Método modificado para la síntesis de hidrocloruro de amantadina / A modified method for synthesis of amantadine hydrochloride

Introducción: El hidrocloruro de amantadina (I) es conocido como un medicamento antiviral utilizado para prevenir y tratar las infecciones por influenza A. También se utiliza para aliviar los síntomas de la enfermedad de Parkinson en el período inicial. Se han informado varios métodos para la preparación de (I). Estos procedimientos comienzan con adamantano (II) en cuatro o tres pasos de reacción, para producir hidrocloruro de amantadina con rendimientos globales que van del 45 por ciento al 58 por ciento. Objetivo: Mejorar el método para la síntesis de hidrocloruro de amantadina, que puede introducirse a escala industrial. Métodos: La optimización paso a paso para reducir el uso de reactivos, disolventes, así como las condiciones de cada paso, se seleccionaron para ser menos agresivas y más amigables con el medio ambiente. Resultados: Todos los factores relacionados con el rendimiento de la reacción para sintetizar los compuestos intermedios y finales se seleccionaron para obtener el mayor rendimiento de cada etapa. Finalmente, se estableció un procedimiento de dos pasos para la síntesis de (I) a partir de (II), a través de N- (1-adamantil) formamida (III), con un rendimiento global mejorado del 78 por ciento y una pureza del 99,2 por ciento. Se confirmó la estructura del producto por 1H-NMR, 13C-NMR, IR y MS. La síntesis de N- (1-adamantil) formamida (VI) a partir de (II) también se logró con éxito en un solo paso. Este método evita el uso de bromo líquido o ácido sulfúrico gaseoso como reactivos. La conversión posterior de (VI) a (I) se llevó a cabo bajo condiciones de reacción, más suaves sin usar solventes peligrosos. Conclusiones: Se logró la síntesis mejorada del clorhidrato de amantadina (I). Este resultado puede utilizarse en una producción industrialmente conveniente. Las materias primas y reactivos utilizados en esta investigación son baratas y están disponibles. El tiempo total de preparación se redujo significativamente, con ahorro de energía y mano de obra(AU)

Introduction: Amantadine hydrochloride (I) was well-known as an antiviral drug used to prevent and treat influenza A infections. Besides, it also was used to relieve the symptoms of Parkinson's disease in the early period. Several methods for the preparation of I have been reported. These procedures started with adamantane (II) in four or three reaction steps to produce amantadine hydrochloride with overall yields ranging from 45 percent to 58 percent. Objectives: Improving method for synthesis of amantadine hydrochloride could introduce to industrial scale. Methods: Step-by-step optimization to reduce the use of reagents, solvents, as well as the conditions of each step were screened to be milder and more environment-friendly. Results: All factors related to the yield of reaction to synthesize the intermediate and final compounds were screened to give the highest yield of each step. Finally, a two-step procedure for the synthesis of (I) from (II) via N-(1-adamantyl) formamide (III) with improving overall yield of 78 percent and a purity of 99.2 percent was established, and the structure of the product was confirmed by 1H-NMR,13C-NMR, IR and MS. The synthesis of N-(1-adamantyl) formamide (VI) from (II) also was successfully accomplished within only one step. This method avoided the use of liquid bromine or fuming sulfuric acid as reactants. The subsequent conversion of (VI) to (I) was carried out under milder reaction conditions without using hazardous solvents. Conclusions: An improved synthesis for amantadine hydrochloride (I) have been provided. This research can be an industrially convenient production of amantadine hydrochloride. Because the raw materials and reagents used in this research are cheap and available which also were screened to save their use. Moreover, the total preparation time was significantly reduced to save energy as well as labor(AU)

Recycling of expired paracetamol-containing drugs as source of useful reagents for an organic synthesis

All types of pharmaceutical waste negatively impact on the environment and human health and require specialmethods of utilization. In the current study, it is described that the elaboration of utilization methods of one of the mostcommonly used medicines as paracetamol of various brands and forms on the example of expired and substandarddrugs based on acid hydrolysis providing 4-aminophenol with 16%–87% yields. The actuality of obtaining the4-aminophenol derivatives revealed by their findings in the structure of many biologically active compounds withanticancer, antimicrobial, antioxidant, and cardiovascular activities. In addition, it has been demonstrated that thechemical transformation of paracetamol in capsule and tablet dosage forms providing N-[4-(benzyloxy)phenyl]acetamide as a useful reagent in an organic synthesis in the reaction with benzyl chloride in an alkaline medium. Thestructures of obtained products and purity were established on the basis of mass spectrometry (LCMS+) techniques.As a result, the simple procedure from moderate to good yield is an important feature of paracetamol-containing drugutilization as a source of different useful reagents for an organic synthesis and industrial production.

