Novel derivatives of 4-oxo-3-methylcytisine with phenyl moiety bonded to starting molecule through various spacers were obtained from the 9-amino, -halo, -formyl and 11-halo precursors by reductive alkylation of amines, generation of amide, as well as thio- and carboxamide functions, cross-coupling reactions, aldehyde condensation and reduction of unsaturated 'C-C' bonds. Ability of synthesized compounds to influence the learning and memory was preliminary assessed in conditioned passive avoidance reflex (CPAR) test in rats. It was shown, that derivatives with phenyl group at 11 carbon atom influence the learning and memory in CPAR test more effectively than other compounds. The hit-compound (3-methyl-11-(2-phenylvinyl)-3,5,6-trihydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocine-4,8(1H)-dione) with the best values of 'latency' and 'time spent in the dark compartment' has been identified as a perspective scaffold for synthesis of novel derivatives of (-)-cytisine with potential neuropharmacological activity.

The neurodegenerative diseases have a complex pathogenetic mechanism comprising oxidative stress and receptor system dysfunction caused by various damaging factors such as, for example, brain hypoxia. The purpose of this study was to elucidate the influence of hexahydropyrimidine derivatives on learning, memory, and orientation and locomotor activities in the passive avoidance (PA) and open field (OF) tests and to evaluate these compounds for their potential antihypoxic and antioxidant action on normobaric hypercapnic hypoxia and toxic hypoxia models. We demonstrated that compounds 1a and 1e administered as a single 100 mg/kg dose (p.o.) one hour before the tests increased the latency time to enter the dark compartment for the first time and reduced the time spent in the dark compartment on the 2nd, 7th, and 14th days of PAT and increased the number of squares crossed and hole-pokings in the OF test. It was also shown that single administration of compounds 1a and 1e (in 100 mg/kg dose, p.o.) one hour before generation of hypoxia increased the life span of mice under normobaric hypoxia by 30% (P < 0.05) and, after injection of sodium nitroprusside, they decreased the malondialdehyde (MDA) level and increased the catalase level in the brain of mice. According to molecular docking results, compounds 1a and 1e are bound in the orthosteric active site of M1 muscarinic receptor via supramolecular interactions with a number of functional amino acids. The results indicate that hexahydropyrimidine derivatives have a beneficial effect on the memory, learning processes, and orientation and locomotor activities of rats in an unfamiliar environment and exhibit antihypoxic and antioxidant activities under hypoxia in mice. The cognitive enhancement can be mediated by the effect of lead compounds on the M1 muscarinic acetylcholine receptor.

We performed screening of nootropic properties of 10 new derivatives of quinolizidine alkaloid (-)-cytisine. Compounds with β-endo stereochemistry were more active than α-endo-isomers. Under stress conditions (3aR,4S,8S,12R,12aS,12bR)-10-methyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3',4':3,4]pyrido[1,2-a] [1,5]diazocine-1,3,5(4H)-trione enhanced memory and had a positive effect on cognitive functions of rats. According to molecular docking data, the nootropic activity of the compound can be associated with its affinity for the glutamate-binding subunits GluK1 and GluR2 of the kainate and AMPA receptor, respectively.

Thymidylate synthase (ThS) is a target for antimetabolite antitumor drugs. Such drugs have been used in the clinic although they cause several severe side effects and accumulate in tissues. Therefore, new less toxic ThS inhibitors must be sought and created. The GUSAR 2013 program was used to study the quantitative structure – activity relationship (QSAR) of a series of antifolate ThS inhibitors in the IC50 range 0.52 – 24,800.00 nM. Statistically significant QSAR models were constructed using MNA- and QNA-descriptors and self-consistent regression. They typically predicted highly accurately the structures of the training and test sets (\( {\mathrm{R}}_{\mathrm{train}}^2 \): 0.855 – 0.922; \( {\mathrm{R}}_{\mathrm{train}}^3 \): 0.810 – 0.895;\( {\mathrm{R}}_{\mathrm{test}1}^2 \): 0.734 – 0.790; \( {\mathrm{R}}_{\mathrm{test}2}^2 \): 0.800 – 0.835).

The hepatoprotective and choleretic activities of three levopimaric acid derivatives were studied experimentally using a CCl4-induced acute hepatitis model in rats. It was established that all investigated levopimaric acid derivatives tended to increase bile secretion whereas (5R,9R,13S,18S)-20-isopropyl-5,9-dimethyl-17-{[(4-methylphenyl)sulfonyl]imino}-14-oxopentacyclo[10.6.2.01, 10.04, 9.013, 18]eicosa-15,19-diene-5-carboxylic acid (I) and dimethyl (4bS,8R)-2-isopropyl-3′-4b,8-trimethyl-2′,4′-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10a-ethanophenanthrene-11,5′-[1,3]thiazolidine]-8,12-dicarboxylate (II) reduced transaminase enzyme levels in blood serum.

