Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning

Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation. T. cruzi is auxotroph for polyamines, which are taken up from the extracellular medium by efficient transporters and, to a large extent, incorporated into trypanothione (bis-glutathionylspermidine), the major redox cosubstrate of trypanosomatids. From a 268-compound database containing polyamine analogs with and without inhibitory effect on T. cruzi we have inferred classificatory models that were later applied in a virtual screening campaign to identify anti-trypanosomal compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning) compiled in the DrugBank and Sweetlead databases. Five of the candidates identified with this strategy were evaluated in cellular models from different pathogenic trypanosomatids (T. cruzi wt, T. cruzi PAT12, T. brucei and Leishmania infantum), and in vitro models of aminoacid/polyamine transport assays and trypanothione synthetase inhibition assay. Triclabendazole, sertaconazole and paroxetine displayed inhibitory effects on the proliferation of T. cruzi (epimastigotes) and the uptake of putrescine by the parasite. They also interfered with the uptake of others aminoacids and the proliferation of infective T. brucei and L. infantum (promastigotes). Trypanothione synthetase was ruled out as molecular target for the anti-parasitic activity of these compounds.     

Theoretical characterization of the chemical bonds of some three-membered ring compounds through QTAIM theory

Structural Chemistry - In this paper, we investigate the nature of the carbonyl and the intraring C–C, C–N, C–O, N–N, O–O and N–O bonds of cyclopropanone and the...     

Synthesis, ionisation potentials and electron affinities of hexaazatrinaphthylene derivatives

Several hexaazatrinaphthylene derivatives and a tris(thieno)hexaazatriphenylene derivative have been synthesised by reaction of the appropriate diamines with hexaketocyclohexane. The crystal structure of 2,3,8,9,14,15-hexachloro-5,6,11,12,17,18-hexaazatrinaphthylene has been determined by X-ray diffraction; this reveals a molecular structure in good agreement with that predicted by density functional theory (DFT) calculations and pi-stacking with an average spacing between adjacent molecular planes of 3.18 A. Solid-state ionisation potentials have been measured by using UV photoelectron spectroscopy and fall in the range of 5.99 to 7.76 eV, whereas solid-state electron affinities, measured using inverse photoelectron spectroscopy, vary in the range -2.65 to -4.59 eV. The most easily reduced example is a tris(thieno)hexaazatriphenylene substituted with bis(trifluoromethyl)phenyl groups; DFT calculations suggest that the highly exothermic electron affinity is due both to the replacement of the outermost phenylene rings of hexaazatrinaphthylene with thieno groups and to the presence of electron-withdrawing bis(trifluoromethyl)phenyl groups. The rather exothermic electron affinities, the potential for adopting pi-stacked structures and the low intramolecular reorganisation energies obtained by DFT calculations suggest that some of these molecules may be useful electron-transport materials.     

(1)H NMR and viscometric studies on cationic gemini surfactants in presence of aromatic acids and salts

In this paper, we are reporting the influence of addition of aromatic acids (anthranilic and benzoic acid) and their sodium salts on the micellar morphological changes in three cationic gemini surfactant solutions, viz. 5 mM tetramethylene-1,4-bis(N-hexadecyl-N,N-dimethylammonium bromide), 10 mM pentamethylene-1,5-bis(N-hexadecyl-N,N-dimethylammonium bromide), and 10 mM hexamethylene-1,6-bis(N,-hexadecyl-N,N-dimethylammonium bromide). The solubilization site of the counterions (obtained from the additives) near the micellar surface are inferred by 1H NMR. The behavior is explained in the light of binding of counterions to the micelle as well as the nature of the functional group attached to the additive.     

Formation Mechanism of Laser‐Synthesized Iron–Manganese Alloy Nanoparticles,Manganese Oxide Nanosheets and Nanofibers

Laser ablation in liquids (LAL) has emerged as a versatile approach for the synthesis of alloy particles and oxide nanomaterials. However, complex chemical reactions often take place during synthesis due to inevitable atomization and ionization of the target materials and decomposition/hydrolysis of solvent/solution molecules, making it difficult to understand the particle formation mechanisms. In this paper, a possible route for the formation of FeMn alloy nanoparticles as well as MnO_x nanoparticles, ‐sheets, and ‐fibers by LAL is presented. The observed structural, compositional, and morphological variations are clarified by transmission electron microscopy (TEM). The studies suggest that a reaction between Mn atoms and Fe ions followed by surface oxidation result in nonstoichiometric synthesis of Fe‐rich FeMn@FeMn₂O₄ core–shell alloy particles. Interestingly, a phase transformation from Mn₃O₄ to Mn₂O₃ and finally to Ramsdellite γ‐MnO₂ is accompanied by a morphology change from nanosheets to nanofibers in gradually increasing oxidizing environments. High‐resolution TEM images reveal that the particle‐attachment mechanism dominates the growth of different manganese oxides.     