Synthesis of new 2-{2,3-dihydro-1, 4-benzodioxin-6-yl[(4-methylphenyl) sulfonyl]amino}-N-(un/substituted-phenyl)acetamides as α-glucosidase and acetylcholinesterase inhibitors and their in silico study

The aim of the present research work was to investigate the enzyme inhibitory potential of some new sulfonamides having benzodioxane and acetamide moieties. The synthesis was started by the reaction of N-2,3-dihydrobenzo[1,4]-dioxin-6-amine (1) with 4-methylbenzenesulfonyl chloride (2) in the presence of 10% aqueous Na2CO3 to yield N-(2,3-dihydrobenzo[1,4]-dioxin-6-yl)-4-methylbenzenesulfonamide (3), which was then reacted with 2-bromo-N-(un/substituted-phenyl)acetamides (6a-l) in DMF and lithium hydride as a base to afford various 2-{2,3-dihydro-1,4-benzodioxin-6-yl[(4-methylphenyl)sulfonyl]amino}-N-(un/substituted-phenyl)acetamides (7a-l). All the synthesized compounds were characterized by their IR and 1H-NMR spectral data along with CHN analysis data. The enzyme inhibitory activities of these compounds were tested against a-glucosidase and acetylcholinesterase (AChE). Most of the compounds exhibited substantial inhibitory activity against yeast a-glucosidase and weak against AChE. The in silico molecular docking results were also consistent with in vitro enzyme inhibition data.

Contribution of the IAM Pathway to IAA Pool in Developing Rice Grains

A possible role for the indole-3-acetamide (IAM) pathway in the indole-3-acetic acid (IAA) production was investigated in developing rice grains. IAM-hydrolase proposed to convert IAM to IAA primarily through the identification of IAM and IAM-hydrolase activity in some plant species. Expression profiles of the two putative rice IAM-hydrolase genes, OsAMI1&2, were compared to the previously quantified IAA level. The abrupt increase in IAA level between 4 and 7 days after anthesis (DAF) was not found to correlate with changes in the expression of OsAMI1 or OsAMID2 suggesting that the IAM pathway may not contribute significantly to IAA pool in rice grains. Production of a biological compound other than IAA may explain the high activity of OsAMI1&2 in developing rice grains. OsAMI1 that reported to be conserved across the plant kingdom showed higher expression level in most analyzed reproductive rice tissues whereas OsAMID2 showed more fluctuation in expression comparing to OsAMI1. Role of the IAM pathway in IAA production was also discussed in other plant systems and Arabidopsis seed was recommended as an ideal tissue to identify enzyme(s) convert(s) tryptophan to IAM as well as physiological effects of IAA produced via this pathway.

Synthesis, potential anticonvulsant and antidepressant effects of 2-(5-methyl-2,3-dioxoindolin-1-yl)acetamide derivatives

A new series of 2-(5-methyl-2,3-dioxoindolin-1-yl)acetamide derivatives were synthesized and evaluated for their anticonvulsive activity in a pentylenetetrazole (PTZ)-evoked convulsion model and antidepressant activity in the forced swimming test (FST) model. Eleven synthesized compounds were found to be protective against PTZ-induced seizure and showed the anticonvulsant activity. In addition, four of the synthesized compounds (4l, 4m, 4p and 4q) showed potent antidepressant-like activity. Among these compounds, compound 4l was found to have the most potent antidepressant-like activity, and significantly reduced the duration of immobility time at 100 mg/kg dose level when compared to the vehicle control, which is similar to the reference drug fluoxetine.

