Innovative antimicrobial substances based on uracil S-derivatives.

The problem of antimicrobial resistance is an important global public health challenge. We propose that a development of new antibiotic compounds around known natural substances is a solution to this problem. We investigate reengineer natural products into potent antibiotics. Uracil fragment is abundant in nature and significant to treat infectious diseases due to its affection to the replication of the bacterial chromosome. 12 new uracil S-derivatives were obtained and tested for their in vitro antimicrobial properties. N3 -(thietan-3-yl)- and N3 -(1,1-dioxothietan-3-yl)uracils derivatives were synthesized by thietanylation of 6-methyluracil with 2-chloromethylthiirane and subsequent oxidation of the thietan ring. A method of their alkylation with ethyl-2-chloroacetate was developed and acetohydrazides containing 3-(thietan-3-yl)- and 3-(1,1-dioxothietan-3-yl)uracilyls fragments in the acetyl group were obtained by hydrazinolysis of 2-(thietanyluracil-1-yl)acetic acid ethyl esters. Their interaction with ß-dicarbonyl compounds, anhydride of mono- and dicarboxylic acids was studied. Antimicrobial activity was determined by the agar diffusion method on test organisms: S. aureus, E. coli, P. vulgaris, K. pneumoniae, C. diversus, E. aerogenes, P. aeruginosa, S. abosit. N-acyl-5-hydroxypyrazolines and N,N'-diacylhydrazines of 6-methyluracil thietanyl- and dioxothietanyl derivatives showed high antimicrobial activity, which is consistent with the results of structure activity relationship analysis (MIC 0.1-10 µg/ml).

The Effect of Whole Blood and Bone Marrow with the Addition of Pyrimidine-2,4(1h,3h)-dione Thietanyl Derivatives on Free Radical Oxidation.

BACKGROUND: It is relevant to study the general patterns and identify non-specific mechanisms of body protective and adaptive reactions violation, which can lead to the various pathological processes and develop principles for the correction of these disorders. One of the therapy and prevention directions is the search for new medicines. In recent years, new derivatives of pyrimidine bases have been synthesized and studied. Pyrimidine-based medicines have a membrane-stabilizing and immunomodulatory effect and can normalize metabolic disorders and increase the oxidative activity of leukocytes. Disruption of the free radical oxidation processes, the generation of reactive oxygen species and lipid peroxidation, including in whole blood and bone marrow, has gained importance in recent years. METHODS: Each reaction was monitored by thin layer chromatography. 1H, 13C, and 15N NMR spectra were recorded (chemical shifts were expressed as δ-values). We studied the effect of 6-methyl-3-(thietan- 3-yl)pyrimidine-2,4(1H,3H)-dione on the generation of reactive oxygen species (ROS) in the whole blood and bone marrow using the study of whole blood spontaneous and stimulated chemiluminescence (CL). CL methods make it possible to quickly and easily assess the studied material (whole blood, bone marrow) effect on free radical oxidation. Using CL methods, it is possible to reveal the presence of medicines' pro- or antioxidant properties, opening up new possibilities in the search for substances with antioxidant properties and comparing their activity. RESULTS: Alkylation of 6-methylpyrimidine-2,4(1H,3H)-dione by 2-chloromethylthiirane in protic solvents in the presence of alkali leads to the formation of an N-thietane derivative. NMR spectroscopy showed that 6-methylpyrimidine-2,4(1H,3H)-dione was alkylated at position 3. The oxidation reactions of N-(thietan-3-yl)pyrimidine-2,4(1H,3H)-dione were studied, and it was determined that, depending on the excess of the oxidizing agent and the duration of the process, N-(1-oxothietan-3-yl)- or N-(1,1-- dioxothietan-3-yl)pyrimidine-2,4(1H,3H)-diones were formed. The effects of free radical oxidation processes of new biologically active pyrimidine-2,4(1H,3H)-diones were studied. CONCLUSION: New pyrimidine-2,4(1H,3H)-diones increase the general adaptive capabilities of the body and have protective effects in extreme conditions.

