Photoproperties of favipiravir and its 6-substituted analogues: fluorescence controlled through halogen substitution and tautomerism.

Herein, we have showed the photophysical properties of favipiravir and its 6-substituted analogues. Also, we interpreted the origin of fluorescence of favipiravir and its 6-substituted analogues as a function of tautomerism modulation in ground and excited states. Favipiravir, the 6-fluorine derivative, showed the best photophysical profile, exhibiting a dominant emission wavelength of 430 nm, a high quantum yield (Q.Y.) of 1.0 and a long-lived state (10 ns). Its analogues also showed a maximum emission at 430 nm, but their Q.Y. values were 5-fold lower than that found for favipiravir, decreasing as a function of 6-substitution as follows: F > Cl > Br > I > H. Pyrazines bearing the least electronegative 6-substituent (X = Br, I, H) showed an extra lifetime, which was shorter (0.2-0.3 ns) and less abundant (>15%) than the main lifetime (10 ns, 85%). Further 2D excitation-emission matrix and solvent studies supported that these 3-hydroxy-2-pyrazinecarboxamides present two emissive states. The first of them (λem = 430 nm), which was the most abundant, most fluorescent and long-lived state, was characterized as "locally excited" (LE). Its fluorescence was favored with an increase of the hydrogen-donor nature of the solvent and for pyrazines having a high enolic characteristic. Thus, the high LE-fluorescence of these types of pyrazines depends on the keto-tautomerization of the ground state using a protic solvent and its feasible enol-tautomerization upon excitation. Finally, the second excited state (λem = 536 nm) was suggested as an excited-state intramolecular proton-transfer (ESIPT), and it was observed only, although discretely, for pyrazines bearing the least electronegative 6-substituent.

Load-velocity Relationship of the Bench Press Exercise is not Affected by Breast Cancer Surgery and Adjuvant Therapy.

We examined the effect of breast cancer surgery and adjuvant therapy on the relationship between bar velocity and relative intensity (load-velocity [L-V] relationship) of the bench press (BP) exercise. Twenty-two breast cancer survivors (age: 48.0±8.2 yr., relative strength: 0.40±0.08) completed a loading test up to the one-repetition maximum (1RM) in the BP using a lightweight carbon bar. General and individual relationships between relative intensity (%1RM) and mean propulsive velocity (MPV) were studied. Furthermore, the mean test velocity (MPVTest) and velocity attained to the 1RM (MPV1RM) were analyzed. These procedures and analyses were also conducted in 22 healthy women (age: 47.8±7.1 yr., relative strength: 0.41±0.09) to examine the differences in velocity parameters derived from these L-V relationships. Polynomial regressions showed very close relationships (R2≥0.965) and reduced estimation errors (≤4.9% 1RM) for both groups. Between-group differences in MPV attained to each %1RM were small (≤0.01 m·s-1) and not significant (p≥0.685). Similarly, the MPVTest (0.59±0.06 m·s-1) and MPV1RM (0.17±0.03 m·s-1) were identical for breast cancer survivors and healthy women. These results suggest that practitioners could use the same velocity parameters derived from the BP L-V relationship to prescribe this exercise in middle-aged women, regardless of whether they have suffered from breast cancer.

In vitro antiviral activity of favipiravir and its 6- and 3-O-substituted derivatives against coronavirus: Acetylation leads to improvement of antiviral activity.

Favipiravir is currently approved for the treatment of the influenza virus and has shown encouraging results in terms of antiviral capacity in clinical studies against severe acute respiratory syndrome coronavirus 2. Favipiravir is a prodrug, where its favipiravir-ribofuranosyl-5B-triphosphate metabolite is capable of blocking RNA replication of the virus. However, the antiviral efficiency of favipiravir is limited by two factors: (i) low accumulation in plasma and rapid excretion/elimination post-administration and (ii) low conversion rate into the active metabolite. To tackle these problems, herein, we have designed new favipiravir analogues focusing on the replacement of the fluorine atom at the 6-position by halogen or hydrogen atoms and 3-O-functionalization with labile groups. The first type of functionalization seeks to increase the antiviral activity because of the better ability of the keto-tautomer as a function of the halogen, and it is hypothesized that the keto-tautomer tends to promote the formation of the ribofuranosyl-5B-triphosphate (RTP) metabolite. Meanwhile, the second type of functionalization seeks to promote lipophilicity and increase accumulation in cells. From the in vitro antiviral activity against two coronavirus models (bovine and human 229E), it was identified that the replacement did not improve the antiviral activity against both the models, which seems to be attributable to the low water solubility of these new 6-functionalized analogues. Meanwhile, with 3-O-functionalization, acetylation provided the most active compounds with higher half-maximal inhibitory concentration and selectivity than favipiravir, whereas benzylation/methanosulfonation yielded the least active compounds. In summary, acetylation is found to be a convenient functionalization to enhance the antiviral profile of favipiravir.

