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Tuberculosis remains one of the leading causes of death from a single infectious agent, surpassing both AIDS and malaria. In recent years, two bicyclic nitroimidazole drugs, delamanid and pretomanid have been approved to treat this airborne infection. This has spurred a renewed interest in developing new and improved nitroimidazole analogs. We have previously identified a new bicyclic heteroaromatic subclass, the nitroimidazopyrazinones, with substituted analogs showing promising activity against Mycobacterium tuberculosis under both aerobic and hypoxic environments. A second generation of nitroimidazopyrazinones with extended biaryl side chain also possessed good antiparasitic activity against Trypanosoma brucei brucei and Trypanosoma cruzi, suggesting the utility of this new scaffold for development into potential candidates against both tuberculosis and the kinetoplastid parasites which cause neglected tropical diseases. In this study, we further evaluated the properties of nitroimidazopyrazinone derivatives by assessing their selectivity against different mycobacterial species, measuring their reduction potential, and determining the kinetic parameters as substrates of the deazaflavin-dependent nitroreductase (Ddn), which is the activating enzyme of delamanid and pretomanid in M. tuberculosis. We also conducted an in vivo evaluation of a lead compound, MCC8967 that demonstrated a favorable pharmacokinetic profile, with good oral bioavailability and efficacy in an acute M. tuberculosis infection model. Two other promising compounds MCC9481 and MCC9482, with good in vitro activity (IC50 = 0.016 and 0.10 µM, respectively) against T. cruzi, the causative agent for Chagas diseases, were similarly tested for in vivo activity. These compounds also exhibited good oral bioavailability, and transiently reduced the acute-stage parasite burden by >98‒99% at doses of 50 mg/kg once or twice daily, similar to benznidazole at 100 mg/kg once daily. Overall, we have demonstrated that active nitroimidazopyrazinones have potential to be developed as clinical candidates against both tuberculosis and Chagas disease.Author SummaryTuberculosis and parasitic infections continue to impose a significant threat to public health and economic growth worldwide. Most of the efforts to control these diseases still rely on drug treatments with limited effectiveness and significant side effects. There is now an urgent need to develop new treatments to combat these infections. Here, we report the in vitro and in vivo profile of a new bicyclic nitroimidazole subclass, namely nitroimidazopyrazinones, against mycobacteria and Trypanosoma cruzi. We found that derivatives with monocyclic side chains are selective against Mycobacterium tuberculosis, the causative agent of tuberculosis, but not active against other nontuberculosis mycobacteria. In an acute mouse model, they were able to reduce the bacterial load in lungs via oral administration. From a biochemistry perspective, we demonstrated that deazaflavin-dependent nitroreductase (Ddn) could act effectively on nitroimidazopyrazinones, indicating the potential of Ddn as an activating enzyme for these new compounds in M. tuberculosis. We also showed that derivatives with extended biaryl side chain were effective in suppressing infection in an acute T. cruzi infected murine model, with satisfactory oral bioavailability. These findings improve the understanding of the biological profile of nitroimidazopyrazinones for further development as potential antitubercular and antiparasitic agents.

Hydration-dependent DNA deformation has been known since Rosalind Franklin recognized that the relative humidity of the sample had to be maintained to observe a single conformation in DNA fiber diffraction. We now report for the first time the crystal structure, at the atomic level, of a dehydrated form of a DNA duplex and demonstrate the reversible interconversion to the hydrated form at room temperature. This system, containing d(TCGGCGCCGA) in the presence of Λ-[Ru(TAP)2(dppz)](2+) (TAP = 1,4,5,8-tetraazaphenanthrene, dppz = dipyrido[3,2-a:2',3'-c]phenazine), undergoes a partial transition from an A/B hybrid to the A-DNA conformation, at 84-79% relative humidity. This is accompanied by an increase in kink at the central step from 22° to 51°, with a large movement of the terminal bases forming the intercalation site. This transition is reversible on rehydration. Seven data sets, collected from one crystal at room temperature, show the consequences of dehydration at near-atomic resolution. This result highlights that crystals, traditionally thought of as static systems, are still dynamic and therefore can be the subject of further experimentation.

We report an atomic resolution X-ray crystal structure containing both enantiomers of rac-[Ru(phen)2dppz](2+) with the d(ATGCAT)2 DNA duplex (phen = phenanthroline; dppz = dipyridophenazine). The first example of any enantiomeric pair crystallized with a DNA duplex shows different orientations of the Λ and Δ binding sites, separated by a clearly defined structured water monolayer. Job plots show that the same species is present in solution. Each enantiomer is bound at a TG/CA step and shows intercalation from the minor groove. One water molecule is directly located on one phenazine N atom in the Δ-enantiomer only.