XP-16, a new xanthono-pyridine derivative, induces apoptosis in human lung carcinoma A549 cells / 中国药理学通报

Aim To investigate the anticancer effect of a new xanthono-pyridine derivative N, N '-( 7-oxo-7H-chromeno[3,2-h] quinoline-5,9-diyl)-bis(2-( pyrroli-din-1-yl)acetamide) (XP-16) on human lung carcino-ma cell line A549 and the potential mechanism. Meth-ods Antiproliferative effect of XP-16 on A549 cells was evaluated by MTT assay, morphological examina-tion and colonial assay. Apoptosis detection was car-ried out using Hoechst 33258 and PI double-dyeing method. Intracellular Ca2+ concentration ( [ Ca2+] i ) and mitochondria membrane potential were detected by fluorospectrophotometer. A549 cells treated with XP-16 were collected for Bad and metallothionein 1 A ( MT-1 A ) transcript analysis by real-time reverse tran-scriptase-polymerase chain reaction ( qRT-PCR) . Re-sults XP-16 inhibited A549 cell proliferation in dose-and time-dependent manner. Typical apoptotic mor- phology such as chromatin aggregation and nuclear fragmentation was observed in A549 cells treated with XP-16 for 24 h, and the apoptosis was showed in a dose-dependent manner. After treated with XP-16, [ Ca2+] i and mitochondria membrane potential of A549 cells were decreased, and relative mRNA level of Bad and MT-1A was up-regulated. Conclusions XP-16 has anticancer effect on A549 cells through apoptosis, which might be associated with decreasing intracellular Ca2+ concentration and mitochondria membrane poten-tial. Up-regulation of MT-1A expression might be the result of decreased [ Ca2+] i .

Anticancer effect of xanthono-pyridine derivative xp-16 on human gastric carcinoma MGC-803 cells / 中国药学杂志

OBJECTIVE: To investigate aticancer effect and potential mechanism of a new xanthono-pyridine derivative N, N'-(7-oxo-7H-chromenoquinoline-5, 9-diyl)-bis(2-(pyrrolidin-1-yl)acetamide) (XP-16) on human gastric carcinoma cell line MGC-803.

Chemical constituents from Scolopendra multidens (I) / 中草药

Objective: To study the chemical constituents from Scolopendra multidens. Methods: Compounds were isolated and purified by a combination of chromatographic techniques including silica gel, ODS, Sephadex LH-20 column chromatography, middle and low pressure preparative chromatograms, and pre-HPLC. The structures were elucidated on the basis of physicochemical properties and spectroscopic analyses. Results: Ten compounds were separated and identified as uracil (1), 7, 8-dimethyl-isoalloxazine (2), indole-3-acetamide (3), N-(2-phenylethyl) acetamide (4), (3S)-1, 2, 3, 4-tetrahydro-β-carboline-3-carboxylic acid (5), cyclo-(L-Ile-L-Pro) (6), cyclo-(L-Leu-L-Pro) (7), cyclo-(L-Phe-L-Pro) (8), cyclo-(L-Phe-L-Tyr) (9), and cyclo-(L-Val-L-Pro) (10). Conclusion: All the compounds are isolated from S. multidens for the first time.

2-Phenitidine derivatives as suitable inhibitors of butyrylcholinesterase

This manuscript reports the synthesis of a series of N-substituted derivatives of 2-phenitidine. First, the reaction of 2-phenitidine (1) with benzene sulfonyl chloride (2) yielded N-(2-ethoxyphenyl) benzenesulfonamide (3), which further on treatment with sodium hydride and alkyl halides (4a-g) furnished into new sulfonamides (5a-g). Second, the phenitidine reacted with benzoyl chloride (6) and acetyl chloride (8) to yield the reported N-benzoyl phenitidine (7) and N-acetyl phenitidine (9), respectively. These derivatives were characterized by infrared spectroscopy, ¹H-NMR, and EI-MS, and then screened against acetylcholinesterase, butylcholinesterase, and lipoxygenase enzyme, and were found to be potent inhibitors of butyrylcholinesterase alone.

