Synthesis and anticonvulsant activity of 6-methyl-2-thioxo-2, 3-dihydropyrimidin-4(1H)-one acetamides

This research aimed at synthesizing new potential anticonvulsants in the series of 2-(4-methyl-6-oxo-1,6-dihydropyrimidin2-yl)thio-acetamides. An initial intermediate 6-methyl-2-thioxo-2,3-dihydro-pyrimidin-4(1Н)-one was obtained by thereaction of thiourea with an acetoacetic ester in the presence of sodium methoxide. The target 2-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl) thioacetamides were synthesized by alkylation of initial 6-methyl-2-thiopyrimidin-4-one withcorresponding 2-chloroacetamides in Dimethylformamide (DMF) in the presence of potassium carbonate. The structureof compounds was confirmed by 1H Nuclear magnetic resonance (NMR)-spectroscopy, LCMS, and elemental analysis.A screening of anticonvulsant activity of synthesized compounds was carried out using the pentylenetetrazole- andmaximal electroshock-induced seizures models. In these studies, the highest anticonvulsant activity demonstrated acompound 5.5 2-[(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]-N-(4-bromophenyl)-acetamide, which decreased thelethality, the number and the severity of seizures, and increased their latent period. For these compound parameters ofЕD50, acute (LD50) and neurotoxicity (TD50), as well as therapeutic (TI) and protective (PI) indexes were determined.Logical structure analysis of anticonvulsant activity screening revealed some patterns of “structure–activity” relationship.

Convergent synthesis of new N -substituted 2-{[5-(1H -indol-3-ylmethyl)-1, 3, 4-oxadiazol-2-yl]sulfanyl}acetamides as suitable therapeutic agents

abstract A series of N-substituted 2-{[5-(1H-indol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}acetamides (8a-w) was synthesized in three steps. The first step involved the sequential conversion of 2-(1H-indol-3-yl)acetic acid (1) to ester (2) followed by hydrazide (3) formation and finally cyclization in the presence of CS2 and alcoholic KOH yielded 5-(1H-indole-3-yl-methyl)-1,3,4-oxadiazole-2-thiol (4). In the second step, aryl/aralkyl amines (5a-w) were reacted with 2-bromoacetyl bromide (6) in basic medium to yield 2-bromo-N-substituted acetamides (7a-w). In the third step, these electrophiles (7a-w) were reacted with 4 to afford the target compounds (8a-w). Structural elucidation of all the synthesized derivatives was done by 1H-NMR, IR and EI-MS spectral techniques. Moreover, they were screened for antibacterial and hemolytic activity. Enzyme inhibition activity was well supported by molecular docking results, for example, compound 8q exhibited better inhibitory potential against α-glucosidase, while 8g and 8b exhibited comparatively better inhibition against butyrylcholinesterase and lipoxygenase, respectively. Similarly, compounds 8b and 8c showed very good antibacterial activity against Salmonella typhi, which was very close to that of ciprofloxacin, a standard antibiotic used in this study. 8c and 8l also showed very good antibacterial activity against Staphylococcus aureus as well. Almost all compounds showed very slight hemolytic activity, where 8p exhibited the least. Therefore, the molecules synthesized may have utility as suitable therapeutic agents.

resumo Uma série de acetamidas 2-{[5-(1H-indol-3-ilmetil)-1,3,4-oxadiazol-2-il]sulfanila} N-substituídas (8a-w) foi sintetizada em três fases. A primeira etapa envolveu a conversão sequencial de ácido 2-(1H-indol-3-il)acético (1) a éster (2), seguido por hidrazida (3) e, finalmente, a e ciclização na presença de CS2 e KOH alcoólico produziu 5-(1H-indol-3-il- metil)-1,3,4-oxadiazole-2-tiol (4). Na segunda etapa, aminas arílicas/aralquílicas(5a-w) reagiram com brometo de 2-bromoacetila (6​​), em meio básico, para se obter acetamidas 2-bromo-N-substituídas (7a-w). Na terceira etapa, estes eletrófilos (7a- w) reagiram com 4, para se obter os compostos alvo (8a-w). A elucidação estrutural de todos os derivados sintetizados foi realizada por 1H-NMR, IR e técnicas de espectrometria de EI-MS. Além disso, eles foram submetidos a triagem de atividade antibacteriana e hemolítica. Análise da inibição enzimática foi bem apoiada pelos resultados de docking molecular. Por exemplo, o composto 8q exibiu melhor potencial inibitório contra α-glicosidase, e os compostos 8g e 8b exibiram, comparativamente, melhor inibição contra butirilcolinesterase (BChE) elipoxigenase (LOX), respectivamente. Do mesmo modo os compostos 8b e 8c mostraram excelente potencial antibacteriano contra SalmonellaTyphi, semelhante ao do ciprofloxacino, antibiótico padrão usado neste estudo. Os compostos 8c e 8l também mostraram excelente potencial antibacteriano contra Staphylococcus aureus . Quase todos os compostos mostraram pequena atividade hemolítica, sendo que o composto 8p apresentou menor atividade. Assim, as moléculas sintetizadas podem ter a sua utilidade como agentes terapêuticos adequados.

