Synthesis and effects on the COX-1 and COX-2 activity in human whole blood ex vivo of derivatives containing the [1]benzothienol-[3, 2-d]pyrimidin-4-one heterocyclic system

Methyl and phenyl derivatives containing the [1]Benzothieno [3, 2-d]pyrimidin-4-one system have been synthesized and tested as inhibitors of COX-1 and COX-2 activities in human whole blood (HWB) ex vivo; all compounds turned out to be weak inhibitors of COX-1 activity, as deduced from the TXB(2) (thromboxane B) generation; the acid phenyl derivative 11 b was an interesting inhibitor of COX-2 activity, as deduced from the PGE(2) (prostaglandine E) generation.     

Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and alpha-adrenolytic activity

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the alpha(1)- and alpha(2)-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK(i) = 6.71 for alpha(1)-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50 )value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.     

Synthesis and in vitro antibacterial evaluation of novel imidazo[2',1':5,1]-1,2,4-triazolo[4,3-c]-quinazoline derivatives of 5-thioxo-1, 2, 4-triazole, 4-oxothiazolidine, and their open-chain counterparts

Two novel series of imidazo[2', 1':5, 1]-1, 2, 4-triazolo[4, 3-c]quinazolines bearing 5-thioxo-1, 2, 4-triazoles, 6a-f, and 4-oxothiazolidines, 7a-f, were synthesized from corresponding thiosemicarbazide derivatives, 5a-f. The stepwise methodology applied to the preparation of compounds 5a-f was initiated with reaction of the parent 3-amino-1, 2, 4-triazolo[4, 3-c]quinazolines, 2, with ethyl 2-chloroacetoacetate resulting in annelation of the imidazole ring to give esters, 3a-c. However, hydrazinolysis of these ester derivatives gave the corresponding acid hydrazides, 4a-c, which on reaction with the appropriate alkyl isothiocyanate yielded compounds 5a-f. In turn, compounds 5, were cyclized with potassium hydroxide or with ethyl bromoacetate to give the corresponding thioxotriazoles 6 and oxothiazolidines 7, respectively. All synthesized compounds were screened for their in vitro antibacterial activity against various Gram-positive and Gram-negative bacteria. Some test compounds were found to possess potent antibacterial activities. Compound, 7f, exhibited much higher potency than the reference standard ciprofloxacin, against both types of bacteria, particularly, Gram-positive organisms.     

Progress in 5H[1]benzopyrano[4,3-d]pyrimidin-5-amine series: 2-methoxy derivatives effective as antiplatelet agents with analgesic activity

A series of 2-methoxy-5H[1]benzopyrano[4,3-d]pyrimidin-5-amines were prepared and screened for their in vitro antiplatelet activity inducing the aggregation by ADP, arachidonic acid (AA) and collagen. In vivo experiments were performed in order to evaluate their antiphlogistic, analgesic and antipyretic activities. Title compounds showed antiplatelet activity in aggregation AA or collagen-induced, and a good analgesic activity without any gastric toxicity. Comparison with a number of analogue benzopyrano[4,3-d]pyrimidine derivatives and some SAR consideration were reported.     

Synthesis and molluscicidal activity of some 1,3,4-triaryl-5-chloropyrazole, pyrano[2,3-c]pyrazole, pyrazolylphthalazine and pyrano[2,3-d]thiazole derivatives

2-(5-Chloro-1,3-diphenyl-1H-pyrazol-4-ylmethylene)-malononitrile 1a reacts with the arylidenes of malononitrile 2a-d to afford the triaryl-5-chloropyrazoles 3a-d, respectively. 1a reacts with the active methylene pyrazolinones 5a, b and 12a, b to afford different products 8, 9, 10, 11, and 14a, b--depending on the substitution in the pyrazole ring. Compound 1a reacts also with the pyridazinone derivative 15 to afford the phthalazinone 16, and with the thiazolinones 17a-c to afford the pyrano[2,3-d]thiazoles 20a-c, respectively. It reacts also with the malononitrile dimer 21a and with ethyl cyanoacetate dimer 21b to yield the pyrazolyl pyridines 22a, b, respectively. The synthesized compounds showed a moderate molluscicidal activity towards Biomphalaria alexandrina snails.     

