(p-ClPhSe)2 modulation on carbohydrate and lipid metabolism requires the insulin-like signaling in Caenorhabditis elegans.

Organoselenium compounds modulate the metabolism by regulating carbohydrate and lipid syntheses and degradation in the liver, muscle, and adipose tissue. Notably, p-chloro-diphenyl diselenide (p-ClPhSe)2 can directly regulate the activities of enzymes involved in glucose metabolism, suggesting an insulin-like effect in rodents; however, there is still a lack of scientific evidence to confirm this hypothesis. The objective of this study was to investigate (p-ClPhSe)2 effects on glucose and lipid metabolism in Caenorhabditis elegans. The contribution of AGE-1/PI3K, AKT-1, AKT-2, PFK-1, DAF-16, and DAF-2 in the (p-ClPhSe)2 effects were also investigated. Our results demonstrate that (p-ClPhSe)2 acute exposure presented some toxicity to the worms, and therefore, lower concentrations were further used. (p-ClPhSe)2 reduced glucose and triglyceride levels to the baseline levels, after induction with glucose or fructose, in wild-type worms. This effect required proteins involved in the insulin/IGF-1 like signaling, such as the DAF-2, AGE-1, AKT-1 and AKT-2, PFK-1, but also DAF-16, which would be negatively regulated by DAF-2 activation. Moreover, the reduction in glucose and triglyceride levels, caused by (p-ClPhSe)2per se was lost in age-1/daf-16 worms, suggesting that insulin/IGF-1-like signaling in a DAF-2 and AGE-1/DAF-16 dependent-manner in C. elegans are necessary to effects of (p-ClPhSe)2. In conclusion, (p-ClPhSe)2 requires proteins involved in the IIS pathway to modulate carbohydrate and lipid metabolism.

KIO3-catalyzed selective oxidation of thiols to disulfides in water under ambient conditions.

Herein, we report a KIO3-catalyzed oxidative coupling of thiols to their corresponding disulfides in water, in a short time and at ambient temperature. The reaction has a broad scope and exhibits good functional group tolerance, resulting in the desired products in excellent yields. This approach allows the reuse of the reaction system in multiple cycles and scale-up. Furthermore, the current protocol demonstrates compatibility for in situ generation of disulfides and post application in C(sp2)-H bond sulfenylation.

Inhibitory effects of 190 compounds against SARS-CoV-2 Mpr o protein: Molecular docking interactions.

COVID-19 has caused many deaths since the first outbreak in 2019. The burden on healthcare systems around the world has been reduced by the success of vaccines. However, population adherence and the occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are still challenging tasks to be affronted. In addition, the newly approved drug presents some limitations in terms of side effects and drug interference, highlighting the importance of searching for new antiviral agents against SARS-CoV-2. The SARS-CoV-2 main protease (Mpr o ) represents a versatile target to search for new drug candidates due to its essential role in proteolytic activities responsible for the virus replication. In this work, a series of 190 compounds, composed of 27 natural ones and 163 synthetic compounds, were screened in vitro for their inhibitory effects against SARS-CoV-2 Mpro . Twenty-five compounds inhibited Mpro with inhibitory constant values (Ki ) between 23.2 and 241 µM. Among them, a thiosemicarbazone derivative was the most active compound. Molecular docking studies using Protein Data Bank ID 5RG1, 5RG2, and 5RG3 crystal structures of Mpro revealed important interactions identified as hydrophobic, hydrogen bonding and steric interactions with amino acid residues in the active site cavity. Overall, our findings indicate the described thiosemicarbazones as good candidates to be further explored to develop antiviral leads against SARS-CoV-2. Moreover, the studies showed the importance of careful evaluation of test results to detect and exclude false-positive findings.

Synthesis of 4-Selanyl- and 4-Tellanyl-1H-isochromen-1-ones Promoted by Diorganyl Dichalcogenides and Oxone.