Torque-Cadence Profile and Maximal Dynamic Force in Cyclists: A Novel Approach.

We aimed to determine the feasibility, test-retest reliability and long-term stability of a novel method for assessing the force (torque)-velocity (cadence) profile and maximal dynamic force (MDF) during leg-pedaling using a friction-loaded isoinertial cycle ergometer and a high-precision power-meter device. Fifty-two trained male cyclists completed a progressive loading test up to the one-repetition maximum (1RM) on a cycle ergometer. The MDF was defined as the force attained at the cycle performed with the 1RM-load. To examine the test-retest reliability and long-term stability of torque-cadence values, the progressive test was repeated after 72 h and also after 10 weeks of aerobic and strength training. The participants' MDF averaged 13.4 ± 1.3 N·kg-1, which was attained with an average pedal cadence of 21 ± 3 rpm. Participants' highest power output value was attained with a cadence of 110 ± 16 rpm (52 ± 5% MDF). The relationship between the MDF and cadence proved to be very strong (R2 = 0.978) and independent of the cyclists' MDF (p = 0.66). Cadence values derived from this relationship revealed a very high test-retest repeatability (mean SEM = 4 rpm, 3.3%) and long-term stability (SEM = 3 rpm, 2.3%); despite increases in the MDF following the 10-week period. Our findings support the validity, reliability and long-term stability of this method for the assessment of the torque-cadence profile and MDF in cyclists.

Tautomerism and Rotamerism of Favipiravir and Halogenated Analogues in Solution and in the Solid State.

Favipiravir is an important selective antiviral against RNA-based viruses, and currently, it is being repurposed as a potential drug for the treatment of COVID-19. This type of chemical system presents different carboxamide-rotameric and hydroxyl-tautomeric states, which could be essential for interpreting its selective antiviral activity. Herein, the tautomeric 3-hydroxypyrazine/3-pyrazinone pair of favipiravir and its 6-substituted analogues, 6-Cl, 6-Br, 6-I, and 6-H, were fully investigated in solution and in the solid state through ultraviolet-visible, 1H nuclear magnetic resonance, infrared spectroscopy, and X-ray diffraction techniques. Also, a study of the gas phase was performed using density functional theory calculations. In general, the keto-enol balance in these 3-hydroxy-2-pyrazinecarboxamides is finely modulated by external and internal electrical variations via changes in solvent polarity or by replacement of substituents at position 6. The enol tautomer was prevalent in an apolar environment, whereas an increase in the level of the keto tautomer was favored by an increase in solvent polarity and, even moreso, with a strong hydrogen-donor solvent. Keto tautomerization was favored either in solution or in the solid state with a decrease in 6-substituent electronegativity as follows: H ≫ I ≈ Br > Cl ≥ F. Specific rotameric states based on carboxamide, "cisoide" and "transoide", were identified for the enol and keto tautomer, respectively; their rotamerism is dependent on the tautomerism and not the aggregation state.

One-step synthesis of favipiravir from Selectfluor® and 3-hydroxy-2-pyrazinecarboxamide in an ionic liquid.

Favipiravir is an important selective antiviral that emerged as an alternative against COVID-19 during the pandemic. Its synthesis has gained great interest and the conventional strategies proceed through multiple-step protocols (6-7 reaction steps), which involve, in addition, several drawbacks with global yields, lower than 34%. Herein, a simple, economical, eco-friendly and scalable (1 g) one-step protocol for the synthesis of favipiravir from the direct fluorination of the available 3-hydroxy-2-pyrazinecarboxamide with Selectfluor® is reported. The reaction proceeds easily in BF4-BMIM through a simple operational work-up, affording the favipiravir with a yield of 50% without the need of a special catalyst/additive. The key point of the present strategy was the use of the ionic liquid of BF4-BMIM, which helps to minimize the several chemical limitations derived from 3-hydroxy-2-pyrazinecarboxamide as a substrate for the direct Selectfluor-mediated fluorination. All these chemical reactivity aspects are also discussed in detail.

