RESUMEN
High-throughput screening was used to find selective inhibitors of human 15-lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3-carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors.
Asunto(s)
Araquidonato 15-Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Pirazoles/química , Pirazoles/farmacología , Amidas/química , Amidas/farmacología , HumanosRESUMEN
Investigation of 1N-substituted pyrazole-3-carboxanilides as 15-lipoxygenase-1 (15-LOX-1) inhibitors demonstrated that the 1N-substituent was not essential for activity or selectivity. Additional halogen substituents on the pyrazole ring, however, increased activity. Further development led to triazole-4-carboxanilides and 2-(3-pyrazolyl) benzoxazoles, which are potent and selective 15-LOX-1 inhibitors.
Asunto(s)
Araquidonato 15-Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Pirazoles/química , Pirazoles/farmacología , Triazoles/química , Triazoles/farmacología , Benzoxazoles/química , Benzoxazoles/farmacología , Humanos , Relación Estructura-ActividadRESUMEN
This paper describes how the introduction of "cationic" aliphatic amino groups in the chalcone scaffold results in potent antibacterial compounds. It is shown that the most favorable position for the aliphatic amino group is the 2-position of the B-ring, in particular in combination with a lipophilic substituent in the 5-position of the B-ring. We demonstrate that the compounds act by unselective disruption of cell membranes. Introduction of an additional aliphatic amino group in the A-ring results in compounds that are selective for bacterial membranes combined with a high antibacterial activity against both Gram-positive and -negative pathogens. The most potent compound in this study (78) has an MIC value of 2 muM against methicillin resistant Staphylococus aureus.
Asunto(s)
Antibacterianos/síntesis química , Chalconas/síntesis química , Compuestos de Amonio Cuaternario/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Cationes , Chalconas/química , Chalconas/farmacología , Recuento de Colonia Microbiana , Diseño de Fármacos , Hemólisis/efectos de los fármacos , Humanos , Técnicas In Vitro , Cinética , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Homologation of (S)-glutamic acid (Glu, 1) and Glu analogues has previously provided ligands with activity at metabotropic Glu receptors (mGluRs). The homologue of ibotenic acid (7), 2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid (HIBO, 8), and the 4-phenyl derivative of 8, compound 9a, are both antagonists at group I mGluRs. Here we report the synthesis and molecular pharmacology of HIBO analogues 9b-h containing different 4-aryl substituents. All of these compounds possess antagonist activity at group I mGluRs but are inactive at group II and III mGluRs.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Isoxazoles/síntesis química , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Animales , Encéfalo/fisiología , Células CHO , Cricetinae , AMP Cíclico/biosíntesis , Electrofisiología , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Hidrólisis , Técnicas In Vitro , Isoxazoles/química , Isoxazoles/farmacología , Fosfatidilinositoles/metabolismo , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadRESUMEN
The wasp toxin philanthotoxin-433 (PhTX-433) is a nonselective and noncompetitive antagonist of ionotropic receptors, such as ionotropic glutamate receptors and nicotinic acetylcholine receptors. Polyamine toxins are extensively used for the characterization of subtypes of ionotropic glutamate receptors, in particular Ca(2+)-permeable AMPA and kainate receptors. We have previously shown that an analogue of PhTX-433 with one of the amino groups replaced by a methylene group, philanthotoxin-83 (PhTX-83) is a selective and potent antagonist of AMPA receptors. We now describe the solid-phase synthesis of analogues of PhTX-83 and the electrophysiological characterization of these analogues on cloned AMPA and kainate receptors. The polyamine portion of PhTX-83 was modified systematically by changing the position of the secondary amino group along the polyamine chain. In another series of analogues, the acyl moiety of PhTX-83 was replaced by acids of different size and lipophilicity. Using electrophysiological techniques, PhTX-56 was shown to be a highly potent (K(i) = 3.3 +/- 0.78 nM) and voltage-dependent antagonist of homomeric GluR1 receptors and was more than 1000-fold less potent when tested on heteromeric GluR1+GluR2, as well as homomeric GluR5(Q) receptors, thus being selective for Ca(2+)-permeable AMPA receptors. Variation of the acyl group of PhTX-83 had only minor effect on antagonist potency at homomeric GluR1 receptors but led to a significant decrease in the voltage-dependence. In conclusion, PhTX-56 is a novel, very potent, and selective antagonist of Ca(2+)-permeable AMPA receptors and is a promising tool for structure/function studies of the ion channel of the AMPA receptor.
