Thiadiazole/Thiadiazine Derivatives as Insecticidal Agent: Design, Synthesis, and Biological Assessment of 1,3,4-(Thiadiazine/Thiadiazole)-Benzenesulfonamide Derivatives as IGRs Analogues against Spodoptera littoralis.

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.

Synthetic Methods and Pharmacological Potentials of Triazolothiadiazines: A Review.

This review article examines the synthetic pathways for triazolothiadiazine derivatives, such as triazolo[3,4-b]thiadiazines, triazolo[5,1-b]thiadiazines, and triazolo[4,3-c]thiadiazines, originating from triazole derivatives, thiadiazine derivatives, or thiocarbohydrazide. The triazolothiadiazine derivatives exhibit several biological actions, including antibacterial, anticancer, antiviral, antiproliferative, analgesic, anti-inflammatory, and antioxidant properties. The review article aims to assist researchers in creating new biologically active compounds for designing target-oriented triazolothiadiazine-based medicines to treat multifunctional disorders.

Potentiating-antibiotic activity and absorption, distribution, metabolism, excretion and toxicity properties (ADMET) analysis of synthetic thiadiazines against multi-drug resistant (MDR) strains.

BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.

Discovery of novel 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivative as a potent tubulin inhibitor with promising in vivo antitumor activity.

Building on our prior research, a novel series of trimethoxyphenoxymethyl- and trimethoxybenzyl-substituted triazolothiadiazine compounds has been designed and achieved successfully via a direct ring-closing strategy. Initial biological evaluation illustrated that the most active derivative B5 exhibited significant cell growth inhibitory activity toward HeLa, HT-29, and A549 giving the IC50 values of 0.046, 0.57, and 0.96 µM, respectively, which are greater or similar with CA-4. The mechanism study revealed that B5 caused the G2/M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, B5 exerted significant antivascular activity in the wound-healing and tube formation assays. Most importantly, B5 remarkably inhibited tumor growth without obvious signs of toxicity in A549-xenograft mice model. These observations indicate that 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine might be considered as the potential lead compound to develop highly efficient anticancer agents with potent selectivity over normal human cells.

Synthesis and biological evaluation of novel 5-substituted/unsubstituted triazolothiadiazines as tubulin depolymerizing and vascular disrupting agents with promising antitumor activity.

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 µM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 µM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.

New insights in the development of positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides: Introduction of (mono/difluoro)methyl groups at the 2-position of the thiadiazine ring.

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position.

Synthesis, X-ray crystal structure, Hirshfeld surface analysis and computational investigation into the potential inhibitory action of novel 6-(p-tolyl)-2-((p-tolyl)thio)methyl-7H-[1.2.4]triazolo[5,1-b][1,3,4]thiadiazine inhibits the main protease of COVID-19.

In recent times, the novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now become a worldwide pandemic. With over 71 million confirmed cases, even though the effectiveness and side effects of the specific drugs and vaccines approved for this disease are still limited. Scientists and researchers from all across the world are working to find a vaccine and a cure for COVID-19 by using large-scale drug discovery and analysis. Heterocyclic compounds are regarded to be valuable sources for the discovery of new antiviral medications against SARS-CoV-2 because virus occurrences are still on the rise, and infectivity and mortality may also rise shortly. In this regard, we have synthesized a new triazolothiadiazine derivative. The structure was characterized by NMR spectra and confirmed by X-ray diffraction analysis. The structural geometry coordinates of the title compound are well reproduced by DFT calculations. NBO and NPA analyses have been performed to determine the interaction energies between bonding and antibonding orbital, and natural atomic charges of heavy atoms. Molecular docking suggests that the compounds may have good affinity for SAR-CoV-2 main protease, RNA-dependent RNA polymerase and nucleocapsid enzymes, particularly the main protease enzyme (binding energy of -11.9 kcal mol-1). The predicted docked pose of the compound is dynamically stable and reports a major van der Waals contribution (-62.00 kcal mol-1) to overall net energy.Communicated by Ramaswamy H. Sarma.

Highly potent anti-inflammatory, analgesic and antioxidant activities of 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones.

