Salophen-type Organocatalysts for the Cycloaddition of CO2 and Epoxides under Solvent, Halide, and Metal-Free Conditions.

8-Formyl-7-hydroxycoumarin (A) and their derived salophen-type organocatalysts L1, L2, and L3 were used for the synthesis of cyclic carbonates from carbon dioxide (CO2) and epoxides under solvent-, halide-, and metal-free conditions. According to previous optimization tests, L1 and L2 had the best catalytic activity presenting 89 and 92% conversion toward the synthesis of 3-chloropropylene carbonate (2c) using 8 bar CO2, 100 °C at 9 h. Therefore, they were used as organocatalysts to complete the catalytic screening with 11 terminal epoxides (1a-k) exhibiting the highest TOF values of 20 and 22 h-1 using 1c and 1b, respectively. Similarly, they were tested with an internal epoxide, such as cyclohexene oxide (1l) exhibiting 72% conversion, becoming the first salophen organocatalyst to obtain cis-cyclohexane carbonate (2l) in the absence of a cocatalyst. In addition, a reaction mechanism was proposed for the formation of cyclic carbonates based on experimental data and computational techniques; these contributed in establishing a probable role of CO2 pressure along the catalysis and the hydrogen bonds that favor the stabilization of the different intermediates of the reaction.

Air-Stable Cobalt(III) and Chromium(III) Complexes as Single-Component Catalysts for the Activation of Carbon Dioxide and Epoxides.

Cobalt(III) and chromium(III) salophen chloride complexes were synthesized and tested for the cycloaddition of carbon dioxide (CO2) with epoxides to obtain cyclic carbonates. The cat1, cat2, cat4, and cat5 complexes presented high catalytic activity without cocatalysts and are solvent-free at 100 °C, 8 bar, and 9 h. At these conditions, the terminal epoxides (1a-1k) were successfully converted into the corresponding cyclic carbonates with a maximum conversion of ∼99%. Moreover, cat5 was highlighted due to its capability of opening internal epoxides such as limonene oxide (1l) with a 36% conversion to limonene carbonate (2l), and from cyclohexene oxide (1m), cyclic trans-cyclohexene carbonate (2m) and poly(cyclohexene carbonate) were obtained with 15% and 85% selectivity, respectively. A study of the coupling reaction mechanism was proposed with the aid of electrospray ionization mass spectrometry (ESI-MS) analysis, confirming the single-component behavior of the complexes through their ionization due to epoxide coordination. In addition, crystallographic analysis of cat1 single crystals grown in a saturated solution of pyridine helped to demonstrate that the substitution of chloride ion by pyridine ligands to form an octahedral coordination occurs (Py-cat1), supporting the proposed mechanism. Also, a recyclability study was performed for cat5, and a total turnover number of 952 was obtained with only minor losses in catalytic activity after five cycles.

Oleic acid abomasal infusion limits lipolysis and improves insulin sensitivity in adipose tissue from periparturient dairy cows.

Excessive adipose tissue (AT) lipolysis around parturition in dairy cows is associated with impaired AT insulin sensitivity and increased incidence of metabolic diseases. Supplementing cows with oleic acid (OA) reduces circulating biomarkers of lipolysis and improves energy balance. Nevertheless, it is unclear if OA alters lipid trafficking in AT. In the liver and skeletal muscle, OA improves mitochondrial function and promotes lipid droplet formation by activating perilipin 5 (PLIN5) and peroxisome proliferator-activated receptor α (PPARα). However, it is unknown if this mechanism occurs in AT. The objective of this study was to determine the effect of OA on AT lipolysis, systemic and AT insulin sensitivity, and AT mitochondrial function in periparturient dairy cows. Twelve rumen-cannulated Holstein cows were infused abomasally following parturition with ethanol (CON) or OA (60 g/d) for 14 d. Subcutaneous AT samples were collected at 11 ± 3.6 d before calving (-12 d), and 6 ± 1.0 d (7 d) and 13 ± 1.4 d (14 d) after parturition. An intravenous glucose tolerance test was performed on d 14. Adipocyte morphometry was performed on hematoxylin and eosin-stained AT sections. The antilipolytic effect of insulin (1 µg/L) was evaluated using an ex vivo explant culture following lipolysis stimulation. PLIN5 and PPARα transcription and translation were determined by real-time quantitative PCR and capillary electrophoresis, respectively. RNA sequencing was used to evaluate the transcriptomic profile of mitochondrial gene networks. In CON cows, postpartum lipolysis increased the percentage of smaller (<3,000 µm2) adipocytes at 14 d compared with -12 d. However, OA limited adipocyte size reduction at 14 d. Likewise, OA decreased lipolysis plasma markers nonesterified free fatty acids and ß-hydroxybutyrate at 5 and 7 d. Over the 14-d period, compared with CON, OA increased the concentration of plasma insulin and decreased plasma glucose. During the glucose tolerance test, OA decreased circulating glucose concentration (at 10, 20, 30, 40 min) and the glucose clearance rate. Moreover, OA increased insulin at 10 and 20 min and tended to increase it at 30 min. Following lipolysis stimulation, OA improved the antilipolytic effect of insulin in the AT at 14 d. PLIN5 and PPARA gene expression decreased postpartum regardless of treatment. However, OA increased PLIN5 protein expression at 14 d and increased PPARA at 7 and 14 d. Immunohistochemical analysis of AT and RNA sequencing data showed that OA increased the number of mitochondria and improved mitochondrial function. However, OA had no effect on production and digestibility. Our results demonstrate that OA limits AT lipolysis, improves systemic and AT insulin sensitivity, and is associated with markers of mitochondrial function supporting a shift to lipogenesis in AT of periparturient dairy cows.