Este trabalho apresenta a síntese de uma série de derivados da 2-fenetidina N-substituídos. Primeiro, a reação da 2-fenetidina (1) com cloreto de benzenossulfonila (2) conduziu à N-(2-etoxifenil)benzenossulfonamida (3) que, após tratamento com hidreto de sódio e haletos de alquila (4a-g), originou novas sulfonamidas (5a-g). Em segundo lugar, a reação da fenetidina com cloreto de benzoíla (6) e cloreto de acetila (8) conduziu, respectivamente, à N-benzoilfenetidina (7) e N-acetilfenetidina (9). A caracterização destes derivados fez-se por IV, ¹H-RMN e EM-IE. Procedeu-se à avaliação da atividade inibidora destes compostos em relação às enzimas acetilcolinesterase, butirilcolinesterase e lipoxigenase. No entanto, apenas revelaram atividade inibidora da butirilcolinesterase.

Efeito protetor da acetamida em bovinos indica monofluoroacetato como princípio tóxico de Palicourea marcgravii (Rubiaceae) / Protective effect of acetamide in cattle indicates that monofluoroacetate is the toxic principle of Palicourea marcgravii (Rubiaceae)

O presente trabalho teve como objetivo avaliar e comparar o efeito protetor da acetamida nas intoxicações experimentais por monofluoroacetato (MF) e por folhas frescas de Palicourea marcgravii em bovinos, no intuito de confirmar, de forma prática, que esse composto é o princípio tóxico responsável pelo quadro clínico-patológico e pela morte dos animais intoxicados por essa planta. Três bovinos receberam MF, por via oral, na dose de 0,5mg/kg e, em seguida, a dois desses animais administraram-se acetamida, por via oral, nas doses de 0,38 e 2,0g/kg. Outros dois bovinos receberam 1,0g/kg de P. marcgravii, em seguida, a um deles administrou-se 1,0 g/kg de acetamida. Acetamida, quando administrada em quantidades suficientes (maior dose), evitou o aparecimento dos sinais clínicos e a morte de todos os animais que receberam MF ou P. marcgravii. Tal efeito protetor foi, de fato, confirmado após uma semana, quando o mesmo protocolo experimental foi repetido, para cada bovino, porém sem a administração de acetamida. Todos os bovinos não tratados com acetamida manifestaram sinais clínicos e morreram subitamente. O quadro clínico-patológico manifestado pelos bovinos intoxicados por MF ou P. marcgravii foi semelhante e, caracterizou-se por "morte súbita". Os animais em geral, apresentaram taquicardia, taquipnéia, tremores musculares, jugular repleta com pulso venoso positivo, polaquiúria, instabilidade, perda de equilíbrio, por vezes, cambaleavam e apoiavam a cabeça no flanco. Na fase final, todos os animais deitavam-se e levantavam-se com maior frequencia, deitavam ou caíam em decúbito lateral, esticavam os membros, faziam movimentos de pedalagem, apresentavam respiração ofegante, arritmia, opistótono, nistagmo, mugiam e morriam. A duração da "fase dramática" variou de 2 a 26min. À necropsia verificaram-se, em geral, aurículas, jugulares, ázigos e pulmonares leve a moderadamente ingurgitadas, leve a acentuado edema da subserosa da vesícula biliar, sobretudo, na sua inserção no fígado, bem como moderada quantidade de líquido espumoso róseo na traquéia e brônquios. O exame histopatológico revelou, no rim de todos os animais, leve até acentuada degeneração hidrópico-vacuolar das células epiteliais dos túbulos uriníferos contornados distais associada à picnose nuclear; no fígado, havia leve a moderada congestão, discreta a moderada tumefação e moderada vacuolização de hepatócitos, predominantemente, centrolobular, necrose de coagulação individual ou de grupos de hepatócitos e corpúsculos de choque. Os dados obtidos neste trabalho comprovam, de forma prática, que MF é o princípio tóxico de P. marcgravii responsável pelo quadro clínico-patológico e a morte dos animais que ingerem e se intoxicam naturalmente por essa planta, uma vez que a acetamida atua como antídoto eficaz (efeito antagônico) de forma idêntica em ambas as intoxicações.