Synthesis and evaluation of anticonvulsant and antimicrobial activities of 3-hydroxy-6-methyl-2-substituted 4h-pyran-4-one derivatives

In this study, thirteen 3-hydroxy-6-methyl-2-substituted 4H-pyran-4-one derivatives were synthesized for the evaluation of their potential anticonvulsant activity. Mannich bases were prepared by the reaction of substituted piperazine derivatives with allomaltol and formaline. The structures of the synthesized compounds were confirmed by IR, (1)H-NMR and elemental analysis. Their anticonvulsant activities were determined in vivo by maximal electroshock (MES), sub-cutaneous Metrazol (scMet), and rotorod toxicity tests for neurological deficits. The antimicrobial activities of the synthesized compounds were investigated in vitro against some bacteria and fungi using the microdilution broth method. Ac-cording to the activity studies, 3-hydroxy-6-methyl-2-[4-(2-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-4H-pyran-4-one (3i) was the compound determined to be most active in the scMet test for all doses at four hours and for the 300 mg/kg dose at half an hour. 2-[4-(4-Chloro-phenyl)-piperazin-1-ylmethyl]-3-hydroxy-6-methyl-4H-pyran-4-one (3f) was found to be protective against MES whereas 2-chlorophenyl derivative (3e) was not. Looking at the antifungal activity results, compounds 3b, 3h, and 3i were determined to have activity against all fungi.     

1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-羧酸衍生物的合成及抗癌活性研究(英文)

本文以2-巯基噻吩为原料,经6步反应合成了5个1,4-二氢噻吩并[3',2':5,6]噻喃并[4,3-c]吡唑-3-羧酸衍生物,并采用人乳腺癌细胞MCF-7对目标化合物的抗肿瘤活性进行初步评价。所合成化合物在100μM浓度下均有一定的抑制MCF-7活性。     

2-取代苯基-1,2,4-三氮唑[5,1-a]并吡啶类衍生物的合成及其溶黄体活性

目的研究2－取代苯基－1，2，4－三氮唑[5,1-a]并吡啶类衍生物的合成及其抗早孕活性。方法 甲基取代吡啶胺化后，通过和取代苯甲腈缩合反应合成目标化合物，利用离体培养大鼠黄体细胞试验进行抗早孕活性筛选。结果 设计合成了14个未见文献报道的2－取代苯基－1，2，4－三氮唑[5,1-a]并唑啶类衍生物，均为新化合物。生物活性实验结果表明：除化合物7k以外，新合成的化合物都有一定溶黄体细胞的作用，其中化合物7b,71的作用更强，它们的ED50分别为0.5μg/mL和1.6μg/mL。结论 新合成的化合物具有一定的损伤黄体细胞的活性，值得进一步研究。     

血吸虫病化学治疗的研究——ⅩⅪⅤ.5-[2-(5-硝基呋喃基-2)-1-取代乙烯基]-1,3,4-噁二唑酮及其1,3,4-噁二唑衍生物的合成

本文报道硝基呋喃乙烯基-1,3,4-噁二唑及其酮类衍生物44个的合成。关键中间体α-取代β-(5-硝基呋喃基-2)丙烯酰彤魄仿照文献已知方法制备的,然后分别与光气或溴化腈作用生成相应的1,3,4-噁二唑衍生物Ⅰ,Ⅱ。经感染日本血吸虫病小白鼠的预防和治疗试验,发现化合物Ⅰ₁具有显著的抗血吸虫作用,并试用于家犬的血吸虫病,证明有一定的疗效。但效果不及呋喃丙胺,故未作临床观察。     