Four series of tetrahydro-2H-1,3,5-thiadiazine-2-thiones (series A and B including two novel enantiopure isomers), tetrahydro-2H-1,3,5-thiadiazine-6-thiones (series C) and N-3 ester derivatives of tetrahydro-2H-1,3,5-thiadiazine-6-thiones (series D) were synthesized and evaluated for their anti-inflammatory, analgesic and anti-oxidant activities. These THTT analogues specially series D were first time examined for their in vitro anti-inflammatory, in vivo analgesic and anti-oxidant activities. Among them lipophilic compounds (series B and D) were found to be highly active for anti-inflammatory evaluation with IC50 values between 5.1-16.9 and 4.1-32.4 µM, respectively when compared with the standard drug ibuprofen IC50 = 11.2 µM. The structure-activity relationship exposed the importance of lipophilic substituents especially ester and n-propyl group for inhibition of inflammation. The molecular docking studies demonstrated that all the active analogues of THTT have notable binding relations with Arg120 of the active sites of COX-1 enzyme either through CS moiety of the THTT nucleus or with COO attached at N-3 of THTT nucleus. In vivo analgesic activity of the selected THTT compounds 14, 17, 18, 19 (series B) and 28 (series D) were also carried out by acetic acid-induced writhing procedure. The compound 28 showed significant anti-nociceptive/analgesic activity at the oral dose of 5 mg/kg body weight with the percent protection (32.05 %) when compared with standard indomethacin at 10 mg/kg (48.83 %). Additionally, these compounds demonstrated the moderate level of antioxidant potential with IC50 values in the range of 60.9 to 93.6 µM (standard butylated hyroxyanisole; IC50 = 44.2 µM). These results indicated that this class of heterocyclic compounds may be a template specially to design better anti-inflammatory and analgesic agents.

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine Derivatives: Synthesis, Anti-Viral In Vitro Study and Target Validation Activity.

This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level.

1,3,5-Thiadiazinane thione derivatives as significant urease inhibitors.

We report the promising urease inhibitory activity of four sets of tetrahydro thiadiazine thiones (THTT) namely 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones: THTT 5-8 (set A) having alkyl/aryl substituents at N-3 and N-5 positions; THTT 9-12 (set B) and THTT 13-14 (set C) with 3-carboxylic acid derivatives and tetrahydro-2H-1,3,5-thiadiazine-6-thione esters 15-16 (set D). Gratifyingly, all four sets of THTT were recognized as promising inhibitors of urease enzyme. Among 12 tested compounds; THTT 6, 8, 10, 14 and 15 from each set respectively, demonstrated significant urease inhibitory activity with IC50 values between 11.2-29.8µM which is mostly found higher than that for thiourea, a standard urease inhibitor with IC50 value of 22.4µM. Furthermore, compound 7 showed almost the same level of inhibition (IC50 = 22.5µM) as of standard. In addition, molecular docking study supported the phenomenon that thiadiazinane ring itself is an active pharmacophore that binds through CH2 groups and S atom via carbon-hydrogen/π-sulfur interactions respectively to the active site of the urease enzyme. The optimistic results from this study suggest the use of thiadiazinane skeleton as a guided template for the advancement of new urease inhibitors in drug discovery.

1-Phenyl ethyl substituted tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives as promising antimicrobial agents.

Seven derivatives of 1-phenyl ethyl group containing 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-thiones (THTT) were prepared and examined for their antibacterial and antifungal properties by using Microplate Alamar Blue Assay (MABA) and agar tube dilution protocol respectively. In vitro antifungal potential was investigated against five human pathogens and compared with the standard drugs amphotericin B and miconazole. In vitro antibacterial activity was investigated against four pathogens and compared with the ofloxacin. All compounds exhibited very promising antifungal activities against all tested pathogens. Structure activity relationship showed the importance of the presence of 1-phenyl ethyl substituent at N-3 of THTT nucleus for antifungal effects. However, these compounds showed significant antibacterial activity only against S. aureus. The compound 6c of the series was found most active compound that displayed promising antifungal potential against all tested pathogens [Growth Inhibition (GI) = 100%], and also showed promising antibacterial potential against S. aureus (GI% = 83.49) which is very much closer to the standard ofloxacin (GI% = 88.05). The study may be useful in the development of improved antimicrobial agents.