The molecular epidemiology and infections risk factors of clinical linezolid-resistant Enterococci isolates / 中华检验医学杂志

Objective To investigate the molecular epidemiology and infectious risk factors of linezolid-resistant Enterococci (LRE) isolates in the First Affiliated Hospital of Chongqing Medical University.Methods Thirteen LRE isolates were collected from 2011 to 2013 and confirmed by broth dilution susceptibility testing.The minimum inhibitory concentrations (MIC) of twelve antimicrobial agents were analyzed using Vitek 2 compact.The molecular epidemiology of LRE isolates was determined by multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and the Diversilab.A casecontrol study was conducted for the analysis of risk factors, and Logistic regression was performed to evaluate the independent risk factors.Results All thirteen LRE isolates showed low-level resistance to linezolid, and most of these isolates were resistant to tetracycline, erythromycin and ciprofloxacin.However, they had high sensitivity to penicillin, ampicillin and tigecycline.Sequence type 480 was predominant in the hospital, and three isolates (isolates 3, 4, and 5) from July to September 2013 were found to have the same ST, PFGE pattern and rep-PCR group, indicating the same resistance clone.Admission to intensive care unit (ICU), peripheral vascular disease, males, hypoalbuminaemia, enema and linezolid therapy were identified as significant risk factors for LRE infections.Among these factors, admission to ICU, enema and linezolid therapy were independent risk factors for the acquisition of LRE.Conclusions Thirteen LRE isolates collected in the hospital showed a multidrug-resistant phenotype, and a small-scale prevalence was detected from 2011 to 2013.Therefore, attention should be paid to monitor the LRE in the hospital to decrease the prevalence of LRE infections.

α-Glucosidase Inhibitory Activity of 4-Aryl-N-(2,4-Thiazolidinedione-5-Acetyl)-1,3-Thiazol-2-Amines.

A series of N-(4-aryl-1,3-thiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamides 3a-k and N- (1,3-benzothiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamides 3l-n are synthesized and evaluated for their α-glucosidase inhibitory activity. N-[4-(m-Chlorophenyl)-1,3-thiazol-2yl]-2-(2,4-dioxo-1,3-thiazolidin-5- yl)acetamide (3g) and N-[4-(o-fluorophenyl)-1,3-thiazol-2-yl]-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamide (3j) have shown very good inhibition. The remaining compounds have exhibited moderate to good activity ranging from 37- 63 % of α-glucosidase enzyme inhibition.

Synthesis of new N-phenyl-N-(1-phenylhex- 5-en-1-yl)acetamides and their ¹H-NMR conformational study / Síntesis de nuevas N-fenil- N-(1-fenilhex-5-en-1-il) acetamidas y su estudio conformacional mediante ¹H-RMN / Síntese de novas N-fenil- N-(1-fenilhex-5-en-1-il) acetamidas e o seu estudo conformacional por ¹H-RMN

Antifungal and antiparasitic activities for N-acetyl derivatives of different N-(prop)butenylamines have been previously evaluated and reported. Consequently, an efficient and versatile synthesis procedure and complete characterization of different N-phenyl-N-(1-phenylhex-5-en-1-yl)acetamides is presented. Two conformational isomers were observed for one of the compounds in their ¹H/13C-NMR spectra. The conformational analysis was carried out using the B3LYP functional with the 6-31+G(2d,p) basis and the NMR spectroscopic data. The dihedral angle values of the allylic system obtained by both computational methods and ¹H-NMR data analysis (Garbisch's equation) were compared and used to successfully determine the conformational structures and the intramolecular interaction responsible for signal duplicity and chemical shifting respectively.