Scarlet Flax Linum grandiflorum (L.) In Vitro Cultures as a New Source of Antioxidant and Anti-Inflammatory Lignans

In vitro cultures of scarlet flax (Linum grandiflorum L.), an important ornamental flax, have been established as a new possible valuable resource of lignans and neolignans for antioxidant and anti-inflammatory applications. The callogenic potential at different concentrations of α-naphthalene acetic acid (NAA) and thidiazuron (TDZ), alone or in combinations, was evaluated using both L. grandiflorum hypocotyl and cotyledon explants. A higher callus induction frequency was observed on NAA than TDZ, especially for hypocotyl explants, with a maximum frequency (i.e., 95.2%) on 1.0 mg/L of NAA. The presence of NAA (1.0 mg/L) in conjunction with TDZ tended to increase the frequency of callogenesis relative to TDZ alone, but never reached the values observed with NAA alone, thereby indicating the lack of synergy between these two plant growth regulators (PGRs). Similarly, in terms of biomass, NAA was more effective than TDZ, with a maximum accumulation of biomass registered for medium supplemented with 1.0 mg/L of NAA using hypocotyls as initial explants (DW: 13.1 g). However, for biomass, a synergy between the two PGRs was observed, particularly for cotyledon-derived explants and for the lowest concentrations of TDZ. The influence of these two PGRs on callogenesis and biomass is discussed. The HPLC analysis confirmed the presence of lignans (secoisolariciresinol (SECO) and lariciresinol (LARI) and neolignan (dehydrodiconiferyl alcohol [DCA]) naturally accumulated in their glycoside forms. Furthermore, the antioxidant activities performed for both hypocotyl- and cotyledon-derived cultures were also found maximal (DPPH: 89.5%, FRAP 866: µM TEAC, ABTS: 456 µM TEAC) in hypocotyl-derived callus cultures as compared with callus obtained from cotyledon explants. Moreover, the anti-inflammatory activities revealed high inhibition (COX-1: 47.4% and COX-2: 51.1%) for extract of hypocotyl-derived callus cultures at 2.5 mg/L TDZ. The anti-inflammatory action against COX-1 and COX-2 was supported by the IC₅₀ values. This report provides a viable approach for enhanced biomass accumulation and efficient production of (neo)lignans in L. grandiflorum callus cultures.     

A surprisingly stable S-nitrosothiol complex

In this work we present for the first time an X-ray structure of a coordinated S-nitrosothiol obtained by reaction of the extremely reactive K[IrCl5NO] with benzylmercaptan in acetonitrile. This surprisingly stable compound, trans-K[IrCl4(CH3CN)N(O)SCH2Ph], was isolated in high yield (80%) and fully characterized by FTIR, 1H NMR, and ESI-MS. To our knowledge this is the first example of a coordinated S-nitrosothiol that has been isolated.     

Vibronic coupling in organic semiconductors: the case of fused polycyclic benzene-thiophene structures

The nature of vibronic coupling in fused polycyclic benzene-thiophene structures has been studied using an approach that combines high-resolution gas-phase photoelectron spectroscopy measurements with first-principles quantum-mechanical calculations. The results indicate that in general the electron-vibrational coupling is stronger than the hole-vibrational coupling. In acenedithiophenes, the main contributions to the hole-vibrational coupling arise from medium- and high-frequency vibrations. In thienobisbenzothiophenes, however, the interaction of holes with low-frequency vibrations becomes significant and is larger than the corresponding electron-vibrational interaction. This finding is in striking contrast with the characteristic pattern in oligoacenes and acenedithiophenes in which the low-frequency vibrations contribute substantially only to the electron-vibrational coupling. The impact of isomerism has been studied as well.     

The use of acridine orange base (AOB) as molecular probe to characterize nonaqueous AOT reverse micelles

The behavior of acridine orange base (AOB) in nonaqueous reverse micelles composed of n-heptane/AOT/polar solvent has been performed. Ethylene glycol (EG), propylene glycol (PG), glycerol (GY), formamide (FA), dimethylformamide (DMF), and dimethylacetamide (DMA) were employed as water substitutes. The studies were performed by static and time-resolved emission spectroscopy. Thus, the distribution of AOB between the two pseudophases of the aggregates was quantified by measuring the partition constants from emission spectra at different surfactant concentration. Similar values to those obtained by means of absorption spectroscopy were obtained. This match is indicating that AOB is not experiencing partition during the lifetime of the excited state. Partitioning to the micelles is strongly favored in micelles containing hydrogen-bond donor (HBD) solvents rather than non-HBD solvents. Variations of fluorescence lifetimes with AOT concentration confirm these results. By the solvatochromic behavior of AOB in the different systems it is shown that the microenvironment at the interface is distinct from that of the bulk polar solvent, indicating that the probe senses no "free" solvent. The steady state anisotropy (r) was measured for EG/AOT/n-heptane and DMF/AOT/n-heptane systems as representatives for HBD and non-HBD polar solvents, respectively. The value of r is higher in the micelles containing EG than that obtained with DMF, and increases with AOT concentration. This is explained as due to highly structured polar solvents in the inner core. EG is interacting with the polar heads of AOT through hydrogen-bond interaction, while DMF can only interact with the Na+ counterions. This is confirmed by the time-resolved emission spectra (TRES) of the probe in the micellar systems, in comparison with the bulk solvents.