Antioxidant Activity, Molecular Docking, Quantum Studies and In Vivo Antinociceptive Activity of Sulfonamides Derived From Carvacrol.

The synthesis and antioxidant, antinociceptive and antiedematogenic activities of sulfonamides derived from carvacrol-a druglike natural product-are reported. The compounds showed promising antioxidant activity, and sulfonamide derived from morpholine (S1) demonstrated excellent antinociceptive and antiedematogenic activities, with no sedation or motor impairment. The mechanism that underlies the carvacrol and derived sulfonamides' relieving effects on pain has not yet been fully elucidated, however, this study shows that the antinociceptive activity can be partially mediated by the antagonism of glutamatergic signaling. Compound S1 presented promising efficacy and was predicted to have an appropriate medicinal chemistry profile. Thus, derivative S1 is an interesting starting point for the design of new leads for the treatment of pain and associated inflammation and prooxidative conditions.

Diaminomaleonitrile derivatives as new potential antichagasic compounds: a study of structure-activity relationships.

Background: Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. Methods & results: In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80-98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog 13 (IC50 = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC50 values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure-activity relationship models for the whole dataset yielded sound correlation coefficients (R2 = 0.844; Q2 = 0.719). Conclusion: These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.

2',6'-dihydroxy-4'-methoxy Dihydrochalcone Improves the Cognitive Impairment of Alzheimer's Disease: A Structure-activity Relationship Study.

BACKGROUND: Chalcones and dihydrochalcones present potent inhibition of acetylcholinesterase, currently considered the most efficient approach for symptomatic treatment of Alzheimer's disease. OBJECTIVE: The present study aimed to explore the potential benefits of 2',6'-dihydroxy-4'-methoxy dihydrochalcone on the cognitive deficits of animals submitted to the streptozotocin-induced Alzheimer's model, as well as evaluating the possible mechanisms of action. METHODS: Learning and memory functions of different groups of animals were submitted to the streptozotocin-induced Alzheimer's model (STZ 2.5 mg/mL, i.c.v.) and subsequently treated with 2',6'-dihydroxy-4'-methoxy dihydrochalcone (DHMDC) administered at doses of 5, 15, and 30 mg/kg (p.o.), respectively. Rivastigmine (0,6 mg/kg, i.p.) and vehicle were evaluated in aversive memory test (inhibitory avoidance test) and spatial memory test (object recognition test). Molecular docking simulations were performed to predict the binding mode of DHMDC at the peripheral site of AChE, to analyze noncovalent enzyme-ligand interactions. DFT calculations were carried out to study well-known acetylcholinesterase inhibitors and DHMDC. RESULTS: DHMDC markedly increased the learning and memory of mice. STZ caused a significant decline of spatial and aversive memories in mice, attenuated by DHMDC (15 and 30 mg/kg). Furthermore, STZ conspicuously increased lipid peroxidation and compromised the antioxidant levels in mice brains. DHMDC pretreatment significantly increased GSH activity and other oxidative stress markers and decreased TBARS level in the brain of STZ administered mice. AChE activity was significantly decreased by DHMDC in the brain of mice. CONCLUSION: The results together point out that DHMDC may be a useful drug in the management of dementia.

Updates in Laboratory Diagnostics for Invasive Fungal Infections.

Appropriate diagnosis of invasive fungal infections (IFIs) is critical due to the high rates of morbidity and mortality, as well as the substantial economic burden, associated with the management of these diseases. The recognition of IFI and differentiation from other infections with similar clinical presentations can be challenging, which can lead to diagnostic error that not only has an impact on individual patient health outcomes but also on antimicrobial drug usage and the growing threat of antimicrobial resistance in bacteria. Therefore, there is a significant need for improved stewardship related to diagnostic testing for and treatment of IFIs. The purpose of this review is to highlight recent advances related to current fungal diagnostics, as well as explore some of the most innovative technology that has emerged with the potential to shift the paradigm of clinical mycology. In general, this review will discuss research related to enhanced fungal culture utilization and identification techniques, expanded applications of fungal antigen testing, and recently developed molecular assays and other novel nonculture fungal diagnostic approaches. Specifically, the application of mass spectrometry, novel glycobiomarker detection, and detection of fungal-specific volatile organic compounds will be reviewed, along with other key updates, to provide the reader with an updated review that extends beyond the basics of IFI laboratory diagnostics. Where appropriate, the reader will be directed to more comprehensive reviews of certain aspects of clinical mycology laboratory testing to provide a broader context for the critical consideration of these updates.