A new method was developed for the synthesis of 4-chalcogenyl-1H-isochromen-1-ones through the 6-endo-dig electrophilic cyclization of 2-alkynylaryl esters and diorganyl dichalcogenides under ultrasound irradiation. The reactions were performed under mild conditions, using Oxone as a green oxidant to promote the cleavage of the chalcogen-chalcogen bond in diorganyl diselenides and ditellurides to generate electrophilic species in situ. A total of 25 compounds were selectively obtained after 30-70 min, in good to excellent yields (74-95%). This procedure was extended to prepare 5H-selenopheno[3,2-c]isochromen-5-ones. Additionally, for the first time, the 4-chalcogenyl-1H-isochromen-1-ones were used as substrates in the thionation reaction, using Lawesson's reagent and microwave irradiation under solvent-free conditions, obtaining the thio derivatives in yields of up to 99% in only 15 min.

Alkynes and Nitrogen Compounds: Useful Substrates for the Synthesis of Pyrazoles.

The easy preparation and functionalization of pyrazoles associated with their innumerable biological properties have made this class of N-heterocycles very attractive for the development of new synthetic routes and applications. The cyclization reactions of alkynes and nitrogen compounds represent a powerful tool for the preparation of pyrazoles. This Review covers the recent advances in the preparation of pyrazoles by reacting alkynes and nitrogen compounds under transition-metal-catalyzed or metal-free conditions.

Synthesis of indoles from alkynes and a nitrogen source under metal-free conditions.

Indoles are an important nucleus of N-heterocycles found in many natural products, active pharmaceuticals, and functional materials. In addition, indoles have various reactive positions, each one with a different reactivity, which may be susceptible to different reactions. This characteristic makes them important substrates for further transformations. This paper deals with the methodologies published in the last ten years, which used metal-free conditions to prepare indoles starting from alkynes and nitrogen compounds.

Genome sequencing of Mycobacterium pinnipedii strains: genetic characterization and evidence of superinfection in a South American sea lion (Otaria flavescens).

BACKGROUND: Mycobacterium pinnipedii, a member of the Mycobacterium tuberculosis Complex (MTBC), is capable of infecting several host species, including humans. Recently, ancient DNA from this organism was recovered from pre-Columbian mummies of Peru, sparking debate over the origin and frequency of tuberculosis in the Americas prior to European colonization. RESULTS: We present the first comparative genomic study of this bacterial species, starting from the genome sequencing of two M. pinnipedii isolates (MP1 and MP2) obtained from different organs of a stranded South American sea lion. Our results indicate that MP1 and MP2 differ by 113 SNPs (single nucleotide polymorphisms) and 46 indels, constituting the first report of a mixed-strain infection in a sea lion. SNP annotation analyses indicate that genes of the VapBC family, a toxin-antitoxin system, and genes related to cell wall remodeling are under evolutionary pressure for protein sequence change in these strains. OrthoMCL analysis with seven modern isolates of M. pinnipedii shows that these strains have highly similar proteomes. Gene variations were only marginally associated with hypothetical proteins and PE/PPE (proline-glutamate and proline-proline-glutamate, respectively) gene families. We also detected large deletions in ancient and modern M. pinnipedii strains, including a few occurring only in modern strains, indicating a process of genome reduction occurring over the past one thousand years. Our phylogenomic analyses suggest the existence of two modern clusters of M. pinnipedii associated with geographic location, and possibly host species, and one basal node associated with the ancient M. pinnipedii strains. Previously described MiD3 and MiD4 deletions may have occurred independently, twice, over the evolutionary course of the MTBC. CONCLUSION: The presence of superinfection (i.e. mixed-strain infection) in this sea lion suggests that M. pinnipedii is highly endemic in this population. Mycobacterium pinnipedii proteomes of the studied isolates showed a high degree of conservation, despite being under genomic decay when compared to M. tuberculosis. This finding indicates that further genomes need to be sequenced and analyzed to increase the chances of finding variably present genes among strains or that M. pinnipedii genome remodeling occurred prior to bacterial speciation.

