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1.
Med Chem ; 15(5): 521-536, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30398121

RESUMO

BACKGROUND: Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices. OBJECTIVE: Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds. METHODS: In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, "open field" test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2. RESULTS: We developed the convenient methods for regioselective methylation of 1-aryl-3- polyfluoroalkylpyrazol-5-ols leading to the synthesis N-methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time, the biological properties of new derivatives were investigated in vitro and in vivo. CONCLUSION: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/análogos & derivados , Antipirina/farmacologia , Fluorcarbonetos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/toxicidade , Antipiréticos/síntese química , Antipiréticos/química , Antipiréticos/farmacologia , Antipiréticos/toxicidade , Antipirina/síntese química , Antipirina/toxicidade , Domínio Catalítico , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Feminino , Fluorcarbonetos/síntese química , Fluorcarbonetos/química , Fluorcarbonetos/toxicidade , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley
2.
Bioorg Med Chem Lett ; 28(5): 952-957, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29426771

RESUMO

As a part of a directed program for development of new active agents, novel heterocyclic derivatives with antipyrine and pyrazolone moieties -incorporated in- have been designed and synthesized. Starting with 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivative 2a,b novel Mannich bases derivatives have been synthesized and biologically evaluated for their anti-inflammatory activity. Furthermore, the activity of such compounds has been tested interestingly as COX-1 and COX-2 inhibitors. Structure elucidation of the synthesized compounds was attained by the use of elemental analysis, IR, 1H NMR, 13C NMR, and Mass spectrometry techniques. Compounds 3b, 3d and 4b represent the high % inhibition values for both COX-1 and COX-2. On the other hand, compound 8 showed little selectivity against COX-2 while compound 10 showed good selectivity against COX-1 only. Structure activity relationship has been discussed and the results were confirmed by molecular docking calculations.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pirazolonas/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antipirina/síntese química , Antipirina/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase/síntese química , Inibidores de Ciclo-Oxigenase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade
3.
Curr Drug Deliv ; 14(8): 1213-1224, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28201966

RESUMO

BACKGROUND: The use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is not up to its potential because of their gastrointestinal side effects. Significant attention has been focused on the growth of bio-reversible derivatives, such as mutual prodrugs, to momentarily mask the acidic group of NSAIDs as a promising means of decreasing or eliminating the GI side effects. The aims of this paper are to synthesize the mutual prodrugs of selected NSAIDs (Ketorolac, niflumic acid, tolfenamic acid) with propyphenazone, a study on their several physicochemical characters, hydrolysis kinetics, antiinflammatory, analgesic activity and ulcerogenicity. METHODS: Mutual prodrugs were synthesized and their structures were confirmed and characterized using IR, 1H NMR, 13C NMR, mass spectroscopy and their purity was established by elemental analysis. Synthesized prodrugs were subjected for pharmacokinetic studies, analgesic, anti-inflammatory activities and ulcerogenic index. RESULTS: In vitro hydrolysis study of synthesized prodrugs in enzyme-free simulated intestinal fluid (SIF, pH 7.4) and 80% human plasma showed encouraging hydrolysis rate following first order kinetics while found stable in simulated gastric fluid (SGF, pH 1.2). Considerable decrease in ulcerogenic index and better anti-inflammatory activities were found in most of the cases as compared to their parent drugs. Among all prodrugs, viz. KE and NG showed excellent pharmacological response. A very less irritation to gastric mucosal was observed with the synthesized prodrugs than their parent drugs and can be considered for sustained drug release. CONCLUSION: Encouraging hydrolysis rate in SIF and 80% human plasma, improved analgesic and anti-inflammatory activities and reduced ulcerogenic liabilities of synthesized prodrugs revealed enhancement in the therapeutic index of the parent drugs. On the basis of above observation, it is concluded that mutual prodrugs approach can be applied to obtain synergistic effect for analgesic and anti inflammatory activities as well as to minimize gastrointestinal toxicity of the drug.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/análogos & derivados , Ácidos Carboxílicos/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Analgésicos/síntese química , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/química , Antipirina/síntese química , Antipirina/química , Antipirina/farmacologia , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Edema/tratamento farmacológico , Mucosa Gástrica/efeitos dos fármacos , Hidrólise , Masculino , Camundongos , Estrutura Molecular , Pró-Fármacos/química , Ratos , Ratos Wistar , Úlcera/tratamento farmacológico
4.
Bioorg Med Chem Lett ; 26(1): 100-4, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26598460

RESUMO

N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.


Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Antipirina/análogos & derivados , Hidrazinas/química , Paládio/química , Dobramento de Proteína/efeitos dos fármacos , Multimerização Proteica/efeitos dos fármacos , Antipirina/síntese química , Antipirina/química , Antipirina/farmacologia , Catálise , Relação Dose-Resposta a Droga , Edaravone , Estrutura Molecular , Compostos Organometálicos/química , Relação Estrutura-Atividade
5.
Artigo em Inglês | MEDLINE | ID: mdl-23711396

RESUMO

Organic compounds are attracting greater attention largely in the recent years owing to their potential applications in the functional materials. Herein we reported the structural and photophysical properties of 4-(3-fluorobenzylideneamino)antipyrine. The studied molecule adopts a trans configuration about the imine bond, and forms a non-planar molecular device consisted of two effectively conjugated π-electron moieties. The stronger vibrational and nonlinear optical activities are tightly related to the molecular structural characteristics revealed by the analysis on vibrational modes and frontier molecular orbitals. The intramolecular electrons can be separated by the electron-transporting with specified photon-absorbing theoretically. The total molecular dipole moment, mean linear polarizability and first-order hyperpolarizability calculated at B3LYP/6-31G(d) level are 1.5390 Debye, 35.6075 Å(3) and 1.5391×10(-29) cm(5)/esu, respectively. The reported results indicate that the compound is a promising candidate of photoresponsive materials.


Assuntos
Antipirina/análogos & derivados , Antipirina/química , Antipirina/síntese química , Luz , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Conformação Molecular , Dinâmica não Linear , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Vibração
6.
Artigo em Inglês | MEDLINE | ID: mdl-22925977

RESUMO

In this work, 4-(2-fluorobenzylideneamino)antipyrine (FBIAAP) was synthesized and characterized by elemental analysis, XRD, FT-IR, FT-Raman and UV-Vis techniques as well as density functional calculations. The studied molecule adopts a trans configuration about the imine CN bond, and adjacent molecules are linked through two kinds of weak hydrogen bonds to form supramolecular layered structures along the ab plane. Vibrational spectral analyses show that the benzene moiety directly attached to the central pyrazoline shows good vibrational isolation from the other moiety of pyrazole-imino-benzene presenting good vibrational resonances. UV-vis absorption bands mainly belong to n→π and π→π according to the electron transfer orbital assignments for the electron absorption spectrum of FBIAAP. The first-order hyperpolarizability of FBIAAP is 44.9 times that of urea theoretically. In addition, the thermodynamic properties were also obtained theoretically from the harmonic frequencies of the optimized structure.


Assuntos
Antipirina/análogos & derivados , Antipirina/química , Antipirina/síntese química , Luz , Modelos Moleculares , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Dinâmica não Linear , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Termodinâmica , Vibração
7.
Artigo em Inglês | MEDLINE | ID: mdl-22842351

RESUMO

Four new antipyrine derivatives were synthesized and characterized by elemental analysis, FT-IR, (1)H NMR, (13)C NMR spectroscopy, and a representative compound 1b was confirmed based on the X-ray crystallographic analysis. The antipyrine-phenylboronic acid 1b crystallizes in the monoclinic space group P2(1)/c, and displays an E configuration about the CN double bond. The absorption and fluorescence spectra of these compounds were investigated. Replacement of a six-membered phenyl group with a five-membered thienyl unit in the antipyrine derivatives resulted in a bathochromic shift approximately 21 nm, while the bithienyl system caused a strong bathochromic effect of 53 nm relative to the substituted phenyl groups. The bithienyl-antipyrine hybrid 1c displayed a turn-on fluorescence response to water, acetic acid (HOAc) and sulfuric acid (H(2)SO(4)) in ethanol solution, but no fluorescence response toward alkali. Whereas the free compound was very weakly fluorescent in ethanol, the addition of water, HOAc and H(2)SO(4) leads to an appearance of strong blue fluorescence and a dramatic increase of emission intensity.


Assuntos
Antipirina/química , Antipirina/síntese química , Absorção , Cristalografia por Raios X , Etanol/química , Fluorescência , Ligação de Hidrogênio , Conformação Molecular , Soluções , Espectrometria de Fluorescência , Água
8.
Bioorg Med Chem ; 20(2): 841-50, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22222158

RESUMO

A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO(x)) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.


