RESUMEN
Potent nanomolar inhibitors of Staphylococcus aureus methionyl tRNA synthetase have been derived from a file compound high throughput screening hit. Optimized compounds show excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics. Compound 11 demonstrated in vivo efficacy in an S. aureus rat abscess infection model.
Asunto(s)
Antibacterianos/síntesis química , Enterococcus/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Metionina-ARNt Ligasa/antagonistas & inhibidores , Quinolonas/síntesis química , Staphylococcus/efectos de los fármacos , Absceso/tratamiento farmacológico , Absceso/microbiología , Animales , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Quinolonas/química , Quinolonas/farmacología , Ratas , Ratas Sprague-Dawley , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/enzimología , Relación Estructura-ActividadRESUMEN
S-Alkyl dithioformates, generated by a cycloreversion process, react as 1,3-dipolarophiles with beta-lactam-based azomethine ylids to provide, after (net) elimination of MeSH, C(2)-unsubstituted penems. The overall cycloreversion/cycloaddition sequence was accelerated by microwave irradiation. [reaction: see text]
RESUMEN
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Biología Computacional , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Azufre/químicaRESUMEN
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Asunto(s)
Amidas/farmacología , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Anilidas/química , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/química , Humanos , Estructura Molecular , Receptores de Somatostatina/metabolismo , Relación Estructura-ActividadRESUMEN
High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
Asunto(s)
Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Etanolaminas/síntesis química , Etanolaminas/farmacología , Fenilalanina-ARNt Ligasa/antagonistas & inhibidores , Staphylococcus aureus/enzimología , Animales , Antibacterianos/farmacología , Diseño de Fármacos , Cinética , Mamíferos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Sensibilidad y Especificidad , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Conformationally restricted analogues of the central linker unit of bacterial methionyl tRNA synthetase (MRS) inhibitors have been prepared. The (1S,2R)-cyclopentylmethyl moiety was identified as the preferred cyclic linker, with significant diastereo- and enantioselectivity of activity. Combination of this linker with an optimal substituted aryl right-hand side has resulted in a compound with exceptionally good antibacterial activity against staphylococci and enterococci, including antibiotic resistant strains.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Metionina-ARNt Ligasa/antagonistas & inhibidores , Animales , Enterococcus faecalis/efectos de los fármacos , Técnicas In Vitro , Indicadores y Reactivos , Hígado/efectos de los fármacos , Hígado/enzimología , Modelos Moleculares , Conformación Proteica , Ratas , Staphylococcus aureus/efectos de los fármacos , EstereoisomerismoRESUMEN
As reported previously (J. R. Jarvest et al., J. Med. Chem. 45:1952-1962, 2002), potent inhibitors (at nanomolar concentrations) of Staphylococcus aureus methionyl-tRNA synthetase (MetS; encoded by metS1) have been derived from a high-throughput screening assay hit. Optimized compounds showed excellent activities against staphylococcal and enterococcal pathogens. We report on the bimodal susceptibilities of S. pneumoniae strains, a significant fraction of which was found to be resistant (MIC, > or =8 mg/liter) to these inhibitors. Using molecular genetic techniques, we have found that the mechanism of resistance is the presence of a second, distantly related MetS enzyme, MetS2, encoded by metS2. We present evidence that the metS2 gene is necessary and sufficient for resistance to MetS inhibitors. PCR analysis for the presence of metS2 among a large sample (n = 315) of S. pneumoniae isolates revealed that it is widespread geographically and chronologically, occurring at a frequency of about 46%. All isolates tested also contained the metS1 gene. Searches of public sequence databases revealed that S. pneumoniae MetS2 was most similar to MetS in Bacillus anthracis, followed by MetS in various non-gram-positive bacterial, archaeal, and eukaryotic species, with streptococcal MetS being considerably less similar. We propose that the presence of metS2 in specific strains of S. pneumoniae is the result of horizontal gene transfer which has been driven by selection for resistance to some unknown class of naturally occurring antibiotics with similarities to recently reported synthetic MetS inhibitors.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Metionina-ARNt Ligasa/antagonistas & inhibidores , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/enzimología , Secuencia de Aminoácidos , Secuencia de Bases , ADN Bacteriano/química , ADN Bacteriano/genética , Farmacorresistencia Bacteriana/genética , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Metionina-ARNt Ligasa/genética , Metionina-ARNt Ligasa/metabolismo , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mutagénesis , Reacción en Cadena de la Polimerasa , Alineación de Secuencia , Streptococcus pneumoniae/genéticaRESUMEN
Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.
Asunto(s)
Indenos/síntesis química , Indenos/farmacología , Isoleucina-ARNt Ligasa/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Aminoácidos/química , Aminoacil-ARNt Sintetasas , Animales , Concentración 50 Inhibidora , Hígado/enzimología , Ratas , Staphylococcus aureus/enzimología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Optimisation of the left-hand-side aryl moiety of a file compound screening hit against Staphylococcus aureus methionyl tRNA synthetase led to the identification of a series of potent nanomolar inhibitors. The best compounds showed excellent antibacterial activity against staphylococcal and enterococcal pathogens, including strains resistant to clinical antibiotics.
Asunto(s)
Antiinfecciosos/síntesis química , Bacterias Grampositivas/efectos de los fármacos , Metionina-ARNt Ligasa/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Farmacorresistencia Bacteriana , Enterococcus/efectos de los fármacos , Enterococcus/enzimología , Bacterias Grampositivas/enzimología , Concentración 50 Inhibidora , Staphylococcus/efectos de los fármacos , Staphylococcus/enzimología , Relación Estructura-ActividadRESUMEN
Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.
Asunto(s)
Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Metionina-ARNt Ligasa/antagonistas & inhibidores , Antibacterianos/farmacología , Enterococcus faecalis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Cinética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Quinolonas , Staphylococcus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.