Synthesis and antiplasmodial activity of 3-furyl and 3-thienylquinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives

The aim of this study was to identify new compounds active against Plasmodium falciparum based on our previous research carried out on 3-phenyl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives. Twelve compounds were synthesized and evaluated for antimalarial activity. Eight of them showed an IC(50) less than 1 microM against the 3D7 strain. Derivative 1 demonstrated high potency (IC(50)= 0.63 microM) and good selectivity (SI=10.35), thereby becoming a new lead-compound.     

Damping of sound waves in the terahertz range and strength of the boson peak

By applying a new two-step line-shape analysis to inelastic neutron and x-ray scattering spectra of glassy systems, we were able to resolve the acoustic excitations from the low-frequency excess modes and to accurately estimate the damping of sound waves in the terahertz frequency range. Using this approach, we estimated the damping parameter for terahertz acoustic waves in a wide class of chemically different glasses and did a quantitative comparison of the results with prediction of theoretical models. By comparing the estimates of the mean-free path of the acoustic modes in different glasses and the corresponding boson peak strengths, we show the existence of a simple correlation between these two quantities. The relationship between attenuation of the terahertz acoustic modes, strength of the boson peak, and fragility is discussed.     

Recognition of cyclic, acyclic, exocyclic, and spiro acetals via structurally diagnostic ion/molecule reactions with the (CH3)2N-C(+)=O acylium ion

Reactions of the model acylium ion (CH3)2N-C(+)=O with acyclic, exocyclic, and spiro acetals of the general formula R(1)O-CR(3)R(4)-OR(2) were systematically evaluated via pentaquadrupole mass spectrometry. Characteristic intrinsic reactivities were observed for each of these classes of acetals. The two most common reactions observed were hydride and alkoxy anion [R(1)O(-) and R(2)O(-)] abstraction. Other specific reactions were also observed: (a) a secondary polar [4(+) + 2] cycloaddition for acetals bearing alpha,beta-unsaturated R(3) or R(4) substituents and (b) OH(-) abstraction for exocyclic and spiro acetals. These structurally diagnostic reactions, in conjunction with others observed previously for cyclic acetals, are shown to reveal the class of the acetal molecule and its ring type and substituents and to permit their recognition and distinction from other classes of isomeric molecules.     

Effect of neutrophil depletion on gelatinase expression,edema formation and hemorrhagic transformation after focal ischemic stroke

Background  

While gelatinase (MMP-2 and -9) activity is increased after focal ischemia/reperfusion injury in the brain, the relative contribution of neutrophils to the MMP activity and to the development of hemorrhagic transformation remains unknown.     

Perturbations of an Acetone‐Based Briggs–Rauscher System by α‐Tocopherol (Vitamin E)

The malonic acid (MA)‐based oscillating Briggs–Rauscher reaction (BR) in batch mode has been shown to be sensitive to various hydrophilic polyphenol antioxidants. Several of these have been shown to cause cessation of oscillations for a period of time before a restart occurs. The length of time before oscillations restart is related to the type of antioxidant and its concentration. Procedures have been devised to use this method as a tool for measuring antioxidant activity from pure compounds and from extracts of natural sources. The antioxidant activity has been related to the reaction of the antioxidants with HOO^. radicals present in the oscillating system. Vitamin E (α‐tocopherol), a typical highly lipophilic antioxidant containing an phenolic OH group, is soluble in acetone that also is a suitable substrate for the BR reaction. Perturbations of a highly concentrated acetone‐based BR oscillator by acetonic solutions of vitamin E were studied. The inhibitory effects were found similar to those provoked by hydrophilic polyphenols in the MA‐based oscillator, but to obtain reasonable inhibition times, the concentration of vitamin E must be at the mM level instead μM . However, there is a region of concentrations where there is a nearly linear relation between concentration and inhibition time. A comparison with a hydrophilic diphenol (2,6‐dihydroxybenzoic acid) in the acetone‐based oscillator showed that the inhibitory reaction is much slower in this system than in the MA one. We were able to model the perturbations by vitamin E assuming its reaction with HOO^. radicals by using the FCA mechanism previously reported with some little modifications.     