Exploring binding chemistry of alkali/alkaline earth cations in solution through modulation of intramolecular charge-transfer in an excited ambidentate organic fluorophore.

Studying the metal-ligand monoligation of alkali/alkaline earth metals (AMs) in solution represents a significant challenge due to the low stabilization of their complexes and the absence of an effective strategy to identify this type of weak binding. Herein, we show that the modulation of the intramolecular charge-transfer (ICT) in an excited ambidentate organic fluorophore is a convenient strategy to characterize the binding chemistry of AM cations in solution through simple steady-state fluorescence and fluorescence lifetime measurements. The key points of the fluorophore as a metal-binding probe were the location of diverse coordination functionalities with different binding abilities (ionic-, pseudo-covalent- and non-covalent-probes) along the donor-acceptor (D-A) chain and the occurrence of an intramolecular charge-transfer (ICT) mechanism upon excitation. The binding of these functionalities with AM-cations generated selective and specific fluorescence responses, which were quantifiable and allowed us to recognize the primary, secondary and tertiary interactions for all the AM cations in the solution. The relative binding affinities for each one of the functionalities with AM cations was estimated, and a general and consistent perspective of the binding of AMs as a function of their location in the Periodic Table, hardness property and ionic radius was established. The binding preferences of the AM cations were supported by DFT calculations. Our strategy allowed us to validate the binding dynamics of AMs in solution for three types of key ligations, which opens a new perspective to recognize weak intermolecular interactions derived from acidic species and rationally design selective AM-cation probes using an ICT-based ambidentate organic fluorophore.

Adaptations in athletic performance and muscle architecture are not meaningfully conditioned by training free-weight versus machine-based exercises: Challenging a traditional assumption using the velocity-based method.

BACKGROUND: Although the superior effectiveness of free-weight over machine-based training has been a traditionally widespread assumption, longitudinal studies comparing these training modalities were scarce and heterogeneous. OBJECTIVE: This research used the velocity-based method to compare the effects of free-weight and machine-based resistance training on athletic performance and muscle architecture. METHODS: Thirty-four resistance-trained men participated in an 8-week resistance training program allocated into free-weight (n = 17) or machine-based (n = 17) groups. Training variables (intensity, intraset fatigue, and recovery) were identical for both groups, so they only differed in the use of a barbell or specific machines to execute the full squat, bench press, prone bench pull, and shoulder press exercises. The velocity-based method was implemented to accurately adjust the planned intensity. Analysis of covariance and effect size (ES) statistics were used to compare both training modalities on a comprehensive set of athletic and muscle architecture parameters. RESULTS: No between-group differences were found for any athletic (p ≥ 0.146) and muscle architecture (p ≥ 0.184) variable. Both training modalities significantly and similarly improved vertical jump (Free-weight: ES ≥ 0.45, p ≤ 0.001; Machine-based: ES ≥ 0.41, p ≤ 0.001) and lower limb anaerobic capacity (Free-weight: ES ≥ 0.39, p ≤ 0.007; Machine-based: ES ≥ 0.31, p ≤ 0.003). Additionally, the machine-based group meaningfully enhanced upper limb anaerobic power (ES = 0.41, p = 0.021), whereas the free-weight group significantly improved the change of direction (ES = -0.54, p = 0.003) and 2/6 balance conditions analyzed (p ≤ 0.012). Changes in sprint capacity (ES ≥ -0.13, p ≥ 0.274), fascicle length, and pennation angle (ES ≤ 0.19, p ≥ 0.129) were not significant for either training modality. CONCLUSION: Adaptations in athletic performance and muscle architecture would not be meaningfully influenced by the resistance modality trained.

Refractive Error Changes Due to COVID-19 Pandemic Confinement in Children from Puerto Rico: A Retrospective Study.

