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1.
Phys Chem Chem Phys ; 22(8): 4749-4757, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32057038

RESUMO

Cyclocurcumin is a turmeric component that has attracted much less attention compared to the well-known curcumin. In spite of the less deep characterization of its properties, cyclocurcumin has shown promising anticancer effects when used in combination with curcumin. Especially, due to its peculiar molecular structure, cyclocurcumin can be regarded as an almost ideal photoswitch, whose capabilities can also be exploited for relevant biological applications. Here, by means of state-of-the-art computational methods for electronic excited-state calculations (TD-DFT, MS-CASPT2, and XMS-CASPT2), we analyze in detail the absorption and photoisomerization pathways leading from the more stable trans isomer to the cis one. The different molecular surroundings, taken into account by means of the electrostatic solvent effect and compared with available experimental data, have been found to be critical in describing the fate of irradiated cyclocurcumin: when in non-polar environments, an excited state barrier prevents photoisomerization and favours fluorescence, whereas in polar solvents, an almost barrierless path results in a striking decrease of fluorescence, opening the way toward a crossing region with the ground state and thus funneling the photoproduction of the cis isomer.

2.
Chembiochem ; 20(7): 911-921, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30512240

RESUMO

The four possible conformers of a new tetrakisguanidino calix[4]arene thought to interact deleteriously with bacterial membranes have been synthesized, characterized, and evaluated for their in vitro cytotoxicity and antibacterial activity against various reference Gram-negative and Gram-positive bacteria, as well as Mycobacterium tuberculosis. It appears that reversal of at least one phenolic unit results in clear increases in their activities. This can be attributed to the evolution towards bolaform structures, which are able to interact more deeply with the bacterial membrane. Indeed, the 1,3-alternate conformer 16 exhibits the best antibacterial activity (MIC<1.0 µg mL-1 on Staphylococcus aureus). Moreover, 16 displays very good antibacterial activities against an isoniazid-resistant strain of M. tuberculosis (MIC=1.2 µg mL-1 ), associated with the lowest cytotoxicity, thus making it the most potent compound of the series; this could open new ways of research in the field of anti-infective drug development to meet the huge current demand.


Assuntos
Antituberculosos/farmacologia , Calixarenos/farmacologia , Guanidinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/toxicidade , Bactérias/efeitos dos fármacos , Calixarenos/síntese química , Calixarenos/toxicidade , Linhagem Celular , Guanidinas/síntese química , Guanidinas/toxicidade , Humanos , Interações Hidrofóbicas e Hidrofílicas , Testes de Sensibilidade Microbiana , Conformação Molecular
3.
Soft Matter ; 12(1): 181-90, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26451711

RESUMO

Behavior of cationic tetra-p-guanidinoethylcalix[4]arene (CX1) and its building block, p-guanidinoethylphenol (mCX1) in model monolayer lipid membranes was investigated using all atom molecular dynamics simulations and surface pressure measurements. Members of two classes of lipids were taken into account: zwitterionic 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and anionic 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine sodium salt (DMPS) as models of eukaryotic and bacterial cell membranes, respectively. It was demonstrated that CX1 and mCX1 accumulate near the negatively charged DMPS monolayers. The adsorption to neutral monolayers was negligible. In contrast to mCX1, CX1 penetrated into the hydrophobic part of the monolayer. The latter effect, which is possible due to a flip-flop inversion of the CX1 orientation in the lipid layer compared to the aqueous phase, may be responsible for its antibacterial activity.


