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Analyses of the human bones failure mechanisms under projectile impact conditions can be made through performing of a large number of ballistic trials. But the amount of data that can be collected during ballistic experiments is limited due to the high dynamics of the process and its destructive character. Numerical analyses may support experimental methodologies allowing to better understand the principles of the phenomenon. Therefore, the main aim of the study was to create and to verify a numerical model of commercially available synthetic bone material-Synbone®. The model could be used in the future as a supporting tool facilitating forensic studies or designing processes of personal protection systems (helmets, bulletproof vests, etc.). Although Synbone® is commonly used in the ballistic experiments, the literature lacks reliable numerical models of this material. In order to define a numerical model of Synbone®, mechanical experiments characterizing the response of the material to the applied loads in a wide range of strains and strain rates were carried out. Based on the mechanical tests results, an appropriate material model was selected for the Synbone® composite and the values of constants in its equations were determined. Material characterization experiments were subsequently reproduced with numerical simulations and a high correlation of the results was obtained. The final validation of the material model was based on the comparison of the ballistic impact experiments and simulation results. High similarity obtained (relative error lower than 10%) demonstrates that the numerical model of Synbone® material was properly defined., (© 2023 The Authors. International Journal for Numerical Methods in Biomedical Engineering published by John Wiley & Sons Ltd.)

The extensive application of zidovudine (ZDV) as a stand-alone anti-HIV drug and a component in antiviral combination therapies, has made its analysis important both in the pharmaceutical and environmental context. The azide group in ZDV structure makes it a ready-to-use substrate for copper-catalyzed azide-alkyne cycloaddition (CuAAC), which is an efficient method for "click chemistry" labeling. In this paper, we describe a ligand-assisted CuAAC procedure for the precolumn derivatization of ZDV. We used propargyl-Fmoc fluorescent label and trans-2-(4-((dimethylamino)methyl)-1H-1,2,3-triazol-1-yl)cyclohexan-1-ol (AMTC) as a copper-binding ligand. We tested the applicability of AMTC for precolumn derivatization and developed chromatographic analytical procedures for ZDV and its formulation (50 mg/5 ml oral solution, Retrovir™ syrup). Our research aimed to improve labeling efficiency with a Cu-chelating ligand, using an accessible and affordable fluorescent probe. We also developed a sustainable mechanochemical synthesis procedure for obtaining propargyl-Fmoc in a gram scale and thus boosted the accessibility of this probe. The advantages of the developed derivatization procedure are its simplicity and easy availability of the propargyl-Fmoc probe. Moreover, the high lipophilicity of the propargyl-Fmoc probe enables efficient separation of the analyte from polar matrix components. In addition, the derivatization procedure can be performed directly on a sample solution. We tested its usability for samples in environmental and biological matrices, including tap water, river water, urine, and human serum., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Lipase-catalyzed hydrolytic kinetic resolution is a method of obtaining optically pure chiral alcohols and amines, which requires additional tools for determining enantiomerical purity. Herein, we present a study on multigram-scale hydrolytic kinetic resolution of trans-2-azidocyclohexyl acetate using Pseudomonas cepacia lipase immobilized on Immobead support. We investigated several parameters of the preparative-scale process: temperature, organic co-solvent, and the influence of calcium ions. Moreover, we have developed an efficient fluorenylmethyloxycarbonyl chloride (Fmoc-Cl) derivatization protocol for 2-azidocyclohexanol, which enabled chiral reversed-phase high-performance liquid chromatography (RP-HPLC) determination of enantiomeric excess., (© 2021 Wiley Periodicals LLC.)