Assuntos
Antipirina/análogos & derivados , Vasodilatadores/síntese química , Animais , Antipirina/síntese química , Antipirina/química , Antipirina/farmacocinética , Estabilidade de Medicamentos , Edaravone , Humanos , Nitratos/metabolismo , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/química , Doadores de Óxido Nítrico/farmacocinética , Nitritos/metabolismo , Permeabilidade , Ratos , Vasodilatadores/química , Vasodilatadores/farmacocinética
9.
Bioorg Chem ; 41-42: 6-12, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22257969

RESUMO

Starting from 4-amino-antipyrine, six new compounds were synthesized and characterized. The new compounds contain moieties with particular properties, such are ionophore (benzo-15-crown-5), fluorescent (nitrobenzofurazan), stable free radical (nitroxide), or other types of biological active residues, like nitroderivatives, antipyrine or isoniazid residues. They were fully characterized by appropriate means ((1)H and (13)C NMR, IR, UV-Vis, fluorescence, EPR, elemental analysis) and some of their biological properties were evaluated. Hydrophobicity (R(M0), log P), total antioxidant capacity (TAC), and antimicrobial properties are also presented and discussed.


Assuntos
Antibacterianos/síntese química , Antioxidantes/síntese química , Antipirina/análogos & derivados , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pirazolonas/síntese química , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Antipirina/síntese química , Antipirina/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/crescimento & desenvolvimento , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Pirazolonas/farmacologia , Espectrometria de Fluorescência , Relação Estrutura-Atividade
10.
Chem Pharm Bull (Tokyo) ; 58(8): 1020-5, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20686253

RESUMO

3-Methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), known as a potent free radical scavenger, has been developed as a medical drug for the treatment of acute cerebral infarction. With the aim of developing radiotracers for imaging free radicals in vivo, 1-(3'-[(125)I]iodophenyl)-3-methy-2-pyrazolin-5-one ((125)I-2) was synthesized by two methods, via isotopic exchange and interhalogen exchange under solvent-free conditions, in which iodo- and bromo-derivatives were used as labeling precursors, respectively. After HPLC purification, (125)I-2 was obtained in modest isolated radiochemical yields (ca. 20%) with high radiochemical purities by both methods. The former gave specific activities of 0.2-0.6 kBq/micromol, whereas the latter approach achieved specific activities of more than 0.14 GBq/micromol. On attempting to prepare an injectable formulation for (125)I-2 with high specific activity, its radiochemical purities dropped to about 60-70%. Unlabeled analog 2 was found to have lipophilic and antioxidant properties similar to edaravone. Intravenous injection of (125)I-2 with low specific radioactivity into normal mice showed signs of distribution profiles similar to reported results for (14)C-labeled edaravone in normal rats.


Assuntos
Antioxidantes/síntese química , Antioxidantes/farmacocinética , Antipirina/análogos & derivados , Pirazolonas/química , Pirazolonas/farmacocinética , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Antipirina/administração & dosagem , Antipirina/síntese química , Antipirina/química , Antipirina/farmacocinética , Estabilidade de Medicamentos , Edaravone , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Pirazolonas/administração & dosagem , Pirazolonas/síntese química , Solubilidade , Distribuição Tecidual
11.
Int J Biol Macromol ; 39(4-5): 250-5, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16712925

RESUMO

The aim of this work was to test a chromatographic affinity support containing methacryloyl antipyrine (MAAP) for penicillin acylase (PA) purification by using pure penicillin acylase and crude extract. First, MAAP as a pseudo-specific ligand was synthesized by using methacryloyl chloride and 4-aminoantipyrine. Polymer beads (average size diameter: 40-120 micro m) were prepared by suspension polymerization of ethylene glycol dimethacrylate (EGDMA) and MAAP. This approach for the preparation of adsorbent has several advantages over conventional preparation protocols. An expensive and time consuming step in the preparation of adsorbent is immobilization of a ligand to the adsorption matrix. In this procedure, affinity ligand MAAP acts as comonomer without further modification steps. Poly(EGDMA-MAAP) beads were characterized by FTIR, NMR and screen analysis. Elemental analysis of MAAP for nitrogen was estimated as 89.3 micro mol/g. The prepared adsorbent was then used for the capture of penicillin acylase in batch system. The maximum penicillin acylase adsorption capacity of the poly(EGDMA-MAAP) beads was found to be 82.2 mg/g at pH 5.0. Chromatography with crude feedstock resulted in 23.2-fold purification and 93% recovery with 1.0 M NaOH.