Improvement of brain perfusion in patients with chronic brain ischemia at epidural spinal cord electrical stimulation.

Objective: Increasing life expectancy and aging of the population is accompanied by a steady increase in the number of elderly patients with chronic cerebral ischemia and age-related cognitive impairment associated with cerebral hypoperfusion and microangiopathy. The aim of this study was to identify long-term changes in cerebral blood flow (CBF) in patients with chronic cerebral ischemia at the epidural electrical stimulation of the spinal cord (SCS). Materials and methods: Changes in cerebral blood flow were studied according to CT perfusion in 59 patients (aged 55-78 years) with vertebrogenic pain syndromes and chronic cerebral ischemia during epidural electrical stimulation of the spinal cord at the cervical (C3-C5) and lower thoracic (Th9-Th10) levels. Results: In all patients, on the 5th day of trial SCS, an increase in cerebral blood flow by from 58.6 ± 1.13 ml/100 ml/min to 64.8 ± 1.21 ml/100 ml/min (p < 0.01) with stimulation at the Th9-Th10 level and from 58.8 ± 1.12 ml/100 ml/min to 68.2 ± 1.42 ml/100 ml/min (p < 0, 01) with stimulation at the C3-C5 level. These changes in brain perfusion were preserved during the follow-up examination 1 year after the implantation of chronic SCS system. The greatest increase in CBF was registered in the frontotemporal regions, subcortical structures and white matter of the brain. Changes in cerebral perfusion did not correlate with the degree of reduction in the severity of the accompanying pain syndrome. The change in CBF in the control group (32 patients) in all periods was not statistically significant. Conclusion: Our results show that SCS is accompanied by a persistent improvement in brain perfusion, which may be potentially useful for developing methods for reducing age-related vascular disorders in the elderly.

The Guidewire-assisted Drainage Catheter Placement in Chronic Subdural Hematoma.

Background: Chronic subdural hematoma (cSDH) is a common neurosurgical pathology associated with older age. The burr hole drainage is a predominant technique with a lower incidence of recurrence and morbidity. The blind placement of the subdural drain could result in intracerebral hemorrhage. This paper describes a simple and reliable technique for drainage catheter placement in cSDH to reduce intracerebral hemorrhage. Methods: Forty-nine consecutive patients with cSDH were treated with The Guidewire-assisted Drainage Catheter Placement Technique between July 2019 and June 2021. Epidemiological, clinical and radiographical data were collected and reviewed. The operative technique consists of an angular guidewire tip and catheter. Under the navigation of the guidewire, the catheter is inserted into the subdural space and the length of catheter remaining in the subdural space was 4-5 cm. The catheter was tunneled subcutaneously and fixed at the point where it emerged from the scalp. Results: Forty-nine consecutive patients underwent 55 The Guidewire-assisted Drainage Catheter Placement. The gender distribution was 37 men and 12 women. The mean age was 69.3 years. The patients presented with headache (31 patients), weakness of limbs (28 patients), speech disturbances (7 patients), and Altered behavior (6 patients). Neither intracerebral hemorrhages nor post-operative seizure occurred. Forty-seven patients were improved after the operation. The recurrence occurred in one patient. Conclusions: The Guidewire-assisted Drainage Catheter Placement Technique is a reliable method for the insertion of a subdural catheter to evacuate of the Chronic Subdural Hematoma, and is associated with an extremely low risk to cortical structures and cerebral veins.

Circulating miRNAs as Diagnostic and Prognostic Biomarkers in High-Grade Gliomas.