Asunto(s)
Calcio/metabolismo , Antagonistas de Aminoácidos Excitadores/síntesis química , Poliaminas/síntesis química , Receptores AMPA/antagonistas & inhibidores , Venenos de Avispas/química , Animales , Antagonistas de Aminoácidos Excitadores/química , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Oocitos , Técnicas de Placa-Clamp , Poliaminas/química , Poliaminas/farmacología , Receptores AMPA/fisiología , Receptores de Ácido Kaínico/antagonistas & inhibidores , Receptores de Ácido Kaínico/fisiología , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
A number of 1-hydroxyazole derivatives were synthesized as bioisosteres of (S)-glutamic acid (Glu) and as analogues of the AMPA receptor agonist (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA, 3b). All compounds were subjected to in vitro pharmacological studies, including a series of Glu receptor binding assays, uptake studies on native as well as cloned Glu uptake systems, and the electrophysiological rat cortical slice model. Compounds 7a,b, analogues of AMPA bearing a 1-hydroxy-5-pyrazolyl moiety as the distal carboxylic functionality, showed only moderate affinity for [3H]AMPA receptor binding sites (IC(50) = 2.7 +/- 0.4 microM and IC(50) = 2.6 +/- 0.6 microM, respectively), correlating with electrophysiological data from the rat cortical wedge model (EC(50) = 280 +/- 48 microM and EC(50) = 586 +/- 41 microM, respectively). 1-Hydroxy-1,2,3-triazol-5-yl analogues of AMPA, compounds 8a,b, showed high affinity for [3H]AMPA receptor binding sites (IC(50) = 0.15 +/- 0.03 microM and IC(50) = 0.13 +/- 0.02 microM, respectively). Electrophysiological data showed that compound 8a was devoid of activity in the rat cortical wedge model (EC(50) > 1000 microM), whereas the corresponding 4-methyl analogue 8b was a potent AMPA receptor agonist (EC(50) = 15 +/- 2 microM). In accordance with this disparity, compound 8a was found to inhibit synaptosomal [3H]D-aspartic acid uptake (IC(50) = 93 +/- 25 microM), as well as excitatory amino acid transporters (EAATs) EAAT1 (IC(50) = 100 +/- 30 microM) and EAAT2 (IC(50) = 300 +/- 80 microM). By contrast, compound 8b showed no appreciable affinity for Glu uptake sites, neither synaptosomal nor cloned. Compounds 9a-c and 10a,b, possessing 1-hydroxyimidazole as the terminal acidic function, were devoid of activity in all of the systems tested. Protolytic properties of compounds 7a,b, 8b, and 9b were determined by titration, and a correlation between the pK(a) values and the activity at AMPA receptors was apparent. Optimized structures of all the synthesized ligands were fitted to the known crystal structure of an AMPA-GluR2 construct. Where substantial reduction or abolition of affinity at AMPA receptors was observed, this could be rationalized on the basis of the ability of the ligand to fit the construct. The results presented in this article point to the utility of 1-hydroxypyrazole and 1,2,3-hydroxytriazole as bioisosteres of carboxylic acids at Glu receptors and transporters. None of the compounds showed significant activity at metabotropic Glu receptors.
Asunto(s)
Azoles/síntesis química , Ácido Glutámico/química , Receptores AMPA/agonistas , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/química , Animales , Azoles/química , Azoles/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiología , Células CHO , Células COS , Proteínas Portadoras/metabolismo , Cricetinae , Electrofisiología , Glutamina/metabolismo , Técnicas In Vitro , Masculino , Modelos Moleculares , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Relación Estructura-Actividad , Sinaptosomas/metabolismoRESUMEN
In this paper, a general applicable synthesis of prenylated aromatic compounds exemplified by prenylated benzaldehydes starting from readily available acetophenones is described. The synthesized benzaldehydes are used to prepare a number of novel analogues of Licochalcone A, a known antibacterial compound, and for the exploration of the pharmacophoric elements that are essential for the antibacterial activity. It is shown that the hydroxyl group in the A ring is essential for the activity and that the hydroxyl group in the B ring has no influence on the antibacterial effect of Licochalcone A. Furthermore, it is shown that the prenyl group at the position 5 of the B ring also has a dominating influence on the activity. This aliphatic group can be replaced by other lipophilic long chained substituents in order to maintain the activity.
Asunto(s)
Benzaldehídos/síntesis química , Chalcona/análogos & derivados , Chalcona/síntesis química , Neopreno/química , Staphylococcus aureus/efectos de los fármacos , Acetofenonas/química , Acetofenonas/metabolismo , Benzaldehídos/farmacología , Chalcona/farmacología , Chalconas , Pruebas de Sensibilidad Microbiana , Prenilación de ProteínaRESUMEN
Chalcones can exist as Z- or E-isomers and it is generally anticipated that both isomers are equipotent. In order to determine the active isomer of anti-plasmodial chalcones a series of analogues locked in the Z- or the E-form were prepared and evaluated for their anti-plasmodial activity. It was shown that the Z-locked analogue was nearly inactive, whereas the E-locked analogues were equipotent to the parent chalcones, indicating that the E-isomer is the active conformation.
Asunto(s)
Antimaláricos/síntesis química , Chalconas/síntesis química , Plasmodium falciparum/efectos de los fármacos , Animales , Antimaláricos/farmacología , Chalconas/química , Chalconas/farmacología , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Hydroxy chalcones, for example, Licochalcone A, has for several years been known to be antibacterial. The low aqueous solubility and the medium antibacterial potency have limited the usefulness of the compounds. We describe the bioisosteric replacement of the essential 4'-hydroxy group in the hydroxy chalcones with bioisosters of varied degrees of acidity resulting in both more potent and more soluble compounds. The more acidic 4'-hydroxy analogues (e.g., 3'-fluoro- or 3',5'-difluoro-) gave almost inactive compounds whereas exchanging the hydroxy group with a carboxy group resulted in a potent compound with a high aqueous solubility. Further optimisation and SAR-analysis resulted in soluble and potent carboxy chalcones [e.g., 3,5-dibromo- and 3,5-di(trifluoromethyl)-].