2-取代-4-氨基噻吩并[3,2-d]嘧啶类化合物的合成及抗增殖活性

目的设计并合成2-取代-4-氨基噻吩并[3,2-d]嘧啶类化合物,评价其体外抗增殖活性。方法以3-氨基-2-噻吩甲酸甲酯为起始原料,经6步反应合成目标化合物;以CP-31398为阳性对照药,采用MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]法测定了目标化合物对肿瘤细胞株H-460和HT-29的抗增殖活性。结果与结论合成16个未见文献报道的化合物,其结构经1H-NMR、MS确证;5个化合物显示较好的抗增殖活性,其中,化合物8n活性突出,为CP-31398的4-5倍。     

含(1',2'-二-O-环亚己基二氧乙基)的二氧代氮杂茂并[3',4'-d]异噁唑啉衍生物对Cdc25A和CD45的抑制作用

在三乙胺的作用下,以α-氯代-1',2'-二-O-环亚己基二氧乙基甲醛肟产生的氧化腈为偶极体,N-芳基-马来酰亚胺为亲偶极体,通过1,3-偶极环加成反应合成了15个3-(1',2'-二-O-环亚己基二氧乙基)-5-芳基-3a,6a-二氢-4,6-二氧代氮杂茂并[3',4'-d]异噁唑啉衍生物(3a～3o),利用1H NMR、IR和元素分析对其结构进行了表征,并进行了初步活性筛选,部分化合物显示了不同程度的抗癌、抗炎及免疫性疾病活性。初步体外抗癌活性结果表明,当样品浓度为20μg.mL 1时,化合物3e、3h、3j和3l对Cdc25A磷酸酯酶的抑制率分别为60.6%、58.6%、51.4%和98.4%,其中3l的抑制率最高,甚至当样品浓度为5μg.mL 1时,化合物3l的抑制率仍为86.97%,值得进一步研究。此外,初步体外白细胞共同抗原活性结果表明,当样品浓度为20μmol.mL 1时,化合物3e、3l和3n对CD45蛋白酪氨酸磷酸酶A的抑制率分别为57.7%、74.4%和77.3%。在此基础上,初步讨论了该类化合物的构效关系。     

5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的制备

目的改进5-羟基-5H-[1]-苯并吡喃[2,3-b]吡啶的合成工艺。方法以2-氯烟酸为起始原料,经亲核取代、环合和还原制得目标化合物。结果总收率68.6%,产物经熔点和1HNMR确证。结论改进后的工艺具有操作简便,对环境友好,收率高等优点。     

新型乙酰胆碱酯酶抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性

目的 寻找作为乙酰胆碱酯酶抑制剂的具有新化学结构类型的化合物。方法 采用分子对接的方法寻找新型的乙酰胆碱酯酶抑制剂,设计并合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物。通过Erlenmeyer-Plöchl反应及缩合反应生成目标化合物6-芳甲基-3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,其结构采用红外光谱、质谱和核磁共振氢谱确证。采用Ellman方法进行体外抑制乙酰胆碱酯酶活性测试。 结果 合成了10个7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物,体外抑制乙酰胆碱酯酶活性测试结果显示所有目标化合物均具有抑制乙酰胆碱酯酶活性,8个目标化合物在10 μmol.L-1浓度水平抑制活性均超过了50%。结论7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物是潜在的乙酰胆碱酯酶抑制剂,是一类具有新骨架结构的AChE抑制剂。     

Synthesis and anticancer activity of Indolin-2-one derivatives bearing the 4-thiazolidinone moiety

A novel series of indolin‐2‐one derivatives containing the 4‐thiazolidinone moiety ( 5a—5p ) was synthesized and the cytotoxicity of these derivatives was evaluated in vitro against three human cancer cell lines (HT‐29, H460 and MDA‐MB‐231) by standard MTT assay. Some prepared compounds exhibited significant cytotoxicity against different human cancer cell lines. Several potent compounds were further evaluated against one normal cell line (WI‐38). In particular, the promising compound 5h showed remarkable cytotoxicity and selectivity against the HT‐29 and H460 cancer cell lines (IC₅₀ = 0.016 µmol/L, 0.0037 µmol/L, respectively).     

