Synthesis of 1,2,4-oxadiazoles (a review)

Methods used for the synthesis of 3,5-substituted 1,2,4-oxadiazoles are reviewed. The syntheses are based mostly on the use of primary amidoximes and acylating agents as the initial reactants. The pathway to another large group of 1,2,4-oxadiazoles proceeding from a broad spectrum of reactants is via their reactions of 1,3-dipolar cycloaddition, in particular, with primary amidoximes. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 10, pp. 32–40, October, 2005.     

Accumulation and distribution of aliphatic (n-nonane), aromatic (1,2,4-trimethylbenzene) and naphthenic (1,2,4-trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation

The concentrations of the C9 hydrocarbons n-nonane, 1,2,4-trimethylbenzene and 1,2,4-trimethylcyclohexane were measured in rat blood, brain and perirenal fat after exposures to 1000 p.p.m. of the individual compounds. Measurements were made by head space gas chromatography at the end of 12 hr exposures on days 1, 3, 7, 10 and 14 of the exposure periods. The relative concentrations of hydrocarbons in each organ were, brain: n-nonane "trimethylcyclohexane approximately trimethylbenzene, blood: trimethylbenzene "n-C9 greater than trimethylcyclohexane and perirenal fat: trimethylbenzene greater than n-nonane greater than trimethylcyclohexane, showing the widely different distribution properties of the different hydrocarbons. Brain/blood ratios of 11.4, 2.0 and 11.4, and fat/blood ratios of 113, 63 and 135 were found for n-nonane, trimethylbenzene and trimethylcyclohexane, respectively. A marked decrease in biological concentrations of trimethylbenzene and trimethylcyclohexane during the initial phase of exposure indicate that these hydrocarbons are capable of inducing their own metabolic conversion resulting in lower steady state levels. A special attention was made to n-nonane showing the highest concentration in brain concomitantly with a low blood concentration. This observation demonstrate that biological monitoring of occupational exposure by blood measurements not should be performed without knowledge of the distribution properties of the compounds investigated.     

与青蒿素相关的1,2,4-三恶烷及臭氧化物的研究进展

疟疾(malaria)是一种在热带、亚热带地区广泛传播的寄生虫病,世界的大半人口生活在这些疟疾流行的地区[1]。据世界卫生组织(WHO)报告,疟疾每年会导致上亿人生病、200多万人死亡,其中大多数为非洲儿童。20世纪60年代,疟原虫对传统的抗疟药物如奎宁、氯喹等开始产生抗药性,使形势     

Distribution and metabolism of 1,2,4-trimethylbenzene (pseudocumene) in the rat

1. Single doses of 1,2,4-trimethylbenzene (124TMB) or 14C-124TMB were administered orally to rats for metabolism and distribution studies. 2. 14C-124TMB was rapidly and widely distributed throughout the body with the highest levels in adipose tissue. No other preferential uptake of 14C-124TMB by any of the organs or tissues examined was evident. 3. Tissue levels declined rapidly within 24 h after dosage, with more than 99% of the administered radioactivity recovered in the urine during this period. 4. A complex mixture of isomeric trimethylphenols, dimethylbenzyl alcohols, dimethylbenzoic acids and dimethylhippuric acids excreted in the urine accounted for more than 81% of the administered dose. The major metabolites were 3,4-dimethylhippuric acid (30.2% dose), 2,4-dimethylbenzyl alcohol (12.7% dose, primarily as sulphate and glucuronide conjugates) and 2,5-dimethylbenzyl alcohol (11.7% dose, primarily as sulphate and glucuronide conjugates).     

Nonquaternary cholinesterase reactivators. 3. 3(5)-Substituted 1,2,4-oxadiazol-5(3)-aldoximes and 1,2,4-oxadiazole-5(3)-thiocarbohydroximates as reactivators of organophosphonate-inhibited eel and human acetylcholinesterase in vitro

As an extension of an earlier investigation (J. Med. Chem. 1984, 27, 1431), we prepared a series of 3-substituted 5-[(hydroxyimino)methyl]-1,2,4-oxadiazoles and the corresponding 5-thiocarbohydroximic acid 2-(N,N-dialkylamino)ethyl S-esters. The compounds were evaluated in vitro as reactivators of phosphonylated electric eel and human erythrocyte (RBC) acetylcholinesterases (AChE). The compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol/buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivating ethyl methylphosphonylated AChE. One compound was also tested for effectiveness in preventing AChE phosphonylation. All of the tested compounds significantly reactivate ethyl methylphosphonylated AChE: the 3-n-octyl- and 3-(1-naphthyl)-substituted aldoximes are as reactive (within a factor of 5-10) toward the inhibited enzymes as the benchmark pyridinium reactivators, 2-PAM and HI-6. All of the substituted thiocarbohydroximic acid S-esters are powerful reversible inhibitors of AChE's: the 3-n-octyl- and 3-(1-naphthyl)-substituted thiocarbohydroximates inhibit eel AChE to 50% initial activity at concentrations less than 5 microM. When added to an eel AChE solution at concentrations between 5 and 50 microM, the 3-phenyl-substituted thiocarbohydroximate effectively antagonizes AChE inhibition by ethyl p-nitrophenyl methylphosphonate (EPMP), suggesting the potential utility of this compound for preventing anti-AChE-agent poisoning.     

