RESUMO
Catalytic activity of certain antibodies was proposed by Linus Pauling for the very first time more than six decades ago. Since then few examples of catalytic antibodies (abzymes) were found in human organism. From late 80's many synthetic abzymes were obtained after immunization by Transition State Analogs (TSA). Another approach is based on functional mimicry of antibody to an active site of an enzyme. Detection of an abzymatic activity requires special immunoassays. This unique strategy can be employed for new methods of drug synthesis, as well as for in vivo therapies. Catalytic antibodies seem to be a promising tool for therapeutic purposes, because of their specifity and stereoselectivity.
Assuntos
Anticorpos Catalíticos/imunologia , Anticorpos Catalíticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/uso terapêutico , Animais , Anticorpos Anti-Idiotípicos/imunologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclização , Humanos , Pró-Fármacos/químicaRESUMO
Beta-blockers are a very important group of drugs widely used for the treatment of cardiovascular diseases. All aryloxyaminopropanols are chiral and show different stereoselectivity in their pharmacodynamic and pharmacokinetic properties for each enantiomer. The more potent beta-adrenoceptor blocking activity is generally associated with (S)-enantiomers. Most beta-blocking agents are sold as racemates although (R)-enantiomers not only show in some cases lack of activity but might be responsible for undesirable effects. Among reports on the direct enzymatic resolution of the most representative beta-blocker propranolol, the most interesting is N-acetylation method with commercially available lipases to yield (S)-N-acetylpropranolol. Another type of the one-step (S)-isomer biocatalytic preparation from racemic mixture of propranolol is the biodegradation with the fungus. Biocatalytic methods of obtaining homochiral beta-blockers that are focused on production of versatile precursors are widely described in literature. The strategies based on the use of glycidol and derivatives as C-3 synthones have been shown to be extremely useful for the introduction of the 2-propanol chain on the aromatic system. Halohydrins are the established intermediates in the preparation of optically active beta-blockers. Its resolution by esterhydrolases has been used as a standard alternative in preparation of the homochiral propranolol. Additionally, the enzymatic resolution of the following intermediates was reported: 1-azido-3-aryloxy-2-propanols, 4-(1-aryloxy)-3-hydroxybutyric acid esters, glycerol and cyanohydrin derivatives. However, even the highly enantioselective lipase-catalyzed process can only provide 50% of the starting racemate in an optically active form. An alternative method such as a reduction of a prochiral ketone by various strains of yeast might quantitatively provide an enantiomeric product with a yield greater than 50%. The reported substrates for microbial reductions were: 1-halo-aryloxypropan-2-ones and 1-acetoxy-aryloxypropan-2-ones.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/química , Catálise , Hidrolases/química , Cinética , EstereoisomerismoRESUMO
This review summarizes the current tendencies observed in the past 5 years in the development of A(1) and A(2A) adenosine receptor antagonists performed in various academia and industry. A(1) and A(2A) AR antagonists are as well xanthines as heteroaromatic derivatives and are most commonly 6:5 fused heteroatomic compounds. Among xanthine-based compounds, some common features could be pointed out. The recent A(1) AR ligands which show good biological profile, possess long alkyl chains in position 1 and 3 as well as bulky C(8)-substituent, while A(2A) AR antagonists with a high A(2A) AR affinity are C(8)-styryl substituted with N(1)-alkyl/alkynyl moiety or fused tricyclic xanthines possessing heteroatom(s) in the third cycle. The research in the field of heteroaromatic A(1) and A(2A) ARs antagonists impressively has a wide range. Ligands are as well non-fused monocyclic substituted compounds as fused bi- and tricyclic derivatives with the nitrogen, oxygen and sulfur heteroatoms. Most often, adenosine A(1) receptor non-xanthine antagonists are adenine-based, having substituted amino group and variable nitrogen atoms positions in the molecules. A(2A) AR ligands show good affinity when furanyl function, which is crucial for binding, is present in the fused bicyclic and tricyclic analogs. Moreover, tricyclic nitrogen containing antagonists in order to be active, frequently possess long-alkylphenyl moiety.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Animais , Desenho de Fármacos , Humanos , Receptores Purinérgicos P1/classificaçãoAssuntos
Corantes Fluorescentes/síntese química , Corantes Fluorescentes/metabolismo , Receptores Histamínicos H3/metabolismo , Linhagem Celular , Proteínas de Ligação ao GTP/química , Humanos , Indicadores e Reagentes , Ligantes , Metilação , Piperidinas/química , Piperidinas/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/química , Receptores Histamínicos/metabolismo , Receptores Histamínicos H3/química , Receptores Histamínicos H3/efeitos dos fármacos , Receptores Histamínicos H4RESUMO
A series of N-alkyl urethanes, potential histamine H3 receptor antagonists, was prepared. Carbamate derivatives were synthesized from appropriate isocyanates and N-piperidinoalkan-1-ols. The novel compounds were evaluated for histamine H3 receptor activity in vitro on the guinea pig ileum. Some selected compounds were tested in vivo after p.o. application to mice and in vitro for selectivity towards other histamine receptors (H1, H2) in functional assays in the guinea pig. The most potent H3 receptor antagonist in vitro was compound 14 (pA2 = 7.2). Compound 14 was equipotent at M3 receptors and lacked H3 receptor activity in vivo. Predictions of octanol-water partition coefficient (Pallas) and metabolic fate (MetabolExpert, METEOR) were used to explore potential reasons for this absence of in vivo activity.