SIGNIFICANCE: The progression of myopia increased in children after the pandemic confinement. A myopic shift in the refractive error of the Hispanic population was found regardless of the refractive status of the school-aged children studied. PURPOSE: This study aimed to evaluate the refractive error in Puerto Rican children before and after the COVID-19 pandemic. We were interested in whether there was a significant change in refractive error attributed to online learning during the pandemic lockdown. METHODS: A retrospective record review of children aged 7 to 18 years who underwent a comprehensive visual evaluation between 2018 and 2021 at the Inter American Eye Institute in Puerto Rico was performed. The spherical equivalent pre- and post-lockdown was compared. The study excluded the best-corrected visual acuities worse than 20/40, any corneal or retinal disease, and amblyopia. RESULTS: In total, 801 records were included in this study. The mean age was 12.7 ± 3.2 years, with 50.3% male and 49.7% female children. The mean spherical equivalent for the right and left eyes was similar ( r = 0.93, P ≤ .001). A significant difference in the mean spherical equivalent was found pre- and post- lockdown (0.22 ± 0.59 D, t800 = 10.44, P ≤ .001). A myopic shift post-lockdown was significant for all ages except those in the 7- (0.13 ± 0.79 D, t28 = 0.84, P = .40) and 8-year-old range (0.12 ± 0.65 D, t40 = 1.22, P = .23), respectively. No significant change was found between sexes before (0.16 ± 0.12 D; t799 = 1.38, P = .16) and after (0.15 ± 0.13 D; t799 = 1.19, P = .23) confinement. CONCLUSIONS: The current study revealed a significant myopic shift in Hispanic school-aged children as a result of the pandemic confinement.

Velocity-Based Method in Free-Weight and Machine-Based Training Modalities: The Degree of Freedom Matters.

ABSTRACT: Hernández-Belmonte, A, Buendía-Romero, Á, Pallares, JG, and Martínez-Cava, A. Velocity-based method in free-weight and machine-based training modalities: the degree of freedom matters. J Strength Cond Res 37(9): e500-e509, 2023-This study aimed to analyze and compare the load-velocity relationships of free-weight and machine-based modalities of 4 resistance exercises. Moreover, we examined the influence of the subject's strength level on these load-velocity relationships. Fifty men completed a loading test in the free-weight and machine-based modalities of the bench press, full squat, shoulder press, and prone bench pull exercises. General and individual relationships between relative intensity (%1RM) and velocity variables were studied through the coefficient of determination ( R2 ) and standard error of the estimate ( SEE ). Moreover, the velocity attained to each %1RM was compared between both modalities. Subjects were divided into stronger and weaker to study whether the subject's strength level influences the mean test (mean propulsive velocity [MPV Test ]) and 1RM (MPV 1RM ) velocities. For both modalities, very close relationships ( R2 ≥ 0.95) and reduced estimation errors were found when velocity was analyzed as a dependent ( SEE ≤ 0.086 m·s -1 ) and independent ( SEE ≤ 5.7% 1RM) variable concerning the %1RM. Fits were found to be higher ( R2 ≥ 0.995) for individual load-velocity relationships. Concerning the between-modality comparison, the velocity attained at each intensity (from 30 to 100% 1RM) was significantly faster for the free-weight variant. Finally, nonsignificant differences were found when comparing MPV Test (differences ≤ 0.02 m·s -1 ) and MPV 1RM (differences ≤ 0.01 m·s -1 ) between stronger and weaker subjects. These findings prove the accuracy and stability of the velocity-based method in the free-weight and machine-based variants but highlight the need to use the load-velocity relationship (preferably the individual one) specific to each training modality.

A New Class of Task-Specific Imidazolium Salts and Ionic Liquids and Their Corresponding Transition-Metal Complexes for Immobilization on Electrochemically Active Surfaces.

Adding to the versatile class of ionic liquids, we report the detailed structure and property analysis of a new class of asymmetrically substituted imidazolium salts, offering interesting thermal characteristics, such as liquid crystalline behavior, polymorphism or glass transitions. A scalable general synthetic procedure for N-polyaryl-N'-alkyl-functionalized imidazolium salts with para-substituted linker (L) moieties at the aryl chain, namely [LPhm ImH R]+ (L=Br, CN, SMe, CO2 Et, OH; m=2, 3; R=C12 , PEGn ; n=2, 3, 4), was developed. These imidazolium salts were studied by single-crystal X-ray diffraction (SC-XRD), NMR spectroscopy and thermochemical methods (DSC, TGA). Furthermore, these imidazolium salts were used as N-heterocyclic carbene (NHC) ligand precursors for mononuclear, first-row transition metal complexes (MnII , FeII , CoII , NiII , ZnII , CuI , AgI , AuI ) and for the dinuclear Ti-supported Fe-NHC complex [(OPy)2 Ti(OPh2 ImC12 )2 (FeI2 )] (OPy=pyridin-2-ylmethanolate). The complexes were studied concerning their structural and magnetic behavior via multi-nuclear NMR spectroscopy, SC-XRD analyses, variable temperature and field-dependent (VT-VF) SQUID magnetization methods, X-band EPR spectroscopy and, where appropriate, zero-field 57 Fe Mössbauer spectroscopy.

