosis and M. kansasii. In addition, the inhibitory profile of photosynthetic electron transport in spinach (Spinacia oleracea L.) chloroplasts was specified. In vitro cytotoxicity of the most effective compounds was tested on the human monocytic leukaemia THP-1 cell line. The activities of N-(3,5-dimethylphenyl)-, N-(3-fluoro-5-methoxy-phenyl)- and N-(3,5-dimethoxyphenyl)-1-hydroxynaphthalene-2-carbox- amide were comparable with or even better than the commonly used standards ampicillin and isoniazid. All promising compounds did not show any cytotoxic effect at the concentration >30 µM. Moreover, an in silico evaluation of clogP features was performed for the entire set of the carboxamides using a range of software lipophilicity predictors, and cross-comparison with the experimentally determined lipophilicity (log k), in consensus lipophilicity estimation, was conducted as well. Principal component analysis was employed to illustrate noticeable variations with respect to the molecular lipophilicity (theoretical/experimental) and rule-of-five violations. Additionally, ligand-oriented studies for the assessment of the three-dimensional quantitative structure–activity relationship profile were carried out with the comparative molecular surface analysis to determine electron and/or steric factors that potentially contribute to the biological activities of the investigated compounds.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

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Bioactivity of Methoxylated and Methylated 1-Hydroxynaphthalene-2-Carboxanilides: Comparative Molecular Surface Analysis

et al. 2019

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“…[ 34 ]. Thus, based on the experience with various substituents on the aniline core a series of novel 22 N -(disubstituted-phenyl)-3-hydroxynaphthalene-2-carboxamides, was synthesized and in vitro tested against several microbial strains [ 26 , 35 , 36 , 37 ]. The similarity related property space assessment for the set of carboxamide derivatives was performed using the principal component analysis (PCA) [ 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Consensus-Based Pharmacophore Mapping for New Set of N-(disubstituted-phenyl)-3-hydroxyl-naphthalene-2-carboxamides

Bąk

Kos

Michnová

et al. 2020

IJMS

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A series of twenty-two novel N-(disubstituted-phenyl)-3-hydroxynaphthalene- 2-carboxamide derivatives was synthesized and characterized as potential antimicrobial agents. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[2-chloro-5-(trifluoromethyl)phenyl]-3-hydroxy- naphthalene-2-carboxamide showed submicromolar (MICs 0.16–0.68 µM) activity against methicillin-resistant Staphylococcus aureus isolates. N-[3,5-bis(trifluoromethyl)phenyl]- and N-[4-bromo-3-(trifluoromethyl)phenyl]-3-hydroxynaphthalene-2-carboxamide revealed activity against M. tuberculosis (both MICs 10 µM) comparable with that of rifampicin. Synergistic activity was observed for the combinations of ciprofloxacin with N-[4-bromo-3-(trifluoromethyl)phenyl]- and N-(4-bromo-3-fluorophenyl)-3-hydroxynaphthalene-2-carboxamides against MRSA SA 630 isolate. The similarity-related property space assessment for the congeneric series of structurally related carboxamide derivatives was performed using the principal component analysis. Interestingly, different distribution of mono-halogenated carboxamide derivatives with the –CF3 substituent is accompanied by the increased activity profile. A symmetric matrix of Tanimoto coefficients indicated the structural dissimilarities of dichloro- and dimetoxy-substituted isomers from the remaining ones. Moreover, the quantitative sampling of similarity-related activity landscape provided a subtle picture of favorable and disallowed structural modifications that are valid for determining activity cliffs. Finally, the advanced method of neural network quantitative SAR was engaged to illustrate the key 3D steric/electronic/lipophilic features of the ligand-site composition by the systematic probing of the functional group.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Strhársky

Jankech

Kos

et al. 2019

The 23rd International Electronic Conference on Synthetic Organic Chemistry

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A series of six di-and tri-halogenated N-arylcinnamanilides designed as anti-inflammatory and antimicrobial agents was prepared and characterized. Since it is known that lipophilicity significantly influences the biological activity of compounds, the hydro-lipophilic properties of these di-and tri-substituted N-arylcinnamanilides were investigated in the study. All the discussed derivatives of cinnamic acid were analyzed using the reversed-phase high performance liquid chromatography method to measure lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, the correlations between the logarithm of the capacity factor k and log P/Clog P values calculated in various ways as well as the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed.

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Design and synthesis of anticancer 1-hydroxynaphthalene-2-carboxanilides with a p53 independent mechanism of action

Cited by 39 publications

References 91 publications

Bioactivity of Methoxylated and Methylated 1-Hydroxynaphthalene-2-Carboxanilides: Comparative Molecular Surface Analysis

Bioactivity of Methoxylated and Methylated 1-Hydroxynaphthalene-2-Carboxanilides: Comparative Molecular Surface Analysis

Consensus-Based Pharmacophore Mapping for New Set of N-(disubstituted-phenyl)-3-hydroxyl-naphthalene-2-carboxamides

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

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