Malaria is still one of the most dangerous infectious diseases and the emergence of drug resistant parasites only worsens the situation. A series of new tetrahydro-β-carbolines were designed, synthesized by the Pictet-Spengler reaction, and characterized. Further, the compounds were screened for their in vitro antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum . Moreover, molecular modeling studies were performed to assess the potential action of the designed molecules and toxicity assays were conducted on the human microvascular endothelial (HMEC-1) cell line and human red blood cells. Our studies identified N -(3,3-dimethylbutyl)-1-octyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indole-3-carboxamide ( 7 ) (a mixture of diastereomers) as the most promising compound endowed with the highest antiplasmodial activity, highest selectivity, and lack of cytotoxicity. In silico simulations carried out for (1 S ,3 R )- 7 provided useful insights into its possible interactions with enzymes essential for parasite metabolism. Further studies are underway to develop the optimal nanosized lipid-based delivery system for this compound and to determine its precise mechanism of action.

The laparoscopic method of recovering oocytes in goats and sheep is one of the minimally invasive methods used in the biotechnology of animal reproduction. It allows for good quality oocytes that are suitable for in vitro maturation and fertilization to be recovered. The limitation of using the laparoscopic ovum pick-up (L-OPU) method in goat and sheep is its changing effectiveness and the lack of repeatability of results, as well as the varying effectiveness of different variants of the method. Therefore, it is necessary to develop effective non-invasive techniques allowing for multiple good quality oocyte recovery that would be suitable for in vitro maturation and fertilization. In this study, four different L-OPU variants were described in goats and sheep. Various techniques of recovering oocytes were discussed, including the techniques of conducting the operation, various tools for recovering oocytes, and different plans of hormonal stimulation. Recovery rates were 35% (Variant I), 57% (Variant II), 72% (Variant III), and 67% (Variant IV). After evaluation, 94% (both Variant I and II), 93% (Variant III), and 84% (Variant IV) of the oocytes were qualified for in vitro maturation. The results of the study show that the proposed technique of laparoscopic recovery of oocytes allows a sufficient number of ovarian cells suitable for in vitro culture to be obtained and as a consequence it makes them useful in in vitro maturation/in vitro fertilization (IVM/IVF) programs or cloning. The method allows for a fast and effective conduct of the operation in a living donor with minimal invasiveness while preserving the excellent condition of animals.

The endocannabinoid (eCB) system plays a significant role in the pathophysiology of depression. The potential participation of this system in the mechanism of action of antidepressants has been highlighted in recent years. The aim of this study was to investigate the expression of cannabinoid (CB) receptors using Western blot and CB 1 receptor density using autoradiography after acute or chronic administration of antidepressant drugs [imipramine (IMI, 15mg/kg), escitalopram (ESC, 10mg/kg) and tianeptine (TIA, 10mg/kg)]. Antidepressants given chronically elevated CB 1 receptor density in the cortical structures and hippocampal areas, while a decrease of CB 1 receptor density was observed in the striatum after IMI and ESC treatment. The CB 1 receptor expression decreases in the dorsal striatum after chronic administration of IMI and ESC or the receptor rise in the hippocampus after chronic ESC and TIA treatment were confirmed using Western blot analyses. An increase in the CB 2 receptor expression was observed in the cortical structures and hippocampus after chronic administration of ESC and TIA, while a decrease in this expression was noted in the striatum and cerebellum after chronic IMI treatment. Our results provide clear evidence that the antidepressant exposures provoke some modulations within the eCB system through CB receptors., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2-aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors.