Objectives: miR-181a/b and miR-410 downregulation and miR-155 upregulation has been shown to play important roles in the oncogenesis and progression of gliomas including high-grade gliomas. However, the potential role of plasma miR-181a/b, miR-410 and miR-155 in the diagnosis and prognosis of high-grade gliomas remains poorly known. Methods: We retrieved published articles from the PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science database and obtained different sets of data on microRNAs (miRNAs) expression profiling in glioma and highlighted the most frequently dysregulated miRNAs and their gene-targets (PDCD4, WNT5A, MET, and EGFR) in high-grade gliomas. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was carried out to measure the pre- and postoperative plasma levels of miR-181a/b, miR-410 and miR-155 in 114 Grade 3-4 glioma patients, 77 Grade 1-2 glioma patients and 85 healthy volunteers as control group. The diagnostic and prognostic value of circulating miR-181a/b, miR-410 and miR-155 as biomarker was estimated by the Receiver Operating Characteristic (ROC) curve and the area under the curve (AUC) and Kaplan-Meier analysis. Results: We found a plasma miRNA signature including three downexpressed miRNAs and one overexpressed (miR-181a, miR-181b and miR-410; miR-155) in high-grade glioma patients in comparison with low-grade glioma patients control group. The ROC curve AUC of these four circulating miRNAs were ≥ 0.75 for high-grade glioma patients in before and after surgery. Higher circulating miR-155 and lower miR-181a/b and miR-410 expression is associated with clinical data, clinic pathological variables, worse overall survival (OS) of patients and negative correlated with potential gene-targets expression. Moreover, Kaplan-Meier analysis showed that miR-181a/b, miR-410 and miR-155 were independent predictors of OS in high-grade glioma patients. Conclusions: Our data, for the first time, demonstrated that circulating miR-181a/b, miR-410 and miR-155 could be a useful diagnostic and prognostic non-invasive biomarkers in high-grade gliomas.

Synthesis and biological activity of 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide derivatives.

The synthesis and antimicrobial evaluation of new 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide derivatives was investigated. According to the literature, there are a lot of antimicrobial agents among the pyrimidines and hydrazides, and therefore it seems promising to use 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide as a base object for synthesizing new biologically active substances. 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide was obtained by the hydrazinolysis of ethyl thioacetate, using a 3-fold molar excess of 85 % hydrazine hydrate in ethanol, at room temperature. Interaction of 2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide with ketones during boiling in ethanol yielded N-ylidenehydrazides. The solid obtained by concentration was collected, and then purified by recrystallization. The new compounds were characterized by 1H, 13C NMR, IR spectroscopy and elemental analysis. The antibacterial and antifungal activities of the new compounds were analysed using agar diffusion and tenfold broth (pH 7.2 - 7.4) dilution methods, in comparison with the clinical used drugs, ceftriaxone and Pimafucin. The structure-activity studies showed that, depending on the nature of the hydrazide fragment, the newly synthesized compounds exhibited varying degrees of microbial inhibition. Within the same series the antimicrobial activity depends on the nature of the substituent attached to the benzene ring. The investigation of antibacterial screening data revealed that the compounds N'-[1-(4-aminophenyl)ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide, N'-[1-(4-hydroxyphenyl)ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)pyrimidin-2-ylthio]acetohydrazide, N'-[1- (2,5-dihydroxyphenyl) ethylidene]-2-[6-methyl-4-(thietan-3-yloxy)-pyrimidin-2-ylthio]acetohydrazide were found to be more potent than the other synthesized analogues.

Synthesis of new 1,3-thiazol derivatives of maleopimaric acid as anticancer, antibacterial and antifungal agents.

A series of new 1,3-thiazole derivatives of maleopimaric acid 6a-f, 7a-f were synthesized and evaluated for anticancer, antibacterial and antifungal activities. Evaluation of cytotoxic activity against human embryonic kidney 293 cells (HEK293), human neuroblastoma cell line (SH-SY5Y), hepatocellular carcinoma cell line (HepG2) and human T-cell lymphoblast-like line (Jurkat), showed that introduction of the aminothiazole fragment at position 6 of the diterpenoid molecule leads to decrease of cell viability. Substance 3 was found to be the most active against all tested cell lines, inhibiting cell viability with IC50 values in the range of 2-24 µM. The structure-activity relationship of these compounds was studied and the results show that the compounds 6c and 7e exhibited in vitro antifungal activity against Candida albicans and also possessed antibacterial profile against Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Proteus vulgaris.