Relevance. The problem of prevention and treatment of influenza remains relevant due to the consistently high incidence rate of the disease in the population of all age groups, especially children and the elderly. Antiviral drugs have become the most important tools in the fight against influenza viruses. The main problem is the search and development of new antiviral drugs that do not have side effects. The aim of the present study is to investigate the effect of a new synthetic drug candidate based on adamantane (NMG 1110) and its combination with ribavirin on the reproduction of influenza A virus in MDCK cell culture. The aim of the present study is to investigate the effects of drugs and their combinations on the reproduction of influenza A virus in MDCK cell culture. Materials and methods. Determination of cytotoxicity and antiviral activity of drugs on MDCK cell line for influenza A(H3N2)/Aichi/1/68 virus at different schemes of drug introduction into cells: immediately after infection, 2 hours after infection, 4 hours after virus infection of cells. Results. It was found that the drugs were low-toxic for MDCK cell culture at the studied concentrations. Using the influenza A(H3N2)/Aichi/1/68 virus model, it was shown that the time of application of the studied samples did not affect the reproduction of the virus in cell culture. The NMG1110 preparation exhibits high antiviral activity at a concentration of 9.7 µg/ml with the chemotherapeutic index of 16.0. At the same time, ribavirin showed a lower effect with a chemotherapeutic index of 8.0. There is a significant suppression of virus reproduction with the combined use of the preparations. A pronounced antiviral effect of the additive nature is observed in the combination of ribavirin and the drug candidate NMG 1110.

1,1-Dibenzyl-3-(1-benzyl-1 1H-pyrazol-4-yl)-2-methylisothioureas containing structural elements both of known antioxidants and glutamate receptor modulators were proposed as compounds with a dual mode of biological action, namely the antioxidant activity and the ability to influence the glutamatergic signaling system. The target compounds were synthesized by the reaction of substituted 4-amino-1-benzylpyrazoles with thiophosgene followed by the condensation of the resulting 1-benzyl-4-isothiocyanato-1H-pyrazoles with dibenzylamine and the subsequent S-methylation of the resulting thioureas. 1,1-Dibenzyl-3-[1-(3,4-dichlorobenzyl)- and 1,1-dibenzyl-3-[1-(2,4-dichlorobenzyl)-1H-pyrazol-4-yl]-2-methylisothioureas were found to have a moderate ability to protect neuroblastoma cells against the toxic effect of hydrogen peroxide, making these compounds interesting for further study of the modulatory activity toward glutamate receptors.

An approach was developed for the synthesis of multitarget compounds based on a tacrine molecule conjugated with a vanillin moiety using alkylimine or alkylamine linkers with different alkyl chain lengths (C2–C4). The synthesized conjugates effectively inhibit cholinesterases, displace propidium from the peripheral anionic site of acetylcholinesterase, which implies potential antiaggregant properties, and exhibit high antioxidant activity.

The synthesis of new hybrid compounds based on the domestic drug amiridine and a seven-membered cyclic homolog of tacrine combined by a thiourea-containing spacer was described. The synthesized conjugates were shown to be highly efficient inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with a nanomolar activity exceeding that of amyridine and tacrine, which was consistent with the molecular docking results. The conjugates also demonstrated a broader spectrum of biological activity uncharacteristic of the parent pharmacophores, namely, the ability to inhibit the AChE-induced and self-aggregation of β-amyloid and antioxidant properties.

New potential multitarget compounds based on 4-amino-2,3-polymethylenequinolines (analogs of tacrine) with different sizes of aliphatic rings conjugated with an ionol molecule as an antioxidant moiety were synthesized. The addition was accomplished through the ethyleneamine linker using an amide bond. The study of the esterase profile of the synthesized compounds showed that they are highly efficient inhibitors of both acetylcholinesterase and butyrylcholinesterase with high selectivity for the latter and exhibit high antioxidant activity in the ABTS test (ABTS is the 2,2–-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)).

An approach for the synthesis of phenothiazine derivatives with a NO-generating fragment, which contains a nitroxy group and is attached to the phenothiazine molecule with various linkers, was developed.

The synthesis of new compounds based on the domestic drug amiridine modified with derivatives of N -mono- and N,N -disubstituted thiourea is described. The compounds were investigated for the anticholinesterase and antioxidant activities and for the ability to inhibit the self-aggregation of β-amyloid (Aβ 42 ). The structure—activity relationships were analyzed. The observed effects were consistent with the results of molecular docking of the compounds into cholinesterases and Aβ 42 . The compounds that effectively inhibit butyrylcholinesterase and demonstrate high antioxidant and antiaggregant activities were identified. The results show promise for further development of this class of compounds as potential multifunctional agents for the treatment of Alzheimer’s disease.