Synthesis and antimycobacterial activity of pyridylmethylsulfanyl and naphthylmethylsulfanyl derivatives of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbothioamide/-2-carbonitrile

A set of four types of benzazoles, 1, 2, 4-triazole, and pyridine-2-carbonitrile/-2-carbothioamide substituted with 1-naphthylmethylsulfanyl or pyridylmethylsulfanyl was prepared to modify the structure of benzylsulfanyl derivatives of the above-mentioned heterocycles. The compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. avium, and two strains of M. kansasii. The activities were expressed as the minimum inhibitory concentration (MIC). The MIC values fall into a range of 2 to >1000 micromol/L. Introduction of a pyridyl moiety into the molecule mostly decreased the activity. A naphthyl moiety did not influence the activity in comparison with a phenyl. The most active substances were 4-(3-pyridylmethylsulfanyl)pyridine-2-carbothioamide (7b) (MIC = 2 - >62.5 micromol/L) and 4-(1-naphthylmethylsulfanyl)pyridine-2-carbothioamide (7d) (MIC = 2 - >32 micromol/L).     

Synthesis and cytostatic properties of some 6H-Indolo[2, 3-b][1, 8]naphthyridine derivatives

The new and efficient synthesis of the title heterocyclic ring system is described starting from suitable 2-chloro-1, 8-naphthyridines. The synthesized 6H-indolo[2, 3-b][1, 8]naphthyridine derivatives were tested in vitro on 55 tumor cell lines for their anticancer properties. The presence of the acetylamino moiety at position 3 in the main ring system proved to be crucial for the cytostatic activity of this class of compounds.     

Synthesis and development of new 2-substituted 1-[3-(4-arylpiperazin-1-yl)propyl]-pyrrolidin-2-one derivatives with antiarrhythmic, hypotensive, and alpha-adrenolytic activity

A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.     

Synthesis and morphine enhancement activity of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives

The synthesis of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives is reported. The structures of these compounds are supported by their IR, (1)H-NMR and mass spectra. Conformational analysis and superimposition of energy minima conformers of these compounds on L-365, 260, a known 3-ureido-1, 4-benzodiazepine CCK-B antagonist, showed that the aromatic rings fell in the same contour. Morphine analgesia enhancement evaluation of the synthesized compounds in comparison with a control group showed that compounds 8a, 8c, 8h-8j, 8l, 8o have significant effects.     

Antitumor activity of novel pyrrolo[2,3-d]pyrimidin-4-ones

Pyrrolo[2,3-d]pyrimidine is known to have a broad spectrum of biological activities, including antitumor activity. The cytotoxic properties of six novel pyrrolo[2,3-d]pyrimidin-4-ones in vitro were investigated on four different human cancer cell lines. Meanwhile, the role of apoptosis was explored. Malignant cells were cultured in RPMI medium and incubated with different concentrations. Cell viability was quantitated by MTT assay. Apoptotic cells were determined using DAPI (4′-6-diamidino-2-phenylindole) and propidium iodide staining of DNA fragmentation by flow cytometry (sub-G1 peak). We have identified new analogs as a novel class of antiproliferative agents by a cell-based screening method. All compounds inhibited the growth of malignant cells in a dose-dependent manner. The IC₅₀ of compounds 4 and 5 as the two most potent analogs was determined as 122.4 and 106.7 μM in HeLa cells, respectively. Compounds 4 and 5 induced a sub-G1 peak in the flow-cytometry histogram of treated cells, compared to control, indicating that apoptotic cell death is involved in compound 4– and 5–induced toxicity. In conclusion, compounds 4 and 5 exert cytotoxic effects in different cancer cell lines in which apoptosis plays an important role. Thus, compounds 4 and 5 could be considered as potential chemotherapeutic agents.