3-Halochromones Through Oxidative α-Halogenation of Enaminones and its Photophysical Investigation: Another Case of Photo-induced Partially Aromatised Intramolecular Charge Transfer?

A versatile synthesis strategy for fluorescent 3-halo-4H-chromen-4-one derivatives is reported. The method involves the oxidative α-halogenation of enaminones performed by an efficient and sustainable oxidation system. The use of Oxone® in combination with KCl, KBr, or KI enables the preparation of 3-chloro-, 3-bromo-, or 3-iodo-4H-chromen-4-one in good to excellent yields, with great functional group tolerance where the protocol is amenable to gram-scale synthesis. The analysis of the photophysical properties of the presented 4H-chromen-4-one showed absorption in the UV region and fluorescence emission in the violet-to-cyan region with a relatively large Stokes shift. In solution, all compounds present a dual fluorescence emission, regardless of the solvent, assigned to a partially aromatised intramolecular charge transfer mechanism, considering the presence of a pseudo-aromatic ring in the chromone scaffold and the absence of the influence of substituent electronic features in optical behaviour.

Genomic analysis of the first multidrug-resistant ESBL-producing high-risk clonal lineage Klebsiella pneumoniae ST147 isolated from a cat with urinary tract infection.

Urinary tract infections (UTIs) are pervasive in human and veterinary medicine, notably affecting companion animals. These infections frequently lead to the prescription of antibiotics, contributing to the rise of antimicrobial-resistant bacteria. This escalating concern is underscored by the emergence of a previously undocumented case: a high-risk clone, broad-spectrum cephalosporin-resistant K. pneumoniae ST147 strain, denoted USP-275675, isolated from a cat with UTI. Characterized by a multidrug-resistant (MDR) profile, whole genome sequencing exposed several antimicrobial-resistance genes, notably blaCTX-M-15, blaTEM-1B, blaSHV-11, and blaOXA-1. ST147, recognized as a high-risk clone, has historically disseminated globally and is frequently associated with carbapenemases and extended-spectrum ß-lactamases. Notably, the core-genome phylogeny of K. pneumoniae ST147 strains isolated from urine samples revealed a unique aspect of the USP-276575 strain. Unlike its counterparts, it did not cluster with other isolates. However, a broader examination incorporating strains from both human and animal sources unveiled a connection between USP-276575 and a Portuguese strain from chicken meat. Both were part of a larger cluster of ST147 strains spanning various geographic locations and sample types, sharing commonalities such as IncFIB or IncR plasmids. This elucidates the MDR signature inherent in widespread K. pneumoniae ST147 strains carrying these plasmids, highlighting their pivotal role in disseminating antimicrobial resistance (AMR). Finally, discovering the high-risk clone K. pneumoniae ST147 in a domestic feline with a UTI in Brazil highlights the urgent need for thorough AMR surveillance through a One Health approach.

Polymicrobial Septic Peritonitis Caused by Enterococcus faecium and Enterococcus casseliflavus following Uterine Rupture in a Goat.

A one-year-old female miniature goat was presented to an emergency service after calving a dead goatling. Physical and ultrasonographic examination revealed the presence of a viable fetus; therefore, the goat was submitted to an emergency cesarean section. In the postoperative period, the animal had septic peritonitis caused by Enterococcus faecium and Enterococcus casseliflavus. Both bacterial strains showed contrasting antimicrobial resistance profiles. Laparohysterectomy and abdominal cavity lavage were performed, but, once the animal had adhesions and necrotic lesions in abdominal organs, euthanasia was executed. A post-mortem examination revealed fibrino-necrotic septic peritonitis secondary to uterine rupture. To the authors' knowledge, this is the first detailed report of polymicrobial septic peritonitis in a miniature goat and the first report of septic peritonitis caused by E. faecium and E. casseliflavus.

Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice.

This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17ß-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests.

2-Phenylethynyl-butyltellurium enhances learning and memory impaired by scopolamine in mice.

Taking into account the memory-enhancing properties of 2-phenylethynyl-butyltellurium (PEBT) and the constant search for drugs that improve cognitive performance, the present study was designed to investigate the effect of PEBT on cognitive impairment induced by scopolamine in mice. PEBT (10 mg/kg, gavage) was administered to mice 1 h before the probe trial in the Morris water maze task. Memory impairment was induced by scopolamine (1 mg/kg, intraperitoneally) 30 min before the probe trial. PEBT significantly ameliorated the scopolamine-induced impairment of long-term memory, as indicated by a decrease in escape latency and an increase in the number of crossings of the platform location when compared with the amnesic mice. To evaluate the effect of PEBT on different phases of memory (acquisition, consolidation, and retrieval) impaired by scopolamine, the step-down inhibitory avoidance task was used. Scopolamine was administered 30 min before training (acquisition), test (retrieval), or immediately after training (consolidation). PEBT, administered 30 min before scopolamine, increased step-down latency in memory-impaired mice, improving the consolidation and retrieval stages, but not acquisition. No significant alterations in locomotor or exploratory behaviors were found in animals treated with PEBT and/or scopolamine. PEBT improved memory deficits during consolidation and retrieval induced by scopolamine.

Bis-vinyl selenides obtained via iron(III) catalyzed addition of PhSeSePh to alkynes: synthesis and antinociceptive activity.

In the present study the synthesis and antinociceptive activity of bis-vinyl selenides, prepared via FeCl(3) promoted reaction addition of diorganyl dichalcogenides to alkynes, is described. The pharmacological results demonstrated that bis-vinyl selenides 3a, 3d, 3h and 3t elicited antinociceptive effect in the mouse formalin test. The antinociceptive effects of bis-vinyl selenides are not sensitive to electronic effects of the substituents on the aromatic ring directly bonded to the selenium atom. Bis-vinyl selenides 3h and 3t were the most promising molecules for pharmacological purposes since these bis-vinyl selenides were effective in both phases of the formalin test and against edema. A single dose of bis-vinyl selenides 3a, 3d, 3h and 3t did not cause acute toxicity in mice.

Mycobacterium kansasii isolation from captive South American coati (Nasua nasua).

Three of six captive South American coatis (Nasua nasua) presented with respiratory distress and died despite treatment. Postmortem examination performed on two of these animals revealed granulomatous pleuropneumonia associated with acid-fast bacilli. Because of the possible diagnosis of mycobacterial infection, the three remaining asymptomatic coatis were anesthetized. Tracheal washes were sampled and submitted for microbiology, and the animals were euthanatized and postmortem examinations performed. One of these asymptomatic adult males had whitish granulomas in multiple organs and tissues. Additionally, the isolate from this male's tracheal wash was identified as Mycobacterium kansasii by molecular analysis. To the authors' knowledge, this is the first report of M. kansasii infection in Nasua nasua.

Green Approach for the Synthesis of Chalcogenyl- 2,3-dihydrobenzofuran Derivatives Through Allyl-phenols/ Naphthols and Their Potential as MAO-B Inhibitors.

This work presents the design, synthesis, and MAO-B inhibitor activity of a series of chalcogenyl-2,3-dihydrobenzofurans derivatives. Using solvent- and metal-free methodology, a series of chalcogen-containing dihydrobenzofurans 7-9 was obtained with yields ranging from 40% to 99%, using an I2 /DMSO catalytic system. All compounds were fully structurally characterized using 1 H and 13 C NMR analysis, and the unprecedented compounds were additionally analyzed using high-resolution mass spectrometry (HRMS). In addition, the mechanistic proposal that iodide is the most likely species to act in the transfer of protons along the reaction path was studied through theoretical calculations. Finally, the compounds 7b-e, 8a-e, and 9a showed great promise as inhibitors against MAO-B activity.

