4-Arylthieno[2,3-b]pyridine-2-carboxamides Are a New Class of Antiplasmodial Agents

Malaria causes hundreds of thousands of deaths every year, making it one of the most dangerous infectious diseases worldwide. Because the pathogens have developed resistance against most of the established anti-malarial drugs, new antiplasmodial agents are urgently needed. In analogy to similar antiplasmodial ketones, 4-arylthieno[2,3-b]pyridine-2-carboxamides were synthesized by Thorpe-Ziegler reactions. In contrast to the related ketones, these carboxamides are only weak inhibitors of the plasmodial enzyme PfGSK-3 but the compounds nevertheless show strong antiparasitic activity. The most potent representatives inhibit the pathogens with IC50 values in the two-digit nanomolar range and exhibit high selectivity indices (>100)

Structure-activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines.

BACKGROUND: Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. METHODS:4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. RESULTS:The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was shown that the (+)-enantiomer acts as eutomer. CONCLUSIONS:The attachment of alkylamino side chains leads to the improvement of antiplasmodial activity and aqueous solubility of selective PfGSK-inhibitors belonging to the class of 4-phenylthieno[2,3-b]pyridines. These molecules show axial chirality, a feature of high impact for biological activity. The findings can be exploited for the development of improved selective PfGSK-3 inhibitors

90-річчя члена-кореспондента НАН України Г.К. Степанковської

The p(T)-differential production cross section of electrons from semileptonic decays of heavy-flavor hadrons has been measured at midrapidity in proton-proton collisions at root s = 2.76 TeV in the transverse momentum range 0.5 < p(T) < 12 GeV/c with the ALICE detector at the LHC. The analysis was performed using minimum bias events and events triggered by the electromagnetic calorimeter. Predictions from perturbative QCD calculations agree with the data within the theoretical and experimental uncertainties

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

7-Iodo-1H-indole-3-carbonitrile

The title compound was prepared by a Friedel–Crafts acylation-oxime synthesis-decarboxylation/dehydration sequence starting from commercially available 7-iodoindole with 2-(7-iodo-1H-indol-3-yl)-2-oxoacetic acid as isolated intermediate. The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, EI-MS), and purity was assessed by two independent HPLC methods

7-Iodo-1H-indole-3-carbonitrile

The title compound was prepared by a Friedel–Crafts acylation-oxime synthesis-decarboxylation/dehydration sequence starting from commercially available 7-iodoindole with 2-(7-iodo-1H-indol-3-yl)-2-oxoacetic acid as isolated intermediate. The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR, EI-MS), and purity was assessed by two independent HPLC methods

Underlying Event measurements in pp collisions at root s=0.9 and 7 TeV with the ALICE experiment at the LHC

We present measurements of Underlying Event observables in pp collisions at root s = 0 : 9 and 7 TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p(T),L-T in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p(T) thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2-3 between the lower and higher collision energies, depending on the track p(T) threshold considered. Data are compared to PYTHIA 6.4, PYTHIA 8.1 and PHOJET. On average, all models considered underestimate the multiplicity and summed p(T) in the Transverse region by about 10-30%

Light vector meson production in pp collisions at root s=7 TeV ALICE Collaboration

The ALICE experiment has measured low-mass dimuon production in pp collisions at root s = 7 TeV in the dimuon rapidity region 2.5 < y < 4. The observed dimuon mass spectrum is described as a superposition of resonance decays (eta, rho, omega, eta', phi) into muons and semi-leptonic decays of charmed mesons. The measured production cross sections for omega and phi are sigma(omega)(1 < p(t) < 5 GeV/c. 2.5 < y < 4) = 5.28 +/- 0.54(stat) +/- 0.49(syst) mb and sigma(phi)(1 < p(t) < 5 GeV/c. 2.5 < y < 4) = 0.940 +/- 0.084(stat) +/- 0.076(syst) mb. The differential cross sections d(2)sigma/dy dp(t) are extracted as a function of p(t) for omega and phi. The ratio between the rho and omega cross section is obtained. Results for the phi are compared with other measurements at the same energy and with predictions by models. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved

Measurement of quarkonium production at forward rapidity in pp collisions at sqrt(s) =7 TeV

The inclusive production cross sections at forward rapidity of J/\u3c8, \u3c8(2S),\u3d2(1S) and\u3d2(2S) are measured in pp collisions at 1as = 7 TeV with the ALICE detector at the LHC. The analysis is based on a data sample correspondingto an integrated luminosity of 1.35 pb 121. Quarkonia are reconstructed in the dimuon-decay channel and the signal yields are evaluated by fitting the \u3bc+\u3bc 12 invariant mass distributions. The differential production cross sections are measured as a function of the transverse momentum pT and rapidity y, over the ranges 0 < pT < 20 GeV/c for J/\u3c8, 0 < pT < 12 GeV/c for all other resonances and for 2.5 < y < 4. The measured cross sections integrated over pT and y, and assuming unpolarized quarkonia, are: \u3c3J/\u3c8 = 6.69 \ub1 0.04 \ub1 0.63 \u3bcb, \u3c3\u3c8(2S) = 1.13 \ub1 0.07 \ub1 0.19 \u3bcb, \u3c3\u3d2(1S) = 54.2 \ub1 5.0 \ub1 6.7 nb and \u3c3\u3d2(2S) = 18.4 \ub1 3.7 \ub1 2.9 nb, where the first uncertainty is statistical and the second one is systematic. The results are compared to measurements performed by other LHC experiments and to theoretical models

Multiparticle azimuthal correlations in p -Pb and Pb-Pb collisions at the CERN Large Hadron Collider

Measurements of multiparticle azimuthal correlations (cumulants) for charged particles in p-Pb at root s(NN) = 5.02 TeV and Pb-Pb at root s(NN) = 2.76 TeV collisions are presented. They help address the question of whether there is evidence for global, flowlike, azimuthal correlations in the p-Pb system. Comparisons are made to measurements from the larger Pb-Pb system, where such evidence is established. In particular, the second harmonic two-particle cumulants are found to decrease with multiplicity, characteristic of a dominance of few-particle correlations in p-Pb collisions. However, when a vertical bar Delta eta vertical bar gap is placed to suppress such correlations, the two-particle cumulants begin to rise at high multiplicity, indicating the presence of global azimuthal correlations. The Pb-Pb values are higher than the p-Pb values at similar multiplicities. In both systems, the second harmonic four-particle cumulants exhibit a transition from positive to negative values when the multiplicity increases. The negative values allow for a measurement of v(2){4} to be made, which is found to be higher in Pb-Pb collisions at similar multiplicities. The second harmonic six-particle cumulants are also found to be higher in Pb-Pb collisions. In Pb-Pb collisions, we generally find v(2){4} similar or equal to v(2){6} not equal 0 which is indicative of a Bessel-Gaussian function for the v(2) distribution. For very high-multiplicity Pb-Pb collisions, we observe that the four-and six-particle cumulants become consistent with 0. Finally, third harmonic two-particle cumulants in p-Pb and Pb-Pb are measured. These are found to be similar for overlapping multiplicities, when a vertical bar Delta eta vertical bar > 1.4 gap is placed