Background: Cannabinoid Receptor 2 (CB2R) is a key target in cancer therapy, with several potential therapeutic applications still to be explored. CB2R ligands, including agonists, antagonists, and inverse agonists, represent a diverse class of compounds with promising effects in various biological contexts. However, their full therapeutic potential remains underexplored. In this study, we investigate the effects of the CB2R agonist CB65 and the inverse agonist JTE907 for antibacterial, antifungal, anti-Candida, and anticancer activities using both in vitro and in silico approaches. Method: In vitro assays were conducted to evaluate the antibacterial, antifungal, anti-Candida, and anticancer effects of CB65 and JTE907. Antibacterial activity was assessed against Gram-positive and Gram-negative bacteria. Antifungal and anti-Candida effects were tested on various fungal and Candida species. Anticancer activity was measured using the MTT assay on MDA-MB231 breast cancer cells. Additionally, in silico docking simulations were carried out using Maestro software to investigate the compounds’ mechanisms of action. Result:Both CB65 and JTE907 showed negligible antibacterial activity against E.coli, K. pneumoniae, and S.aureus. However, both compounds demonstrated significant antifungal activity against filamentous fungi, including Alternaria sp., Sclerotinia sclerotiorum, and Fusarium equiseti. The mean growth inhibition values were 2.61 ± 0.18, 2.26 ± 0.13, and 3.15 ± 0.24 for CB65, and 2.90 ± 0.05, 2.73 ± 0.19, and 2.64 ± 0.15 for JTE907. Neither compound exhibited anti-Candida activity against Candida albicans, Candida dubliniensis, or Candida parapsilosis. For anticancer activity, CB65 and JTE907 showed IC50 values of 59.38 µM and 18.23 µM, respectively, in MDA-MB231 breast cancer cells. In silico docking results supported the experimental data, revealing possible mechanisms of action for both compounds. Conclusion: CB65 and JTE907 exhibited significant antifungal activity against filamentous fungi and anticancer potential in MDA-MB231 cells, but showed limited antibacterial and anti-Candida effects. These findings were supported by in silico studies, which suggested underlying mechanisms of action.

The study aimed to comprehensively investigate the effect of various forms of oligonucleotides (ORNs) (acidic, salt, and complexes with mannitol) and mononucleotides on the conformational stability and aggregation properties of interferon α2b (IFN α2b), a key protein in the antiviral response.

Circular dichroism (CD) was used to analyse the secondary structure of the protein, and fluorescence spectroscopy with thioflavin T was used to assess its tendency to aggregate. CD spectroscopy data clearly demonstrated that protein concentration significantly affects the results of the analysis. At a low concentration of 0.6 mM, the α-helix content was higher (up to 18.4%) than in 1.6 mM IFN α2b samples, where it did not exceed 4.2%. Importantly, during six months of observation with 6 freeze-thaw cycles, no statistically significant changes in the secondary structure of the protein were detected for any of the concentrations, indicating no degradation or significant conformational change of IFN α2b over time.

To assess thermal stability, thermal denaturation experiments were performed. It was found that the addition of the studied ligands (ORN and their complexes with mannitol) leads to an increase in the melting temperature (Tₘ) of the protein from 62 °C to 63.8–64 °C, indicating a slight stabilising effect. This confirms the binding of ligands to the protein and their impact on its conformational state. In addition, fluorescence studies with thioflavin T did not reveal any signs of pathological amyloid aggregate formation under the influence of any of the studied compounds.

Thus, the results of the study indicate that oligonucleotides and their complexes do not cause destabilisation or harmful aggregation of interferon α2b, but rather demonstrate a moderate stabilising effect. The data obtained confirm the potential safety and compatibility of such compounds with protein therapeutics, which may be important for the development of new combined immunomodulatory and antiviral drugs.

Giant cancer cells are abnormal tumor cells that often arise after ionizing radiation (IR) treatment. Their persistence is associated with tumor resistance, recurrence, and poor clinical outcomes, highlighting the need for strategies that can eliminate them effectively. Radiotherapy (RT), which uses IR to damage tumor DNA, remains an indispensable method of choice in cancer therapy. Photodynamic therapy (PDT), by contrast, involves a photosensitizing drug and light activation to produce reactive oxygen species (ROS) that destroy cancer cells. Importantly, photosensitizers may also act as radiosensitizers, making them promising candidates for combination therapy.