Interactive hyperspectral approach for exploring and interpreting DESI-MS images of cancerous and normal tissue sections

Desorption electrospray ionization (DESI) is an ambient mass spectrometry (MS) technique that can be operated in an imaging mode. It is known to provide valuable information on disease state and grade based on lipid profiles in tissue sections. Comprehensive exploration of the spatial and chemical information contained in 2D MS images requires further development of methods for data treatment and interpretation in conjunction with multivariate analysis. In this study, we employ an interactive approach based on principal component analysis (PCA) to interpret the chemical and spatial information obtained from MS imaging of human bladder, kidney, germ cell and prostate cancer and adjacent normal tissues. This multivariate strategy facilitated distinction between tumor and normal tissue by correlating the lipid information with pathological evaluation of the same samples. Some common lipid ions, such as those of m/z 885.5 and m/z 788.5, nominally PI(18 : 0/20 : 4) and PS(18 : 0/18 : 1), as well as ions of free fatty acids and their dimers, appeared to be highly characterizing for different types of human cancers, while other ions, such as those of m/z 465.5 (cholesterol sulfate) for prostate cancer tissue and m/z 795.5 (seminolipid 16 : 0/16 : 0) for germ tissue, appeared to be extremely selective for the type of tissue analyzed. These data confirm that lipid profiles can reflect not only the disease/health state of tissue but also are characteristic of tissue type. The manual interactive strategy presented here is particularly useful to visualize the information contained in hyperspectral MS images by automatically connecting regions of PCA score space to pixels of the 2D physical object. The procedures developed in this study consider all the spectral variables and their inter-correlations, and guide subsequent investigations of the mass spectra and single ion images to allow one to maximize characterization between different regions of any DESI-MS image.     

Building β-peptide H10/12 foldamer helices with six-membered cyclic side-chains: fine-tuning of folding and self-assembly

The ability of the β-peptidic H10/12 helix to tolerate side-chains containing six-membered alicyclic rings was studied. cis-2-Aminocyclohex-3-ene carboxylic acid (cis-ACHEC) residues afforded H10/12 helix formation with alternating backbone configuration. Conformational polymorphism was observed for the alternating cis-ACHC hexamer, where chemical exchange takes place between the major left-handed H10/12 helix and a minor folded conformation. The hydrophobically driven self-assembly was achieved for the cis-ACHC-containing helix which was observed as vesicles ~100 nm in diameter.     

Chromenol Derivatives as Novel Antifungal Agents: Synthesis,In Silico and In Vitro Evaluation

Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a–3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.     

Kinetics and mechanism of the oxidation of guanosine derivatives by Pt(IV) complexes

The kinetics of redox reactions of the PtIV complexes trans-Pt(d,l)(1,2-(NH2)2C6H10)Cl4 ([PtIVCl4(dach)]) and Pt(NH2CH2CH2NH2)Cl4 ([PtIVCl4(en)]) with 5'- and 3'-dGMP (G) have been studied. These redox reactions involve substitution followed by an inner-sphere electron transfer. The substitution is catalyzed by PtII and follows the classic Basolo-Pearson PtII-catalyzed PtIV-substitution mechanism. We found that the substitutution rates depend on the steric hindrance of PtII, G, and PtIV with the least sterically hindered PtII complex catalyzing at the highest rate. 3'-dGMP undergoes substitution faster than 5'-dGMP, and [PtIVCl4(en)] substitutes faster than [PtIVCl4(dach)]. The enthalpies of activation of the substitution, DeltaH double dagger s, of 3'-dGMP is only 70% greater than that of 5'-dGMP (50.4 vs 30.7 kJ mol(-1)), but the entropy of activation of the substitution, DeltaS double dagger s, of 3'-dGMP is much greater than that of 5'-dGMP (-59.4 vs -129.5 J K(-1) mol(-1)), indicating that steric hindrance plays a major role in the substitution. The enthalpy of activation of electron transfer, DeltaH double dagger e, of 3'-dGMP is smaller than that of 5'-dGMP (88.8 vs 137.8 kJ mol(-1)). The entropy of activation of electron transfer, DeltaS double dagger e, of 3'-dGMP is negative, but that of 5'-dGMP is positive (-27.8 vs +128.8 J K-1 mol-1). The results indicate that 5'-hydroxo has less rotational barrier than 5'-phosphate, but it is geometrically unfavorable for internal electron transfer. The electron-transfer rate also depends on the reduction potential of PtIV. Because of its higher reduction potential, [PtIVCl4(dach)] has a faster electron transfer than [PtIVCl4(en)].