Synthesis, evaluation of biological activity and SAR of new thioalkyl derivatives of pyridine.

BACKGROUND: Pyridine and its derivatives play a vital role in medicinal chemistry, serving as key scaffolds for drugs. The ability to bind to biological targets makes pyridine compounds significant, sparking interest in creating new pyridine-based drugs. Thus, the purpose of the research is to synthesize new thioalkyl derivatives of pyridine, predict their biological spectrum, study their psychotropic properties, and based on these findings, perform structure-activity relationships to assess pharmacophore functional groups. METHODS: Classical organic methods were employed for synthesizing new thioalkyl derivatives of pyridine, with a multifaceted pharmacological profiles. Various software packages and methods were employed to evaluate the biological spectrum of the newly synthesized compounds. For the evaluation of neurotropic activity of new synthesized compounds, some biological methods were used according to indicators characterizing anticonvulsant, sedative and antianxiety activity as well as side effects. RESULTS: Effective synthetic methods for 6-amino-4-phenyl-2-thio-2H-thiopyran-5-carboxylic acid ethyl ester, 2-amino substituted thiopyridine derivatives and 6-cycloamino-2-thioalkyl-4-phenylnicotinate derivatives were obtained in high yield. Predicted biological spectra and pharmacokinetic data indicated high gastrointestinal absorption and low blood-brain barrier passage for most compounds and demonstrated potential various biological effects, particularly psychotropic properties. Studied compounds demonstrated high anticonvulsant activity through antagonism with pentylenetetrazole. They exhibited low toxicity without inducing muscle relaxation in the studied doses. In psychotropic studies, the compounds displayed activating, sedative, and anxiolytic effects. Notably, the 6-amino-2-thioalkyl-4-phenylnicotinate derivatives demonstrated significant anxiolytic activity (about four times more compared to diazepam). They also exhibited pronounced sedative effects. Ethyl 2-({2-[(diphenylmethyl)amino]-2-oxoethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate exhibited anxiolytic activity even two times greater than diazepam. Moreover, all studied compounds showed statistically significant antidepressant effects. Noteworthy ethyl 2-({2-oxo-2-[(tetrahydrofuran-2-ylmethyl)amino]ethyl}thio)-4-phenyl-6-pyrrolidin-1-ylnicotinate showcasing its unique psychotropic effect. CONCLUSIONS: The selected compounds demonstrate anticonvulsant properties, activating behavior, and anxiolytic effects, while simultaneously exhibiting antidepressant effects and these compounds as promising candidates for further exploration in the development of therapeutics with a broad spectrum of neuropsychiatric applications.

Synthesis and Psychotropic Properties of Novel Condensed Triazines for Drug Discovery.

The exploration of heterocyclic compounds and their fused analogs, featuring key pharmacophore fragments like pyridine, thiophene, pyrimidine, and triazine rings, is pivotal in medicinal chemistry. These compounds possess a wide array of biological activities, making them an intriguing area of study. The quest for new neurotropic drugs among derivatives of these heterocycles with pharmacophore groups remains a significant research challenge. The aim of this research work was to develop a synthesis method for new heterocyclic compounds, evaluate their neurotropic and neuroprotective activities, study histological changes, and perform docking analysis. Classical organic synthesis methods were used in the creation of novel heterocyclic systems containing pharmacophore rings. To evaluate the neurotropic activity of these synthesized compounds, a range of biological assays were employed. Docking analysis was conducted using various software packages and methodologies. The neuroprotective activity of compound 13 was tested in seizures with and without pentylenetetrazole (PTZ) administration. Histopathological examinations were performed in different experimental groups in the hippocampus and the entorhinal cortex. As a result of chemical reactions, 16 new, tetra- and pentacyclic heterocyclic compounds were obtained. The biologically studied compounds exhibited protection against PTZ seizures as well as some psychotropic effects. The biological assays evidenced that 13 of the 16 studied compounds showed a high anticonvulsant activity by antagonism with PTZ. The toxicity of the compounds was low. According to the results of the study of psychotropic activity, it was found that the selected compounds have a sedative effect, except compound 13, which exhibited activating behavior and antianxiety effects (especially compound 13). The studied compounds exhibited antidepressant effects, especially compound 13, which is similar to diazepam. Histopathological examination showed that compound 13 produced moderate changes in the brain and exhibited neuroprotective effects in the entorhinal cortex against PTZ-induced damage, reducing gliosis and neuronal loss. Docking studies revealed that out of 16 compounds, 3 compounds bound to the γ-aminobutyric acid type A (GABAA) receptor. Thus, the selected compounds demonstrated anticonvulsant, sedative, and activating behavior, and at the same time exhibited antianxiety and antidepressant effects. Compound 13 bound to the GABAA receptor and exhibited antianxiety, antidepressant, and neuroprotective effects in the entorhinal cortex against PTZ-induced changes.

Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability.