High CT-Fluorophore Featuring a Basic Moiety into D-A Chain as a pKa Probe.

The determination of acidity represents a significant challenge within fluorometry, and no effective strategy has been developed successfully yet. It is attributed to the fact that acidity tends to be enhanced upon excitation, giving, in general, an overestimation of the ionization constant, pKa. Herein, we developed a strategy for pKa estimation of Brønsted acids in solution through fluorometry by using a convenient pKa probe, N1-aryl-7-methoxy-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one. It allowed us to obtain a linear log KSV versus pKa correlation derived from the selective quenching response of the probe by an interaction with different Brønsted acids. The key points of N1-aryl-7-methoxy-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one as a pKa probe were (i) the location of a weak basic moiety in the donor-acceptor chain of the fluorophore, which favors a selective quenching of the intramolecular charge-transfer process according to the acidity of acid, and (ii) the high CT character upon excitation that promotes higher quenching magnitudes and favors a wider pKa range (19.5pKa) for the log KSV versus pKa correlation. Other key principles were to delimit the study to pure proton transfer and nonfluorescent acids, which allowed restricting the quenching response to a process dependent mainly on the acid-base equilibrium. All these findings open a new perspective as a proof of concept to design effective fluorescent pKa probes.

Rehabilitation for post-COVID-19 condition through a supervised exercise intervention: A randomized controlled trial.

PURPOSE: The aim of the study was to compare the outcomes of patients with post-COVID-19 condition undergoing supervised therapeutic exercise intervention or following the self-management WHO (World Health Organization) rehabilitation leaflet. METHODS: A randomized controlled trial was carried out that included 39 participants with post-COVID-19 condition who had a chronic symptomatic phase lasting >12 weeks. Comprehensive medical screening, patient-reported symptoms, and cardiorespiratory fitness and muscular strength were assessed. Patients were randomly assigned to a tailored multicomponent exercise program based on concurrent training for 8 weeks (two supervised sessions per week comprised resistance training combined with aerobic training [moderate intensity variable training], plus a third day of monitored light intensity continuous training), or to a control group which followed the WHO guidelines for rehabilitation after COVID-19. RESULTS: After follow-up, there were changes in physical outcomes in both groups, however, the magnitude of the change pre-post intervention favored the exercise group in cardiovascular and strength markers: VO2 max +5.7%, sit-to-stand -22.7% and load-velocity profiles in bench press +6.3%, and half squat +16.9%, (p < 0.05). In addition, exercise intervention resulted in a significantly better quality of life, less fatigue, less depression, and improved functional status, as well as in superior cardiovascular fitness and muscle strength compared to controls (p < 0.05). No adverse events were observed during the training sessions. CONCLUSION: Compared to current WHO recommendations, a supervised, tailored concurrent training at low and moderate intensity for both resistance and endurance training is a more effective, safe, and well-tolerated intervention in post-COVID-19 conditions.

A Novel Model for Vulnerability Analysis through Enhanced Directed Graphs and Quantitative Metrics.

The rapid evolution of industrial components, the paradigm of Industry 4.0, and the new connectivity features introduced by 5G technology all increase the likelihood of cybersecurity incidents. Such incidents are caused by the vulnerabilities present in these components. Designing a secure system is critical, but it is also complex, costly, and an extra factor to manage during the lifespan of the component. This paper presents a model to analyze the known vulnerabilities of industrial components over time. The proposed Extended Dependency Graph (EDG) model is based on two main elements: a directed graph representation of the internal structure of the component, and a set of quantitative metrics based on the Common Vulnerability Scoring System (CVSS). The EDG model can be applied throughout the entire lifespan of a device to track vulnerabilities, identify new requirements, root causes, and test cases. It also helps prioritize patching activities. The model was validated by application to the OpenPLC project. The results reveal that most of the vulnerabilities associated with OpenPLC were related to memory buffer operations and were concentrated in the libssl library. The model was able to determine new requirements and generate test cases from the analysis.

