Synthesis, anticonvulsant, and antinociceptive activity of new 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-2,5-dioxo-pyrrolidin-1-yl-acetamides

The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The most active substance-3- (2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione (6) showed more beneficial ED50 and protective index values than the reference drug-valproic acid (68.30mg/kg vs. 252.74mg/kg in theMES test and 28.20mg/kg vs. 130.64mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds-namely, 6 and 19-was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltagegated sodium and calcium channels, as well as GABAA and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound 6 relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds 6 and 19 were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect

Synthesis, anticonvulsant and antinociceptive activity of new hybrid compounds : derivatives of 3-(3-methylthiophen-2-yl)-pyrrolidine-2,5-dione

The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione and thiophene rings in the structure as potential anticonvulsant and antinociceptive agents. For this purpose, we obtained a series of new compounds and evaluated their anticonvulsant activity in animal models of epilepsy (maximal electroshock (MES), psychomotor (6 Hz), and subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine the mechanism of action of the most active anticonvulsant compounds (3, 4, 6, 9), their influence on the voltage-gated sodium and calcium channels as well as GABA transporter (GAT) was assessed. The most promising compound 3-(3-methylthiophen-2-yl)-1-(3-morpholinopropyl)pyrrolidine-2,5-dione hydrochloride (4) showed higher ED50 value than those of the reference drugs: valproic acid (VPA) and ethosuximide (ETX) (62.14 mg/kg vs. 252.7 mg/kg (VPA) in the MES test, and 75.59 mg/kg vs. 130.6 mg/kg (VPA) and 221.7 mg/kg (ETX) in the 6 Hz test, respectively). Moreover, in vitro studies of compound 4 showed moderate but balanced inhibition of the neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Additionally, the antinociceptive activity of the most active compounds (3, 4, 6, 9) was also evaluated in the hot plate test and writhing tests, and their hepatotoxic properties in HepG2 cells were also investigated. To determine the possible mechanism of the analgesic effect of compounds 3, 6, and 9, the affinity for the TRPV1 receptor was investigated

Synthesis and antiplasmodial activity of novel bioinspired imidazolidinedione derivatives

Malaria is an enormous threat to public health, due to the emergence of Plasmodium falciparum resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their chemical structure. While these drugs are effective, they have many side effects. This paper presents the synthesis and preliminary physicochemical characterisation of novel bioinspired imidazolidinedione derivatives, where the imidazolidinedione core was linked via the alkylene chain and the basic piperazine component to the bicyclic system. These compounds were tested against the asexual stages of two strains of P. falciparum—the chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains. In parallel, in vitro cytotoxicity was investigated on a human keratinocyte cell line, as well as their hemolytic activity. The results demonstrated that the antiplasmodial effects were stronger against the W2 strain (IC50 between 2424.15–5648.07 ng/mL (4.98–11.95 µM)), compared to the D10 strain (6202.00–9659.70 ng/mL (12.75–19.85 µM)). These molecules were also non-hemolytic to human erythrocytes at a concentration active towards the parasite, but with low toxicity to mammalian cell line. The synthetized derivatives, possessing enhanced antimalarial activity against the CQ-resistant strain of P. falciparum, appear to be interesting antimalarial drug candidates

Wykorzystanie technik data mining w analizowaniu czynników wpływających na reaktywność krów podczas doju