The aim of the study was to evaluate and compare the protective effect of acetamide in experimental poisoning by fresh leaves of Palicourea marcgravii and monofluoroacetate (MF) in catlle, in order to prove in a practical way that this compound is the toxic principle responsible for the clinical signs and death of animals that ingested the plant. MF was administered orally in single doses of 0.5mg/kg to three cows; a few minutes later, two of these cows received, orally, single doses of acetamide (0.38 or 2.0g/kg). Two other cows ingested 1.0g/kg of P. marcgravii, and one of these cows received some minutes later 1.0g/kg of acetamide. Adequate doses of acetamide, administered right after the poisoning by P. marcgravii or MF, were able to prevented the onset of clinical signs and avoid the death of all animals. One week later, the experiments were repeated, but without the antidote. All animals not treated with acetamide showed symptoms of poisoning and died suddenly. MF and P. marcgravii caused the same clinical and pathological picture of "sudden death" in cattle. Clinically, the cattle presented palpitation, abdominal breathing, muscle tremors, engorged jugular vein with positive pulse, pollakiuria, slight loss of balance with sometimes swaying gait, the animals laying down and with the head on their flank. In the "dramatic phase", all the animals fell into lateral decubitus, stretched the limbs, made paddling movements, presented opistotonus, arrhythmia, nystagmus, and died. The "dramatic phase" lasted from 2 to 26 minutes. At postmortem examination, the heart auricles, jugulars and pulmonary veins were slightly to moderately ingurgitated; slight to marked edema of the subserosa was seen in fixation sites of gall bladder to the liver. In one cow, pulmonary edema was observed. Histopathology revealed in all cows slight to marked hydropic-vacuolar degeneration of the epithelial cells of the distal convoluted uriniferous tubules associated with nuclear pyknosis. Coagulation necrosis of individual or groups of hepatocytes and slight to moderate hepatic congestion with numerous shock corpuscles were also observed. The experimental results showed in practice that MF is the toxic principle responsible for the clinical-pathological picture and death of the cattle that ingested P. marcgravii, since acetamide acts as an efficient antidote (antagonistic effect), identical in both poisonings.

Synthesis and antimicrobial study of N-[4-(2-piperidine-1-yl-ethoxy) phenyl] acetamide analogues.

In the present study, a novel series of N-[4-(2-piperidine-1-yl-ethoxy) phenyl]- acetamides were synthesized from 4-aminophenol and characterised by IR, 1H-NMR, Mass spectral studies and elemental analysis. The antimicrobial potency of compounds is tested against variety of fungal and bacterial strains by disc agar diffusion technique. in comparison to to fluconazole and chloramphenicol respectively. Some of the synthesized compounds exhibit the potency comparable to that of standard drugs.

Efeito protetor da acetamida sobre as intoxicações experimentais em ratos por monofluoroacetato de sódio e por algumas plantas brasileiras que causam morte súbita / The protective effect of acetamide on experimental poisoning by sodium mono[1]luoroacetate and Brazilian sudden death causing plants in rats