BACKGROUND AND OBJECTIVES:Neurodegenerative diseases and inflammation are always linked to each other; therefore the elaboration of new chemical compounds, which interact with pharmacological targets involved into these two processes, can become one of ways of correction of these types of human CNS pathology. In the field of this problem the anti-inflammatory activity of ten 3-amino derivatives of quinolizidine alkaloid (.)-cytisine (the data about nootropic activity of these compounds are outlined by us previously) was studied by using in vivo, in vitro and in silico approaches.METHODS:The anti-inflammatory activity of novel compounds was investigated on carrageenan- induced model of inflammation in Rat paw following an established protocol. COX-1 (ovin) and COX-2 (human recombinant) inhibition activities of tested compounds assessed using a COX Fluorescent Inhibitor Screening Assay Kit. And as part of an in silico screening the leading compounds were docked into the tyrosine sites of COX-1/COX-2 enzymes (PDB code: 1DIY and 1CVU).RESULTS:It was established that ability of 3-(2-hydroxyphenyl)amino, 3-(4-hydroxyphenyl) amino and 3-(3-phenylprop-2-en-1-yl)amino derivatives of 12-N-metylcytisine to inhibit the carrageenan-induced paw oedema in rats is comparable with reference drug diclofenac. The results of in vitro COX-1/COX-2 inhibition assay showed no significant activity of tested compounds, except compounds with 2-hydroxyphenyl, 3-phenylprop-2-en-1-yl, furyl and thiophenyl fragments which slightly reduce the activity of COX-2.CONCLUSION:The tendency to occurrence of anti-inflammatory properties of synthesized derivatives of quinolizidine alkaloid (-)-cytisine can be explained on the basis of molecular docking results, which assume the possibility of interaction of more potent compounds with key amino acids of COX-1/COX-2 active sites.

Большое количество исследований, проводимых во всем мире, свидетельствует о высокой востребованности мизопростола и мифепристона в акушерстве и гинекологии, а также о продолжающемся поиске оптимальных доз мизопростола для снижения частоты побочных эффектов и выявления отдаленных последствий проведения медикаментозного аборта (МА) с использованием этих препаратов [28, 50]. В работе представлен обзор литературы по применению мизопростола и мифепристона для прерывания беременности в первом, втором и третьем триместрах по различным показаниям; сравнение эффективности данной схемы с хирургическими методами проведения аборта. Проведен анализ эффективности различных способов введения мизопростола, а также сравнение его с другими простагландинами, применяемыми для проведения МА и созревания шейки матки при подготовке к родам. Поиск литературы проведен в базах данных электронных библиотек PubMed, PMC, Elibrary.

The compositions of neutral lipids (NL) and fatty acids (FA) from subterranean parts of the introduced plants Helleborus abchasicus and H. caucasicus (Ranunculaceae) were established and compared with those of the wild species. The FA from diacyl- and triacylglycerides and free FA from these introduced species had elevated contents of unsaturated acids because of 18:2. The lipid-soluble NL constituents included 10 identified sterols, the major ones of which were cholesterol, sitosterol, and lanosterol. NL from H. abchasicus (introduced and wild) and H. caucasicus (wild) exhibited pronounced anti-inflammatory activity at the level of Voltaren and moderate wound-healing activity.

The antihypoxic activity of a series of quinopimaric acid scaffold derivatives was studied. It was shown that compounds 3 , 5 , and 8 increased the lifespan of mice in various hypoxia models.

New 2-hydroxy-1-en-3-ones were prepared by oxidation of 11-deoxoglycyrrhetic acid 3-oxo-derivatives and its 30-methyl ester by atmospheric oxygen in the presence of t -BuOK. 2-Hydroxy-3-oxo-18 β H-olean-1,12-dien-30-oic acid at a dose of 50 mg/kg reduced the blood glucose concentration in the alloxan-induced rat diabetes mellitus model by 34% compared with the control after 120 min.

The mnestic and antihypoxic effects of new derivatives of the quinolizidine alkaloid (−)-cytisine on acquisition of a conditioned passive avoidance reflex (CPAR) were studied in rats; effects on normobaric (jar) hypoxia were studied in mice. Screening studies showed that the benzamide and the N-(12-methylcytidin-3-yl)-N′-phenylurea not only improved learning and memory, but also increased the resistance of the brain to hypoxia.