Previamente se han evaluado y reportado las propiedades antifúngicas y antiparasitarias para derivados de N-acetil procedentes de diferentes N-(prop)butenilaminas. En este sentido, la esta investigación presenta un procedimiento de síntesis versátil y eficiente, con la caracterización completa de diferentes N-fenil-N-(1-fenilhex-5- en-1-yl)acetamidas. Se observaron dos isómeros conformacionales para uno de los compuestos en su espectro ¹H/13CRMN. El análisis conformacional se llevó a cabo usando B3LYP funcional con base en 6-31+G(2d,p) y los datos de espectroscopia RMN. Los valores de ángulo dihedro del sistema alílico -obtenidos por los métodos computacionales citados y el análisis de los datos derivados de ¹H-RMN usando la ecuación de Garbisch-, se compararon y se usaron para determinar exitosamente las estructuras conformacionales isoméricas y la interacción intramolecular responsables de la duplicidad de señales y del desplazamiento químico, respectivamente.

As atividades antifúngicas e antiparasitárias de N-acetil derivados de diferentes N-(prop)butenilaminas têm sido previamente avaliadas e relatadas. Neste trabalho, apresenta-se uma rota de síntese eficiente e a caracterização completa de diferentes N-fenil-N-(1-fenilhex-5-en-1-il)acetamidas. Nos espectros ¹H/13C-RMN foram observados dois isômeros conformacionais para um dos compostos. Foi feita uma análise conformacional usando o funcional B3LYP com bases 6-31+G(2d,p) e os dados de ¹H-RMN. Os valores dos ângulos diedros do sistema alílico obtidos por métodos computacionais e por análise de dados de ¹H-RMN (equação de Garbish) foram comparados e usados para determinar as estruturas dos confôrmeros, o que permitiu determinar as interações intramoleculares responsáveis do diferente deslocamento químico e a conseqüente duplicidade dos sinais no composto que apresentou os dois confôrmeros.

Effect of lacosamide on expression of Nav1.8 in dorsal root ganglia in a rat model of chronic neuropathic pain / 中华麻醉学杂志

Objective To investigate the effect of lacosamide on expression of Nav1 .8 in dorsal root ganglia (DRG) in a rat model of chronic neuropathic pain.Methods Thirty-six female specific-pathogen-free (SPF)SD rats were randomly assigned into 3 groups ( n = 12 each): sham operation group (group S), model group (group M) and lacosamide group (group L) . Chronic neuropathic pain was produced by insertion of a small stainless steel rod (4.00 mm in length and 0.63 mm in diameter) into the L, intervertebral foramen in the rat, producing a chronic steady compression of the DRG in M and L groups. The mechanical threshold was measured 2 days before operation and on the 2, 4, 6, 7, 8, 9 and 10 days after operation (T0-7 ) . Intraperitoneal lacosamide 20mg/kg (in normal saline 0.5 ml) was injected at T4-7, twice a day in S and L groups. In group M, normal saline 0.5 ml was injected at T4-7 twice a day and the mechanical threshold was measured after the last administration everyday . The L, DRG on the operated side was removed after measurement of pain threshold to detect the expression of Na, 1.8 mRNA and protein by RT-PCR and immuno-histochemistry respectively. Results Compared with group S, the mechanical pain threshold was significantly decreased at T1-7 and the expression of Navl .8 mRNA and protein was up-regulated in M and L groups ( P < 0.05) . Compared with group M, the mechanical pain threshold was significantly increased at T4-7 and the expression of Nav 1.8 mRNA and protein was down-regulated in group L ( P < 0.05) . Conclusion The mechanism by which lacosamide reduces chronic neuropathic pain is related to the down-regulation of the expression of Nav 1.8 in rat DRG.