O objetivo deste trabalho é avaliar e comparar o efeito protetor da acetamida nas intoxicações por monofluoroacetato de sódio (MF) e por oito plantas brasileiras que causam "morte súbita" (PBCMS) (Palicourea marcgravii, P. juruana, Pseudocalymma elegans, Arrabidaea bilabiata, Amorimia (Mascagnia) rigida, M. pubiflora, Amorimia (Mascagnia) exotropica e M. aff. rigida) em ratos, bem como descrever o quadro clínico-patológico nos animais intoxicados. Foram utilizados 33 ratos da linhagem Wistar (Rattus norvegicus albinus), nove dos quais ingeriram espontaneamente folhas frescas de P. marcgravii nas doses de 2,0 e 4,0g/kg. Dois desses ratos receberam doses únicas de acetamida de 2,0 e 4,0g/kg, por via oral um minuto antes do fornecimento da planta. Outro rato recebeu 4,0g/kg de acetamida após ingerir 4,0g/kg da planta e manifestar sintomas graves. Nos experimentos com MF, foram administradas a quatro ratos doses de 4,0 e 8,0mg/kg; o intervalo de tempo entre a administração da acetamida e dos extratos concentrados ou do MF variou entre 2 a 4 horas. A dose de acetamida utilizada variou de 2,0 a 8,0g/kg. Nos experimentos com extratos concentrados das oito PBCMS, 20 ratos foram intoxicados por via oral com doses únicas ou repetidas. A acetamida, quando previamente administrada em doses suficientemente altas, evitou o aparecimento dos sinais clínicos ou morte dos animais intoxicados por MF, bem como pelas folhas frescas de P. marcgravii e com os extratos concentrados de cada uma das sete outras PBCMS utilizadas. Todos esses ratos foram novamente submetidos ao mesmo protocolo experimental, porém sem administração de acetamida. Nesses experimentos posteriores todos os ratos manifestaram sinais clínicos e morte (exceto M. aff. rigida, cuja amostra não se revelou tóxica). Todos os ratos apresentaram aurículas de leve a acentuadamente ingurgitadas e, por vezes, também as veias cava cranial e caudal. Havia moderada dilatação cardíaca direita e esquerda em três animais. O fígado de todos os animais apresentava-se de leve a acentuadamente congesto, e em alguns ratos, verificou-se evidenciação do padrão lobular. Observou-se ainda discreta a leve presença de líquido espumoso na superfície de corte dos pulmões em três ratos. O exame histopatológico evidenciou nos rins de seis dos 30 ratos leve a moderada tumefação citoplasmática dos túbulos uriníferos contornados distais e, por vezes, também nos túbulos coletores, mas somente em quatro (dois intoxicados por P. marcgravii, um por P. elegans e outro por A. exotropica) havia a clássica lesão de degeneração hidrópico-vacuolar com picnose nuclear evidente. No fígado de 26 animais havia congestão e, destes, três apresentaram estreitamento compressivo dos cordões hepáticos, oito corpúsculos de choque; em outros três, necrose focal de discreta a moderada. Observou-se ainda, de discreta a moderada vacuolização de hepatócitos em 16 animais. Este trabalho demonstra que a acetamida possui acentuado efeito protetor, capaz de prevenir os sinais clínicos e evitar a morte dos ratos intoxicados por MF, folhas frescas de P. marcgravii e extratos concentrados de outras sete PBCMS. O quadro clínico-patológico observado nos ratos intoxicados pelo MF e pelas PBCMS deste estudo, associado ao efeito protetor da acetamida, confirma que o MF é o princípio tóxico responsável pela morte dos ratos, e, por extensão, também dos bovinos que ingeriram PBCMS.

The protective effect of acetamide in poisoning by sodium monofluoroacetate (MF) and by eight Brazilian sudden death causing plants (BSDCP) (Palicourea marcgravii, P. juruana, Pseudocalymma elegans, Arrabidaea bilabiata, Amorimia (Mascagnia) rigida, M. pubiflora, Amorimia (Mascagnia) exotropica and M. aff. rigida) was studied using rats. Additionally the clinical and pathological picture of the poisoning was described. In these experiments 33 Wistar rats (Rattus norvegicus albinus) were used. Nine rats ate spontaneously the fresh leaves of P. marcgravii at amounts of 2.0 and 4.0g/kg. Two of the rats received orally single doses of acetamide (2.0 and 4.0g/kg) one minute before the plant was supplied. A third rat received 4.0g/kg of acetamide after consumption of 4.0g/kg of the plant and showed severe symptoms of poisoning. In the experiments with MF, doses of 4.0 and 8.0mg/kg were administered to four rats. The interval between the administration of either acetamide and concentrated plant extracts or MF ranged from 2 to 4 hours; the dose of acetamide ranged from 2.0 to 8.0g/ kg. In the experiments with concentrated extracts of eight BSDCP, 20 rats were orally poisoned with single or repeated doses. Acetamide, when previously administered, prevented the appearance of clinical signs and death in all of the rats poisoned by MF, as well as of the ones poisoned by fresh P. marcgravii leaves and by the concentrated extracts of each of the other BSDCP. These rats were re-subjected to the same experimental protocol, yet without the administration of acetamide. In these experiments, all of the rats evidenced clinical signs and death (except M. aff. rigida). All of the rats showed mild to markedly engorged atria, and sometimes also of the cranial and caudal vena cava. In three of the rats, there was a moderate right and left cardiac dilatation. The liver of all rats was slightly or markedly congested, with lobular pattern in some. There was frothy liquid on the cut surface of the lungs in three of the rats. The histopathology of the kidneys in six rats showed slight cytoplasmic swelling of the distal convoluted tubules and sometimes also of the collecting tubules. But only in four rats a vacuolar-hydropic degeneration with nuclear pyknosis was seen. Twenty-six rats showed liver congestion, three of them with compressive narrowing of the hepatic cords, and in eight rats shock corpuscles were observed; another three rats showed slight to moderate focal liver necrosis. A slight to moderate vacuolation of hepatocytes was observed in 16 rats. It can be concluded that acetamide had a protective effect, capable to prevent clinical signs and death of the rats poisoned by MF, and by fresh P. marcgravii leaves and concentrated extracts of seven other BSDCP. The clinical and pathological picture observed in the rats poisoned by MF and BSDCP, associated with the protective effect of acetamide, indicate that MF is the toxic principle responsible for death of the rats, and by extension, for the death of cattle that ate BSDCP.