Assuntos
Penicilina Amidase/isolamento & purificação , Adsorção , Marcadores de Afinidade/síntese química , Marcadores de Afinidade/química , Antipirina/análogos & derivados , Antipirina/síntese química , Antipirina/química , Cromatografia de Afinidade , Concentração de Íons de Hidrogênio , Ligantes , Ressonância Magnética Nuclear Biomolecular , Tamanho da Partícula , Penicilina Amidase/metabolismo , Penicillium chrysogenum/enzimologia , Ácidos Polimetacrílicos/síntese química , Ácidos Polimetacrílicos/química , Espectroscopia de Infravermelho com Transformada de Fourier
12.
Chem Commun (Camb) ; (6): 583-93, 2006 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-16446819

RESUMO

In the last few years, we have demonstrated that the halogen/magnesium-exchange reaction is a unique method for preparing a variety of new functionalized aryl, alkenyl, heteroaryl magnesium compounds which has considerably extended the range of functionalized Grignard reagents available for synthetic purposes. A variety of functional groups such as an ester, nitrile, iodide, imine and even sensitive groups like nitro, hydroxyl and boronic ester can be tolerated in these organomagnesium compounds. We wish to describe the application of this halogen/magnesium-exchange reaction for the preparation of a broad range of five- and six-membered functionalized heteroaryl magnesium compounds and their reactions with various electrophiles providing a new entry to a range of polyfunctional heterocycles such as thiophene, furan, pyrrole, imidazole, thiazole, antipyrine, pyridine, quinoline and uracil derivatives.


Assuntos
Técnicas de Química Combinatória , Compostos Heterocíclicos/síntese química , Magnésio/química , Compostos Organometálicos/química , Antipirina/síntese química , Ésteres/química , Furanos/síntese química , Imidazóis/síntese química , Iminas/química , Iodetos/química , Modelos Químicos , Nitrilos/química , Piridinas/síntese química , Pirróis/síntese química , Quinolinas/síntese química , Tiazóis/síntese química , Tiofenos , Uracila/análogos & derivados , Uracila/síntese química
13.
Redox Rep ; 8(3): 157-61, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12935313

RESUMO

Two metabolites of a free radical scavenger, edaravone, were synthesized. Edaravone glucuronate was synthesized by glycosylation of a glucuronic acid precursor using silver (I) trifluoromethane-sulfonate with edaravone. Edaravone sulfate was synthesized by sulfonylation of edaravone using a sulfur trioxide-pyridine complex. The two synthesized metabolites were identical to isolated metabolites. X-ray analysis identified edaravone glucuronate as beta-O-glucuronate, although there were three possible edaravone glucuronate tautomers.


Assuntos
Antipirina/análogos & derivados , Antipirina/síntese química , Depuradores de Radicais Livres/síntese química , Glucuronatos/síntese química , Sulfatos/síntese química , Antipirina/metabolismo , Edaravone , Depuradores de Radicais Livres/metabolismo , Estrutura Molecular
14.
Eur J Pharm Sci ; 17(3): 121-30, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12393139

RESUMO

Naproxen-propyphenazone (NAP-PP) esters were synthesized as prodrugs with the aim of improving the therapeutic index through prevention of gastrointestinal irritation and bleeding. The structures of the synthesized NAP-PP hybrid esters were confirmed by IR and 1H NMR spectroscopy and their purity was established by elemental analysis, HPLC and TLC. The release of NAP as well as PP derivatives, from the ester prodrugs was studied. A validated analytical HPLC method for the estimation of the NAP, and the prodrugs was developed. Also the enzymatic hydrolysis products of the ester were identified by GC-MS and in conjugation with HPLC. The kinetics of ester hydrolysis was studied in two different non-enzymatic buffer solutions, at pH 1.2, and 7.4 as well as in liver homogenates. Study of analgesic and anti-inflammatory properties in comparison with the reference compounds has shown that both analgesic and anti-inflammatory activities were present at the same doses of the investigated compounds. The ester III was found to be less irritating to gastric mucosal membrane than the parent drugs. These results suggest that the synthesized prodrugs are characterized by better therapeutic index than the parent drugs.


Assuntos
Antipirina/análogos & derivados , Antipirina/farmacocinética , Naproxeno/farmacocinética , Medição da Dor/efeitos dos fármacos , Pró-Fármacos/farmacocinética , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Antipirina/síntese química , Antipirina/farmacologia , Química Farmacêutica , Masculino , Camundongos , Naproxeno/síntese química , Naproxeno/farmacologia , Medição da Dor/métodos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Ratos , Ratos Sprague-Dawley
15.
Eur J Med Chem ; 36(7-8): 685-9, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11600237

RESUMO

The synthesis of some triazolyl-antipyrine derivatives starting from 4-chloroacetamidoantipyrine and 3-(aryloxyalkyl)-4-ethyl/phenyl-5-mercapto-1,2,4-triazoles is described. The chemical structures of the compounds were elucidated by IR, 1H-NMR and mass spectral studies. These compounds were tested for analgesic activity.