Twenty four new N-[(dimethylphenoxy)alkyl]aminoalkanols have been synthesized and evaluated for anticonvulsant activity in a series of in vivo tests: the maximum electroshock (MES), 6 Hz, and subcutaneous metrazole (ScMet). The compounds were also evaluated for possible neurotoxicity in the rotarod test. The majority of the achieved compounds exhibit quantified anticonvulsant activity. The most active compound 4: R-(-)-2N-[(2,6-dimethylphenoxy)ethyl]aminopropan-1-ol is active in MES with ED50=5.34 (male mice, ip), 22.28 (female mice, ip), 51.19 (male mice, po), 7.43 (rats, ip), and 28.60 (rats, po). Thermal analysis proved that its hydrochloride (4a) can exist in polymorphic forms. The compound binds to σ, 5-HT1A, and α2 receptors as well as 5-HT transporter and it does not exhibit mutagenic properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A series of new N-(2,5-dimethylphenoxy)- and N-(2,3,5-trimethylphenoxy)alkylaminoalkanols [I-XVII] was synthesized and evaluated for anticonvulsant activity. Pharmacological tests included maximal electroshock (MES) and subcutaneous pentetrazole seizure threshold (scMet) assays as well as neurotoxicity (TOX) evaluation in mice after intraperitoneal (i.p.) administration and/or in rats after oral (p.o.) administration. The most active compound was R-2N-[(2,3,5-trimethylphenoxy)ethyl]aminobutan-1-ol, which exhibited 100% activity in MES at the dose of 30 mg/kg body weight (mice, i.p.) and 75% activity in MES at 30 mg/kg b.w. (rats, p.o.) without neurotoxicity at the active doses.

A series of 17 new aminoalkanol derivatives of 6-methoxy- or 7-chloro-2-methylxanthone as well as 6-methoxy-4-methylxanthone was synthesized and evaluated for anticonvulsant activity. All compounds were verified in mice after intraperitoneal (ip) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scMet) induced seizures as well as neurotoxicity assessment. Eleven of the tested substances showed protection against electrically evoked seizures in the majority of the tested mice at the dose of 100 mg/kg. Additionally, one was effective at the dose of 30 mg/kg. Five substances were active at the dose of 300 mg/kg or at the dose of 100 mg/kg in the minority of the tested mice. The most promising compound revealed ED(50) value of 47.57 mg/kg in MES (mice, ip, 1h after administration) and at the same time its TD(50) was evaluated as above 400 mg/kg. Those values gave PI (calculated as TD(50)/ED(50)) of more than 8.41. Three other synthesized xanthone derivatives also proved to act as anticonvulsants and showed ED(50) values in MES test (mice, ip) ranged 80-110 mg/kg. Results were quite encouraging and suggested that in the group of xanthone derivatives new potential anticonvulsants might be found., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α(1)-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals' models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED(50) value of 0.69 mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED(50) = 0.88 mg/kg and 0.89 mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol. Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The investigated beta-carboline derivatives were synthesized to elucidate their activity as 5-HT(1A) and 5-HT(2A) receptor ligands. Compounds containing a carboline ring system belong to a large family of biological active indoles, which are very important for the function of the central nervous system. The research was carried out to determine antioxidative or oxidative properties of these derivatives. Analysis of antioxidative capacity as indication of oxidative stress was based on ability to scavenge free radicals by DPPH (free radical scavenging activity test) and FRAP test. The results were compared to those of standard substances like vitamin C, trolox, quercetin and curcumin. The research of derivatives of beta-carboline shows antioxidative activity comparable to vitamin C. Compounds 1, 5 and 6, but only in low concentration, have antioxidative activity. Substance 10 was classified as that with prooxidative activity.

A series of 1,4-piperazine derivatives was synthesized and evaluated for anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). The compounds were only moderately effective. The anticonvulsant activity was accompanied by neurotoxicity. 1-[(4-Chlor-3-methylphenoxy)-acetyl]-4-(2-methoxyphenyl)-piperazine was also evaluated in six hertz seizure test (6-Hz) and showed good activity. At the dose of 100 mg/kg b. w. the compound produced 100% protection after 0.5 h without neurotoxic effect.

A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for alpha(1)- and beta(1)-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures.