In our study, we tested whether combining PDT and RT could improve cancer cell killing and reduce giant cell formation. HeLa (cervical carcinoma) and A431 (epidermoid carcinoma) cells were treated with Photosens (NIOPIK, Russia), followed by light exposure at 20 J/cm². IR was delivered using a Novalis TX electron accelerator at 600 Gy/hour, with doses guided by the LD50 for both HeLa and A431 cancer cell line (6 Gy).

The combined treatment showed a strong cytotoxic effect and, importantly, caused a marked reduction in the proportion of giant cancer cells formed compared to IR alone. Our results suggest that combining PDT with RT provides a dual attack strategy that not only improves tumor cell killing but also reduces the formation of giant cells, which may translate into more effective and durable cancer control in clinical practice.

The study was supported by the Ministry of Education and Science of the Russian Federation (State assignment FSWR-2023-0032).

Oxidative stress plays a central role in the pathogenesis of neurodegenerative, cardiovascular, and inflammatory disorders, as well as cancer. In this sense, the discovery of novel antioxidant agents has a critical priority in medicinal chemistry. Organoselenium derivatives stand out in this context for their ability to modulate redox processes, frequently mimicking the activity of glutathione peroxidase (GPx) .At the same time, the tetrazole nucleus functions as a bioisosteric moiety, widely employed in clinically approved drugs due to its favorable pharmacokinetic and pharmacodynamic properties. The strategic combination of these two pharmacophoric elements results in selenotetrazoles, molecules with promising biological potential and new perspectives for therapeutic development . The compounds were obtained via [3+2] cycloaddition between SeCN-containing precursors and sodium azide. In this work, the antioxidant activity of the newly synthesized selenotetrazoles was evaluated through radical scavenging assays (ABTS•+ and DPPH•) to investigate their redox-modulating potential. In the ABTS•+ assay, which measures the ability of molecules to neutralize radicals in aqueous medium, ethyl 3-(1H-tetrazol-5-yl)selanyl benzoate and ethyl 4-(1H-tetrazol-5-yl)selanyl benzoate at 200 µM showed significant antioxidant activity, comparable to ascorbic acid (positive control, 25 µM). Conversely, in the DPPH• assay, which evaluates electron transfer in apolar medium, the compounds showed no significant activity. This selectivity suggests that their antioxidant effect is not based on electron transfer in nonpolar systems, but rather occurs in aqueous environments, consistent with a GPx-like mechanism . In conclusion, the synthesized selenotetrazoles present selective antioxidant activity, redox stability and multitarget potential, consolidating them as promising scaffolds for the development of antioxidant, anti-inflammatory, neuroprotective and/or anticancer agents.

Peptidomimetics represent a promising class of biologically active compounds with broad therapeutic potential. In general, peptidomimetics mimic the functions of natural peptides in the human body while overcoming their inherent limitations (e.g., low stability or poor bioavailability), thus finding application in the treatment of a wide range of diseases. This study focuses on the synthesis and cytotoxic properties of short original ornithine-based peptidomimetics derived from substituted O-benzyl-protected salicylic acid (salicylamides), where L-ornithine is further modified with various aromatic amines, and on the evaluation of their biological activity against the A549 human lung carcinoma cell line. Salicylic acid–based peptidomimetics have previously been synthesized by our research group, demonstrating both anticancer and antimicrobial activity. Ornithine-containing peptidomimetics represent synthetic precursors leading to arginine-based peptidomimetics. Arginine peptidomimetics exhibit a broad spectrum of biological activities, including antimicrobial, antiviral, antifungal, anticancer (e.g., cilengitide), and activity against cardiovascular (e.g., argatroban) and neurodegenerative diseases. The A549 cell line is a standard in vitro model for testing novel candidate anticancer agents against non-small cell lung carcinoma (NSCLC), the most prevalent clinical form of lung cancer. In this study, short ornithine-derived and specific salicylamide derivatives with potential biological activity against the A549 cell line were prepared. The peptidomimetic backbone was synthesized via Steglich amidation, and the side chain was modified. The anticancer activity of the synthesized compounds was determined in vitro against the A549 cell line, for final compounds as well as for their precursors. The presentation will address the structure–activity relationships observed in this series.