Assuntos
Analgésicos/síntese química , Analgésicos/uso terapêutico , Antipirina/análogos & derivados , Antipirina/síntese química , Antipirina/uso terapêutico , Dor/tratamento farmacológico , Triazóis/síntese química , Triazóis/uso terapêutico , Animais , Camundongos , Medição da Dor/métodos
16.
Radiat Res ; 151(2): 167-76, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9952301

RESUMO

To elucidate the kinetics of the induction of DNA strand breaks by low-energy Auger electron emitters, we compared the yields of DNA breaks in supercoiled pUC19 DNA after the decay of 125I (1) in proximity to DNA after minor-groove binding (125I-iodoHoechst 33342, 125IH) and (2) at a distance from DNA (125I-iodoantipyrine, 125IAP). Iodine-125 bound to the minor groove in DNA or free in solution is equally effective per decay in producing single-strand breaks (SSBs), while 125I bound to the minor groove is 6.7-fold more efficient than 125I free in solution in producing double-strand breaks (DSBs) (1.08 +/- 0.13 compared to 0.16 +/- 0.01 DSB/decay). Consequently, SSB to DSB ratios for 125IAP and gamma radiation (20.7 +/- 2.9 and 43.8 +/- 1.5, respectively) are greater than that for 125IH (2.9 +/- 0.4). Finally, the decay of 125IH leads to fragmentation of plasmid DNA beyond SSBs and DSBs.


Assuntos
Dano ao DNA , DNA Super-Helicoidal/efeitos da radiação , Radioisótopos do Iodo/química , Antipirina/análogos & derivados , Antipirina/síntese química , Antipirina/química , Benzimidazóis/síntese química , Benzimidazóis/química , DNA/química , DNA/efeitos da radiação , DNA Super-Helicoidal/química , Elétrons , Raios gama , Cinética , Plasmídeos/genética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química
17.
Farmaco ; 50(5): 361-4, 1995 May.
Artigo em Inglês | MEDLINE | ID: mdl-7626172

RESUMO

The synthesis of 12 new 4-[(N,N-disubstituted thiocarbamoylthio)acetamido]antipyrines and their antifungal activity are reported. Of these compounds, only 3e, showed good antifungal activity against C. tropicalis KUEN 1021, C. krusei KUEN 1001, C. stellatoidea KUEN 1018, C. pseudotropicalis KUEN 1012, C. albicans ATCC 10231 when compared with clotrimazole and miconazole (MIC = 12.5 micrograms/ml).


Assuntos
Antifúngicos/farmacologia , Antipirina/farmacologia , Antifúngicos/síntese química , Antipirina/análogos & derivados , Antipirina/síntese química , Estrutura Molecular
19.
J Pharmacol Toxicol Methods ; 28(3): 129-35, 1992 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1489983

RESUMO

The well-controlled microdialysis (MD) study of substance permeation into brain extracellular fluid (ECF) and cerebrospinal fluid requires consideration of blood-brain barrier (BBB) integrity, which might be compromised by microdialysis probe implantation. Others have assessed BBB integrity with radionuclide markers. A nonradionuclide marker may be desirable in many studies. A charged antipyrine analogue may be useful to determine BBB integrity with concomitant antipyrine characterization of probe efficiency (Yokel et al., 1992, J Pharmacol Toxicol Methods 27:135-142), and may not require another analytical technique. We synthesized, validated, and evaluated 4-trimethylammonium antipyrine (4TMA-AP) as a BBB integrity marker. BBB permeation was determined by calculation of a BBB integrity percentage (Pi) from brain/blood concentrations. The PiS of Evan's blue, which does not permeate the intact BBB, and 4TMA-AP were not significantly different in rats without known BBB disruption, suggesting a lack of 4TMA-AP permeation through the intact BBB. When MD probes were slowly implanted into the frontal cortex, 4TMA-AP PiS were usually zero. Intracarotid oleic acid injection to open the BBB significantly increased 4TMA-AP PiS, suggesting that 4TMA-AP entered brain ECF when the BBB was compromised. Rapid probe implantation produced increased 4TMA-AP PiS, suggesting BBB disruption. The predicted appearance of 4TMA-AP in brain ECF suggests that it is a BBB integrity marker.


Assuntos
Antipirina/análogos & derivados , Barreira Hematoencefálica/fisiologia , Compostos de Amônio Quaternário , Animais , Antipirina/síntese química , Antipirina/farmacocinética , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Diálise , Azul Evans , Masculino , Compostos de Amônio Quaternário/síntese química , Compostos de Amônio Quaternário/farmacocinética , Ratos , Ratos Sprague-Dawley
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