Reductive alkylation of 3-amino-12-N-methylcytisine by aromatic aldehydes synthesized a series of secondary amines. The nootropic activity of the synthesized compounds was studied in vivo (mnestic and antihypoxic properties) and in vitro (antiradical properties and ability to affect transcription factor HIF-1 DNA-binding activity). The cytotoxicity of the synthesized compounds was assessed. The lead compound was identified.

Docking of a series of methanepyrido[1,2- a ][1,5]diazocin[(-)-cytisine derivatives to the active center of the nicotinic acetylcholine receptor was used to generate a set of potential substances for the treatment of cognitive dysfunction. The results from these studies led to the conclusion that six of the 21 structures were potential inhibitors of the nicotinic acetylcholine receptor. Experimental testing confirmed that the study compounds had nootropic actions and allowed the most active of these to be selected for further investigation.

Методом докирования ряда производных метанпиридо[1,2-a][1,5]диазоцина[(-)-цитизина] в активный центр никотинового ацетилхолинового рецептора осуществлен отбор перспективных веществ для лечения когнитивной дисфункции. На основе полученных данных можно заключить, что 6 структур из 21 могут являться потенциальными ингибиторами никотинового ацетилхолинового рецептора. Экспериментальное тестирование подтвердило наличие ноотропного действия у изученных соединений и позволило отобрать наиболее активные из них для дальнейших исследований.

Изучена мнестическая и противогипоксическая активность новых производных хинолизидинового алкалоида (—)-цитизина при выработке условного рефлекса пассивного избегания (УРПИ) у крыс и нормобарической (баночной) гипоксии у мышей. В результате скрининга установлено, что бензамид и N-(12-метилцитизин-3-ил)-N’-фенилмочевина не только улучшают обучение и память, но и повышают устойчивость мозга к гипоксии.

Using the GUSAR program, structure-activity relationships on inhibition of cyclooxygenase-2 (COX-2) catalytic activity were quantitatively analyzed for twenty-six derivatives of 4,5,6,7-tetrahydro-2H-isoindole, 2,3-dihydro-1H-pyrrolyzine, and benzothiophene in the concentration range of 0.6–700 nmol/liter IC 50 values. Six statistically significant consensus QSAR models for prediction of IC 50 values were designed based on MNA- and QNA-descriptors and their combinations. These models demonstrated high accuracy in the prediction of IC 50 values for structures of both training and test sets. Structural fragments of the COX-2 inhibitors capable of strengthening or weakening the desired property were determined using the same program. This information can be taken into consideration on molecular design of new COX-2 inhibitors. It was shown that in most cases, the influence of structural fragments on the inhibitory activity of the studied compounds revealed with the GUSAR program coincided with the results of expert evaluation of their effects based on known experimental data, and this can be used for optimization of structures to change the value of their biological activity.

The structural characteristics typical of highly and moderately effective antagonists of BLT 1 and BLT 2 receptors were identified and the extents of their influences on the target property were evaluated. Two models for predicting inhibitory activity were constructed for series of sulfur-, nitrogen- and oxygen-containing heterocyclic compounds with significant prognostic levels of greater than 80% using two methods based on sample recognition theory. These structural patterns can be used for virtual screening of potential drugs for antiallergic activity associated with blockade of leukotriene LTB 4 -sensitive BLT 1 and BLT 2 receptors.

New 1-hydroxy-1-en-3-one derivatives of 18β- and 18α-glycyrrhetic acids were synthesized via oxidation of the 3-ketotriterpenoids by atmospheric oxygen in the presence of an excess of t-BuOK. 2-Hydroxy-3,11-dioxo-18αH-olean-1,12-dien-30-oic acid exhibited pronounced hypoglycemic activity and decreased the blood glucose concentration by 42.7% compared with a control after 120 min at a dose of 50 mg/kg in a rat alloxan-induced diabetes model.

The structural characteristics typical of highly and moderately effective antagonists of BLT1 and BLT2 receptors were identified and the extents of their influences on the target property were evaluated. Two models for predicting inhibitory activity were constructed for series of sulfur-, nitrogen- and oxygen-containing heterocyclic compounds with significant prognostic levels of greater than 80% using two methods based on sample recognition theory. These structural patterns can be used for virtual screening of potential drugs for antiallergic activity associated with blockade of leukotriene LTB4-sensitive BLT1 and BLT2 receptors.