- 3-Hydroxynaphthalene-2-carboxanilides and their antitrypanosomal activity
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Abstract: Series of ring-substituted 3-hydroxynaphthalene-2-carboxanilides were screened for their in vitro activity against wild-type S427 (bloodstream form) of Trypanosoma brucei brucei. 3-Hydroxy-N-(3-trifluoromethylphenyl)- and 3-hydroxy-N-(4-trifluoromethylphenyl)naphthalene-2-carboxamides showed the highest biological activity (MIC?=?1.56 and 2.08?μmol/dm3, respectively). Antitrypanosomal activity was correlated with the experimentally determined lipophilicity and acid–base dissociation constants of the compounds as well as with the calculated electronic properties of individual anilide substituents expressed as Hammett’s σ parameters. The substitution in the meta- or para-position of anilide of derivatives with higher lipophilicity by an electron-withdrawing moiety is favourable for higher activity. The optimum thermodynamic pKa T value was found to be ca. 7.5. The structure–activity relationships of all compounds are discussed. Graphical abstract: [Figure not available: see fulltext.].
- Kos, Jiri,Kapustikova, Iva,Clements, Carol,Gray, Alexander I.,Jampilek, Josef
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p. 887 - 892
(2018/02/12)
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- Antibacterial and herbicidal activity of ring-substituted 3-hydroxynaphthalene-2-carboxanilides
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In this study, a series of twenty-two ring-substituted 3-hydroxy- Nphenylnaphthalene- 2-carboxanilides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four Staphylococcus strains and against two mycobacterial species. 3-Hydroxy-N-(2-methoxyphenyl)naphthalene-2-carboxamide showed high biological activity (MIC = 55.0 μmol/L) against S. aureus as well as methicillinresistant strains. N-(2-Fluorophenyl)-3-hydroxynaphthalene-2- carboxamide showed higher activity (MIC = 28.4 μmol/L) against M. marinum than the standard isoniazid and 3-hydroxy-N-(4-nitrophenyl)naphthalene-2- carboxamide expressed higher activity (MIC = 13.0 μmol/L) against M. kansasii than the standard isoniazid. Cytotoxicity assay of effective antimicrobial compounds was performed using the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide was 16.9 μmol/L. The structure-activity relationships of all compounds are discussed.
- Kos, Jiri,Zadrazilova, Iveta,Pesko, Matus,Keltosova, Stanislava,Tengler, Jan,Gonec, Tomas,Bobal, Pavel,Kauerova, Tereza,Oravec, Michal,Kollar, Peter,Cizek, Alois,Kralova, Katarina,Jampilek, Josef
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p. 7977 - 7997
(2013/08/23)
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- Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription
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CREB (cyclic AMP-response element binding protein) is a downstream transcription factor of a multitude of signaling pathways emanating from receptor tyrosine kinases or G-protein coupled receptors. CREB is not activated until it is phosphorylated at Ser133 and its subsequent binding to CREB-binding protein (CBP) through kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. Tumor tissues from various organs present higher level of expression and activation of CREB. Thus CREB has been proposed as a promising cancer drug target. We previously described naphthol AS-E (1a) as a small molecule inhibitor of CREB-mediated gene transcription in living cells. Here we report the structure-activity relationship (SAR) studies of 1a by modifying the appendant phenyl ring. All the compounds were evaluated for in vitro inhibition of KIX-KID interaction, cellular inhibition of CREB-mediated gene transcription and inhibition of proliferation of four cancer cell lines (A549, MCF-7, MDA-MB-231 and MDA-MB-468). SAR indicated that a small and electron-withdrawing group was preferred at the para-position for KIX-KID interaction inhibition. Compound 1a was selected for further biological characterization and it was found that 1a down-regulated the expression of endogenous CREB target genes. Expression of a constitutively active CREB mutant, VP16-CREB in MCF-7 cells rendered the cells resistant to 1a, suggesting that CREB was critical in mediating its anticancer activity. Furthermore, 1a was not toxic to normal human cells. Collectively, these data support that 1a represents a structural template for further development into potential cancer therapeutics with a novel mechanism of action.
- Li, Bingbing X.,Yamanaka, Kinrin,Xiao, Xiangshu
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p. 6811 - 6820
(2013/01/15)
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- Synthesis and β-adrenergic blocking activity of naphthyloxypropylamines
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A series of 1-isopropylamino-3-(3′-substituted-2′-naphthyloxy)- 2-propanols have been synthesized and their structures have been confirmed by spectral analysis. All the derivatives have shown β-adrenergic blocking effect when tested on perfused frog heart. Compound 4e exhibited 100% blockade of adrenaline response.
- Vattipalli, Ramya,Shirodkar, Prabhakar Y.,Somani, Rakesh R.,Kadam, Vilasrao J.
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experimental part
p. 1587 - 1590
(2009/04/07)
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- Salicylanilides as inhibitors of the protein tyrosine kinase epidermal growth factor receptor
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A pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase and a putative binding mode of 4-anilinoquinazoline suggest that a salicylic acid function could serve as the pharmacophore replacement of a pyrimidine ring. Superpositions by CAMM of salicylanilides with the potent EGFR tyrosine kinase inhibitor 4-[(3′-chlorophenyl)amino]-6,7-dimethoxyquinazoline showed that salicylanilides should act as tyrosine kinase inhibitors. A series of salicylanilides was synthesized and their inhibitory activity against tyrosine kinases determined. Some of them indeed proved to be potent and selective EGFR tyrosine kinase inhibitors. The most potent ones being 28, 16, 20, 6, and 15, with IC50 in the 23-71 nM range.
- Liechti, Christoph,Sequin, Urs,Bold, Guido,Furet, Pascal,Meyer, Thomas,Traxler, Peter
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