Assuntos
Carbamatos/síntese química , Carbamatos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Biotransformação , Carbamatos/farmacocinética , Fenômenos Químicos , Físico-Química , Simulação por Computador , Cobaias , Íleo/efeitos dos fármacos , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Piperidinas/farmacocinética , Receptor Muscarínico M3/efeitos dos fármacos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacosRESUMO
Novel carbamates as derivatives of 3-(1H-imidazol-4-yl)propanol with an N-alkyl chain were prepared as histamine H3-receptor antagonists. Branching of the N-alkyl side chain with methyl groups led to chiral compounds which were synthesized stereospecifically by a Mitsunobu protocol adapted Gabriel synthesis. The optical purity of some of the chiral compounds was determined (ee > 95%) by capillary electrophoresis (CE). The investigated compounds showed pronounced to high antagonist activity (Ki values of 4.1-316 nM) in a functional test for histamine H3 receptors on rat cerebral cortex synaptosomes. Similar H3-receptor antagonist activities were observed in a peripheral model on guinea pig ileum. No stereoselective discrimination for the H3 receptor for the chiral antagonists was found with the in vitro assays. All compounds were also screened for central H3-receptor antagonist activity in vivo in mice after po administration. Most compounds were potent agents of the H3-receptor-mediated enhancement of brain Ntau-methylhistamine levels. The enantiomers of the N-2-heptylcarbamate showed a stereoselective differentiation in their pharmacological effect in vivo (ED50 of 0.39 mg/kg for the (S)-derivative vs 1.5 mg/kg for the (R)-derivative) most probably caused by differences in pharmacokinetic parameters. H1- and H2-receptor activities were determined for some of the novel carbamates, demonstrating that they have a highly selective action at the histamine H3 receptor.
Assuntos
Carbamatos/síntese química , Antagonistas dos Receptores Histamínicos/síntese química , Receptores Histamínicos H3/efeitos dos fármacos , Administração Oral , Animais , Carbamatos/química , Carbamatos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Avaliação Pré-Clínica de Medicamentos , Eletroforese Capilar , Cobaias , Átrios do Coração/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Íleo/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Ratos , Receptores Histamínicos H1/efeitos dos fármacos , Receptores Histamínicos H2/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Sinaptossomos/efeitos dos fármacosRESUMO
In our search for new compounds acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of arylidene imidazo[2,1-b]thiazines was synthesized. The 1,2- and 2,3- cyclized derivatives of mono- and di-substituted Z-5-arylidene-2-thiohydantoins were examined (the X-ray crystal structure of Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one was determined) and compared with the diphenyl derivatives. To investigate the influence of the type of annelated ring on the biological activity, imidazo[2,1-b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives were obtained. The method used in annelation (1,2- and 2,3-cyclized isomers with the exception of fused arylidene imidazothiazines), the substitution pattern (arylidene towards diphenyl) as well as the character of the annelated ring had minor influence on the benzodiazepine receptor affinity of the investigated compounds. It appears that the greatest influence on the biological activity has the character and position of the substituents on the arylidene ring.
Assuntos
Diazepam/análogos & derivados , Diazepam/síntese química , Pirimidinonas/metabolismo , Receptores de GABA-A/metabolismo , Tiazinas/metabolismo , Animais , Ligação Competitiva , Córtex Cerebral/metabolismo , Diazepam/metabolismo , Diazepam/farmacologia , Desenho de Fármacos , Antagonistas de Receptores de GABA-A , Concentração Inibidora 50 , Modelos Moleculares , Pirimidinonas/síntese química , Pirimidinonas/química , Pirimidinonas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/química , Tiazinas/farmacologia , Difração de Raios XRESUMO
The synthesis of various 5-arylidene-2-thiohydantoins and results of the primary assay in vitro for their antimycobacterial activity is reported. Eight of those compounds exhibited > 90% inhibition of Mycobacterium tuberculosis growth and for them the minimum inhibitory concentrations, cytotoxicity (IC50) and the selectivity index values were determined. The most active structure, (5Z)-5-(1,1'-biphenyl-4-ylmethylene)-2-thioxoimidazolidin-4-one, showed MIC = 0.78 microg/ml. For all compounds log P and log D (pH 6.5) values were calculated.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Hidantoínas/síntese química , Hidantoínas/farmacologia , Mycobacterium/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Fenômenos Químicos , Físico-Química , Chlorocebus aethiops , Ensaios de Seleção de Medicamentos Antitumorais , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Células VeroRESUMO
Mercaptoalkyl derivatives of 5,5-diphenyl- and 5-arylidene hydantoins were synthesized as the result of hydrolytic cleavage of bicyclic imidazothiazoles, -thiazines, and -thiazepines. The title compounds were evaluated as potential antioxidants and free radical scavengers using the enzymic generation of O2- and non-enzymic lipid peroxidation tests. Examined compounds were inactive in both applied tests, where reference substances (flavonoids, nitric oxide donors and Ticlopidine) inhibited non-enzymic lipid peroxidation and scavenged superoxide anions.