Anorectic interaction and safety of 5-hydroxytryptophan/carbidopa plus phentermine or diethylpropion in rat.

Drug combinations are being studied as potential therapies to increase the efficacy or improve the safety profile of weight loss medications. This study was designed to determine the anorectic interaction and safety profile of 5-hydroxytryptophan (5-HTP)/carbidopa + diethylpropion and 5-HTP/carbidopa + phentermine combinations in rats. The anorectic effect of individual drugs or in combination was evaluated by the sweetened milk test. Isobologram and interaction index were employed to determine the anorectic interaction between 5-HTP/carbidopa and diethylpropion or phentermine. Plasma serotonin (5-HT) was measured by ELISA. Safety of repeated doses of both combinations in rats was evaluated using the tail sphygmomanometer, cardiac ultrasound, hematic biometry and blood chemistry. A single oral 5-HTP, diethylpropion or phentermine dose increased the anorectic effect, in a dose-dependent fashion, in 12 h-fasted rats. A dose of carbidopa at 30 mg/kg reduced the 5-HTP-induced plasmatic serotonin concentration and augmented the 5-HTP-induced anorectic effect. Isobologram and interaction index indicated a potentiation interaction between 5-HTP/30 mg/kg carbidopa + diethylpropion and 5-HTP/30 mg/kg carbidopa + phentermine. Chronic administration of experimental ED40 of 5-HTP/30 mg/kg carbidopa + phentermine, but not 5-HTP/30 mg/kg carbidopa + diethylpropion, increased the mitral valve leaflets area. Moreover, there were no other significant changes in cardiovascular, hematic or blood parameters. Both combinations induced around 20% body weight loss after 3 months of oral administration. Results suggest that 5-HTP/30 mg/kg carbidopa potentiates the anorectic effect of diethylpropion and phentermine with an acceptable safety profile, but further clinical studies are necessary to establish their therapeutic potential in the obesity treatment.

Are the Assioma Favero Power Meter Pedals a Reliable Tool for Monitoring Cycling Power Output?

This study aimed to examine the validity and reliability of the recently developed Assioma Favero pedals under laboratory cycling conditions. In total, 12 well-trained male cyclists and triathletes (VO2max = 65.7 ± 8.7 mL·kg-1·min-1) completed five cycling tests including graded exercises tests (GXT) at different cadences (70-100 revolutions per minute, rpm), workloads (100-650 Watts, W), pedaling positions (seated and standing), vibration stress (20-40 Hz), and an 8-s maximal sprint. Tests were completed using a calibrated direct drive indoor trainer for the standing, seated, and vibration GXTs, and a friction belt cycle ergometer for the high-workload step protocol. Power output (PO) and cadence were collected from three different brand, new pedal units against the gold-standard SRM crankset. The three units of the Assioma Favero exhibited very high within-test reliability and an extremely high agreement between 100 and 250 W, compared to the gold standard (Standard Error of Measurement, SEM from 2.3-6.4 W). Greater PO produced a significant underestimating trend (p < 0.05, Effect size, ES ≥ 0.22), with pedals showing systematically lower PO than SRM (1-3%) but producing low bias for all GXT tests and conditions (1.5-7.4 W). Furthermore, vibrations ≥ 30 Hz significantly increased the differences up to 4% (p < 0.05, ES ≥ 0.24), whereas peak and mean PO differed importantly between devices during the sprints (p < 0.03, ES ≥ 0.39). These results demonstrate that the Assioma Favero power meter pedals provide trustworthy PO readings from 100 to 650 W, in either seated or standing positions, with vibrations between 20 and 40 Hz at cadences of 70, 85, and 100 rpm, or even at a free chosen cadence.

Anticancer potential of new 3-nitroaryl-6-(N-methyl)piperazin-1,2,4-triazolo[3,4-a]phthalazines targeting voltage-gated K+ channel: Copper-catalyzed one-pot synthesis from 4-chloro-1-phthalazinyl-arylhydrazones.

