Selective inhibition of an apicoplastic aminoacyl-tRNA synthetase from Plasmodium falciparum.

The resistance of malaria parasites to available drugs continues to grow, and this makes the need for new antimalarial therapies pressing. Aminoacyl-tRNA synthetases (ARSs) are essential enzymes and well-established antibacterial targets and so constitute a promising set of targets for the development of new antimalarials. Despite their potential as drug targets, apicoplastic ARSs remain unexplored. We have characterized the lysylation system of Plasmodium falciparum, and designed, synthesized, and tested a set of inhibitors based on the structure of the natural substrate intermediate: lysyl-adenylate. Here we demonstrate that selective inhibition of apicoplastic ARSs is feasible and describe new compounds that that specifically inhibit Plasmodium apicoplastic lysyl-tRNA synthetase and show antimalarial activities in the micromolar range.

Protein translation in Plasmodium parasites.

The protein translation machinery of the parasite Plasmodium is the target of important anti-malarial drugs, and encompasses many promising targets for future drugs. Plasmodium parasites have three subcellular compartments that house genomes; the nucleus, mitochondrion and apicoplast, and each requires its own compartmentalized transcription and translation apparatus for survival. Despite the availability of the complete genome sequence that should reveal the requisite elements for all three compartments, our understanding of the translation machineries is patchy. We review what is known about cytosolic and organellar translation in Plasmodium and discuss the molecules that have been identified through genome sequencing and post-genomic analysis. Some translation components are yet to be found in Plasmodium, whereas others appear to be shared between translationally active organelles.

Analysis of time-dependent conjugation of gold nanoparticles with an antiparkinsonian molecule by using curve resolution methods.

In this work, the time-dependent conjugation process between a thiolated molecule (with anti-parkinsonian properties) and gold nanoparticles has been monitored and studied by the combined use of fast acquisition Ultra Violet-Visible (UV-Vis) spectra and the ability of Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) technique. From the highly informative kinetic profiles obtained it was possible to extract quantitative and qualitative information of the conjugation process which includes i) time-dependent concentration profiles and pure spectra of species involved on conjugation process, ii) estimation of molecule concentration necessary for the completeness of the conjugation reaction, iii) molecule footprint and iv) free energy of molecule adsorption.

The unexpected role of pyridine-2-carboxylic acid in manganese based oxidation catalysis with pyridin-2-yl based ligands.

A number of manganese-based catalysts employing ligands whose structures incorporate pyridyl groups have been reported previously to achieve both high turnover numbers and selectivity in the oxidation of alkenes and alcohols, using H(2)O(2) as terminal oxidant. Here we report our recent finding that these ligands decompose in situ to pyridine-2-carboxylic acid and its derivatives, in the presence of a manganese source, H(2)O(2) and a base. Importantly, the decomposition occurs prior to the onset of catalysed oxidation of organic substrates. It is found that the pyridine-2-carboxylic acid formed, together with a manganese source, provides for the observed catalytic activity. The degradation of this series of pyridyl ligands to pyridine-2-carboxylic acid under reaction conditions is demonstrated by (1)H NMR spectroscopy. In all cases the activity and selectivity of the manganese/pyridyl containing ligand systems are identical to that observed with the corresponding number of equivalents of pyridine-2-carboxylic acid; except that, when pyridine-2-carboxylic acid is used directly, a lag phase is not observed and the efficiency in terms of the number of equivalents of H(2)O(2) required decreases from 6-8 equiv. with the pyridin-2-yl based ligands to 1-1.5 equiv. with pyridine-2-carboxylic acid.

Manganese catalyzed cis-dihydroxylation of electron deficient alkenes with H(2)O(2).