Influenza and coronavirus infections are especially dangerous due to being capable of causing pandemics and clinical complications in the nervous and cardiovascular systems, as well as exacerbation of chronic diseases (diabetes mellitus, heart failure, chronic obstructive bronchopneumonia, etc.), which can cause delayed death, especially in children under two years of age, the elderly, and individuals with poor health. The aim of the study was to search for compounds effective against these two topical viruses which possess constant epidemic activity — influenza virus and betacoronavirus — among new adamantane derivatives containing a NO-donor fragment or a dopamine residue. Another purpose of the study was determination of cytotoxicity and antiviral activity of compounds on cell lines permissive for influenza virus and betacoronavirus. The antiviral activity of 6 adamantane derivatives against strains of the influenza virus (H1N1) and betacoronavirus was studied. It was established that the NO-donor derivative of aminoadamantane succinate and the dopamine derivative of adamantanebenzoic acid had the greatest ability to suppress the development of the influenza virus with a chemotherapeutic index above 60. No promising compounds against betacoronavirus were identified.

A series of novel conjugates of 4-amino-2,3-polymethylene quinolines and phenolic antioxidant vanillin was synthesized by the condensation of aminoquinolines with vanillin followed by reduction of imines with sodium borohydride. The conjugates effectively inhibit AChE and BChE with preferable BChE inhibition and displace propidium from the PAS AChE. Compounds with aminoalkyl spacer have preferable esterase profile being more potent cholinesterases inhibitors with lower anti-CES activity and are the most potent antioxidants in ABTS and FRAP tests.

New hybrids of 4-amino-2,3-polymethylenequinoline with different sizes of the aliphatic ring linked to butylated hydroxytoluene (BHT) by enaminoalkyl (7) or aminoalkyl (8) spacers were synthesized as potential multifunctional agents for Alzheimer’s disease (AD) treatment. All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. Lead compound 8c, 2,6-di-tert-butyl-4-{[2-(7,8,9,10- tetrahydro-6H-cyclohepta[b]quinolin-11-ylamino)-ethylimino]-methyl}-phenol exhibited an IC50(AChE) = 1.90 ± 0.16 µM, IC50(BChE) = 0.084 ± 0.008 µM, and 13.6 ± 1.2% propidium displacement at 20 μM. Compounds possessed low activity against carboxylesterase, indicating likely absence of clinically unwanted drug-drug interactions. Kinetics were consistent with mixed-type reversible inhibition of both cholinesterases. Docking indicated binding to catalytic and peripheral AChE sites; peripheral site binding along with propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. Compounds demonstrated high antioxidant activity in ABTS and FRAP assays as well as inhibition of luminol chemiluminescence and lipid peroxidation in mouse brain homogenates. Conjugates 8 with amine-containing spacers were better antioxidants than those with enamine spacers 7. Computational ADMET profiles for all compounds predicted good blood-brain barrier distribution (permeability), good intestinal absorption, and medium cardiac toxicity risk. Overall, based on their favorable pharmacological and ADMET profiles, conjugates 8 appear promising as candidates for AD therapeutics.

Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1, and 13,14-dihydro-15-keto-PGE1. Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective.

Cholines acylated with unsaturated fatty acids are a recently discovered family of endogenous lipids. However, the data on the biological activity of acylcholines remain very limited. We hypothesized that acylcholines containing residues of arachidonic (AA-CHOL), oleic (Ol-CHOL), linoleic (Ln-CHOL), and docosahexaenoic (DHA-CHOL) acids act as modulators of the acetylcholine signaling system. In the radioligand binding assay, acylcholines showed inhibition in the micromolar range of both α7 neuronal nAChR overexpressed in GH4C1 cells and muscle type nAChR from Torpedo californica, as well as Lymnaea stagnalis acetylcholine binding protein. Functional response was checked in two cell lines endogenously expressing α7 nAChR. In SH-SY5Y cells, these compounds did not induce Ca2+ rise, but inhibited the acetylcholine-evoked Ca2+ rise with IC50 9 to 12 μM. In the A549 lung cancer cells, where α7 nAChR activation stimulates proliferation, Ol-CHOL, Ln-CHOL, and AA-CHOL dose-dependently decreased cell viability by up to 45%. AA-CHOL inhibited human erythrocyte acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BChE) by a mixed type mechanism with Ki = 16.7 ± 1.5 μM and αKi = 51.4 ± 4.1 μM for AChE and Ki = 70.5 ± 6.3 μM and αKi = 214 ± 17 μM for BChE, being a weak substrate of the last enzyme only, agrees with molecular docking results. Thus, long-chain unsaturated acylcholines could be viewed as endogenous modulators of the acetylcholine signaling system.