Assuntos
Calixarenos/química , Bicamadas Lipídicas/química , Simulação de Dinâmica Molecular , Dimiristoilfosfatidilcolina/química , Interações Hidrofóbicas e Hidrofílicas , Unitiol/química
4.
Bioorg Med Chem ; 23(17): 5410-8, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26254828

RESUMO

Seven polycharged species, incorporating 1, 2, 3, 4 and 6 guanidine arms organized around a benzene core were synthesized and assayed as anti-mycobacterial agents against Mycobacterium tuberculosis. They display MIC values comprised between 25 and 12.5 µM (close to ethambutol EMB) for the mono- and the hexa-substituted derivatives, and 0.8 µM (close to isoniazid and streptomycin) for the tri-substituted derivative. The three bi- and the tetra-substituted analogs displayed MIC values of ca. 6.5-3.0 µM. The latter were also evaluated against the isoniazid-resistant MYC5165 strain, resulting in highly interesting micromolar or sub-micromolar MIC, ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Guanidina/análogos & derivados , Guanidina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Humanos , Modelos Moleculares , Tuberculose/tratamento farmacológico
5.
Bioorg Med Chem Lett ; 24(20): 4791-3, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25257200
6.
Arch Pharm (Weinheim) ; 346(4): 321-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23447412

RESUMO

Thionyl chloride reacts with 1,ω-bis-(1-tosylamidrazone)alkanes 1 to give a series of 1,ω-bis-(4-alkyl-2-tosyl-1,2,3,5-thiatriazol-5-yl)alkanes 2. All the newly synthesized compounds were characterized by IR, 1H NMR, 13C NMR, elemental analysis, and ESI-MS spectral data. All the new compounds were screened for their inhibitory effect on key enzymes related to diabetes and obesity, such as α-amylase and lipase. In vitro and in vivo studies revealed that these thiatriazole derivatives exert an inhibitory action against these key enzymes. Moreover the administration of these compounds to surviving diabetic rats induced a significant decrease in plasma glucose level. Additively 2d significantly protected the liver-kidney functions and modulated lipid metabolism, which were evidenced by the decrease in aspartate transaminase (AST), alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) activities and creatinine, urea albumin, LDL-cholesterol and triglycerides levels as well as an increase in the HDL-cholesterol level in surviving diabetic rats. Overall, the findings of the current study indicate that 2d exhibits attractive properties and can, therefore, be considered for future application in the development of anti-diabetic and hypolipidemic drugs.


Assuntos
Alcanos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Triazóis/farmacologia , Alcanos/síntese química , Alcanos/química , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Rim/efeitos dos fármacos , Rim/patologia , Lipase/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Espectroscopia de Ressonância Magnética/métodos , Masculino , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray/métodos , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , alfa-Amilases/antagonistas & inibidores
7.
J Phys Chem A ; 116(37): 9404-11, 2012 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-22931189

RESUMO

We analyze the structure, hydration, and pK(a) values of p-guanidinoethyl-phenol through a combined experimental and theoretical study. These issues are relevant to understand the mechanism of action of the tetrameric form, the antibacterial compound tetra-p-guanidinoethyl-calix[4]arene (Cx1). The investigated system can also be useful to model other pharmaceutical drugs bearing a guanidine function in the vicinity of an ionizable group and the effect of arginine on the pK(a) of vicinal ionizable residues (in particular tyrosine) in peptides. The p-guanidinoethyl-phenol monomer (mCx1) has two ionizable groups. One important particularity of this system is that it exhibits high molecular flexibility that potentially leads to enhanced stabilization in folded structures by direct, strong Coulombic interactions between the ionizable groups. The first pK(a) corresponding to ionization of the -OH group has experimentally been shown to be only slightly different from usual values in substituted phenols. However, because of short-range Coulombic interactions, the role of intramolecular interactions and solvation effects on the acidities of this compound is expected to be important and it has been analyzed here on the basis of theoretical calculations. We use a discrete-continuum solvation model together with quantum-mechanical calculations at the B3LYP level of theory and the extended 6-311+G(2df,2p) basis set. Both intra- and intermolecular effects are very large (~70 kcal/mol) but exhibit an almost perfect compensation, thus explaining that the actual pK(a) of mCx1 is close to free phenol. The same compensation of environmental effects applies to the second pK(a) that concerns the guanidinium group. Such a pK(a) could not be determined experimentally with standard titration techniques and in fact the theoretical study predicts a value of 14.2, that is, one unit above the pK(a) of the parent ethyl-guanidinium molecule.

