Peter C. Junk

Leishmaniasis: Current Treatment and Prospects for New Drugs and Vaccines

Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. WHO estimates that the disease results in 2 million new cases a year, threatens 350 million people in 88 countries and that there are 12 million people currently infected worldwide. Current treatment is based on chemotherapy, which relies on a handful of drugs with serious limitations such as high cost, toxicity, difficult route of administration and lack of efficacy in endemic areas. Pentavalent antimonials have been the mainstay of antileishmanial therapy for over 70 years with second line drugs, Amphotericin B and Pentamidine, used in case of antimonial failure. Since the introduction of miltefosine at the beginning of this century, no new antileishmanial compounds have been approved for human treatment. Leishmaniasis is considered one of a few parasitic diseases likely to be controllable by vaccination. However, to date no such vaccine is available despite substantial efforts by many laboratories. The development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. This review outlines the current status of vaccine development and looks at the currently available chemotherapy as well as examples of drugs in development and different approaches to antileishmanial drug discovery and identification of novel antiparasitic compounds.

Dual Effect of Ceramide on Human Endothelial Cells Induction of Oxidative Stress and Transcriptional Upregulation of Endothelial Nitric Oxide Synthase

Background—Generation of the second-messenger molecule ceramide by stimulated sphingomyelinase activity has been implicated in the inflammatory processes contributing to the pathogenesis of atherosclerosis. However, reports of stimulatory effects of ceramide on endothelial NO production in animal models suggest antiatherosclerotic effects of the molecule. Therefore, we investigated long-term effects of ceramide on NO generation in human endothelial cells. Methods and Results—In human umbilical vein endothelial cells (HUVECs) and in HUVEC-derived EA.hy 926 endothelial cells, C6-ceramide (N-hexanoyl-d-erythro-sphingosine) reduced the generation of bioactive NO (RFL-6 reporter-cell assay). At the same time, the signaling molecule increased endothelial NO synthase (eNOS) mRNA (RNase protection assay) and protein expression (Western blot). C6-ceramide stimulated eNOS transcription by a signaling mechanism involving protein phosphatase PP2A but did not modify the stability of the eNOS mRNA. Endothelial generation of reactive oxygen species (ROS) was increased by C6-ceramide [5-(and-6)-chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) oxidation-based fluorescence assay], and this effect was partially reversed by the NOS inhibitor NG-nitro-l-arginine methyl ester (L-NAME). On the other hand, (6 R)-5,6,7,8-tetrahydro-l-biopterin (BH4) normalized in part the ceramide-induced reduction in bioactive NO. Conclusions—Ceramide produces oxidative stress in human endothelial cells, thereby reducing bioactive NO. The partial reversal of this reduction by BH4 and the diminution of ROS generation by L-NAME suggest that ceramide promotes NADPH oxidase activity of eNOS, leading to ROS formation at the expense of NO synthesis. The ceramide-induced upregulation of eNOS gene transcription can be considered an ineffective compensatory mechanism. The decreased bioavailability of NO is likely to favor a proatherogenic role of ceramide.

Formation of elastomeric polypropylene promoted by the dynamic complexes [TiCl2{N(PPh2)2}2] and [Zr(NPhPPh2)4]

Abstract The homoleptic phosphinoamide complex [Zr(NPhPPh 2 ) 4 ] ( 1 ) and the bisamido complex [TiCl 2 {N(PPh 2 ) 2 } 2 ] ( 2 ) were prepared from ZrCl 4 and four equivalents of LiNPhPPh 2 and from TiCl 4 and one equivalent of [Li(THF)N(PPh 2 ) 2 ] 2 . In the solid state, the four NPhPPh 2 ligands in 1 exhibit η 2 coordination. The ZrN 4 P 4 fragment is highly symmetrical and almost of D 2 symmetry. Hence, the complex is chiral, and the two enantiomers cocrystallize in the asymmetric unit. In solution, 1 exhibits signals for the six-coordinate complex [Zr(η 2 -NPhPPh 2 ) 2 (η 1 -NPhPPh 2 ) 2 ]. In the presence of methylalumoxane (MAO), 1 and 2 are active catalysts for the formation of high-molecular-weight elastomeric polypropylene. The formation of elastomeric polypropylene is a consequence of an epimerization mechanism of the last-inserted monomer, indicating no detachment of the growing polymer chain from the metal center during this process. Fractionation studies of all the elastomeric polymers show no atactic fractions. As corroboration for this mechanism, we have shown that these complexes are active catalysts for the isomerization and oligomerization of 1-octene, as well as for the rapid isomerization of allylbenzene to trans -methylstyrene.

(3+3)-Cyclocondensation of the enantiopure and racemic forms of trans-1,2-diaminocyclohexane with terephthaldehyde. Formation of diastereomeric molecular triangles and their stereoselective solid-state stacking into microporous chiral columns

Abstract The non-templated reaction of both the homochiral as well as the racemic form of trans-1,2-diaminocyclohexane with terephthaldehyde affords (3+3)-cyclocondensed molecular triangles in practically quantitative yields. The configuration of the diastereomeric products resulting in the individual reactions has been determined by 1H and 13C NMR spectroscopy. Unambiguous proof has been obtained by X-ray crystal structure analysis of both alternative diastereomers, revealing also a stereoselective stacking of the triangles into microporous chiral columns.