Catalyst- and metal-free C(sp2)-H bond selenylation of (N-hetero)-arenes using diselenides and trichloroisocyanuric acid at room temperature.

In this paper, we report an eco-friendly approach for the C(sp2)-H bond selenylation of imidazopyridines and other N-heteroarenes as well as simple arenes at ambient temperature. This new protocol consists of the reaction between (N-hetero)-arenes and the diorganyl-diselenides and trichloroisocyanuric acid (TCCA)-ethanol reagent system. In a short reaction time, the desired selenylated products were obtained regioselectively in good yields, with tolerance for a wide range of functional groups.

Versatile Electrochemical Synthesis of Selenylbenzo[b]Furan Derivatives Through the Cyclization of 2-Alkynylphenols.

We report an electrochemical oxidative intramolecular cyclization reaction between 2-alkynylphenol derivatives and different diselenides species to generate a wide variety of substituted-benzo[b]furans. Driven by the galvanostatic electrolysis assembled in an undivided cell, it provided efficient transformation into oxidant-, base-, and metal-free conditions in an open system at room temperature. With satisfactory functional group compatibility, the products were obtained in good to excellent yields.

Synthesis and investigation of the trypanocidal potential of novel 1,2,3-triazole-selenide hybrids.

Chagas Disease is caused by the protozoan Trypanosoma cruzi and is considered a tropical neglected disease by the World Health Organization (WHO). The main drugs used in the therapy of the disease are obsolete and, as a result, it still kills millions of people every year. Therefore, the development of new drugs is urgent, as is the research reported in this article, in which new triazole selenides were synthesized through a simple methodology and to evaluate their potential against T. cruzi, through a combination of in vitro and in silico assays. With the combination of two molecular scaffolds already known for this activity, sixteen new hybrid compounds were obtained, showing yields ranging from 40 to 90%, and their biological potentials were tested. Two of the evaluated hybrids showed potent trypanocidal activity (11m and 11n), comparable to the positive control benznidazole. Density functional theory (DFT) studies were correlated with cyclic voltammetry assays to investigate the LUMO energy, which demonstrated a correlation with the observed trypanocidal activity. These results are promising, considering 11m and 11n as hit compounds in the development of new antichagasic drugs.

Genomic analysis of an outbreak of bovine tuberculosis in a man-made multi-host species system: A call for action on wildlife in Brazil.

We report on a 15-year-long outbreak of bovine tuberculosis (bTB) in wildlife from a Brazilian safari park. A timeline of diagnostic events and whole-genome sequencing (WGS) of 21 Mycobacterium bovis isolates from deer and llamas were analyzed. Accordingly, from 2003 to 2018, at least 16 animals, from eight species, died due to TB, which is likely an underestimated number. In three occasions since 2013, the deer presented positive tuberculin tests, leading to the park closure and culling of all deer. WGS indicated that multiple M. bovis strains were circulating, with at least three founding introductions since the park inauguration in 1977. Using a previously sequenced dataset of 71 M. bovis genomes from cattle, we found no recent transmission events between nearby farms and the park based on WGS. Lastly, by discussing socio-economic and environmental factors escaping current regulatory gaps that were determinant of this outbreak, we pledge for the development of a plan to report and control bTB in wildlife in Brazil.

Natural Products with Tandem Anti-inflammatory, Immunomodulatory and Anti-SARS-CoV/2 Effects: A Drug Discovery Perspective against SARS-CoV-2.

BACKGROUND: COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CLpro) and papain-like protease (PLpro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2. OBJECTIVE: This paper is a compilation of natural products that inhibit SARS-CoV 3CLpro and PLpro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CLpro and PLpro as targets to propose a list of hit compounds. METHODS: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages. RESULTS: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PLpro and 3CLpro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature. CONCLUSION: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.