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations in the NMD factor gene UPF3B, which disrupts a branch of the NMD pathway, cause various forms of intellectual disability (ID). Using Epstein Barr virus-immortalized B cells, also known as lymphoblastoid cell lines (LCLs), from ID patients that have loss-of-function mutations in UPF3B, we investigated the genome-wide consequences of compromised NMD and the role of NMD in neuronal development and function. We found that ~5% of the human transcriptome is impacted in UPF3B patients. The UPF3B paralog, UPF3A, is stabilized in all UPF3B patients, and partially compensates for the loss of UPF3B function. Interestingly, UPF3A protein, but not mRNA, was stabilised in a quantitative manner that inversely correlated with the severity of patients' phenotype. This suggested that the ability to stabilize the UPF3A protein is a crucial modifier of the neurological symptoms due to loss of UPF3B. We also identified ARHGAP24, which encodes a GTPase-activating protein, as a canonical target of NMD, and we provide evidence that deregulation of this gene inhibits axon and dendrite outgrowth and branching. Our results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells.

Proton-deuterium exchange of acetone catalyzed in imidazolium-based ionic liquid-D2O mixtures.

The reaction of the proton-deuterium exchange of acetone in imidazolium-based ionic liquid (IL)-deuterium oxide mixtures was studied in detail via NMR spectroscopy. Certain ILs exhibit considerable catalytic properties and contribute to the course of reaction up to the complete deuteration. The efficiency of deuterium exchange crucially depends on the features of ILs; the type of anion and chain length of cation. The linear secondary isotope effects on the NMR chemical shifts of the 13C atoms in acetone were observed depending on the deuteration level of the molecule.

Post-Renal Transplant Metabolic Acidosis: A Neglected Entity.

Metabolic acidosis is a prevalent yet overlooked entity among renal transplant recipients (RTRs) and incurs adverse effects on graft function. Although graft dysfunction and calcineurin inhibitor usage have been linked with renal tubular acidosis (RTA), there is no Indian data on prevalence or risk factors of post-transplant acidosis. A cross-sectional study was conducted on 106 adult RTRs, with a transplant duration of >6 months and an estimated glomerular filtration rate (GFR) >40 ml/min/1.73 m2. Acidosis was diagnosed on basis of plasma bicarbonate and arterial pH. Serum and urine electrolytes with anion gap were determined to diagnose and type RTA. Acidosis was diagnosed in 44 of 106 patients (41.5%) with 23 (52.27%) having severe acidosis. Type I RTA was the most common subtype (52.5%) followed by type IV (30.9%) and type II RTA (7.5%). The correlation between estimated glomerular filtration rate and acidosis was minimally linear (r = 0.1088), with multivariate analysis revealing previous acute rejection episodes, current serum tacrolimus levels, cotrimoxazole usage and intake of animal proteins to be independent risk factors. The serum albumin levels were low in the acidosis group and showed linear correlation with bicarbonate levels (r = 0.298). There is a high prevalence of metabolic acidosis in RTRs with type I RTA being most common subtype. Screening of RTRs on a regular basis is a feasible approach for early diagnosis and intervention. However, prospective studies are needed to demonstrate the effect of acidosis on graft survival and benefit of bicarbonate therapy in RTRs.

Volume Assessment in Hemodialysis: A Comparison of Present Methods in Clinical Practice with Sonographic Lung Comets.

Dry weight assessment in dialysis patients remains a challenging endeavor owing to the limitations of the available methods for volume assessment. Lung ultrasound is emerging as an invaluable tool to assist in the appropriate assessment and assignment of dry weight. The objectives of this study are (1) to determine the reliability of clinical signs and symptoms for volume assessment, (2) to compare lung ultrasound with High Resolution Computed Tomography (HRCT) chest-A noninvasive gold standard tool for detecting pulmonary congestion and with inferior vena cava diameter (IVCD) - another time-tested volume assessment method, and (3) to analyze if lung ultrasound could detect dialysis induced fluid status variations. The cross-sectional study involves 50 patients on maintenance hemodialysis. Lung ultrasound for B line estimation and ultrasonographic measurement of IVCD performed before and after hemodialysis by a nephrologist trained in ultrasonography. Limited HRCT was obtained just before hemodialysis. Edema, crackles, and dyspnea had a poor sensitivity of 37.9%, 11.5%, and 52.6%, respectively, to detect clinically significant pulmonary congestion by lung ultrasound. A highly significant correlation was obtained between B-line score and HRCT signs of pulmonary congestion (P < 0.001) before dialysis. B lines showed statistically significant reduction with dialysis. The absolute reduction of B lines showed significant correlation with ultrafiltration volume and weight loss. Bedside lung ultrasound appears a sensitive tool for evaluating real-time changes in extravascular lung water and would serve to optimize volume status in dialysis patients.

Insulin-Mediated Changes in Tau Hyperphosphorylation and Autophagy in a Drosophila Model of Tauopathy and Neuroblastoma Cells.