The relaxation dynamics of photoexcited carriers in water-soluble, penicillamine-capped, optically active and luminescent chiral CdSe quantum dots (QDs) were investigated. Three pump–probe techniques, namely broad-band UV–visible transient absorption (TA), picosecond time-resolved infrared (ps-TRIR) transient absorption, and nanosecond laser flash photolysis spectroscopy, were used to record transient decays from the picosecond up to the millisecond time scale. Picosecond experiments were carried out at a range of energies per unit area down to ca. 30 μJ cm–2, where only single photon excitation is expected. Whereas ps-UV–visible TA spectra show both bleach and transient features which are associated with depopulation of the lowest lying electron quantized state, the infrared transient bands are broad and structureless. The mid-IR transient absorption and excitonic bleach recovery is only partial, and its decay kinetics were found to be multiexponential in nature. The initial picosecond decay component is...

We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form Trypanosoma brucei and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. S-Enantiomer 7d was the most active derivative against T. brucei (IC(50) = 6.8 nM) and T. cruzi (IC(50) = 0.21 μM).

An extensive study of the time dependence of DNA wrapping in single-walled nanotube (SWNT) dispersions has been carried out, revealing a number of unusual phenomena. SWNTs were dispersed in water with salmon testes DNA and monitored over a three-month period. Between 20 and 50 days after the sample was first prepared, the SWNT photoluminescence (PL) intensity was observed to increase by a factor of 50. This increase was accompanied by a considerable sharpening of the van Hove absorption peaks. High-resolution transmission electron microscopy (HRTEM) images showed the progressive formation of a coating of DNA on the walls of the nanotubes over the three-month period. HRTEM and circular dichroism spectroscopy studies showed that the improvement in both the NIR PL intensity and the van Hove absorption peaks coincided with the completion of a monolayer coating of DNA on the SWNT walls. HRTEM images clearly showed the DNA wrapping helically around the SWNTs in a surprisingly ordered fashion. We suggest that the initial quenching of NIR photoluminescence and broadening of absorption peaks is related to the presence of protonated surface oxides on the nanotubes. The presence of an ordered DNA coating on the nanotube walls mediates both deprotonation and removal of the surface oxides. An extensive DNA coating is required to substantially restore the photoluminescence, and thus, the luminescence switch-on and subsequent saturation indicate the completion of the DNA-wrapping process. The temperature dependence of the PL switch-on, and thus of the wrapping process, was investigated by measuring as functions of temperature both the time before PL switch-on and the time required for the PL intensity to saturate. This allowed the calculation of the activation energies for both the process preceding PL switch-on and the process limiting the rise of PL intensity, which were found to be 31 and 41 kJ mol (-1), respectively. The associated entropies of activation were -263 and -225 J mol (-1) K (-1), respectively. These negative activation entropies suggest that the rate-limiting step is characterized by a change in the system from a less-ordered to a more-ordered state, consistent with the formation of an ordered DNA coating.

Natural salmon testes DNA has been used to disperse single-walled carbon nanotubes (SWNTs) in water. It has been found that the primary factor controlling the nanotube bundle size distribution in the dispersion is the nanotube concentration. As measured by AFM, the mean bundle diameter tends to decrease with decreasing concentration. The number fraction of individual nanotubes increases with decreasing concentration. At low nanotube concentrations, number fractions of up to 83% individual SWNTs, equating to a mass fraction of 6.2%, have been obtained. Both the absolute number density and mass per volume of individual nanotubes initially increased with decreasing concentration, displaying a peak at ∼0.027 mg/mL. This concentration thus yields the largest quantities of individually dispersed SWNTs. The AFM data for populations of individual nanotubes was confirmed by infrared photoluminescence spectroscopy. The photoluminescence intensity increased with decreasing concentration, indicating extensive debundl...

Vibrational spectra (1100−1800 cm-1) of the ground state and two excited electronic states, populated following the 5 ps, 440 nm excitation, of the [Ru(phen)2dppz]+2 (phen = 1,10-phenanthroline and dppz = dipyrido[3,2-a:2‘,3‘-c] phenazine) complex in aqueous solution are measured by coherent anti-Stokes Raman scattering (CARS). The band origin positions of vibrational features in the picosecond resonance CARS (PR/CARS) spectrum of ground state [Ru(phen)2dppz]+2 obtained with ω1 (probe) wavelengths of 491 and 530 nm are the same to within

The changes in the absorption, steady-state emission, and luminescent lifetime properties, upon binding of binuclear complexes of type [(bpy)2Ru(Mebpy)−(CH2)n−(bpyMe)Ru(bpy)2]4+ (bpy = 2,2‘-bipyridine; Mebpy− = 4-methyl-2,2‘-bipyridine-4‘-; 1b, n = 5; 1c, n = 7) to double-stranded DNA, have been compared relative to those for the monometallic analogue [Ru(bpy)2(Me2bpy)]2+ (1a) (Me2bpy = 4,4‘-dimethyl-2,2‘-bipyridine). Mc Ghee von Hippel analysis indicates that the binuclear complexes 1b and 1c bind more than 100 times as strongly to DNA as does 1a. Luminescence lifetime analysis in the presence and absence of DNA resolves at least two distinct binding modes which exhibit markedly different accessibility to oxygen and dissimilar behavior under physiological salt conditions. The binding to DNA by the binuclear complexes shows a much greater resistance to increased NaCl concentration relative to that of the monometallic complex, while plots of log Kobs versus log [Na+] indicate that for both the mononuclear ...