Assuntos
Antioxidantes/síntese química , Sequestradores de Radicais Livres/síntese química , Imidazóis/síntese química , Compostos de Sulfidrila/síntese química , Animais , Antioxidantes/farmacologia , Fenômenos Químicos , Físico-Química , Cromatografia em Camada Fina , Sequestradores de Radicais Livres/farmacologia , Imidazóis/farmacologia , Técnicas In Vitro , Peroxidação de Lipídeos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Malondialdeído/metabolismo , Espectrometria de Massas , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Espectrofotometria Infravermelho , Compostos de Sulfidrila/farmacologia , Superóxidos/metabolismoRESUMO
Basic amide derivatives of imidazolidine-2,4-dione and pyrrolidine-2,5-dione were synthesized as potential antiarrhythmic agents. Some of them have shown antiarrhythmic activity in the chloroform, barium chloride or adrenaline induced arrhythmia.
Assuntos
Amidas/farmacologia , Antiarrítmicos/farmacologia , Imidazóis/farmacologia , Pirrolidinas/farmacologia , Amidas/síntese química , Animais , Antiarrítmicos/química , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Imidazóis/síntese química , Masculino , Camundongos , Estrutura Molecular , Pirrolidinas/síntese química , Ratos , Ratos WistarRESUMO
Synthesis and physicochemical properties of new 2-N-(phthalimido)-1-alkyl esters are described. Esters were synthesized from aromatic and heterocyclic acids with appropriate bromoalkyl phthalimides in the presence of 1,8-diazabicyclo[5,4,0]-undec-7-ene or triethylamine. The obtained compounds were evaluated for anticonvulsant activity. The display protection against MES and ScMet-induced seizures.
Assuntos
Anticonvulsivantes/síntese química , Ftalimidas/síntese química , Convulsões/prevenção & controle , Animais , Anticonvulsivantes/farmacologia , Convulsivantes , Eletrochoque , Camundongos , Pentilenotetrazol , Ftalimidas/farmacologia , Convulsões/induzido quimicamenteRESUMO
Previous results of histamine H3-receptors investigations allowed to formulate a general structure of H3-receptor antagonists. According to this model a series of compounds were obtained. As heterocycles they contained a theophylline moiety connected with a polar group (amine, ester, amide, and thiourea function) via an alkyl chain linked by a spacer to a lipophilic residue. The common distance between xanthine moiety and lipophilic rest was a six-link-chain. Selected compounds did not show significant H3-receptor antagonist activity and were weak antagonists at histamine H1-receptors.
Assuntos
Antagonistas dos Receptores Histamínicos/síntese química , Receptores Histamínicos H3/efeitos dos fármacos , Teofilina/análogos & derivados , Teofilina/farmacologia , Animais , Cobaias , Antagonistas dos Receptores Histamínicos/farmacologia , Íleo/efeitos dos fármacos , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Teofilina/síntese químicaRESUMO
A series of bicyclic derivatives based on 5,5-diphenylhydantoin (DPH) and/or 5-arylidene-hydantoin skeletons (BZH) are discussed as potential anticonvulsants. In preliminary pharmacological tests a few of these agents showed some anticonvulsant activities, like the parent DPH. The electronic parameters (molecular electrostatic potential, MEP, and dipole moment orientation) for the DPH molecule used as a model differed significantly from those calculated for the bicyclic molecules. These parameters were derived from semiempirical quantum chemistry calculations applying the PM3 method.