O antagonismo com acetamida em experimentos com ovinos, caprinos e coelhos indica monofluoroacetato como princípio tóxico de Pseudocalymma elegans Bignoniaceae / Antagonism of acetamid in experiments with sheep, goats and rabbits indicates that monofluoroacetate is the toxic principle of Pseudoca lymma elegans Bignoniaceae

O presente trabalho teve como objetivo avaliar o efeito protetor da acetamida nas intoxicações experimentais por Pseudocalymma elegans em ovinos, caprinos e coelhos, com a finalidade de comprovar indiretamente que o monofluoroacetato (MF) é responsável pelos sinais clínicos e a morte dos animais que ingerem essa planta. Foram realizados experimentos para determinar a dose letal da planta coletada em Rio Bonito, RJ, em diferentes épocas do ano para ovinos e caprinos e ajustar a dose de acetamida a ser administrada. - No primeiro experimento, dois ovinos e dois caprinos receberam 1,0g/kg de P. elegans fresca e um animal de cada espécie foi tratado previamente com 2,0g/kg de acetamida. Nenhum animal apresentou alterações clínicas ou morreu. Ao que tudo indica a planta poderia estar menos tóxica, já que foi coletada no fim da estação das águas. - No segundo experimento, dois ovinos e dois caprinos receberam 0,67 e 1,0g/kg da planta dessecada, após tratamento prévio, com 2,0 e 3,0g/kg de acetamida, respectivamente. Todos os animais morreram, pois administramos doses muito altas de P. elegans. - No terceiro experimento, dois ovinos e dois caprinos receberam 0,333g/kg de P. elegans dessecada, após administração prévia de 2,0 g/kg de acetamida. Uma semana depois, o protocolo acima foi repetido, porém sem o antídoto. Nos experimentos com coelhos, foram administradas doses de 0,5 e 1,0g/kg de elegans dessecada após a administração de 3,0g/kg de acetamida. Sete dias depois, repetiu-se o protocolo, com exceção da administração de acetamida. Esta, quando administrada previamente, evitou o aparecimento dos sinais clínicos e a morte dos ovinos, caprinos e coelhos, já os animais não tratados com acetamida apresentaram sintomatologia e morreram. Clinicamente, os ovinos e caprinos manifestaram taquicardia, jugulares ingurgitadas, pulso venoso positivo, decúbito esternal e tremores musculares. Na "fase dramática", os animais caíam em decúbito lateral, esticavam ...