New hybrid compounds of 4-amino-2,3-polymethylene-quinoline containing different sizes of the aliphatic ring and linked to p-tolylsulfonamide with alkylene spacers of increasing length were synthesized as potential drugs for treatment of Alzheimer’s disease (AD). All compounds were potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with selectivity toward BChE. The lead compound 4-methyl-N-(5-(1,2,3,4-tetrahydro-acridin-9-ylamino)-pentyl)-benzenesulfonamide (7h) exhibited an IC50 (AChE) = 0.131 ± 0.01 µM (five times more potent than tacrine), IC50(BChE) = 0.0680 ± 0.0014 µM, and 17.5 ± 1.5% propidium displacement at 20 µM. The compounds possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. Kinetics studies were consistent with mixed-type reversible inhibition of both cholinesterases. Molecular docking demonstrated dual binding sites of the conjugates in AChE and clarified the differences in the structure-activity relationships for AChE and BChE inhibition. The conjugates could bind to the AChE peripheral anionic site and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation, thereby exerting a disease-modifying effect. All compounds demonstrated low antioxidant activity. Computational ADMET profiles predicted that all compounds would have good intestinal absorption, medium blood-brain barrier permeability, and medium cardiac toxicity risk. Overall, the results indicate that the novel conjugates show promise for further development and optimization as multitarget anti-AD agents.

Glioblastoma (GBM) is an aggressive and lethal form of brain cancer with a high invasion capacity and a lack of effective chemotherapeutics. Retinoid bexarotene (BXR) inhibits the neurospheroidal colony formation and migration of primary glioblastoma cells but has side effects. To enhance the BXR glioblastoma selectivity and cytotoxicity, we chemically modified it at the carboxyl group with either nitroethanolamine (NEA) bearing a NO-donating group (a well-known bioactivity enhancer; BXR-NEA) or with a dopamine (DA) moiety (to represent the highly toxic for various tumor cells N-acyldopamine family; BXR-DA). These two novel compounds were tested in the 2D (monolayer culture) and 3D (multicellular tumor spheroids) in vitro models. Both BXR-DA and BXR-NEA were found to be more toxic for rat C6 and human U-87MG glioma cells than the initial BXR. After 24 h incubation of the cells (monolayer culture) with the drugs, the IC50 values were in the range of 28-42, and 122-152 tiM for BXR derivatives and BXR, respectively. The cell death occurred via apoptosis according to the annexin staining and caspase activation. The tumor spheroids demonstrated higher resistance to the treatment compared to that one of the monolayer cultures. BXR-DA and BXR-NEA were more specific against tumor cells than the parental drug, in particular the selectivity index was 1.8-2.7 vs. 1.3-1.5, respectively. Moreover, they inhibited cell migration more effectively than parental BXR according to a scratch assay. Cell spreading from the tumor spheroids was also inhibited. Thus, the obtained BXR derivatives could be promising for glioblastoma treatment.

We synthesized conjugates of tacrine with 1,2,4-thiadiazole derivatives linked by two different spacers, pentylaminopropene (compounds 4) and pentylaminopropane (compounds 5), as potential drugs for the treatment of Alzheimer's disease (AD). The conjugates effectively inhibited cholinesterases with a predominant effect on butyrylcholinesterase (BChE). They were also effective at displacing propidium from the peripheral anionic site (PAS) of acetylcholinesterase (AChE), suggesting that they could block AChE-induced β-amyloid aggregation. In addition, the compounds exhibited high radical-scavenging capacity. Conjugates 5 had higher anti-BChE activity and greater anti-aggregant potential as well relatively lower potency against carboxylesterase than compounds 4. Quantum-mechanical (QM) characterization agreed with NMR data to identify the most stable forms of conjugates for docking studies, which showed that the compounds bind to both CAS and PAS of AChE consistent with mixed reversible inhibition. Conjugates 4 were more potent radical scavengers, in agreement with HOMO localization in the enamine-thiadiazole system. Computational studies showed that all of the conjugates were expected to have good intestinal absorption, whereas conjugates 4 and 5 were predicted to have medium and high blood-brain barrier permeability, respectively. All conjugates were predicted to have medium cardiac toxicity risks. Overall, the results indicated that the conjugates are promising candidates for further development and optimization as multifunctional therapeutic agents for the treatment of AD.

An approach to the synthesis of adamantane derivatives with NO-generating fragment containing nitroxy group has been developed. 1-Aminoadamantane, memantine, and adamantanecarboxylic acid have been used as initial compounds. The prepared compounds have shown ability to generate nitric oxide in a system mimicking biological reactions of nitro group reduction.