Simple preparation of new N-aryl-N-(3-indolmethyl) acetamides and their spectroscopic analysis / Preparación sencilla de nuevas N-aril-N-(3-indolmetil) acetamidas y su análisis espectroscópico / Preparação simples de novas N-aril-N-(3-indolmetil) acetamidas e sua análise espectroscópica

Objectives. To prepare new indolic molecules and characterize them by spectroscopic methods. Materials and methods: All reagents were purchased from Aldrich, commercial grade. The purity of the products and the composition of the reaction mixtures were monitored by thin layer chromatography over Silufol UV254 0.25 mm-thick chromatoplates. Product isolation and purification were performed by column chromatography (SiO2), using ethyl acetate-petroleum ether mixtures as eluents. Results. The synthesis of new N-aryl-N-(3-indolmethyl) acetamides based on first step iminization reaction of indol-3-carbaldehyde is accomplished. The structures of the C-3 substituted indoles were confirmed by ¹H-NMR and 13C-NMR studies supported by inverse-detected 2D NMR experiments and also through monocrystal X-ray diffraction. Conclusions. An efficient, economic, and fast synthetic route was designed to the construction of the N-aryl-N-(3-indolmethyl) acetamides, structural analogues of some alkaloids.

Objetivos: Preparar nuevas moléculas indólicas y caracterizarlas por los métodos espectroscópicos. Materiales y métodos. Todos los reactivos fueron adquiridos de Aldrich, de grado comercial. La pureza de los productos y composición de las mezclas de reacción fueron monitoreadas por la cromatografía en capa delgada, Silufol UV254 0.25 mm-grosor de cromatoplacas. El aislamiento y purificación de los productos fueron realizados por la cromatografía en columna (SiO2), usando mezclas de acetato de etilo y éter de petróleo como eluentes. Resultados. Se ha realizado la síntesis de nuevas N-aril-N-(3-indolmetil) acetamidas, basada en la reacción de iminización del indol-3-carbaldehído. Las estructuras de los indoles C-3 sustituidos fueron confirmadas por estudios de ¹H, 13C -RMN, experimentos de 2D RMN y también por difracción monocristal de Rayos X. Conclusiones. Se ha diseñado una nueva ruta de síntesis eficiente, económica y rápida para la construcción de las N-aril-N-(3-indolmetil) acetamidas, análogos estructurales de diversos alcaloides.

Objetivos. Preparar novas moléculas indólicas e caracterizar-las através de métodos espectroscópicos. Materiais e métodos. Todos os reagentes foram obtidos de Aldrich, de tipo comercial. A pureza dos produtos e a composição das misturas de reação foram monitoradas por cromatografia em camada fina, Silufol UV254 0,25 mm de espessura das cromatoplacas. O isolamento e a purificação dos produtos foram feitos através de cromatografia em coluna (SiO2), utilizando misturas de acetato de etila e éter de petróleo como eluente. Resultados. Realizou-se a síntese de novas N-aril-N-(3-indolmetil)acetamidas, baseada na reação de iminización do indol-3-carbaldeído. As estruturas dos indóis C-3 substituídos foram confirmadas por estudos de ¹H, 13C -RMN, experimentos de 2D RMN e também por difração monocristal dos Rayos X. Conclusões. Desenhou-se una nova rota de síntese eficiente, econômica e rápida para a construção das N-aril-N-(3-indolmetil) acetamidas, análogos estruturais de vários alcalóides.

13C-methacetin breath test as a quantitative liver function assessment in non-alcoholic fatty liver / 中国医师杂志

Objective To investigate and assess 13C-methacetin breath test as a method to quantitatively evaluate the liver function of non-alcoholic fatty liver. Methods Twenty-four male Wistar rats were randomly divided into the following 2 groups, control group given a standard chow and model group given high-fat diet (88 % standard chow + 10% lard +2% cholesterol). At the 8th week and 12th week, the isotope-selective nondispersive infrared spectrometer (NDIRS) was applied to 13C-methacetin breath test. Peak value of breathing (DOB), the duration to peak (T), and cumulative expiration within 60 min (CUM60min) were determined. Then, the two groups of rats were executed respectively. The level of endotoxin in the portal vein and abdominal aorta was detected respectively, and the specific tissue of liver was fixed in 10% buffered formalin, processed, and embedded in paraffin for hematoxylin eosin (H&E). Results Compared with the control group, DOB increased in the model group at the 12th week but not at the 8th week. The trend was corresponded to the degree of path-ological lesion in the liver of rats. At the 8th week and 12th week, endotoxin levels in the portal vein of model group were significantly in-creased compared with control group. The breath test results were positively related to emlotoxin levels in the portal vein. Conclusion 13C-methacetin breath test may be a non-invasive method to evaluate the pathological changes of non-alcoholic fatty liver.