Some of appropriate aminoisopropanoloxy derivatives of 4-xanthone were tested for their effect on circulatory system (protection against adrenaline-, barium-, and calcium chloride-induced arrhythmias, as well as hypotensive activity and acute toxicity). The most prominent hypotensive activity was demonstrated by (+/-)-1-[4-(hydroxyethyl)-1-(piperazinyl)]-3-(4-xanthonoxy)-2-propanol dihydrochloride (II), which diminished arterial blood pressure by about 40% during one hour observation. The investigated compounds did not prevent adrenaline- and barium-induced arrhythmias. In calcium-induced model of arrhythmia compound II slightly intensified blocks (about 7%), but delayed extrasystoles (37%), efficiently prevented bigeminy (70%, p <0.01) and diminished (53%, p <0.05) mortality of animals. All investigated compounds decreased heart rate by 10 - 18%, prolonged P-Q section, QRS complex and Q-T interval. The most potent and significant negative chronotropic effect and markedly prolonged duration of P-Q section was demonstrated by compound II. The influence of investigated compounds on ECG components suggests that activity of compound IV is similar to class 1a anti-arrhythmic compounds according to Voughan-Williams classification of antiarrhythmic drugs, because of prolongation of P-Q and Q-T intervals and extension of QRS complex. Compounds II and IV were also evaluated for anticonvulsant activity in the maximal electroshock seizures (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). The anti-MES activity in mice was found for IV, which in a dose of 100 mg/kg within 0.5 h after ip administration showed 75% anticonvulsant protection with 50% neurotoxicity.

A series of some derivatives of 2-xanthone was synthesized and evaluated for their activity against M. tuberculosis in primary and/or secondary microbiological assays. The cytotoxic activity of some compounds was also evaluated. The most active compounds were: [I] 2-(2-(4-(2-(4-chloro-3-methylphenoxy)ethyl)piperazin-1-yl)ethoxy)-9H-xanthen-9-one, [III] 2-((4-(2-(4-chlor-3-methylphenoxy)ethyl)piperazin-1-yl)methyl)-9H-xanthen-9-one dihydrochloride and [XVIII] ethyl 4-(2-hydroxy-3-(9-oxo-9H-xanthen-2-yloxy)propyl) piperazine-1-carboxylate, which displayed 98%, 98% and 94% inhibition of M. tuberculosis growth, respectively. Furthermore, compounds III and XVIII revealed their cytotoxic activity (SI < 1). Other structures varied greatly in their anti M. tuberculosis activity, however, several trends in their structure in relation to their antituberculous activity have been observed.

A variety of appropriate [4-(benzyloxy) benzoyl]- and [4-(benzyloxy) benzyl] aminoalkanol derivatives [I-XVII] was synthesized and evaluated for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet) tests in mice and rats. Neurotoxicity (TOX) was determined by the rotorod test. The most active compounds in the MES test in mice were the appropriate 4-(benzyloxy) benzyl derivatives of (R,S)- and S-(+)-2-amino-1-butanol [XI, XIII], 3-[4-(benzyloxy) benzyl] amino-3-methyl-1-butanol [XV], and S-(+)-2-[4-(benzyloxy) benzyl] amino-3-methyl-1-butanol [XVI]--all exhibiting 100% anti-MES protection (at 30 mg/kg, mice, i.p.) and non-toxic in the active doses. 4-[4-(Benzyloxy) benzyl] amino-1-butanol [X] exhibited activity in both MES and ScMet (100 mg/kg, mice, i.p., 100% anticonvulsant protection, 0.5 h and 4 h after administration, respectively).

During December mating periods of 2000-2003, wool and meat breeds crossed with East Friesian milk sheep and rams of prolific breeds (Finn or Romanov) were examined laparoscopically. Ovine ovaries were examined between 4 and 9 days after mating. The litter size was recorded and compared with the number of ovulations. The fertility of the analyzed animals was 69.6%, with 192.6% prolificacy. The difference between the average number of corpora lutea found on ovaries and the mean number of lambs born was 0.35 and ranged from 0.32 to 0.41 according to age group, from 0.22 to 0.41 according to sheep birth type, and from 0 to 0.52 lamb per ewe according to percentage of prolific breeds.