Synthesis of 1-(3-aminopropyl)-4-phenyl-1,2,4-triazolin-5-one and 1-(3-aminopropyl)-3,4-diphenyl-1,2,4-triazolin-5-one

The reaction of 4-phenyl-1,2,4-triazolin-5-one [Ia] and 3,4-diphenyl-1,2,4-triazolin-5-one [Ib] with 1-bromo-3-chloropropane was carried out. The obtained compounds [IIa, b] were subjected to the reaction with secondary amines and ethylenediamine with resulted in 1-(3-aminopropyl)-1,2,4-triazolin-5-one derivatives.     

Structure-activity relationships for NAMI-A-type complexes (HL)[trans-RuCl4L(S-dmso)ruthenate(III)] (L = imidazole, indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole): aquation, redox properties, protein binding, and antiproliferative activity

Imidazolium [trans-tetrachloro(1H-imidazole)(S-dimethylsulfoxide)ruthenate(III)] (NAMI-A) and indazolium [trans-tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) are the most promising ruthenium complexes for anticancer chemotherapy. In this study, the azole ligand of NAMI-A was systematically varied (from imidazole of NAMI-A to indazole, 1,2,4-triazole, 4-amino-1,2,4-triazole, and 1-methyl-1,2,4-triazole), and the respective complexes were evaluated with regard to the rate of aquation and protein binding, redox potentials, and cytotoxicity by means of capillary zone electrophoresis, electrospray ionization mass spectrometry, cyclic voltammetry, and colorimetric microculture assays. Stability studies demonstrated low stability of the complexes at pH 7.4 and 37 degrees C and a high reactivity toward proteins (binding rate constants in the ranges of 0.02-0.34 and 0.01-0.26 min-1 for albumin and transferrin, respectively). The redox potentials (between 0.25 and 0.35 V) were found to be biologically accessible for activation of the complexes in the tumor, and the indazole-containing compound shows the highest antiproliferative activity in vitro.     

Synthesis and some pharmacological properties of 3-(4-phenyl-5-oxo-1,2,4-triazolin-1-ylmethyl)-1,2,4-triazolin-5-thione derivatives

In the reaction of (4-phenyl- or 3,4-diphenyl-5-oxo-1,2,4-triazeolin-1-ylmethyl)-carbohydrazide (IIa, IIb) with isothiocyanates the thiosemicarbazide derivatives [IIIa, b - IXa, b] were obtained. Cyclization of those compounds in the presence of 2% or 10% NaOH led to formation of derivatives with the 1,2,4-triazolin-5-thione system [Xa, b - XV[a, b]. Molecular structure proposed for this group of compounds was confirmed by X-ray structure analysis of Xa and XIVa. Compounds Xa, XIIa and XIVa were investigated pharmacologically for their central properties in mice. It was shown that only compound XIIa produced antinociceptive effects in mice.     

4(H)-1,2,4-triazole derivatives with expected biological activity.

Three isomeric 4-(carboxyphenyl)-3,5-diphenyl-1,2,4-triazoles (III) were prepared by condensation of bis(alpha-chlorobenzylidene)hydrazine (I) with ethyl aminobenzoate and subsequent alkaline hydrolysis of the ethyl esters (II) of III. III were also obtained by hydrolysis of the cyano compounds (IV) and by oxidation of the methyl derivatives (VI). A similar condensation of I with aminopyridines led to 4-pyridyl-3,5-diphenyl-1,2,4-triazoles (VII). Reduction of three isomeric 4-(nitrophenyl)-3,5-diphenyl-1,2,4-triazoles (X) (Fe/AcOH) gave the corresponding amino derivatives (XI). In the preparation of X, the method employing N-(nitrophenyl)-benzimidoyl chloride (VIII) and benzhydrazide (IX) proved to be most advantageous. Slight bacteriostatic activity of the triazoles prepared was observed in standard in vitro tests.     

4-叔丁基-5-(1,2,4-三唑-1-基)-2-苄亚氨基噻唑的体外抗癌活性研究

目的 研究4-叔丁基-5-(1,2,4-三唑-1-基)-2-苄亚氨基噻唑类衍生物对宫颈癌细胞系Hela、肝癌细胞系Bel 7402、鼻咽癌细胞系CNE 2的体外抗癌活性.方法 细胞抑制率采用四甲基偶氮噻蓝(MTT)法测定.每种试样设置5个浓度梯度(0.025、0.05、0.1、0.25、0.5 μmol/ml),每个浓...