Exploring the potential of taurolidine in inducing mobilization and detachment of colon cancer cells: a preliminary in-vitro study.

BACKGROUND: Recently, taurolidine has been intensively studied on a variety of in-vitro cancer cell-lines and first data exhibit encouraging antitumoral effects. While the clinical use of taurolidine is considered, some studies with in-vivo experiments contradict this beneficial effect and even indicate advanced cancer growth. The aim of this study is to further investigate this paradox in-vivo effect by taurolidine and closely analyze the interaction of cancer cells with the surrounding environment following taurolidine exposure. METHODS: HT-29 (ATCC® HTB-38™) cells were treated with taurolidine at different concentrations and oxaliplatin using an in-vitro model. Morphological changes with respect to increasing taurolidine dosage were visualized and monitored using electron microscopy. Cytotoxicity of the agents as well as extent of cellular detachment by mechanical stress was measured for each substance using a colorimetric MTS assay. RESULTS: Both taurolidine and oxaliplatin exhibit cell toxicity on colon cancer cells. Taurolidine reshapes colon cancer cells from round into spheric cells and further induces cluster formation. When exposed to mechanical stress, taurolidine significantly enhances detachment of adherent colon carcinoma cells compared to the control (p < 0.05) and the oxaliplatin group (p < 0.05). This effect is dose dependent. CONCLUSIONS: Beside its cytotoxic effects, taurolidine could also change mechanical interactions of cancer cells with their environment. Local cancer cell conglomerates could be mechanically mobilized and may cause metastatic growth further downstream. The significance of changes in cellular morphology caused by taurolidine as well as its interaction with the microenvironment must be further addressed in clinical cancer therapies. Further clinical studies are needed to evaluate both the safety and efficacy of taurolidine for the treatment of peritoneal surface malignancies.

Autophagy induced by taurolidine protects against polymicrobial sepsis by promoting both host resistance and disease tolerance.

Sepsis, septic shock, and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Disease resistance and tolerance are two evolutionarily conserved yet distinct defense strategies that protect the host against microbial infection. Here, we report that taurolidine administered at 6 h before septic challenge led to strong protection against polymicrobial sepsis by promoting both host resistance and disease tolerance characterized by accelerated bacterial clearance, ameliorated organ damage, and diminished vascular and gut permeability. Notably, taurolidine administered at 6 h after septic challenge also rescued mice from sepsis-associated lethality by enhancing disease tolerance to tissue and organ injury. Importantly, this in vivo protection afforded by taurolidine depends on an intact autophagy pathway, as taurolidine protected wild-type mice but was unable to rescue autophagy-deficient mice from microbial sepsis. In vitro, taurolidine induced light chain 3-associated phagocytosis in innate phagocytes and autophagy in vascular endothelium and gut epithelium, resulting in augmented bactericidal activity and enhanced cellular tolerance to endotoxin-induced damage in these cells. These results illustrate that taurolidine-induced autophagy augments both host resistance and disease tolerance to bacterial infection, thereby conferring protection against microbial sepsis.

Vision on Synthetic and Medicinal Facets of 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazine Scaffold.

The present review article strives to compile the latest synthetic approaches for the synthesis of triazolothiadiazine and its derivatives, along with their diverse pharmacological activities, viz. anticancer, antimicrobial, analgesic and anti-inflammatory, antioxidant, antiviral, enzyme inhibitors (carbonic anhydrase inhibitors, cholinesterase inhibitors, alkaline phosphatase inhibitors, anti-lipase activity, and aromatase inhibitors) and antitubercular agents. The review focuses particularly on the structure-activity relationship of biologically important 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines, which have profound importance in drug design, discovery and development. In silico pharmacokinetic and molecular modeling studies have also been summarized. It is hoped that this review article will be of help to researchers engaged in the development of new biologically active entities for the rational design and development of new target-oriented 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine-based drugs for the treatment of multifunctional diseases.

Inheritance and fitness cost of buprofezin resistance in a near-isogenic, field-derived strain and insecticide resistance monitoring of Laodelphax striatellus in China.