Previous results of histamine H3-receptors investigations allowed to formulate a general structure of H3-receptor antagonists. According to this model a series of compounds were obtained. As heterocycles they contained a theophylline moiety connected with a polar group (amine, ester, amide, and thiourea function) via an alkyl chain linked by a spacer to a lipophilic residue. The common distance between xanthine moiety and lipophilic rest was a six-link-chain. Selected compounds did not show significant H3-receptor antagonist activity and were weak antagonists at histamine H1-receptors.

Three series of compounds containing a 4-aryl-1-piperazinylalkyl fragment attached to a different position of the indole (A) or 1,2,3,4-tetrahydro-beta-carboline (B, C) have been prepared. The quantitative relationship between the structure of some derivatives and their sedative effect was found using the Free-Wilson approach.

A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group (6-13) or an ethylenediamine chain (15-20) in position 2 were synthesized and their 5-HT1A and 5-HT2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT2A affinity are additive and could be described quantitatively. In a behavioral model it was also demonstrated that 6-11 are 5-HT2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d1 = 5.2-8.4 A, d2 = 5.7-8.5 A, and d3 = 4.6-7.3 A) define the molecular topography of the 5-HT2A receptor antagonists under study.

The 5-HT1A and 5-HT2 receptor affinity of 2- and 3-substituted 1,2,3,4-tetrahydro-beta-carbolines 1-8, 10 and 12-15 has been determined. It has been found that the specific 5-HT1A affinity of the protonated form (KiAH+) 2-n-hexyl derivatives 4, 8, 14 and (+)-LSD is of the same order. It has been shown by means of molecular modelling methods that pharmacophores of all the active compounds can adopt a common position at the 5-HT1A receptor model. The model also offers an explanation for the observed stereoselectivity chiral compounds.

The effect of a steric hindrance around the protonation center of the model 4-substituted 1-(3-chlorophenyl)-piperazines 1-9 and 11-14 on their affinity for 5-HT1A and 5-HT2 receptor sites was investigated. Additional evidence for hydrophobic interactions between the N-4 hydrocarbon substituents and 5-HT1A receptors has been presented. However, the hydrophobic forces play a minor role in stabilization of the bioactive complex with 5-HT2 receptors. It has also been found that even bulky substituents around the protonation center of 1-aryl-piperazines are well tolerated at both 5-HT1A and 5-HT2 sites.

The effect of the hydrocarbon chain of the model 4-substituted 1-(3-chlorophenyl)piperazines 12-31 on their affinity for 5-HT1A receptor sites was investigated. It was found that elongation of the 4-n-alkyl chain strongly increases the 5-HT1A affinity of the investigated compounds. The affinity reaches the maximum (Ki = 2.67 nM) for the n-hexyl derivative 20. It was shown that hydrophobic interactions of N-4 substituents of 1-arylpiperazines significantly contribute to their 5-HT1A affinity. The specific binding constant was defined as the receptor affinity of the protonated species of compounds under physiological conditions. The range of Ki(AH+) = 1 - 3 x 10(-11) M is a specific affinity limit of the investigated class of compounds at the 5-HT1A receptor sites.

The aim of this paper is to analyse examples of stereoselective binding of drugs to receptor sites. Selected examples are also given for the binding of drugs to serum albumin and for stereochemical aspects of drug metabolism.

Nine new N-acyl derivatives of 2-amino-1-alcohols and 1-amino-2-alcohols with a potential arrhythmic activity have been obtained. In the preliminary screening 2-[N-(7-theophyllineacetyl)-amino]-2-methyl-1-propanol, 5, was more active in the chloroform-induced arrhythmia than quinidine. Unlike to propranolol and quinidine, compound 5 in doses of 5-30 mg/kg, iv, did not prevent distortions of the cardiac rhythm evoked by adrenaline and strophanthine. When administered at the peak of arrhythmia, it did not abolish disturbances of the cardiac rhythm. Compound 5 had a low toxicity (LD50 = 3000 mg/kg, ip), did not change the control ECG curve, showed no cardiodepressive activity, and had weaker local anesthetic properties than lignocaine.