8.
Bioorg Med Chem ; 20(6): 2035-41, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22361273

RESUMO

Various polycharged calix[4]arenes were assayed as anti-mycobacterial agents against Mycobacterium tuberculosis, H(37)Rv strain. The sulfonate, carboxylate and phosphonate anionic species displayed no activity. Cationic derivatives integrating four aminoethyl groups at the upper rim and two 6,6'-dimethyl-2,2'-bipyridyl- or 4,4'-dimethyl-2,2'-bithiazolyl subunits at the lower rim were also found inactive against M. tuberculosis, while the unsubstituded and the 5,5'-dimethyl-2,2'-bipyridyl-analogues exhibited MIC values of 3.2 and 0.8µM respectively. Introduction of guanidinoethyl groups at the upper rim resulted, except for the 6,6'-dimethyl-2,2'-bipyridyl-derivative, in high anti-mycobacterial activities for the unsubstituted, the 5,5'-dimethyl-2,2'-bipyridyl- and the 4,4'-dimethyl-2,2'-bithiazolyl analogues, with MIC values of 0.8, 0.8 and 1.6µM, respectively, similar to those of current commercial anti-tuberculosis agents. The five more active substances were also evaluated against the isoniazid-resistant strain MYC5165, resulting in highly interesting micromolar or sub-micromolar MIC and IC(50), ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fenóis/química , Fenóis/farmacologia , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacologia , Ânions/química , Ânions/farmacologia , Guanidina/química , Guanidina/farmacologia , Humanos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Tuberculose/tratamento farmacológico
9.
Bioorg Med Chem ; 18(1): 36-45, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19944610

RESUMO

Nine anionic water-soluble calix[4]arene species, incorporating sulfonate, carboxylate or phosphonate groups, six of them incorporating two 2,2'-bithiazole subunits in alternate position at the lower rim, have been synthesised and evaluated as anti-HIV agents on various HIV strains and cells of the lymphocytic lineage (HIV-1 III B/MT4, HIV-1 LAI/CEM-SS, HIV-1 Bal/PBMC), using AZT as reference compound. A toxicity was detected for a minority of compounds on PBMC whereas for the others no cellular toxicity was measured at concentrations up to 100 microM. Most of the compounds have an antiviral activity in a 10-50 microM range, and one of them, sulfonylated, displays its activity, whatever the tropism of the virus, at a micromolar concentration.


Assuntos
Fármacos Anti-HIV/farmacologia , Calixarenos/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Calixarenos/síntese química , Calixarenos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Tiazóis/síntese química , Tiazóis/química , Água/química
10.
Bioorg Med Chem ; 17(15): 5496-509, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19596201

RESUMO

The tetra-para-guanidinoethyl-calix[4]arene, its distally-disubstituted ether derivatives involving 2,2'-bithiazolyl- or 2,2'-bipyridyl-methyl groups, as well as the para-guanidinoethylphenol and its analogous derivatives have been synthesized, fully characterized and evaluated as antibacterial agents towards both gram positive and gram negative reference bacteria. The simple phenolic species showed lower activity than their calixarene analogues, confirming the hypothesis that a synergistic effect should result from the spatial organization of guanidinium and heterocycles on a macrocyclic scaffold. Introduction of the bithiazole and bipyridine substituents enhanced the activity of simple phenol derivatives, reaching, for the two Staphylococcus aureus strains in particular, the values obtained for their calixarenic parents. MTT viability assays were carried out to determine selectivity indexes.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Guanidinas/síntese química , Antibacterianos/química , Bactérias/crescimento & desenvolvimento , Benzamidinas/síntese química , Benzamidinas/química , Benzamidinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Guanidinas/química , Guanidinas/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Fenol/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
11.
Bioorg Med Chem Lett ; 19(10): 2679-82, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19395263

RESUMO

A water-soluble calixarene-based heterocyclic podand incorporating a quinolone antibiotic subunit, the nalidixic acid, was synthesised and fully characterised. Its prodrug behaviour was assessed in vitro by HPLC, demonstrating the release of the tethered quinolone in model biological conditions. Microbiological studies performed on various Gram-positive and Gram-negative reference strains showed very interesting antibacterial activities.