Assuntos
Anticonvulsivantes/química , Hidantoínas/química , Cristalografia por Raios X , Eletrochoque , Pentilenotetrazol , Fenitoína/análogos & derivados , Fenitoína/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ten carbamate derivatives have been prepared from appropriate isocyanates and omega-piperidino-1-alkanols. All compounds belong to the new generation of non-imidazole histamine H3-receptor ligands which may have beneficial pharmacokinetic properties compared with the classical imidazole-containing H3-receptor antagonists. The carbamates were evaluated in vitro for antagonist activity at guinea-pig (gp) H3, H2, H1, and M3 receptors, respectively. They displayed moderate affinity for H3 receptors (pA2 5.8-7.0 in the gp ileum assay) as well as low to moderate selectivities vis-à-vis H2 (gp atrium), H1 (gp ileum), and M3 (gp ileum) receptors. A typical member of this series is 7-piperidino-1-heptyl N-(4-phenyl-1-butyl)carbamate (17) with pA2 values of 7.02 (H3), 5.92 (H1), and 6.38 (M3), respectively, and a pD'2 value of 5.46 (H2).
Assuntos
Carbamatos/síntese química , Carbamatos/farmacologia , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Fenômenos Químicos , Físico-Química , Feminino , Cobaias , Átrios do Coração/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Íleo/efeitos dos fármacos , Técnicas In Vitro , Indicadores e Reagentes , Ligantes , Espectroscopia de Ressonância Magnética , Masculino , Antagonistas Muscarínicos/farmacologia , Músculo Liso/efeitos dos fármacos , Piperidinas/síntese química , Receptor Muscarínico M3 , Receptores Muscarínicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Recently novel leads for histamine H3 receptor antagonists of the non-imidazole type have been described. As a continuation of this research eleven new carbamate derivatives possessing an additional ether functionality were prepared. The compounds were evaluated in vitro for their antagonist activity on isolated organs of guinea-pig (GP) H3 as well as H2, H1, and M3 receptors, respectively. All compounds investigated possessed moderate antagonist affinities at guinea-pig histamine H3 receptors (pA2 6.11-6.76). An ether functionality introduced in different places of the lipophilic part of carbamates differently influenced activity and selectivity toward H3, M3, and other histamine receptors tested.
Assuntos
Carbamatos/síntese química , Carbamatos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Estimulação Elétrica , Éteres/química , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Íleo/efeitos dos fármacos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Receptor Muscarínico M3 , Receptores Muscarínicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The synthesis of new chloro-benzylidene substituted derivatives of hydantoin and their antimicrobial activity is reported. The structure-activity relationships showed that the antibacterial effect of investigated compounds depends on the distance of the phenyl ring from the amine residue and the kind of substitutes on the phenyl ring. In the investigated group of derivatives, 5-(2-chlorobenzylidene)-2-(4-fluorobenzylamine)-imidazoline-4-one and 5-(2-chlorobenzylidene)-2-(2-phenylethylamine)-imidazoline-4-one showed the best antibacterial activity against Moraxella catarrhalis.
Assuntos
Antibacterianos/síntese química , Imidazóis/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Cromatografia em Camada Fina , Imidazóis/farmacologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrofotometria InfravermelhoRESUMO
In order to evaluate changes in the lipophilic part of designed carbamates concerning their potential histamine H3-receptor antagonist properties a new series of O-[3-(1H-imidazol-4-yl)propanol]carbamates was derived containing N-mono- or di-alkenyl, alkynyl, cycloalkyl, or double-branched alkyl substituents. The compounds were tested in vitro for their H3-receptor antagonist activity on synaptosomes of rat cerebral cortex and shared moderate to high antagonist activity in vitro. In this series 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate (4) was the most potent compound in vitro (Ki = 6.3 nM). H3-receptor antagonist activity in the central nervous system (CNS) was detected for most compounds in the in vivo H3-receptor assay based upon measurement of brain N tau-methylhistamine levels after p.o. administration to mice. The most effective carbamate in vivo, 3-(1H-imidazol-4-yl)propyl N-(allyl)carbamate (3), showed higher CNS potency (ED50 = 0.48 mg/kg p.o.) than the reference antagonist thioperamide. For some novel carbamates their histamine H1- and H2-receptor activities were determined on isolated organs of guinea-pig thereby demonstrating their high H3-receptor selectivity.
Assuntos
Carbamatos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Química Encefálica/efeitos dos fármacos , Carbamatos/química , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Fenômenos Químicos , Físico-Química , Cobaias , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacocinética , Íleo/efeitos dos fármacos , Técnicas In Vitro , Indicadores e Reagentes , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Ratos , Receptores Histamínicos H3/química , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
A series of glycinamides, derivatives of diphenyl imidazolon-4-one was designed and obtained as potential ligands of the glycine binding site of NMDA receptors. The compounds were evaluated in vitro for their affinity for the glycine binding site of NMDA receptors using [3H]-L-689,560 as radioligand. Their anticonvulsant activity was estimated in vivo in a maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scMet) tests. The volume and the surface of the molecules seem to be important in elucidating the relation between the structure and the pharmacological properties.