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1.
ACS Chem Biol ; 10(6): 1511-20, 2015 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-25786639

RESUMEN

Streptococcus pneumoniae is a leading cause of life-threatening bacterial infections, especially in young children in developing countries. Pneumococcal infections can be treated with ß-lactam antibiotics, but rapid emergence of multidrug-resistant strains of S. pneumoniae over the past two decades has emphasized the need to identify novel drug targets. Pneumococcal surface antigen A (PsaA) is one such target, found on the cell surface of S. pneumoniae. It functions as a high-affinity substrate-binding protein, facilitating acquisition of Mn(2+), which has an important role in protecting S. pneumoniae from reactive oxygen species and, hence, oxidative stress. Consequently, PsaA is essential for bacterial survival and an important virulence factor, which makes it a promising target for antibiotic drug development. To design novel PsaA inhibitors, we used a combination of de novo fragment-based drug discovery and in silico virtual screening methods. We profiled a collection of low molecular weight compounds that were selected based on their structural diversity and ability to bind to apo-PsaA in a virtual docking experiment. The screening resulted in two initial hits that were further optimized by structural variation to improve their potency while maintaining their ligand efficiency and favorable physicochemical properties. The optimized hits were validated using a cell-based assay and molecular dynamics simulations. We found that virtual screening substantially augmented fragment-based drug design approaches, leading to the identification of novel pneumococcal PsaA inhibitors.


Asunto(s)
Antibacterianos/síntesis química , Diseño de Fármacos , Lipoproteínas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Adhesinas Bacterianas/química , Adhesinas Bacterianas/genética , Antibacterianos/farmacología , Antígenos Bacterianos/química , Antígenos Bacterianos/genética , Bioensayo , Cationes Bivalentes , Descubrimiento de Drogas , Ligandos , Lipoproteínas/química , Lipoproteínas/genética , Manganeso/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Streptococcus pneumoniae/química , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/metabolismo , Relación Estructura-Actividad , Zinc/química
2.
Bioorg Med Chem ; 22(16): 4490-8, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-25023540

RESUMEN

An azide-functionalised analogue of the oxazolidinone antibiotic linezolid was synthesised and shown to retain antimicrobial activity. Using facile 'click' chemistry, this versatile intermediate can be further functionalised to explore antimicrobial structure-activity relationships or conjugated to fluorophores to generate fluorescent probes. Such probes can report bacteria and their location in a sample in real time. Modelling of the structures bound to the cognate 50S ribosome target demonstrates binding to the same site as linezolid is possible. The fluorescent probes were successfully used to image Gram-positive bacteria using confocal microscopy.


Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Azidas/farmacología , Colorantes Fluorescentes/análisis , Bacterias Grampositivas/citología , Bacterias Grampositivas/efectos de los fármacos , Oxazolidinonas/farmacología , Antibacterianos/síntesis química , Azidas/química , Química Clic , Diseño de Fármacos , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacología , Bacterias Grampositivas/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Microscopía Confocal , Modelos Moleculares , Estructura Molecular , Oxazolidinonas/química , Relación Estructura-Actividad
3.
Chem Commun (Camb) ; 49(75): 8407-9, 2013 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-23939425

RESUMEN

A new method for the synthesis of N-substituted isoindolinones and 3-arylaminophthalides was developed through aza-Wittig/cyclisation. The reaction of o-phthalaldehydic acid methyl ester with benzylic, aromatic and aliphatic azides gave N-isoindolinones whereas reaction of o-phthalaldehydic acid with the aromatic azides gave 3-arylaminophthalides.


Asunto(s)
Ácidos/química , Benzofuranos/síntesis química , Isoindoles/síntesis química , Éteres Metílicos/química , o-Ftalaldehído/química , Azidas/química , Ciclización , Estereoisomerismo
4.
Bioorg Med Chem Lett ; 23(6): 1667-70, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23416004

RESUMEN

Anacardic acid derivatives exhibit a broad range of biological activities. In this report, an efficient method for the synthesis of anacardic acid derivatives was explored, and a small set of salicylic acid variants synthesised retaining a constant hydrophobic element (a naphthyl tail). The naphthyl side chain was introduced via Wittig reaction and the aldehyde installed using directed ortho-metalation reaction of the substituted o-anisic acids. The failure of ortho-metalation using unprotected carboxylic acid group compelled us to use directed ortho-metalation in which a tertiary amide was used as a strong ortho-directing group. In the initial route, tertiary amide cleavage during final step was challenging, but cleaving the tertiary amide before Wittig reaction was beneficial. The Wittig reaction with protected carboxylic group (methyl ester) resulted in side-products whereas using sodium salt resulted in higher yields. The novel compounds were screened for antibacterial activity and cytotoxicity. Although substitution on the salicylic head group enhanced antibacterial activities they also enhanced cytotoxicity.