Assuntos
Antibacterianos/síntese química , Calixarenos/síntese química , Ácido Nalidíxico/química , Fenóis/química , Pró-Fármacos/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Calixarenos/química , Calixarenos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Ácido Nalidíxico/sangue , Ácido Nalidíxico/farmacocinética , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Água/química
12.
J Antimicrob Chemother ; 60(3): 575-81, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17626025

RESUMO

OBJECTIVES: Emergence of multidrug-resistant bacteria has encouraged vigorous efforts to develop antimicrobial agents with new mechanisms of action. In this study, the in vitro antibacterial activity of para-guanidinoethylcalix[4]arene was evaluated and compared with that of its constitutive monomer, para-guanidinoethylphenol. Hexamidine, a widely used antiseptic, and synthalin A, an old antidiabetic and anti-trypanosomal compound, were chosen as references. METHODS: MIC and MBC were determined for five reference strains (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923 and ATCC 29213, Enterococcus faecalis ATCC 29212 and Pseudomonas aeruginosa ATCC 27853), as well as five antibiotic-resistant clinical isolates. Toxicity on MRC-5 and HaCaT eukaryotic cell lines was also evaluated by MTT and Neutral Red assays. RESULTS: No antibacterial activity was observed for para-guanidinoethylphenol (MIC >or= 512 mg/L) and synthalin A (MIC >or= 64 mg/L). Conversely, para-guanidinoethylcalix[4]arene and hexamidine: (i) showed a broad antibacterial spectrum, both on Gram-positive and on Gram-negative bacteria (MIC = 4 mg/L against E. coli and 8 mg/L against S. aureus for para-guanidinoethylcalix[4]arene), to a lesser degree against E. faecalis and P. aeruginosa (MIC = 32 mg/L); (ii) were bacteriostatic (MBC >or= 256 mg/L); and (iii) MICs and MBCs obtained for clinical isolates were similar to those obtained with reference strains. Both compounds, the monomer and the calixarene, showed no apparent cytotoxicity, whereas hexamidine and synthalin A had significant toxic effects that increased with time and concentration and in a range of 100-1000 times that for calixarene. CONCLUSIONS: In conclusion, results confirm para-guanidinoethylcalix[4]arene as a broad-spectrum new agent or an auxiliary in antimicrobial chemotherapy.


Assuntos
Antibacterianos/farmacologia , Calixarenos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Antibacterianos/química , Benzamidinas/farmacologia , Calixarenos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Guanidinas/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Vermelho Neutro , Relação Estrutura-Atividade , Sais de Tetrazólio , Tiazóis
13.
Bioorg Med Chem Lett ; 16(11): 2960-3, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16563763

RESUMO

The antibacterial activities of the para-guanidinoethylphenol and of its cyclic tetramer, the tetra-para-guanidinoethyl-calix[4]arene, have been evaluated on reference gram-positive and gram-negative bacteria. Antibiotic disk diffusion assays completed by micromethod technique were employed to determine if a synergistic effect could be expected from the spatial organisation of the monomer into its cyclic tetrameric analogue. Disk diffusion assays and microdilution experiments revealed better properties for the calixarene species, with a real and important gain of activity with regards to the monomer.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Guanidinas/química , Guanidinas/farmacologia , Antibacterianos/síntese química , Difusão , Guanidinas/síntese química , Testes de Sensibilidade Microbiana , Conformação Molecular
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