The reactions of (η6-arene)Mo(CO)2(Sol) and M(CO)5(Sol) with CO have been studied in a range of alkane solvents (Sol), and the kinetic and activation parameters have been determined (M = Cr, Mo, or W). For M = Cr the ΔH⧧ is constant (22 ± 2 kJ mol-1), while the ΔS⧧ term becomes less negative as the alkane chain length increases. For the larger metals the variation in kinetic and activation parameters is less significant. Solvent displacement by CO involves an interchange mechanism for the Cr system, while for Mo or W complexes the mechanism is more associative in character. The photochemistry of (η6-arene)Mo(CO)3 (arene = benzene, mesitylene, p-xylene, or hexamethylbenzene) compounds was investigated by laser flash photolysis, supported by matrix isolation and time-resolved infrared spectroscopy (TRIR). In contrast to the behavior to the analogous (η6-arene)Cr(CO)3, it is found that the efficiency for photochemical expulsion of CO from (η6-mesitylene)Mo(CO)3 is markedly wavelength dependent (ΦCO = 0.587, ...

Near-UV or visible light irradiation of Ru(tap)2(bpy)2+ (1) (tap = 1,4,5,8-tetraazaphenanthrene; bpy = 2,2‘-bipyridyl) in the presence of duplex DNA induces the formation of covalent adducts with g...

The electroluminescence (EL) of Tb 3+ -doped anodic Ta 2 O 5 films in the presence of H 2 O 2 was studied. Since the EL of the dopant Tb 3+ ion shows the same potential (U) dependence as the background EL, light emission from Tb 3+ can be used to monitor electrochemical processes at the oxide/solution interface. In the rising part of the (EL,U) curve, both the hole injection rate and the radiative recombination efficiency increase. This gives rise to a quadratic dependence of the intensity on the current. The EL is not influenced by the rotation rate; ring-disk experiments show the hole injection current to be kinetically limited

Time-resolved infrared spectroscopy identified the first observable species following nanosecond laser photolysis of (benzene)Cr(CO) 3 in alkane solution as (benzene)Cr(CO) 2 (alkane). UV/vis-monitored laser flash photolysis was used to observe the reaction of this species with CO. The reactivity toward CO of the primary photoproducts derived from related arene complexes (arene = C 6 H 5 Cl, C 5 H 5 Me, p-ClC 6 H 4 Me, C 6 H 5 Et, C 6 H 5 Bu t , o-and p-C 6 H 4 Me 2 , C 6 H 3 Me 3 , C 6 Me 6 , C 6 Et 6 ) were also determined by this technique

Usually, labeling of proteins involves the modification of amino acid side chains. These include tyrosines, the e-amino groups of lysines, carboxyl groups of glutamic and aspartic acids, and sulfhydryl groups generated by mild reduction of cysteines (14). The site at which modification takes place has special significance when labeling of immunoglobulins is involved. The polypeptide moieties of immunoglobulins impart their specific antigen binding ability, and modification of the amino acid side chains may result in partial or complete loss of immunological activity. In contrast, the carbohydrate moieties of immunoglobulins are not involved in the antigen binding properties of these molecules, and modification should not directly affect antigen binding (15). The albumins and IgG have therefore been conjugated to the reporter molecule through both the e-amino group of the lysine residues and also through modification of the carbohydrate moieties on these proteins.

Rare earth doped anodic Ta 2 O 5 layers can show characteristic light emission. In the case of Eu 3+ photoluminescence, excitation is restricted to common charge transfer and 4f shell transitions. No electroluminescence can be observed. This is different for the case of Tb 3+ . Experiments involving irradiation with suprabandgap light and hole injection by H 2 O 2 show that charge carriers can recombine on terbium ions

Etude en fonction de la force ionique de la vitesse du transfert electronique entre l'analogue du systeme [Ru(bpy) 3 ] 2+ dans les copolymeres et le methylviologene, le propylviologene sulfonate et l'ion ferrique. Les rendements des centres Ru(III) et de l'extincteur reduit ont ete mesures par photolyse eclair laser

Formation par excitation laser (265 ou 353 nm) de M(CO) 6 , d'especes transitoires tres reactives se complexant avec CO, M(CO) 6 , cyclohexane ou N 2 avec des constantes de vitesse depassant 10 9 dm 3 •mole −1 •S −1 . Spectres d'absorption visible de M 2 (CO) 11 et M(CO) 5 (cyclohexane) et cinetique des reactions de Cr 2 (CO) 11 et Cr(CO) 5 (cyclohexane) avec CO