Bioisosteric Replacement in the Search for Biologically Active Compounds: Design, Synthesis and Anti-Inflammatory Activity of Novel [1,2,4]triazino[2,3-c]quinazolines DOI Creative Commons

Oleksandr Grytsak,

Kostiantyn Shabelnyk, Hanna Severina

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(11), P. 1437 - 1437

Published: Oct. 28, 2024

Background: Designing novel biologically active compounds with anti-inflammatory properties based on condensed quinazolines is a significant area of interest in modern medicinal chemistry. In the present study, we describe development promising new bioactive molecules through bioisosteric replacement carbon atom sulfur agents, specifically 3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)butanoate. Methods: Design and synthetic studies have led to series previously unknown substituted 2-[((3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)methyl)thio]carboxylic acids their esters. These were synthesized by reacting 6-chloroalkyl-3-R-2H-[1,2,4]triazino[2,3-c]quinazolin-2-ones sulfanylalkyl carboxylic functional derivatives. The purity structure obtained confirmed using set physicochemical methods, including elemental analysis, HPLC-MS, 1H NMR spectroscopy. Molecular modeling, predicted toxicity, drug-likeness, pharmacokinetics data used select for evaluation effects acute aseptic inflammation (carrageenan-induced paw edema test) markers inflammatory process. Results: compound 2-((1-(3-methyl-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)ethyl)thio)acetic acid (compound 2e) was identified as most agent (AA = 53.41%), demonstrating inhibition both generation pro-inflammatory cytokines mediators. Conclusions: Results from docking analysis “structure-affinity” correlations revealed that these are candidates further modification detailed investigation activity

Language: Английский

Targeting Mitochondrial Dysfunction in Cerebral Ischemia: Advances in Pharmacological Interventions DOI Creative Commons
И. Ф. Беленичев, Olena Popazova, Nina Bukhtiyarova

et al.

Antioxidants, Journal Year: 2025, Volume and Issue: 14(1), P. 108 - 108

Published: Jan. 18, 2025

The study of mitochondrial dysfunction has become increasingly pivotal in elucidating the pathophysiology various cerebral pathologies, particularly neurodegenerative disorders. Mitochondria are essential for cellular energy metabolism, regulation reactive oxygen species (ROS), calcium homeostasis, and execution apoptotic processes. Disruptions function, driven by factors such as oxidative stress, excitotoxicity, altered ion balance, lead to neuronal death contribute cognitive impairments several brain diseases. Mitochondrial can arise from genetic mutations, ischemic events, hypoxia, other environmental factors. This article highlights critical role progression diseases discusses need targeted therapeutic strategies attenuate damage, restore enhance neuroprotection.

Language: Английский

Citations

3
Possibility of Using NO Modulators for Pharmacocorrection of Endothelial Dysfunction After Prenatal Hypoxia DOI Creative Commons
И. Ф. Беленичев, Olena Popazova, Oleh Yadlovskyi

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(1), P. 106 - 106

Published: Jan. 16, 2025

Prenatal hypoxia (PH) is a key factor in the development of long-term cardiovascular disorders, which are caused by various mechanisms endothelial dysfunction (ED), including those associated with NO deficiency. This emphasizes potential therapeutic agents modulator properties, such as Thiotriazoline, Angiolin, Mildronate, and L-arginine, treatment PH. Methods: Pregnant female rats were given daily intraperitoneal dose 50 mg/kg sodium nitrite starting on 16th day pregnancy. A control group pregnant received saline instead. The resulting offspring divided into following groups: Group 1-intact rats; 2-rat pups subjected to prenatal treated physiological saline; Groups 3 6-rat exposed from 1st 30th after birth. Levels sEPCR, Tie2 tyrosine kinase, VEGF-B, SOD1/Cu-Zn SOD, GPX4, GPX1 heart's cytosolic homogenate assessed using ELISA. expression VEGF VEGF-B mRNA was analyzed via real-time polymerase chain reaction, nuclear area myocardial microvessel cells evaluated morphometrically. Results: We have shown that only two representatives this group-Angiolin Thiotriazoline-are able exert full effect indices PH decrease increase Tie-2, mRNA, Cu/ZnSOD, GPX cytosol, endotheliocyte nuclei 1- 2-month-old comparison control. Conclusions: Our results experimentally substantiate necessity early postnatal cardio- endothelioprotection modulators, taking account role NO-dependent pathogenesis system disorders neonates

Language: Английский

Citations

1
Angiotensin II: Role in oxidative stress, endothelial dysfunction, and diseases DOI
Amir Ajoolabady, Domenico Praticò, Jun Ren

et al.