Asunto(s)
Ácidos Anacárdicos/química , Antibacterianos/síntesis química , Ácidos Anacárdicos/farmacología , Ácidos Anacárdicos/toxicidad , Antibacterianos/farmacología , Antibacterianos/toxicidad , Supervivencia Celular/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Células HEK293 , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Ácido Salicílico/química , Relación Estructura-Actividad
5.
ACS Comb Sci ; 14(10): 527-30, 2012 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-22946559

RESUMEN

The copper-catalyzed azide-alkyne cycloaddition click reaction is a valuable process for the synthesis of libraries of drug candidates, derivatized polymers and materials, and a wide variety of other functional molecules. In some circumstances, the removal of the copper catalyst is both necessary and inconvenient. We describe here two immobilized forms of a Cu-binding ligand that has been shown to accelerate triazole formation under many different conditions, using different resin supports that are appropriate for aqueous or organic solvents. Copper leaching from these resins was modest, allowing them to be reused in many reaction/filtration cycles without recharging with metal ion. The utility of this catalyst form was demonstrated in the convenient synthesis of 20 N-acetylgalactosamine derivatives for biological testing.


Asunto(s)
Alquinos/química , Azidas/química , Química Clic , Cobre/química , Compuestos Organometálicos/química , Resinas Sintéticas/química , Acetilglucosamina/síntesis química , Acetilglucosamina/química , Catálisis , Ciclización , Ligandos , Estructura Molecular , Solventes/química , Agua/química
6.
Bioorg Med Chem Lett ; 22(7): 2428-33, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22406152

RESUMEN

The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and pharmacokinetics of two drugs to ensure both concentrations remain within the range of therapeutic efficacy whilst avoiding adverse effects. Hybrid drugs, where two drugs are linked together with a flexible linker, have been explored, but the resultant large, flexible molecules can have poor bioavailability. We have developed a chimeric approach using click chemistry where the pharmacophores of two drugs are overlapped into a single smaller, more drug-like molecule. Design and selection of compounds were assisted by in silico structural docking. We prepared a series of compounds that include candidates showing activity against the targets of both trimethoprim; dihydrofolate reductase, and ciprofloxacin; DNA gyrase and topoisomerase IV. The resultant triazole containing molecules show modest, but broad spectrum activities against drug sensitive and resistant Gram-negative and Gram-positive bacteria, with no observable cytotoxicity.


Asunto(s)
Antibacterianos/síntesis química , Simulación por Computador , Antagonistas del Ácido Fólico/síntesis química , Triazoles/síntesis química , Antibacterianos/farmacología , Ciprofloxacina/química , Química Clic , Girasa de ADN/química , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/química , Diseño de Fármacos , Farmacorresistencia Microbiana , Antagonistas del Ácido Fólico/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/crecimiento & desarrollo , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/crecimiento & desarrollo , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Relación Estructura-Actividad , Tetrahidrofolato Deshidrogenasa/química , Inhibidores de Topoisomerasa II , Triazoles/farmacología , Trimetoprim/química
7.
J Am Chem Soc ; 134(4): 1978-81, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22280495

RESUMEN

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.


Asunto(s)
Acetilgalactosamina/química , Receptor de Asialoglicoproteína/química , Acetilgalactosamina/análogos & derivados , Humanos , Ligandos , Estructura Molecular , Estereoisomerismo
8.
Chem Soc Rev ; 39(4): 1252-61, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20309485

RESUMEN

Combinatorial approaches to the discovery of new functional molecules are well established among chemists and biologists, inspired in large measure by the modular composition of many systems and molecules in Nature. Many approaches rely on the synthesis and testing of individual members of a candidate combinatorial library, but attention has also been paid to techniques that allow the target to self-assemble its own binding agents. These fragment-based methods, grouped under the general heading of target-guided synthesis (TGS), show great promise in lead discovery applications. In this tutorial review, we review the use of the 1,3-dipolar cycloaddition reaction of organic azides and alkynes in a kinetically-controlled TGS approach, termed in situ click chemistry. The azide-alkyne reaction has several distinct advantages, most notably high chemoselectivity, very low background ligation rates, facile synthetic accessibility, and the stability and properties of the 1,2,3-triazole products. Examples of the discovery of potent inhibitors of acetylcholinesterases, carbonic anhydrase, HIV-protease, and chitinase are described, as are methods for the templated assembly of agents that bind DNA and proteins.


Asunto(s)
Productos Biológicos/química , Alquinos/química , Azidas/química , Productos Biológicos/metabolismo , Inhibidores de Anhidrasa Carbónica/química , Catálisis , Quitinasas/antagonistas & inhibidores , Quitinasas/metabolismo , Inhibidores de la Colinesterasa/química , Técnicas Químicas Combinatorias , ADN/química , ADN/metabolismo , Inhibidores de la Proteasa del VIH/química , Unión Proteica
9.
J Org Chem ; 74(21): 8417-20, 2009 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-19827757

RESUMEN

Gold(III) activation of unprotected propargyl glycosyl donors has been shown to be effective for the synthesis of saccharides. Terminal propargyl glycosides of glucose, galactose, and mannose required heating at reflux in acetonitrile with 5% AuCl(3) for reaction with various primary alcohol acceptors, the latter used in 10-fold molar excess relative to donor. Donors containing the 2-butynyl group were more reactive, giving good yields of glycoside products at lower temperatures. Secondary alcohols could also be used but with diminished efficiency. The propargylic family of donors is especially convenient because they can be easily prepared on large scale by Fischer glycosylation and stored indefinitely before chemoselective activation by the catalyst.


Asunto(s)
Alquinos/química , Glicosilación , Espectroscopía de Resonancia Magnética
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