Influence of prior appendectomy and cholecystectomy on Clostridioides difficile infection recurrence and mortality.

BACKGROUND: Remote appendectomy was linked to increased incidence of Clostridioides difficile infection (CDI). We evaluated the effect of absence of vermiform appendix and/or gallbladder on recurrence rate and severity of CDI. METHODS: We assessed a systemwide patient cohort diagnosed with initial CDI in 2014 (n = 250). The primary outcome was recurrence. RESULTS: Appendix and gallbladder were absent among 47 and 64 patients, respectively. CDI recurrence rate was similar among patients without and with appendix (24/47, 51.1% versus 90/203 patients, 44.3%; p = 0.404) and similar among patients without and with gallbladder (29/64 patients, 45.3% versus 85/186 patients, 45.7%; p = 0.957). Mortality was similar between appendectomy versus appendix in situ patients (3/47, 6.4% versus 9/203, 4.4%; p = 0.573), but higher mortality rate was seen among those without gallbladder (7/64 patients with prior cholecystectomy, 10.9% versus 5/186 patients with intact gallbladder, 2.7%; p = 0.008). CONCLUSION: Clostridioides difficile recurrence rate is not affected by remote appendectomy or cholecystectomy. Patients with prior cholecystectomy experience higher mortality rates associated with their CDI.

Molecular Docking and Quantum Studies of Lawsone Dimers Derivatives: New Investigation of Antioxidant Behavior and Antifungal Activity.

BACKGROUND: In general, fungal species are characterized by their opportunistic character and can trigger various infections in immunocompromised hosts. The emergence of infections associated with high mortality rates is due to the resistance mechanisms that these species develop. METHODS: This phenomenon of resistance denotes the need for the development of new and effective therapeutic approaches. In this paper, we report the investigation of the antioxidant and antifungal behavior of dimeric naphthoquinones derived from lawsone whose antimicrobial and antioxidant potential has been reported in the literature. RESULTS: Seven fungal strains were tested, and the antioxidant potential was tested using the combination of the methodologies: reducing power, total antioxidant capacity and cyclic voltammetry. Molecular docking studies (PDB ID 5V5Z and 1EA1) were conducted which allowed the derivation of structureactivity relationships (SAR). Compound 1-i, derived from 3-methylfuran-2-carbaldehyde showed the highest antifungal potential with an emphasis on the inhibition of Candida albicans species (MIC = 0.5 µg/mL) and the highest antioxidant potential. CONCLUSION: A combination of molecular modeling data and in vitro assays can help to find new solutions to this major public health problem.

Antioxidant and Antibacterial Activity of Sulfonamides Derived from Carvacrol: A Structure-Activity Relationship Study.

BACKGROUND: Bacterial resistance to antibiotics is a growing problem in all countries and has been discussed worldwide. In this sense, the development of new drugs with antibiotic properties is highly desirable in the context of medicinal chemistry. METHODOLOGY: In this paper we investigate the antioxidant and antibacterial potential of sulfonamides derived from carvacrol, a small molecule with drug-like properties. Most sulfonamides had antioxidant and antibacterial potential, especially compound S-6, derived from beta-naphthylamine. RESULTS: To understand the possible mechanisms of action involved in biological activity, the experimental results were compared with molecular docking data. CONCLUSION: This research allows appropriate discussion on the identified structure activity relationships.

Percepción de usuarios de Cali-Colombia acerca de medicamentos genéricos / Perception of users of Cali-Colombia about generic medicines

RESUMEN En la población en general existe gran controversia alrededor del uso de medicamentos innovadores y de sus copias llamadas medicamentos genéricos. El objetivo de este estudio es cuantificar la aceptación de los pacientes, del Sistema General de Seguridad Social en Salud de Colombia (SGSSS) a la prescripción de medicamentos genéricos. Se realizó un estudio de tipo descriptivo con un diseño transversal en 63 hombres y 57 mujeres, todos adultos pacientes que asistieron a consulta externa de los sitios de práctica de una Facultad de Medicina de Cali-Colombia. Se concluye que si se usan medicamentos genéricos, se requiere que los médicos y los usuarios tengan confianza en él. Los resultados del presente estudio muestran que, aunque no en forma mayoritaria, todavía un porcentaje importante de los consumidores entrevistados dudan de la calidad y de los resultados terapéuticos de los genéricos. De manera preocupante, casi una cuarta parte de los participantes en el estudio piensa que los medicamentos genéricos son productos fraudulentos.

SUMMARY In the general population, there is a great controversy surrounding the use of innovative drugs and their copies called generic drugs. The objective of this study is to quantify the acceptance of patients from the General System of Social Security in Health of Colombia (SGSSS) to the prescription of generic drugs. A descriptive study was carried out with a transversal design. The universe was 63 men and 57 women, all adult patients who attended external consultation of the practice sites of the Faculty of Medicine of Cali-Colombia. It is concluded that if generic drugs are used, it is necessary that doctors and users have confidence in it, the results of the present study show that, although not in the majority, still a significant percentage of the consumers interviewed doubt the quality and the therapeutic results of generics. Worryingly, nearly a quarter of study participants think that generic drugs are fraudulent products.