Neuroinflammation, primarily mediated by activated microglia, plays a central role in the onset and progression of neurodegenerative diseases. In search of effective modulators of these processes, we investigated the antioxidant and anti-neuroinflammatory potential of hydroxybenzoic acid esters. A library of 42 esters and their three parent acids was evaluated through molecular docking against proteins of the lipopolysaccharide (LPS) signaling pathway, including LPS-binding protein (LBP), CD14, and TLR4/MD2. The best-scoring compounds were synthesized and subjected to in vitro validation. Several derivatives, particularly isopentyl, octyl, and benzyl esters of 2-, 2,4-, and 3,4,5-hydroxybenzoic acids, demonstrated favorable docking interactions and were further examined. Antioxidant assays (ABTS and DPPH) revealed radical scavenging activities comparable to vitamin C, with 3,4,5-hydroxybenzoic derivatives exhibiting the highest efficacy. In BV2 microglial cells, selected esters reduced reactive oxygen species (ROS) and nitric oxide (NO) production following stimulation with hydrogen peroxide or LPS, thereby restoring cellular metabolic activity. Furthermore, supernatants from ester-treated microglia attenuated neurotoxicity in SH-SY5Y cells, confirming their neuroprotective effects. Importantly, these compounds displayed no cytotoxicity toward fibroblasts or microglia at tested concentrations, supporting their biocompatibility. Taken together, this study highlights hydroxybenzoic acid esters as promising multifunctional agents with dual antioxidant and anti-neuroinflammatory properties. Their ability to modulate microglial activation and protect SH-SY5Y cells suggests potential therapeutic relevance in managing neurodegeneration. Future work will focus on in vivo validation and preclinical development to advance these compounds toward medicinal applications.

Gonadotropin preparations with luteinizing hormone (LH) activity are widely used to stimulate ovulation, but they have a number of side effects. Low-molecular allosteric LH receptor agonists, including our developed compound TP03, may be an alternative. TP03 was obtained with the acylation of 5-amino-4-(3-aminophenyl)-N-(tert-butyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxamide, and, according to high-resolution mass spectrometry, this MW was 515.1304 (the calculated MW for [M+Na⁺] was 515.1294). Being a hydrophobic compound, TP03 is able to penetrate the transmembrane tunnel of the LH receptor, interacting with the transmembrane allosteric site. The aim of this study was to investigate the effect of TP03 on ovarian steroidogenesis and ovulation in immature female rats, as well as to investigate its pharmacokinetics in blood plasma and its distribution in ovaries and liver. Immature female rats stimulated with Follimag were administered TP03 (15 mg/kg, i.p. in DMSO), after which the levels of estradiol and progesterone in blood and the number of preovulatory follicles and corpora lutea in ovaries were assessed for 24 h. Using reversed-phase HPLC with tandem mass spectrometry, TP03 levels were measured in blood plasma, ovaries and liver. TP03 increased blood progesterone levels and, after 16–24 hours, led to the formation of corpora lutea in ovaries. The maximum plasma concentration of TP03 was 3530 ng/mL, and the time to reach maximum concentration was 15 min, indicating rapid absorption of TP03. The elimination constant, characterizing the rate of TP03 elimination, was 0.24 h^-1, and the half-life of TP03 was 2.94 h. Thus, TP03 is a long-lived compound in the bloodstream. Rapid accumulation of TP03 in ovaries and liver was demonstrated 1 hour after administration. Thus, the high efficacy of TP03 as an ovulation inducer is largely due to its rapid absorption in ovaries and long half-life in the bloodstream. The study was supported by the RSF (No 19-75-20122).

Conventional medical therapy of inflammatory diseases relies on the use of non-steroidal anti-inflammatory drugs that reduce fever, pain, and other symptoms of inflammation. The mechanism of action of these drugs involves inhibition of cyclooxygenase (COX) enzymes, which mediate prostaglandin synthesis. However, severe adverse effects, particularly on the gastrointestinal tract, highlight the need for safer gastroprotective agents that selectively suppress inflammatory cytokine production. The aim of the study was to evaluate the binding affinities of five novel oxaprozin derivatives and the reference drug against the COX-1 and COX-2 isoenzymes. Ligand conformer data were generated using OMEGA, while molecular docking was performed using the OEDocking software, employing the FRED algorithm for fast exhaustive rigid docking. Docking results revealed that in the COX-1 active site, compounds 2 and 4 showed the lowest docking scores, comparable to oxaprozin (positive control), while compound 5 exhibited considerably higher values. Compounds 1 and 2 demonstrate similar behavior n the COX-2 binding pocket, forming a conventional hydrogen interaction with Ser353, π-cation electrostatic interaction with Arg120, several hydrophobic interactions with Val349, Leu352, Leu359, Val523, and Ala527. In addition, compound 2 establishes conventional hydrogen bonds with His90 and Arg513, further stabilizing the enzyme-ligand complex and likely accounts for its more favorable docking score compared to oxaprozin.

The emergence of non-tuberculous mycobacteria (NTM) infections is outstripping that of Mycobacterium tuberculosis. Some species cause opportunistic infections in humans. In people with bronchiectasis or chronic respiratory disease, 80% of infections are related to NTM, and among these, Mycobacterium avium complex (MAC) is the most common. Guidelines-based treatment consists of a combination of a macrolide, a rifamycin and ethambutol. This treatment is prescribed for at least 12 months and its effectiveness is estimated at 52%, due to the development of macrolide resistance in MAC. These drugs can cause inconveniences or serious effects. Drug interactions can also occur, e.g., clarithromycin and rifampicin are strong inducers of cytochrome P450. Consequently, there is an urgent need to develop safer molecules with novel mechanisms of action that also minimize the risk of antibiotic resistance.

The quinoline-based pharmacophore is found in mefloquine (MQ). MQ has moderate anti-NTM activity in vitro (MIC = 4 µg/mL on MAC), high in vitro toxicity (CC₅₀ = 2.6 µg/mL on HepG2 cells) and a low maximum tolerated in vivo dose (40 mg/kg).

Our aim is to develop new amino-alcohol-quinolines (AAQ), analogues of MQ, by modulating the structural positions of the MQ core, particularly the amino-alcohol chain, in order to improve efficacy and reduce toxicity. Two series of AAQ were developed and thirty-one compounds were obtained. One hit was identified, with the highest selectivity index (SI) on M. avium (SI = 5.8). Additionally, checkerboard assay was demonstrated an additive effect with the antibiotics used in the reference treatment. Finally, this hit was evaluated in BALB/c mice and excellent tolerance was revealed (tolerate dose ≥ 500 mg/kg).

The following topics will be presented: i) the design and synthesis of AAQ, ii) their in vitro activity and toxicity, iii) the potential in vitro synergistic effects of one hit compound, and iv) the in vivo toxicity of this promising compound.

Obesity is often accompanied by hypothyroidism, the severity of which worsens with aging, which may be due to a decrease in the sensitivity of thyrocytes to thyroid-stimulating hormone (TSH). Thyroid hormone replacement therapy is usually used to compensate for thyroid hormone (TH) deficiency, but it has significant limitations. Allosteric TSH receptor agonists, including our developed TPY3m, a thieno[2,3-d]-pyrimidine derivative, may be proposed as an alternative. The aim of this study was to compare the effects of TPY3m and thyroliberin (TRH) on TH and TSH levels in the blood of aging rats, including obese ones. Male rats (18-month-old) were administered TPY3m (20 mg/kg, i.p.) and TRH (100 μg/rat, intranasally). Obesity was induced by a 12-week high-fat diet (OB). Hormone levels (fT4, fT3, tT3, TSH) were assessed using ELISA, calculating the index of peripheral conversion ([fT3]/[fT4], IPC) and the integral thyroid index ([fT3]+[fT4]/[TSH], ITI). In aging obese rats, the fT3 level, ICI and ITI were reduced. Treatment of the OB group with TRH increased TSH and fT4 levels, but to a lesser extent than in the control. The ITI index remained reduced. TPY3m increased fT4 and fT3 levels in the OB and control groups, but, unlike TRH, did not affect the TSH level, increased the ITI, and normalized the ICI. Thus, TPY3m similarly stimulated TH production in aging rats with and without obesity, whereas the stimulatory effects of TRH were reduced in obesity, indicating that the sensitivity of the TSH receptor to allosteric agonists is preserved in aging and obesity.
The study was supported by the RSF (No 19-75-20122).