RESUMEN
Novel quinolone antibacterial agents bearing (3S)-amino-(4R)-ethylpiperidines were designed by using low energy conformation analysis and synthesized by applying a conventional coupling reaction of the quinolone nuclei with new piperidine side chains. These compounds were tested in MIC assays and found to be highly potent against Gram-positive and Gram-negative organisms. In particular, the new compounds exhibited high activity against the resistant pathogens Staphylococcus aureus (MRCR) and Streptococcus pneumoniae (PR). Importantly, when the (3S)-amino-(4R)-ethylpiperidinyl quinolones were compared with marketed quinolones sharing the same quinolone nuclei but different side chains at the C-7 position, the new quinolones showed superior activity against Gram-positive organisms, including resistant pathogens.
Asunto(s)
Antibacterianos/síntesis química , Bacterias/efectos de los fármacos , Farmacorresistencia Bacteriana , Piperidinas/síntesis química , Quinolonas/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Girasa de ADN/química , Girasa de ADN/efectos de los fármacos , ADN Superhelicoidal/química , ADN Superhelicoidal/efectos de los fármacos , Escherichia coli/enzimología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Piperidinas/química , Piperidinas/farmacología , Quinolonas/química , Quinolonas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Amelogenins make up over 90% of the protein present during enamel formation and have been demonstrated to be critical in proper enamel development, but the mechanism governing this control is not well understood. Leucine-rich amelogenin peptide (LRAP) is a 59-residue splice variant of amelogenin and contains the charged regions from the full protein thought to control crystal regulation. In this work, we utilized neutron reflectivity (NR) to investigate the structure and orientation of LRAP adsorbed from solutions onto molecularly smooth COOH-terminated self-assembled monolayer (SAM) surfaces. Sedimentation velocity (SV) experiments revealed that LRAP is primarily a monomer in saturated calcium phosphate (SCP) solutions (0.15 M NaCl) at pH 7.4. LRAP adsorbed as â¼32 Å thick layers at â¼70% coverage as determined by NR. Rosetta simulations of the dimensions of LRAP in solution (37 Å diameter) indicate that the NR determined z dimension is consistent with an LRAP monomer. SV experiments and Rosetta simulations show that the LRAP monomer has an extended, asymmetric shape in solution. The NR data suggests that the protein is not completely extended on the surface, having some degree of structure away from the surface. A protein orientation with the C-terminal and inner N-terminal regions (residues â¼8-24) located near the surface is consistent with the higher scattering length density (SLD) found near the surface by NR. This work presents new information on the tertiary and quaternary structure of LRAP in solution and adsorbed onto surfaces. It also presents further evidence that the monomeric species may be an important functional form of amelogenin proteins.
Asunto(s)
Proteínas del Esmalte Dental/química , Adsorción , Secuencia de Aminoácidos , Fosfatos de Calcio/química , Proteínas del Esmalte Dental/metabolismo , Concentración de Iones de Hidrógeno , Datos de Secuencia Molecular , Neutrones , Estructura Terciaria de Proteína , Refractometría , Propiedades de SuperficieRESUMEN
The sulfamic acid phosphotyrosine mimetic was coupled with a previously known malonate template to obtain highly selective and potent inhibitors of HPTPbeta. Potentially hydrolyzable malonate ester functionalities were replaced with 1,2,4-oxadiazoles without a significant effect on HPTPbeta potency.
Asunto(s)
Química Farmacéutica/métodos , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Cristalografía por Rayos X , Diseño de Fármacos , Enlace de Hidrógeno , Hidrólisis , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores , Relación Estructura-ActividadRESUMEN
High-throughput screening of the P&GP corporate repository against several protein tyrosine phosphatases identified the sulfamic acid moiety as potential phosphotyrosine mimetic. Incorporation of the sulfamic acid onto a 1,2,3,4-tetrahydroisoquinoline scaffold provided a promising starting point for PTP1B inhibitor design.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Ácidos Sulfónicos/farmacología , Tetrahidroisoquinolinas/química , Sitios de Unión , Unión Competitiva , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ligandos , Modelos Moleculares , Imitación Molecular , Fosfotirosina/metabolismo , Unión Proteica , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas/metabolismo , Relación Estructura-Actividad , Ácidos Sulfónicos/síntesis química , Ácidos Sulfónicos/química , Dominios Homologos srcRESUMEN
Quinolones without the usual 6-fluorine substituent have been recently described as potent antibacterial agents. A series of non-fluorinated analogues of the antibacterial quinolone Levofloxacin were synthesized and tested.