Rapid mechanochemical synthesis of two new Cd(II)-based metal–organic frameworks with high removal efficiency of Congo red

Two new three-dimensional porous Cd(II)-based metal–organic frameworks, [Cd2(oba)2(4-bpdb)2]n·(DMF)x (TMU-8) and [Cd(oba)(4,4′-bipy)]n·(DMF)y (TMU-9), have been synthesized via mechanosynthesis by using nonlinear dicarboxylate and linear N-donor ligands and then characterized by single-crystal X-ray crystallography. The effect of using different N-donor ligands 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene (4-bpdb) and 4,4′-bipyridine (4,4′-bipy) as pillars on the final structure has been studied. Also, the removal efficiency and order reaction kinetics of these MOFs in the presence of Congo red were investigated.

Synthesis and characterisation of bulky guanidines and phosphaguanidines: precursors for low oxidation state metallacycles

Reactions of alkali metal amides or phosphides with the bulky carbodiimide, ArNCNAr (Ar = C6H3Pri2-2,6), followed by aqueous work-ups, have yielded several guanidines, ArNC(NR2)N(H)Ar (R = cyclohexyl (GisoH) or Pri (PrisoH); NR2 = cis-NC5H8Me2-2,6 (PipisoH)), a bifunctional guanidine, {ArNCN(H)Ar}2{μ-N(C2H4)2N} (Pip(GisoH)2), and two phosphaguanidines, ArNC(PR2)N(H)Ar (R = cyclohexyl (CyP-GisoH) or Ph (PhP-GisoH)). A very bulky guanidine, ArNC{N(Ar)SiMe3}N(H)Ar (ArSi-Giso), and an aryl coupled bifunctional guanidine, {ArN(H)C(NPri2)NC6H2Pri2-2,6-}2 (PrisoH)2, have been prepared by other routes. All compounds have been crystallographically characterised and shown to exist in a number of isomeric forms in the solid state. These appear to be largely retained in solution. The deprotonation of GisoH with BunLi in either hexane or THF led to crystallographically characterised dimeric and monomeric complexes respectively, viz. [Li{Li(κ2-N,N′-Giso)2}] and [Li(THF)(η1-N,η3-Ar-Giso)]. Deprotonation of PrisoH and Pip(GisoH)2 with K[N(SiMe3)2] gave the unsolvated polymer, [{K(η1-N,η6-Ar-Priso)}∞], and the solvated complex, [{K(THF)2}{Pip(Giso)2}{K(THF)3}], respectively.

Homoleptic lanthanide(II)–bis(guanidinate) complexes, [Ln(Giso)2] (Giso = [(ArN)2CN(C6H11)2]−, Ar = C6H3Pri2-2,6): planar 4-coordinate (Ln = Sm or Eu) vs distorted tetrahedral (Ln = Yb) geometries

The first homoleptic lanthanide(II)-guanidinate complexes have been prepared and shown to have differing coordination geometries (including unprecedented examples of planar 4-coordination) that depend on the size of the lanthanide metal.

Inhibition of Corrosion on AA2024-T3 by New Environmentally Friendly Rare Earth Organophosphate Compounds

Abstract The combination of rare earth metals (REM), such as Ce, La, Pr, or the less-refined mischmetal (consisting of a combination of REM) with dibutyl phosphate or diphenyl phosphate, provides a complex that shows excellent corrosion inhibition for AA2024-T3 (UNS A92024) in aqueous chloride environments. In some instances, it is equal to the inhibition provided by the chromate compounds, which are still used by the aircraft industry. The addition of these compounds as an inhibiting pigment in an epoxy coating also shows efficient suppression of filiform corrosion from scribes in the coating, under both alternate immersion and high-humidity conditions. Surface characterization of AA2024-T3 specimens immersed in solutions of these complex salts suggests that a film containing both the organic and rare earth components deposits on the alloy surface. The electrochemical data indicate that this film is acting as a mixed inhibitor, suppressing both the anodic and cathodic processes on the surface.

One dimensional energy transfer in lanthanoid picolinates. Correlation of structure and spectroscopy

Optical and structural properties of rare earth complexes with 2-pyridine carboxylic acid (‘Hpic’) are evaluated by luminescence spectroscopy, decay measurements, X-ray crystal structure determination, FTIR, DTA and metal content analysis. Corresponding Tb3+and Eu3+ complexes of this ligand are extraordinarily efficient with respect to their luminescence. In the crystalline state the series is isostructural and composed of M[Ln(pic)4]·nH2O (M = Na, NH4; Ln = Eu, Gd, Tb, Ho) with pic-linked [Ln(pic)4]− units forming a chain-like structure, which gives rise to a one-dimensional exchange communication between the rare earth ions; this energy transfer being confined to the chains. Energy transfer of the Coulomb type between the ligands appears to be of significance only, if suitable rare earth acceptor states are not accessible, as is shown for a series of [La(pic)4]− series, in which La3+ is gradually substituted by Tb3+ or Eu3+.

Bismuth(III) complexes derived from non-steroidal anti-inflammatory drugs and their activity against Helicobacter pylori.

The formation of bismuth(III) complexes of carboxylates and benzoates derived from the 1 : 3 reaction of BiPh(3) with the common non-steroidal anti-inflammatory drugs (NSAIDs) ketoprofen, naproxen, ibuprofen, mefenamic acid, diflunisal, 5-chlorosalicylic acid, fenbufen, sulindac, tolfenamic acid and flufenamic acid, has been achieved using both solvent-free and solvent-mediated methods. The thermochemical profiles of the solvent-free reactions were studied using DSC-TGA. All reactions produced the tris-substituted complexes of general formula [BiL(3)](n), with the complexes derived from ketoprofen and sulindac having an additional single bismuth bound H(2)O molecule in the inner coordination sphere. The complexes are stable in air over a period of six months, do not undergo significant decomposition when suspended overnight in water, but decompose in 1 M HCl solution to release the free acid form of the NSAID. All ten complexes show excellent in vitro activity against Helicobacter pylori with MIC values of > or = 6.25 microg mL(-1).