Motor activity of 158 Polish Holstein-Friesian cows was evaluated 5 times (before and during milking in a DeLaval 2*10 milking parlour) for both the morning and evening milking, on a 5-point scale, according to the method of Budzyńska et al. (2007). The statistical analysis used multiple logistic regression and classification trees (Enterprise Miner 7.1 software which comes in with SAS package). In the evaluation of motor activity, cows that were among the first ten to enter the milking parlour were more often given a score of 3 points before (11.5%) and during milking (23.5%) compared to the other cows. Cows’ activity tended to decrease (both before and during milking) with advancing lactation. The cows’ reduced activity was accompanied by shorter teat cup attachment times and lower milk yields. The criteria calculated for the quality of models based on classification tree technique as well as logistic regression showed that similar variables were responsible for the reactivity of cows before milking (teat cup attachment time, day of lactation, number of lactation, side of the milking parlour) and during milking (day of lactation, side of the milking parlour, morning or evening milking, milk yield, number of lactation). At the same time, the applied methods showed that the determinants of the cow reactivity trait are highly complex. This complexity may be well explained using the classification tree technique.Aktywność ruchową (przed i w czasie doju w hali udojowej DeLaval 2 * 10) 158 krów phf oceniono 5-krotnie, uwzględniając każdorazowo dój ranny i wieczorny, w skali 5 pkt., według metodyki Budzyńskiej i wsp. (2007). W opracowaniu statystycznym wykorzystano wieloraką regresję logistyczną i drzewa klasyfikacyjne (oprogramowanie Enterprise Miner 7.1 wchodzące w skład pakietu SAS). Stwierdzono, że krowy, które wchodziły do hali udojowej w pierwszej dziesiątce, w ocenie aktywności ruchowej przed i podczas doju częściej (11,5% oraz 23,5%) niż w przypadku pozostałych uzyskiwały 3 pkt. Odnotowano tendencję do zmniejszenia aktywności ruchowej krów (zarówno przed jak i w czasie doju) wraz z zaawansowaniem laktacji. Wykazano, że w wraz z mniejszą aktywnością ruchową krów skracał się czas zakładania kubków udojowych, jednocześnie też zmniejszała się wydajność mleka. Obliczone kryteria jakości modeli budowanych w oparciu o technikę drzew klasyfikacyjnych oraz regresji logistycznej wskazały podobne zmienne odpowiedzialne za reaktywność krów przed (czas zakładania kubków, kolejny dzień laktacji, kolejna laktacja i zajmowana strona hali udojowej) i w trakcie doju (kolejny dzień laktacji, zajmowana strona hali udojowej, dój ranny lub wieczorny, wydajność mleka oraz kolejna laktacja). Jednocześnie zastosowane metody wskazały znaczną złożoność uwarunkowania cechy, jak jest reaktywność krów. Złożoność ta może być dobrze wyjaśniona za pomocą techniki drzew klasyfikacyjnych

Serotonin transporter activity of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives in aspect of their acid–base properties

Affinities of arylpiperazinylalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione for serotonin transporter and their acid–base properties were evaluated. The dissociation constant (pK(a)) of compounds 1–22 were determinated by potentiometric titration and calculated using pKalc 3.1 module of the Pallas system. The data from experimental methods and computational calculations were compared and suitable conclusions were reached

Reversed-phase high performance liquid chromatography study of lipophilicity of imidazo[2,1-f]theophylline derivatives

The present study is a part of our physicochemical and pharmacological studies in a group of tricyclic theophylline derivatives. The investigated compounds exhibit different pharmacological profiles in comparison to theophylline and have been tested as potential antidepressant and/or antipsychotic agents. The differences in pharmacological action between theophylline and their tricyclic derivatives can be explained by their various physicochemical properties, especially lipophilicity. The chromatographic behavior of twenty three derivatives of imidazo[2,1-f]theophylline was investigated, using reversed-phase high performance liquid chromatography (RP-HPLC) method. Moreover, partition coefficients and selected pharmacokinetic parameters were calculated computationally. Principal component analysis (PCA) method was used to establish the relationship between obtained experimental and computational parameters

Evaluation of antiarrythmic activity of novel imidazo[2,1-F]purine-2,4-dione and imidazolidine-2,4-dione derivatives with aminoalkyl moieties

The main goal of this study was to assess antiarrhythmic activity of novel aminoalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione exerting α1 and 5-HT1A receptors affinity. Tested compounds produced prophylactic and therapeutic antiarrhythmic activity in an adrenaline-induced model of arrhythmia. The strongest antiarrhythmic activity as well as the highest α1-adrenoreceptor affinity (Ki = 13.9 nM) was found for 5-methyl-5-phenyl-3-[3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl]-imidazolidine-2,4- dione (12). The results indicated a correlation between α1-adrenoreceptor affinities and antiarrhythmic activity

Impact of N-alkylamino substituents on serotonin receptor (5-HTR) affinity and phosphodiesterase 10A (PDE10A) inhibition of isoindole-1,3-dione derivatives

In this study, a series of compounds derived from 4-methoxy-1H-isoindole-1,3(2H)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1H-isoindole-1,3(2H)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT1A and 5-HT7 receptor affinities. Based on in vitro studies, the most potent compound, 18 (2-[4-(1H-benzimidazol-2-yl)butyl]-4-methoxy-1H-isoindole-1,3(2H)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound 18 in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound 18 in a behavioral model of schizophrenia were also investigated