Almost 50 million people in the world are affected by dementia; the most prevalent form of which is Alzheimer's disease (AD). Although aging is considered to be the main risk factor for AD, growing evidence from epidemiological studies suggests that type 2 diabetes mellitus (T2DM) increases the risk of dementia including AD. Defective brain insulin signaling has been suggested as an early event in AD and other tauopathies but the mechanisms that link these diseases are largely unknown. Tau hyperphosphorylation is a hallmark of neurofibrillary pathology and insulin resistance increases the number of neuritic plaques particularly in AD. Utilizing a combination of our Drosophila models of tauopathy (expressing the 2N4R-Tau) and neuroblastoma cells, we have attempted to decipher the pathways downstream of the insulin signaling cascade that lead to tau hyperphosphorylation, aggregation and autophagic defects. Using cell-based, genetic, and biochemical approaches we have demonstrated that tau phosphorylation at AT8 and PHF1 residues is enhanced in an insulin-resistant environment. We also show that insulin-induced changes in total and phospho-tau are mediated by the crosstalk of AKT, glycogen synthase kinase-3ß, and extracellular regulating kinase located downstream of the insulin receptor pathway. Finally, we demonstrate a significant change in the levels of the key proteins in the mammalian target of rapamycin/autophagy pathway, implying an increased impairment of aggregated protein clearance in our transgenic Drosophila models and cultured neuroblastoma cells.

Derivatives of a new heterocyclic system - pyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines: synthesis, docking analysis and neurotropic activity.

8-Hydrazino derivatives of pyrano[3,4-c]pyridines and derivatives of the new heterocyclic system 3-thioxopyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines on the basis of methanesulfonates of pyrano[3,4-c]pyridinium were synthesized by optimization of a previously used method. Derivatives of alkylsulfonyl pyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines were also synthesized. All compounds were evaluated for their neurotropic activity. Among all the compounds tested for anticonvulsant activity by pentylenetetrazole and maximal electric shock seizure (MES) tests, six compounds (5a, 5b, 5e, 5g, 5j, and 5p) appeared to be active. These compounds were also evaluated for their anxiolytic as well as antidepressant activities using "open field", "elevated plus maze" (EPM), and "forced swimming" tests, respectively. It should be mentioned that compounds tested by the "rotating rod" method did not affect neuromuscular coordination. The most active compound appeared to be 5g in all tests. Docking studies of the most active compounds were performed on the GABAA receptor, SERT and 5-HT1A receptor.

The downward spiral of tau and autolysosomes: a new hypothesis in neurodegeneration.

A growing body of research has connected autophagy to neurodegenerative diseases such as Alzheimer disease (AD). In autopsied AD brain, large multivesicular bodies accumulate in neurons. Knockout mice deficient for key autophagy genes demonstrate age-dependent neurodegeneration. Most neurodegenerative diseases are characterized by accumulation of insoluble protein species; the type of protein and the location of aggregates within the nervous system help to define the type of disorder. It has been hypothesized that the inability to degrade such aggregates is a major causative factor in neuronal dysfunction and eventual neuronal death. As neurons are postmitotic and thus cannot regenerate themselves, mechanisms of protein clearance have received much attention in the field. The function of the ubiquitin-proteasome system (UPS) is impaired in models of neurodegeneration, and overexpression of chaperone proteins, such as those in the HSP70 family, leads to beneficial effects in many models of proteinopathies. Recently, studies of the effects of autophagy as a clearance mechanism have uncovered compelling evidence that inducing autophagy can alleviate many pathogenic and behavioral symptoms in animal and cellular models of neurodegeneration.

Steroid sulfatase is a potential modifier of cognition in attention deficit hyperactivity disorder.

Deletions encompassing the X-linked STS gene (encoding steroid sulfatase) have been observed in subjects with neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD). Recently, two single nucleotide polymorphisms (SNPs) within STS (rs12861247 and rs17268988) have been reported to be associated with ADHD risk and inattentive symptoms in ADHD, respectively. Using a UK sample of ADHD subjects (aged 5-18 years), we tested the hypothesis that rs12861247 is associated with ADHD risk using a case-control approach (comparing 327 ADHD cases with 358 male controls from the Wellcome Trust Case Control Consortium). Using a subset of males from the ADHD sample, we also examined whether variation within STS is associated with symptomatology/cognitive function in ADHD. We then tested whether SNPs associated with cognitive function in ADHD were also associated with cognitive function in healthy male subjects using a German sample (n = 143, aged 18-30 years), and whether STS was expressed in brain regions pertinent to ADHD pathology during development. We did not replicate the previously identified association with rs12861247. However, in ADHD males, variation at rs17268988 was associated with inattentive symptoms, while variation within STS was significantly associated with performance on three cognitive measures. Three SNPs associated with cognitive function in ADHD males were not associated with cognitive function in healthy males. STS was highly expressed in the developing cerebellar neuroepithelium, basal ganglia, thalamus, pituitary gland, hypothalamus and choroid plexus. These data suggest that genetic variants affecting STS expression and/or activity could influence the function of brain regions perturbed in ADHD.