A practical method for the multigram scale selective cis-dihydroxylation of electron deficient alkenes such as diethyl fumarate and N-alkyl and N-aryl-maleimides using H(2)O(2) is described. High turnovers (>1000) can be achieved with this efficient manganese based catalyst system, prepared in situ from a manganese salt, pyridine-2-carboxylic acid, a ketone and a base, under ambient conditions. Under optimized conditions, for diethyl fumarate at least 1000 turnovers could be achieved with only 1.5 equiv. of H(2)O(2) with d/l-diethyl tartrate (cis-diol product) as the sole product. For electron rich alkenes, such as cis-cyclooctene, this catalyst provides for efficient epoxidation.

Adenosine A2A receptor-antagonist/dopamine D2 receptor-agonist bivalent ligands as pharmacological tools to detect A2A-D2 receptor heteromers.

Adenosine A(2A) (A(2A)R) and dopamine D(2) (D(2)R) receptors mediate the antagonism between adenosinergic and dopaminergic transmission in striatopallidal GABAergic neurons and are pharmacological targets for the treatment of Parkinson's disease. Here, a family of heterobivalent ligands containing a D(2)R agonist and an A(2A)R antagonist linked through a spacer of variable size was designed and synthesized to study A(2A)R-D(2)R heteromers. Bivalent ligands with shorter linkers bound to D(2)R or A(2A)R with higher affinity than the corresponding monovalent controls in membranes from brain striatum and from cells coexpressing both receptors. In contrast, no differences in affinity of bivalent versus monovalent ligands were detected in experiments using membranes from cells expressing only one receptor. These findings indicate the existence of A(2A)R-D(2)R heteromers and of a simultaneous interaction of heterobivalent ligands with both receptors. The cooperative effect derived from the simultaneous interaction suggests the occurrence of A(2A)R-D(2)R heteromers in cotransfected cells and in brain striatum. The dopamine/adenosine bivalent action could constitute a novel concept in Parkinson's disease pharmacotherapy.

Enantioselective synthesis of beta2-amino acids using rhodium-catalyzed hydrogenation.

A series of protected beta2-dehydroamino acids has been prepared in three steps from commercially available starting materials in good yields. These were used as substrates in rhodium-catalyzed asymmetric hydrogenation applying a mixed ligand system of monodentate phosphoramidites and phosphines. Optimization of the catalyst structure was achieved by high throughput experimentation. High enantioselectivities were obtained (up to 91%) with full conversion for a number of beta-amino acids.

PegPhos: a monodentate phosphoramidite ligand for enantioselective rhodium-catalysed hydrogenation in water.

A BICOL derived monodentate phosphoramidite ligand gives ee's up to 89% in the enantioselective Rh-catalysed hydrogenation of N-acyl dehydroalanine using water as the solvent.

PipPhos and MorfPhos: privileged monodentate phosphoramidite ligands for rhodium-catalyzed asymmetric hydrogenation.

A library of 20 monodentate phosphoramidite ligands has been prepared and applied in rhodium-catalyzed asymmetric hydrogenation. This resulted in the identification of two ligands, PipPhos and MorfPhos, that afford excellent and in several cases unprecedented enantioselectivities in the hydrogenation of N-acyldehydroamino acid esters, dimethyl itaconate, acyclic N-acylenamides, and cyclic N-acylenamides. In addition, a method for the parallel enantioselectivity determination of eight acylated amines is presented.

Catechol-based phosphoramidites: a new class of chiral ligands for rhodium-catalyzed asymmetric hydrogenations.

[reaction: see text] The synthesis and application of a new class of catechol-based phosphoramidites is described. Ees up to 99% were obtained in the rhodium-catalyzed asymmetric hydrogenation of dehydroamino acids and enamides.

First examples of improved catalytic asymmetric C-C bond formation using the monodentate ligand combination approach.

[reaction: see text] Using a combination of chiral monodentate phosphoramidite ligands in the rhodium-catalyzed conjugate addition of boronic acids to three different substrates, we have shown for the first time that the ligand combination approach is applicable for C-C bond formation. Chiral catalysts based on hetero-combinations of ligands are found to be more effective than the homo-combinations. (31)P NMR experiments show that the hetero-combinations are formed in excess over the homo-combinations.