Combination with tomatidine improves the potency of posaconazole against Trypanosoma cruzi

Azoles such as posaconazole (Posa) are highly potent against Trypanosoma cruzi. However, when tested in chronic Chagas disease patients, a high rate of relapse after Posa treatment was observed. It appears that inhibition of T. cruzi cytochrome CYP51, the target of azoles, does not deliver sterile cure in monotherapy. Looking for suitable combination partners of azoles, we have selected a set of inhibitors of sterol and sphingolipid biosynthetic enzymes. A small-scale phenotypic screening was conducted in vitro against the proliferative forms of T. cruzi, extracellular epimastigotes and intracellular amastigotes. Against the intracellular, clinically relevant forms, four out of 15 tested compounds presented higher or equal activity as benznidazole (Bz), with EC50 values </=2.2 muM. Ro48-8071, an inhibitor of lanosterol synthase (ERG7), and the steroidal alkaloid tomatidine (TH), an inhibitor of C-24 sterol methyltransferase (ERG6), exhibited the highest potency and selectivity indices (SI = 12 and 115, respectively). Both were directed to combinatory assays using fixed-ratio protocols with Posa, Bz, and fexinidazole. The combination of TH with Posa displayed a synergistic profile against amastigotes, with a mean SigmaFICI value of 0.2. In vivo assays using an acute mouse model of T. cruzi infection demonstrated lack of antiparasitic activity of TH alone in doses ranging from 0.5 to 5 mg/kg. As observed in vitro, the best combo proportion in vivo was the ratio 3 TH:1 Posa. The combination of Posa at 1.25 mpk plus TH at 3.75 mpk displayed suppression of peak parasitemia of 80% and a survival rate of 60% in the acute infection model, as compared to 20% survival for Posa at 1.25 mpk alone and 40% for Posa at 10 mpk alone. These initial results indicate a potential for the combination of posaconazole with tomatidine against T. cruzi

Polarons as Nucleation Droplets in Non-Degenerate Polymers

We present a study of the nucleation mechanism that allows the decay of the metastable phase (trans-cisoid) to the stable phase (cis-transoid) in quasi one-dimensional non-degenerate polymers within the continuum electron-phonon model. The electron-phonon configurations that lead to the decay, i.e. the critical droplets (or transition state), are identified as polarons of the metastable phase. We obtain an estimate for the decay rate via thermal activation within a range of parameters consistent with experimental values for the gap of the cis-configuration. It is pointed out that, upon doping, the activation barriers of the excited states are quite smaller and the decay rate is greatly enhanced. Typical activation energies for electron or hole polarons are $\approx 0.1$ eV and the typical size for a critical droplet (polaron) is about $20 \AA$. Decay via quantum nucleation is also studied and it is found that the crossover temperature between quantum nucleation and thermal activation is of order $T_c \leq 40 ^oK$. Metastable configurations of non-degenerate polymers may provide examples for mesoscopic quantum tunneling.Comment: REVTEX 3.0, 28 PAGES, 3 FIGURES AVAILABLE UPON REQUEST, PITT 94-0

Photoinduced absorption and photoluminescence in poly(2,5-dimethoxy-p- phenylene vinylene)

We report a study of the photoexcited states in the conjugated polymer poly(2,5-dimethoxy-p-phenylene vinylene). Photoluminescence due to radiative recombination of singlet excitons is observed at energiesjust below the onset of the pi-pi* absorption band at 2.1 eV. Photoinduced absorption at 80 K shows bands peaking at 0.68, 1.35, and 1.80 eV. The features at 0.68 and 1.8 eV are associated with the same excited state which we propose is a doubly charged bipolaron, while the third at 1.35 eV is unrelated. We assign this 1.35-eV absorption to a triplet-triplet transition of a triplet exciton. The bipolarons are long lived with significant numbers surviving in excess of 100 ms at 80 K, and have a weak temperature dependence such that photoinduced absorption is readily detectable even at room temperature. The triplet exciton has a lifetime of order 2.5 ms at 80 K but this falls rapidly at higher temperature and the response is not detected at room temperature. We contrast these results with those obtained previously for the related poly(arylene vinylene) polymers poly(p-phenylene vinylene), and poly(2,5-thienylene vinylene) and for other conjugated polymers, and draw attention to the important role played in the photophysics of these materials by neutral excited states

Synthesis of trans-A(2)B(2)- and trans-A(2)BC-Porphyrins with Polar 4 '-(Dimethylamino)tolan-4-yl Substituents, and a Screening Protocol for Vapor-Phase Deposition on Metal Surfaces

The role of polar 4-[p-(dimethylamino) phenylethynyl] phenyl substituents, with a calculated dipole moment of 3.35 Debye, in the self-assembly of trans-A(2)B(2)- and A(2)BC-substituted porphyrins was explored in the solid state by X-ray crystallography, and on an Au(111) surface by scanning tunneling microscopy (STM). Our results demonstrate that the dipolar character of these substituents blocks the 2D self-assembly of porphyrins into larger ordered domains on Au(111) at low coverage, whereas antiparallel dipole-dipole interactions govern the molecular ordering in the crystal. The STM analysis revealed an adaptation of the conformation of the prochiral building blocks and a site-selectivity of the adsorption. We present a general protocol for testing the suitability of higher-molecular-weight compounds, such as porphyrins, to be deposited on surface by sublimation in ultra-high vacuum (UHV). This protocol combines classical methods of chemical analysis with typical surface science techniques

Opto-Electronic Properties of Fluorene-Based Derivatives as Precursors for Light-Emitting Diodes

This paper reports optical absorption spectra of oxidized fluorene copolymers obtained by chemical oxidation with Ce(IV) and by pulse radiolysis experiments in chlorinated solvents. Comparison of the results observed by the two techniques is used to provide spectral data on the copolymer radical ions and information on stability of the oxidized species. In addition, a detailed quantum chemical characterization is presented, concerning the electronic and optical properties of three series of charged oligomers containing alternating fluorene and phenylene or thienylene or benzothiadiazole units, respectively. The introduction of the comonomer strongly influences the optical properties, leading to a red shift in the absorption spectra of the charged oligomers. This shift is more pronounced in the case of fluorene benzothiadiazole anions due to the strong electron-accepting character of the benzothiadiazole moieties. The charge distribution of the fluorene benzothiadiazole anion is different from that corresponding to fluorene phenylene and fluorene thienylene anions. The negative charge of the latter oligomers is evenly distributed over the fluorene units, while the former oligomer localizes the negative charge on the benzothiadiazole units. The charge distribution correlates with the optical absorption spectra. When the positive charge is localized on a different unit than the negative charge, the cation and anion spectra are different. Similar spectra are obtained if both the positive and negative charges are localized on the same unit