Molecular and Cellular Endocrinology, Journal Year: 2024, Volume and Issue: 592, P. 112309 - 112309

Published: June 10, 2024

Language: Английский

Citations

5
Optimization Of The Search For Neuroprotectors Among Bioflavonoids DOI Open Access
И. Ф. Беленичев,

Victor Ryzhenko,

Olena Popazova

et al.

Published: June 11, 2024

For the first time to optimize creation of new neuroprotective agents based on bioflavonoids, we applied information technologies - docking analysis calculate binding candidate molecules pharmacological target protein transthyretin, as well program virtual screening NO scavengers. As a result this approach, substance catechin was isolated from quercetin, catechin, Epicatechin gallate, Epicatechin, Procyanidin B1, B2, B3, Catechin-3-gallate according analysis. screening, identified potential scavenger (55.15% prediction). The results prediction were confirmed by in vitro experiments. Course administration animals with experimental multiple sclerosis (MS) against background methylprednisolone completely eliminated lethal cases, reduced number diseased 20%, prevented development severe neurological symptoms 20% (compared group) and 60% compared control group. leads decrease neurodegradation markers cytosol rats EAE: NSE 37%, S-100 54.8%. combined significantly exceeds combination reference drug mexidol degree reduction. obtained indicate significant effect ocular combinations catechin. above-mentioned confirms correctness bioflavonoid selection help program.

Language: Английский

Citations

4
Immune control of brain physiology DOI
Mariángeles Kovacs, Amaia Dominguez-Belloso, Samir Ali-Moussa

et al.

Nature reviews. Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Language: Английский

Citations

0
Antioxidant Mechanisms of the Protective Action of Selenase in Experimental Chronic Generalized Periodontitis DOI Creative Commons
V. I. Salnykov, И. Ф. Беленичев, Lyudmyla Makyeyeva

et al.

Current Issues in Molecular Biology, Journal Year: 2025, Volume and Issue: 47(3), P. 186 - 186

Published: March 12, 2025

Inflammatory periodontal diseases, despite all the efforts of modern dentistry, remain an important predictor tooth loss worldwide. Oxidative stress plays a crucial role in pathogenesis periodontitis, making use antioxidants attractive option for its treatment. Our attention was drawn to selenium compound Selenase as antioxidant therapeutic agent. In this study, we modeled calcium-deficient prooxidant chronic generalized periodontitis (CGP) model white non-linear rats. Then, after 14 days, (50 μg/kg) and Mexidol (250 mg/kg) were administered intragastrically. Blood samples from animals analyzed using ELISA biochemical methods determine Cu-Zn SOD, nitrotyrosine, GPX-4, iNOS, NOx, GSH, GSSG levels. The CGP led typical clinical signs including hyperemia, edema, gingival pocket formation, bleeding, mobility, well increase molecular–biochemical markers nitrosative reduction endogenous blood. resulted decrease manifestations CGP, reduced NOx levels, SOD GPX-4 compared control group (p < 0.05). had less pronounced effect on these

Language: Английский

Citations

0
Oxygen Depletion and the Role of Cellular Antioxidants in FLASH Radiotherapy: Mechanistic Insights from Monte Carlo Radiation-Chemical Modeling DOI Creative Commons

Israth Rabeya,

Jintana Meesungnoen, Jean‐Paul Jay‐Gerin

et al.

Antioxidants, Journal Year: 2025, Volume and Issue: 14(4), P. 406 - 406

Published: March 28, 2025

FLASH radiotherapy is a novel irradiation modality that employs ultra-high mean dose rates exceeding 40–150 Gy/s, far surpassing the typical ~0.03 Gy/s used in conventional radiotherapy. This advanced technology delivers high doses of radiation within milliseconds, effectively targeting tumors while minimizing damage to surrounding healthy tissues. However, precise mechanism differentiates responses between tumor and normal tissues not yet understood. study primarily examines ROD hypothesis, which posits oxygen undergoes transient radiolytic depletion following pulse. We developed computational model investigate effects rate on radiolysis an aqueous environment mimics confined cellular space subjected instantaneous pulses energetic protons. employed multi-track chemistry Monte Carlo simulation code, IONLYS-IRT, has been optimized this homogeneous aerated medium. medium composed water, alongside carbon-based biological molecules (RH), radiation-induced bio-radicals (R●), glutathione (GSH), ascorbate (AH−), nitric oxide (●NO), α-tocopherol (TOH). Our closely monitors temporal variations these components, specifically focusing consumption, from initial picoseconds one second after exposure. Simulations reveal transiently depleted through its reaction with R● radicals, consistent prior research, but also disulfide radical anions (GSSG●−) roughly equal proportions. Notably, we show that, contrary some reports, peroxyl radicals (ROO●) formed are neutralized by recombination reactions. Instead, rapidly antioxidants present irradiated cells, AH− ●NO proving be most effective preventing propagation harmful peroxidation chain Moreover, our identifies critical threshold below effect, as predicted cannot fully manifest. By comparing findings existing experimental data, determine hypothesis alone entirely explain observed effect. indicate might significantly contribute effect mitigating and, turn, enhancing radioprotection. Additionally, lends support may partially insufficient phenomenon, suggesting involvement additional mechanisms or factors warranting further investigation.

Language: Английский

Citations

0
HSP70 Modulators for the Correction of Cognitive, Mnemonic, and Behavioral Disorders After Prenatal Hypoxia DOI Creative Commons
E. Aliyeva, И. Ф. Беленичев, Іван Михайлович Білай

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 982 - 982

Published: April 17, 2025

Background/Objectives: Prenatal hypoxia (PH) is a leading cause of nervous system disorders in early childhood and subsequently leads to decline the cognitive mnemonic functions central (such as memory impairment, reduced learning ability, information processing). It also increases anxiety risk brain adulthood. Compensatory–adaptive mechanisms mother–placenta–fetus system, which enhance fetus’s CNS resilience, are known, including activation endogenous neuroprotection response hypoxic injury through pharmacological modulation HSP70. Methods: To evaluate effect HSP70 modulators—Cerebrocurin, Angiolin, Tamoxifen, Glutaredoxin, Thiotriazoline, HSF-1 (heat shock factor 1 protein), well Mildronate Mexidol—on motor skills, exploratory behaviors, psycho-emotional activities, learning, memories offspring after PH. Experimental PH was induced by daily intraperitoneal injections sodium nitrite solution into pregnant female rats from 16th 21st day pregnancy at dose 50 mg/kg. The newborns received Angiolin (50 mg/kg), Thiotriazoline Mexidol (100 Cerebrocurin (150 µL/kg), L-arginine (200 Glutaredoxin µg/kg), or mg/kg) for 30 days. At month, were tested open field test, 2 months, they trained working spatial radial maze. Results: Modeling led persistent impairments activity, behavior, decrease cognitive–mnestic CNS. found that had most pronounced effects on indicators activity status 1-month-old animals They exhibited significant cognitive-enhancing memory-supporting during training evaluation skill retention maze 2-month-old Conclusions: first time, we obtained experimental data modulators following intrauterine hypoxia. Based results this study, identified agents promising neuroprotective perinatal

Language: Английский

Citations

0
Unlocking the gut-liver axis: microbial contributions to the pathogenesis of metabolic-associated fatty liver disease DOI Creative Commons
Mykhailo Buchynskyi, Iryna Kamyshna, Iryna Halabitska

et al.

Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 16

Published: April 25, 2025

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex metabolic disorder characterized by hepatic lipid accumulation and subsequent inflammation. This condition closely linked to syndrome obesity, with its prevalence rising due sedentary lifestyles high-calorie diets. The pathogenesis of MAFLD involves multiple factors, including insulin resistance, lipotoxicity, oxidative stress, inflammatory responses. gut microbiota plays crucial role in development, dysbiosis contributing inflammation through various mechanisms, such as enhanced intestinal permeability the translocation bacterial products like lipopolysaccharide (LPS). Microbial metabolites, short-chain acids (SCFAs) bile acids, influence function immune responses, potential implications for progression. Specific microbiome signatures have been identified patients, offering diagnostic therapeutic targets. Moreover, gut-derived toxins, endotoxins, lipopolysaccharides, trimethylamine-N-oxide significantly damage inflammation, highlighting interplay between health. review comprehensively examines MAFLD, focusing on underlying pathogenic biomarkers, emerging microbiome-targeted strategies management.

Language: Английский

Citations

0
Meningeal lymphatic drainage: novel insights into central nervous system disease DOI Creative Commons
Qiang Zhang, Yin Niu,

Yingpei Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: May 4, 2025

Abstract In recent years, increasing evidence has suggested that meningeal lymphatic drainage plays a significant role in central nervous system (CNS) diseases. Studies have indicated CNS diseases and conditions associated with dysfunction include neurodegenerative diseases, stroke, infections, traumatic brain injury, tumors, functional cranial disorders, hydrocephalus. However, the understanding of regulatory damage mechanisms lymphatics under physiological pathological is currently limited. Given importance profound interplay between this review covers seven key aspects: development structure vessels, methods for observing lymphatics, function molecular relationships vessels potential conclusions outstanding questions. We will explore relationship development, structure, current both animal models humans, identify unresolved points research. The aim to provide new directions future research therapeutic strategies targeting by critically analyzing advancements field, identifying gaps knowledge, proposing innovative approaches address these gaps.

Language: Английский

Citations

0