A series of six 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines were prepared through a facile and efficient one-pot copper-catalyzed procedure from 4-chloro-1-phthalazinyl-arylhydrazones with relatively good yields (62-83%). The one-pot copper-catalytic procedure consists of two simultaneous reactions: (i) a direct intramolecular dehydrogentaive cyclization between ylidenic carbon and adjacent pyrazine nitrogen to form 1,2,4-triazolo ring and, (ii) a direct N-amination on carbon-chlorine bond. Then, an in vitro anticancer evaluation was performed for the synthesized compounds against five selected human cancer cells (A549, MCF-7, SKBr3, PC-3 and HeLa). The nitro-derivatives were significantly more active against cancer strains than against the rest of tested compounds. Specifically, compound 8d was identified as the most promising anticancer agent with significant biological responses and low relative toxicities on human dermis fibroblast. The cytotoxic effect of compound 8d was more significant on PC3, MCF-7 and SKBr3 cancer cells with low-micromolar IC50 value ranging from 0.11 to 0.59 µM, superior to Adriamycin drug. Mechanistic experimental and theoretical studies demonstrated that compounds 8d act as a K+ channel inhibitor in cancer models. Further molecular docking studies suggest that the EGFR Tyrosine Kinase enzyme may be a potential target for the most active 3-aryl-6-(N-methylpiperazin)-1,2,4-triazolo[3,4-a]phthalazines.

Peaceful End of Life in an Unviable Newborn: A Case Report.

The limit of viability is a period of uncertainty regarding the prognosis and treatment, where palliative care (PC) is important to dignify death, although, in several countries, they are not implemented as in Colombia. The peculiarities of newborns make PC differ from care at other stages of life and which are rarely accepted by professionals who consider them overwhelming. The case of a newborn of 23 weeks of gestation is exposed where nursing care is revealed to the newborn and his family according to the theory of the peaceful end of life (PEL). The theory of the PEL is useful in the development of neonatal PC, which must be differentiated, improving well-being, and family support. Furthermore, health systems must recognize emotional risks for professionals.

Hydroxamate Titanium-Organic Frameworks and the Effect of Siderophore-Type Linkers over Their Photocatalytic Activity.

The chemistry of metal-organic frameworks (MOFs) relies on the controlled linking of organic molecules and inorganic secondary building units to assemble an unlimited number of reticular frameworks. However, the design of porous solids with chemical stability still remains limited to carboxylate or azolate groups. There is a timely opportunity to develop new synthetic platforms that make use of unexplored metal binding groups to produce metal-linker joints with hydrolytic stability. Living organisms use siderophores (iron carriers in Greek) to effectively assimilate iron in soluble form. These compounds make use of hard oxo donors as hydroxamate or catecholate groups to coordinate metal Lewis acids such as iron, aluminum, or titanium to form metal complexes very stable in water. Inspired by the chemistry of these microorganisms, we report the first hydroxamate MOF prepared by direct synthesis. MUV-11 (MUV = materials of Universidad de Valencia) is a crystalline, porous material (close to 800 m2·g-1) that combines photoactivity with good chemical stability in acid conditions. By using a high-throughput approach, we also demonstrate that this new chemistry is compatible with the formation of single-crystalline phases for multiple titanium salts, thus expanding the scope of accessible precursors. Titanium frameworks are regarded as promising materials for photocatalytic applications. Our photoelectrochemical and catalytic tests suggest important differences for MUV-11. Compared to other Ti-MOFs, changes in the photoelectrochemical and photocatalytic activity have been rationalized with computational modeling, revealing how the chemistry of siderophores can introduce changes to the electronic structure of the frontier orbitals, relevant to the photocatalytic activity of these solids.

Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats.

BACKGROUND: Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which H2S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in H2S-induced hyperalgesia in diabetic rats. RESULTS: Streptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exogenous donor of H2S, 3-100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3-3 µg/paw), HC-030031 (100-316 µg/paw) and SKF-96365 (10-30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3-30 µg/paw), HC-030031 (100-1000 µg/paw) and SKF-96365 (10-100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced flinching behavior. Hyperglycemia, at 21 days, also increased protein expression of cystathionine-ß-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expression, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-induced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fiber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons. CONCLUSIONS: Our data suggest that H2S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fibers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy.