Abstract: 4’4 bromophenyl 4’piperidinol derivatives were synthesized, and evaluated as multifactorial agents for the treatment of Alzheimer’s disease (AD). Among all the analogues, AB11 and AB14 showed the best activity against acetylcholinesterase (AChE) with IC₅₀ = 0.029 μM and 0.038 μM respectively. Both compounds also acted as a good antioxidant agents (IC₅₀ = 26.38 μM for AB11 and 23.99 μM for AB14) while AB11 is the only molecule that displayed moderate inhibition of amyloid beta (Aβ) (43.25% at 500 μM). AB11 and AB14 were found selective against monoamine oxidase-B (MAO-B) with IC₅₀ values of 866 μM and 763 μM respectively. AB10, AB17, and AB70 exhibited activity against both MAO-A and MAO-B and showed inhibitory potential against acetylcholinesterase, moreover, all analogues are capable of disassembling the well-structured Aβ fibril. Molecular modeling of selected compounds displayed interactions with the active site of human MAO-B and AChE enzyme. The results suggested that AB11 is a promising multi-target hit that can be optimized further as a successful drug molecule for the treatment of AD.

Bis(maltolato)oxidovanadium(IV) ([V^IVO(malt)₂] or BMOV, where malt is maltolato) and bis(ethylmaltolato)oxidovanadium(IV) (BEOV) are among the most potent orally active insulin-mimetic agents. They have undergone extensive pre-clinical testing. Even though these experimentations were temporarily stopped due to renal problems of several patients and financial problems of Akesis Pharmaceuticals, BMOV is usually considered the reference for the new molecules with insulin-mimetic action. Surprisingly, recently the tests on BMOV are continued by CFM Pharma (CFM10, Vanadis) and now it is arrived to the phase II for the treatment of patients with injuries on secondary tissues caused by accidents or fire and with myocardial infarction. Proteins play a central role in the biospeciation of V compounds in the organism, because of both their high affinity toward V and their high concentration in biological fluids. Here, the interaction of BMOV with two model proteins has been analyzed by X-ray crystallography. Data indicate both non-covalent binding of cis-[VO(malt)₂(H₂O)] and [VO(malt)(H₂O)₃]⁺ and covalent binding of [VO(H₂O)_3-4]²⁺ and cis-[VO(malt)₂] and other V-containing fragments to the side chains of Glu, Asp and to the C-terminal carboxylate. Thus, our results suggest a multiple and variable interaction of BMOV with proteins. Our data can help to better understand the BMOV solution chemistry and contribute to define the molecular basis of the mechanism of action of this intriguing metallodrug.

According to WHO report from 2020, cancer constitutes one of the leading causes of death worldwide. The number of cancer deaths is estimated to be approximately 10 million per year. These epidemiological data confirm that cancer is increasingly a global healthcare problem that needs urgent action. From the biological point of view, the basic feature of cancer is the uncontrolled growth and spread of abnormal cells from the place of origin to another part of the body. Inhibition of uncontrolled proliferation is one of the main goals of anticancer therapy. During our preliminary studies, we identified a group of thiosemicarbazide-based human DNA topoisomerase II inhibitors that decreased the viability of cancer cells and inhibited intracellular biosynthesis of their DNA much stronger than etoposide - i.e., clinically relevant topoisomerase II inhibitor. What is also important, the investigated compounds were recognized as topoisomerase II poisons because of their ability to stabilize DNA-topoII cleavable complex. The investigated thiosemicarbazide derivatives were examined as potential anticancer agents against a panel of ten cancer cell lines. Moreover, we have discovered and described the first-in-class dual inhibitors of human DNA topoisomerase II/indoleamine-2,3-dioxygenase 1 (IDO1) that can lead to the future use of thiosemicarbazide derivatives as relevant components of anticancer immunotherapy.

Mesoporous silica nanoparticles (MSNs) represent a novel platform for drug delivery systems, reducing the cytotoxicity of the drug and being able to be functionalized to increase its effectiveness. Its activity is currently being investigated in numerous diseases, among which cancer stands out. Cancer is the main malignant neoplasm in women and the second worldwide, with more than 2.2 million new cases diagnosed in 2020. Of these, 15% belong to the triple negative subtype (TNBC), defined by the absence of receptors for both hormones and the epidermal growth factor HER2, which makes it difficult to develop treatments. In this work, the antitumor effect of MSNs loaded with a proapoptotic drug against TNBC has been confirmed by cell viability techniques and apoptosis assays, confirming the mechanism of action.

[Background/Aims] In order to prevent obesity and diabetes, it is important to avoid overeating, especially carbohydrates. Therefore, we evaluated the effect of taking jumbo leek bulb before a meal on the decomposition and absorption inhibition of carbohydrates after a meal. In this case, we used a product that was heat-treated after promoting phase transition of its content by rapid and synchronized dormancy-breaking (RSDB), and investigated by decreasing two enzyme activities, namely pancreatic α-amylase and α-glucosidase, and report the results.

[Results] In pancreatic α-amylase, 6.5% inhibition of enzyme activity was observed in the untreated (heat and lyophilized) without RSDB compared to the control. In contrast, the RSDB inhibited it more effectively by 12.5%. In the case of α-glucosidase, 9.1% of inhibition of enzyme activity was observed in the untreated, whereas 14.6% was inhibited by the RSDB treatment, about 1.6 times more effective than the untreated. Thus, the RSDB jumbo leek bulb, when taken before a meal, was found to inhibit postprandial carbohydrate decomposition and absorption (postprandial hyperglycemia prevention effect). It is possible that the inulin in the jumbo leek has an inhibitory effect on glucose absorption by wrapping the carbohydrates, but the RSDB treatment may have accelerated the effect. Furthermore, an enhancement effect of insulin production and efficiency is expected by organosulfur compounds. In conclusion, the high efficacy of the RSDB jumbo leek in suppressing postprandial carbohydrate degradation and absorption was observed in a model experiment. The RSDB jumbo leek bulb is expected to be effective in preventing obesity and diabetes.

As a continuation of our previous investigations aimed at the synthesis of novel nitrogen-containing heterocycles and their metal complexes, we have now prepared two series of compounds incorporating a phthalazine ring at the position C₂ of 4,5-dihydro-1H-imidazole.

The starting phthalazine (I) in the reaction with 2-chloroimidazoline (II) gives rise to the formation of pseudobase III. Then, compound III upon treatment with HOSA yields betaine which under basic conditions gives 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (IV). In turn, the reactions of compound IV with variety of acyl and sulfonyl chlorides lead to the formation of benzamides (V) and benzenesulfonamides (VI). Moreover, compounds V and VI can be transformed into corresponding 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one derivatives VII and VIII.

Such ligands are susceptible to the reaction with CuCl₂ giving rise to the formation of corresponding copper(II) complexes: dichloro[2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine]copper(II) (1), dichloro[2-(1-benzoyl-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]copper(II) (2) and dichloro{bis-[2-(1-(phenylsulfonyl)-4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-one]}copper(II) (3).

The most promising results of biological studies were obtained for complex 1 towards the HeLa cell line (IC₅₀ = 2.13 μM) without a toxic effect against fibroblasts BALB/3T3 (IC₅₀ = 135.30 μM), which pointed towards its selectivity as a potential antitumor agent. It should be pointed out, that corresponding free ligand 2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (IV) was less active than its metal complex (IC₅₀ = 87.74 μM).

Over the last decade, a huge number of herbal supplements have been introduced into the practice of sports medicine in order to increase physical performance. Medicinal plants are a valuable source of a large number of secondary metabolites such as polyphenols, triterpenes, adaptogens. This determines the ability of herbal medicines to compensate for the deficiency of nutrients in the human body. The use of secondary products of processing provides an opportunity to obtain additional products of high biological value and purposeful spending of natural resources reserves.

Based on the literature data on the properties of leuzea and ursolic acid, the researchers of the Laboratory of Pharmacological Research NIOCH SB RAS developed a composition of two plant components - extracts of leuzea and cranberry meal, containing 0.31% ecdysten and 40% ursolic acid, respectively.

The aim of this work is to study the effect of the composition of leuzea and cranberry meal extracts and its individual components on performance in the treadmill test in male CD-1 mice.

To confirm the increase in physical performance, the concentration of lactate and blood glucose was determined. After a seven-day acclimation, test compounds were administered daily for two weeks, with all mice receiving exercise (at least 24 hours between each run). At the end of the experiment, the concentration of lactate and glucose in the blood was measured.

The composition of leuzea and cranberry meal extracts significantly reduced the concentration of lactate and glucose in the blood, which indicates its ability to increase physical performance.

Paddlewheel diruthenium complexes have interesting pharmaceutical properties. The diruthenium tetracetate complex ([Ru₂Cl(O₂CCH₃)₄]), the prototype of the diruthenium compound family, has been used to prepare promising anticancer agents (i.e., against glioma tumor models and glioblastoma). The interaction of [Ru₂Cl(O₂CCH₃)₄] with proteins has been already investigated: diruthenium moieties bind Asp side chains upon releasing of one acetate ligand; a second acetate is replaced by two water molecules in each diruthenium center. Recently, it has been suggested that the use of bulky equatorial substituents may constitute an approach to increase the selectivity of diruthenium complexes toward anticancer targets. To study the effect of equatorial ligand replacement on the reactivity of diruthenium compounds with proteins, we solved high-resolution X-ray structures of adducts formed upon reaction of the model protein lysozyme with some monosubstituted complexes [Ru₂Cl(L-L)(O₂CCH₃)₃] (L-L = N,N’-donor or N,O-donor bridging ligands). Results indicate that these complexes bind the protein via coordination of the Ru-Ru core to the side chain of Asp residues at the equatorial coordination site, losing only one acetate ligand. Protein binding occurs cis or trans to the L-L ligands that remain attached to the dimetallic center. The side chain of a Lys and even main chain carbonyl groups can coordinate diruthenium core at the axial site. Data help to understand the reactivity of paddlewheel diruthenium complexes with proteins, providing useful information for the design of new diruthenium compounds with improved pharmacological properties.

Introduction: Cellulose is a semicrystalline, water insoluble polymer having D-anhydroglucopyranose ring as the repeating unit. Microcrystalline cellulose (MCC) is the crystalline form of cellulose obtained by acid-treatment which dissolves the amorphous portion and the crystalline form remains intact. When an aliphatic amine group is introduced into the cellulose molecule, it has the ability to show antibacterial activity in acidic conditions.

Methodology: Using above approach of modification, we planned to introduce epoxide moiety followed by epoxide ring opening. In the first step, MCC was epoxy modified by introduction of epoxy ring using the reagent epichlorohydrin under basic conditions. This was followed by epoxide ring opening by addition of a primary aliphatic amine. The newly chemically modified cellulose was characterized by IR, NMR and SEM techniques.

Conclusion: This aminated epoxy MCC showed an intrinsic antimicrobial activity against Staphylococcus aureus. Such an epoxy modified cellulose molecule can be used in wound healing to prevent infections. In addition, it can be used in food packing to prevent the spoilage of food and extent its shelf life.

Urea transporters (UTs) are a kind of transmembrane proteins that specifically permeate urea and play an important role in the mechanism of urine concentration. Selective knockout of UT can concentrate urea without affecting water and electrolytes, resulting in selective diuresis, which is a promising new diuretic target. Most of the currently reported UT inhibitors are obtained from small molecular libraries screened for poor oral activity. We subjected the methanolic extract of celery seed to silica gel column chromatography analysis and screened the column chromatographic fractions of celery seed for UT-B inhibitory activity using the reported erythrocyte lysis model, and the UT-B inhibitory activity was screened for the fractions of celery seed separated by column chromatography using the reported erythrocyte lysis model. The chemical composition of the active site was identified using UPLC-TOF-MS, and the active compounds were screened in combination with molecular docking and ADMET prediction. Screening of the extracted parts of celery seed using an erythrocyte lysis model yielded nine small molecules with good inhibitory activity, namely esters, phenols, and organic acids. This experiment shows that compounds with UT-B inhibitory effects can be found in ethnic medicinal materials, which not only provides new ideas for the discovery of UT-B inhibitors but also contributes to the development of ethnic medicines.