BACKGROUND: Laodelphax striatellus is one of the most destructive pests of rice and other cereal crops. Chemical control is still the most efficient way to control this pest, but insecticide resistance always threatens this approach. RESULTS: Monitoring data (2003-2020) showed that Chinese field populations of L. striatellus developed high-level buprofezin resistance within the first four years. This high-level resistance to buprofezin was stable for about ten years and persisted even when buprofezin selection pressure was absent. An established near-isogenic strain (YN-NIS) with 90.8-fold resistance to buprofezin had resistance inheritance of autosomal and incomplete dominance, and the resistance was controlled by multiple genes with no obvious fitness costs (relative fitness of 0.8707). Furthermore, the susceptibility of 29 field populations to another seven insecticides (2014-2020) showed that: (i) low-level resistance to pymetrozine, dinotefuran, sulfoxaflor and thiamethoxam was first detected in 2014 (eight years after introduction), 2016 (three years after), 2017 (four years after) and 2019 (19 years after), respectively, (ii) moderate resistance levels to chlorpyrifos were found for all populations across multiple years, and (iii) no resistance was detected for nitenpyram and triflumezopyrim. CONCLUSION: The fast buprofezin resistance development in L. striatellus would be caused by incomplete dominant resistance with almost no fitness cost in the resistant strain. Nitenpyram and triflumezopyrim showed no resistance and can be used as the main insecticide for the control of L. striatellus. These findings provide key fundamental information for controlling L. striatellus.

Preventative treatment with Fluorothiazinon suppressed Acinetobacter baumannii-associated septicemia in mice.

The high prevalence of multidrug-resistant Acinetobacter baumannii has emerged as a serious problem in the treatment of nosocomial infections in the past three decades. Recently, we developed a new small-molecule inhibitor belonging to a class of 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones, Fluorothiazinon (FT, previously called CL-55). FT effectively suppressed the T3SS of Chlamydia spp., Pseudomonas aeruginosa, and Salmonella sp. without affecting bacterial growth in vitro. In this study, we describe that prophylactic use of FT for 4 days prior to challenge with resistant clinical isolates of A. baumannii (ABT-897-17 and 52TS19) suppressed septic infection in mice, resulting in improved survival, limited bacteraemia and decreased bacterial load in the organs of the mice. We show that FT had an inhibitory effect on A. baumannii biofilm formation in vitro and, to a greater extent, on biofilm maturation. In addition, FT inhibited Acinetobacter isolate-induced death of HeLa cells, which morphologically manifested as apoptosis. The mechanism of FT action on A. baumannii is currently being studied. FT may be a promising candidate for the development of a broad-spectrum anti-virulence drug to use in the prevention of nosocomial infections.

EDTA and Taurolidine Affect Pseudomonas aeruginosa Virulence In Vitro-Impairment of Secretory Profile and Biofilm Production onto Peritoneal Dialysis Catheters.

Peritoneal catheter-associated biofilm infection is reported to be the main cause of refractory peritonitis in peritoneal dialysis patients. The application of antimicrobial lock therapy, based on results on central venous catheters, may be a promising option for treatment of biofilm-harboring peritoneal catheters. This study investigated the effects of two lock solutions, EDTA and taurolidine, on an in vitro model of Pseudomonas aeruginosa biofilm-related peritoneal catheter infection. Silicone peritoneal catheters were incubated for 24 h with a bioluminescent strain of P. aeruginosa. Then, serial dilutions of taurolidine and/or EDTA were applied (for 24 h) once or twice onto the contaminated catheters, and P. aeruginosa viability/persistence were evaluated in real time up to 120 h using a Fluoroskan reader. On selected supernatants, high-performance liquid chromatography mass spectrometry (HPLC-MS) analysis was performed to measure the production of autoinducers (AI), phenazines, and pyocyianines. Taurolidine alone or in combination with EDTA caused a significant decrease of bacterial load and biofilm persistence on the contaminated catheters. The treatment did not lead to the sterilization of the devices, yet it resulted in a substantial destructuration of the catheter-associated P. aeruginosa biofilm. HPLC-MS analysis showed that the treatment of biofilm-harboring catheters with taurolidine and EDTA also affected the secretory activity of the pathogen. EDTA and taurolidine affect P. aeruginosa biofilm produced on peritoneal catheters and profoundly compromise the microbial secretory profile. Future studies are needed to establish whether such lock solutions can be used to render peritoneal catheter-related infections more susceptible to antibiotic treatment. IMPORTANCE An in vitro model allows studies on the mechanisms by which the lock solutions exert their antimicrobial effects on catheter-associated biofilm, thus providing a better understanding of the management of devise-associated infections.

TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats.

The N-methyl-d-aspartate receptor antagonist, ketamine, exhibits rapid and sustained antidepressant activity in patients with treatment-resistant depression (TRD), but its use is associated with psychotomimetic side effects. Evidence has suggested that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors followed by activation of the mechanistic target of rapamycin (mTOR) signaling pathway and production of brain derived neurotrophic factor (BDNF) protein may underlie the antidepressant efficacy of ketamine. In this study, we characterized the antidepressant-like effects of TAK-653, a novel AMPA receptor potentiator with virtually no agonistic activity. In rat primary cortical neurons, TAK-653 significantly increased phosphorylated and activated forms of mTOR and p70S6 kinase and their upstream regulators Akt and extracellular signal-regulated kinase (ERK). TAK-653 also significantly increased BDNF protein levels in rat primary cortical neurons. Ketamine at 30 mg/kg, i.p. produced antidepressant-like effects in the reduction of submissive behavior model (RSBM) in rats. Ketamine's antidepressant-like effect was blocked by pretreatment with the AMPA receptor antagonist NBQX at 10 mg/kg, i.p., indicating the essential role of AMPA receptor activation in the antidepressant-like effect of ketamine. Consistent with this finding, a sub-chronic administration of TAK-653 for 6 days produced significant antidepressant-like effect in the rat RSBM. Unlike ketamine, however, TAK-653 did not induce a hyperlocomotor response in rats, which is a behavioral index associated with psychotomimetic side effects in humans. TAK-653 may be a promising drug for the treatment of major depressive disorders including TRD with the potential for an improved safety profile compared with ketamine.

Antimicrobial activity of hemodialysis catheter lock solutions in relation to other compounds with antiseptic properties.

Proper protection of vascular access after haemodialysis is one of the key measures for the prevention of catheter-related infections. Various substances with bactericidal and anticoagulant properties are used to fill catheters, but due to the unsatisfactory clinical effects and occurrence of adverse reactions, the search for new substances is still ongoing. In the present paper, we compared the in vitro antimicrobial activity of solutions used for tunnelled catheter locking (taurolidine, trisodium citrate) and solutions of substances that could potentially be used for this purpose (sodium bicarbonate, polyhexanide-betaine). The studies have been conducted on bacteria that most commonly cause catheter-related infections. The values of both minimum inhibitory concentration and minimum biofilm eradication concentration of the substances were determined. The ability of the tested substances to eradicate biofilm from the dialysis catheter surface was also evaluated. The results showed that polyhexanide-betaine inhibited the growth of all microbes comparably to taurolidine, even after ≥ 32-fold dilution. The activity of trisodium citrate and sodium bicarbonate was significantly lower. Polyhexanide exhibited the highest activity in the eradication of bacterial biofilm on polystyrene plates. The biofilm formed on a polyurethane dialysis catheter was resistant to complete eradication by the test substances. Polyhexanide-betaine and taurolidine showed the highest activity. Inhibition of bacterial growth regardless of species was observed not only at the highest concentration of these compounds but also after dilution 32-128x (taurolidine) and 32-1024x (polyhexanide-betaine). Therefore, it can be assumed that taurolidine application as a locking solution prevents catheter colonization and systemic infection development. Taurolidine displays high antimicrobial efficacy against Gram-positive cocci as well as Gram-negative bacilli. On the contrary, the lowest antibacterial effect displayed product contained sodium bicarbonate. The inhibitions of bacterial growth were not satisfactory to consider it as a substance for colonization prevention. Polyhexanidine-betaine possessed potent inhibitory and biofilm eradication properties comparing to all tested products. PHMB is applied as a wound irrigation solution worldwide. However, based on our results, we assume that the PHMB is a promising substance for catheter locking solutions thanks to its safety and high antimicrobial properties.