This study aimed to evaluate the protective effect of acetamid in experimental poisoning by Pseudocalymma elegans in sheep, goats and rabbits, in order to prove indirectly that monofluoroacetate (MF) is responsible for the clinical signs and death of animals that ingested the plant. Experiments were performed to determine for sheep and goats the lethal dose of P. elegans collected in Rio Bonito, RJ, in different seasons, and to adjust the dose of acetamid to be administered. - In the first experiment, two sheep and two goats received 1.0g/kg of fresh P. elegans, and two (one sheep and one goat) were pretreated with 2.0g/kg of acetamid. None of the animals showed clinical signs or died. Possibly, the plant could be less toxic, since it was collected at the end of the rainy season. - In the second experiment, two sheep and two goats received 0.67 and 1.0g/kg of the dried plant, after pretreatment with 2.0 and 3.0g/kg of acetamid, respectively. All animals died, as the administered doses of P. elegans were very high. - In the third experiment, two sheep and two goats received 0.333g/kg of dried P. elegans after previous administration of 2.0g/kg of acetamid; a week later, the protocol above was repeated, but without the antidote. In experiments with rabbits, doses of 0.5 and 1.0g/kg of dried P. elegans were given after administration of 3.0g/kg of acetamid; seven days later, the same protocol was repeated, except the administration of acetamide. This procedure, when acetamid was administered before, prevented the appearance of clinical signs and death of sheep, goats and rabbits. But the animals not treated with acetamid showed symptoms of poisoning and died. Clinically, the sheep and goats had tachycardia, engorged jugular vein, positive venous pulse, lateral recumbence, and muscle tremors. In the "dramatic phase", the animals fell into lateral position, stretched the limbs, were paddling and died within minutes. The rabbits showed apathy, ...

Screening of chemokine receptor CCR4 antagonists by capillary zone electrophoresis / 药物分析学报

CC chemokine receptor 4 (CCR4) is a kind of G-protein-coupled receptor, which plays a pivotal role in allergic inflammation. The interaction between 2-(2-(4-chloro-phenyl)-5-{[(naphthalen-1-ylmethyl)-carbamoyl]-methyl}-4-oxo-thiazolidin-3-yl)-N-(3-morpholin-4-yl-propyl)-acetamide (S009) and the N-terminal extracellular tail (ML40) of CCR4 has been validated to be high affinity by capillary zone electrophoresis (CZE). The S009 is a known CCR4 antagonist. Now, a series of new thiourea derivatives have been synthesized. Compared with positive control S009, they were screened using ML40 as target by CZE to find some new drugs for allergic inflammation diseases. The synthesized compounds XJH-5, XJH-4, XJH-17 and XJH-1 displayed the interaction with ML40, but XJH-9, XJH-10, XJH-11, XJH-12, XJH-13, XJH-14, XJH-3, XJH-8, XJH-6, XJH-7, XJH-15, XJH-16 and XJH-2 did not bind to ML40.Both qualification and quantification characterizations of the binding were determined. The affinity of the four compounds was valued by the binding constant, which was similar with the results of chemotactic experiments. The established CEZ method is capable of sensitive and fast screening for a series of lactam analogs in the drug discovery for allergic inflammation diseases.

Synthesis and anxiolytic effects of 2-aryl imidazo1,2-apyridine-3- acetamide derivatives / 国际药学研究杂志

Objective: To search for new compounds with better water-solubility and higher antianxiety activities. Methods: A series of 2-arylimidazo[1,2-a] pyridine-3-acetamide derivitives were designed and synthesized. The anxiolytic activities were evaluated by BZDR competitive binding assay in vitro and the elevated-plus maze test in mice, the structure-activity relationship (SAR) has been studied. Results and Conclusion: Twenty-eight new compounds have been synthesized. Their structures were confirmed by 1H NMR and MS. According to the results of BZDR affinity test, compounds I1, I 8, I10, I13, I19 showed as good affinity as the positive control (Ro5-4864). The corresponding inhibition was 87%, 89%, 85%, 89% and 76% respectively at the concentration of 100 nmol/L, while that of Ro5-4864 was 82%. I8 and I10, which display better water-solubility and better BZDR affinity in vitro, show significant antianxiety effects in vivo.

Studies on the chemical constituents of the ear of Schizonepeta Mulifida / 中国药学杂志

OBJECTIVE:To investigate the chemical constituents of the ear of Schizonepeta mulifida (L.)Briq. METHODS：Ingredients of the ear of this plant were separated by means of solvent extraction and chromatography on silica gel and polyamide and activated charcoal. RESULTS：Three components were isolated. Their structures were elucidated based on the spectral analysis. One of them is a known compound i.e. dehydrosylvestrene (V). The other two were new compound,named neoenneaanetetraoic acid (Ⅶ)，and 3-imino-N-nitrogen substituted acetamide cyclic buty amide (Ⅷ). CONCLUSION：These 3 compounds were isolated from the plant for the first time.By the way, a mixture of n-alkane was also obtained which contains seventeen n-alkane compounds proved by GC-MS.