4-(4-烷氧基苯基)-3-乙基-1H-1,2,4-三唑-5(4H)-酮类化合物的合成及其抗惊厥活性

目的设计合成一系列4-(4-烷氧基苯基)-3-乙基-1H-1,2,4-三唑-5(4H)-酮类化合物,并评价其抗惊厥活性和神经毒性。方法以对乙酰氨基酚为起始原料,经烷基化、水解、环合等反应合成1,2,4-三唑-5(4H)-酮类化合物。通过最大电惊厥实验(MES)和神经毒性实验(NT),分别测定目标化合物的抗惊厥活性和神经毒性。结果与结论合成了20个新化合物,其结构经IR、1H-NMR和ESI-MS确证。药理学实验结果表明,所有化合物在不同剂量下都显示出抗惊厥活性。其中,3-乙基-4-(4-戊氧基苯基)-1H-1,2,4-三唑-5(4H)-酮(4e)的活性最强,其半数有效量ED50值为26.9 mg·kg-1,保护指数(PI)为11.0,虽然该化合物的活性低于阳性对照药卡马西平,但其保护指数优于卡马西平(PI=6.4);3-乙基-4-(4-(3-氟苄氧基)苯基)-1H-1,2,4-三唑-5(4H)-酮(4n)的ED50值为61.1 mg·kg-1,但其PI大于17.0,明显优于卡马西平,具有进一步研究的价值。     

1,2,4-三唑并[4,3-a]喹啉衍生物的合成及其抗惊厥活性

目的 设计合成一系列1,2,4-三唑并[4,3-a]喹啉衍生物,并评价其抗惊厥活性和神经毒性.方法 以4-羟基喹啉-2(1H)酮为起始原料,经烷基化、氯代、肼代、环合等反应合成1,2,4-三唑并[4,3-a]喹啉衍生物.通过最大电惊厥实验(MES)和旋转棒法(Rotarod),分别测定目标化合物的抗惊厥活性和神经毒性....     

1-[2-(N-甲基-N-取代苄基)氨基-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物的合成及抗真菌活性

目的:1-[2-(N-甲基-N-取代苄基)氨基-2-(2,4-二氟苯基) 乙基]-1H-1,2 ,4-三唑类化合物的合成及抗真菌活性研究。方法:通过付-克反应、三唑烷基化、酮亚胺还原和Leuckart 反应,得到关键中间体,然后通过N-烷基化反应制得目标化合物,并用二倍稀释法测定了体外抑菌活性。结果:合成了23 个1-[2-(N-甲基-N-取代苄基) 氨基-2-(2,4-二氟苯基)乙基]-1H-1 ,2,4-三唑类化合物,均为首次报道。所有目标化合物对8 种致病真菌均有不同程度的抗真菌活性。大部分化合物对Candida.albicans 和Candida.parapsilosis 的抗菌活性明显高于布替萘芬,其中1 ,2 ,6 ,13,14 ,19 对Candida.albicans 的抗菌活性是益康唑的8～32 倍,2,13 对Cryptococcu.neoformans 的抗菌活性是布替萘芬的4～8 倍,是益康唑64 ～128 倍。所有化合物对Microsporum .canis 的抗菌活性均高于或相当于益康唑。结论:其中一些化合物显示了较强抗真菌的活性,值得进一步研究。     

5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮的合成

丙酰肼与三光气缩合环化得到5-乙基-1,3,4-噁二唑-2(3H)-酮,继与2-苯氧乙胺反应后在碱性条件下环合得到抗抑郁药奈法唑酮中间体5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮,总收率66.3%.     

1-[2-(N-甲基-N 取代苄基)氨基-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物的合成及抗真菌活性

目的:1[2(N甲基N取代苄基)氨基2(2,4二氟苯基) 乙基]1H1,2 ,4三唑类化合物的合成及抗真菌活性研究。方法:通过付克反应、三唑烷基化、酮亚胺还原和Leuckart 反应,得到关键中间体,然后通过N烷基化反应制得目标化合物,并用二倍稀释法测定了体外抑菌活性。结果:合成了23 个1[2(N甲基N取代苄基) 氨基2(2,4二氟苯基)乙基]1H1 ,2,4三唑类化合物,均为首次报道。所有目标化合物对8 种致病真菌均有不同程度的抗真菌活性。大部分化合物对Candida.albicans 和Candida.parapsilosis 的抗菌活性明显高于布替萘芬,其中1 ,2 ,6 ,13,14 ,19 对Candida.albicans 的抗菌活性是益康唑的8～32 倍,2,13 对Cryptococcu.neoformans 的抗菌活性是布替萘芬的4～8 倍,是益康唑64 ～128 倍。所有化合物对Microsporum .canis 的抗菌活性均高于或相当于益康唑。结论:其中一些化合物显示了较强抗真菌的活性,值得进一步研究     

3-次苄基硫色满酮类化合物的合成及其体外抗真菌活性

目的:设计合成3-次苄基硫色满酮类化合物,并对其抗真菌活性进行初步评价.方法:以取代苯硫酚为原料,经多步反应制得目标化合物,并采用琼脂2倍浓度稀释法测定目标化合物的抗真菌活性.结果:共合成了6个新化合物,经红外光谱、核磁共振氢谱及元素分析确证其结构.目标化合物对大部分供试真菌具有活性,但弱于对照品克霉唑.结论:3-次苄基硫色满酮在体外具有一定的抗真菌活性.     

1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物的合成及其抗惊厥活性

目的寻找具有抗惊厥活性的1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物.方法以邻苯二甲酸酐为原料,先制备酞乙酸,再依次与氯化亚砜、胺反应合成9个(Z)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物;以氯乙酸为起始原料,依次与氯化亚砜、胺、三苯基膦反应制得季磷盐,再与邻苯二甲酸酐经Wittig反应又合成9个(E)-1(3H)-异苯并呋喃酮-Δ3-乙酰胺类化合物.所有目标化合物的结构均经IR和1H-NMR确证.采用最大电休克发作实验(MES)对目标化合物进行抗惊厥活性筛选.结果合成了18个未见文献报道的新化合物.5e、5h和5i的抗惊厥活性ED50值分别为155.6、184.6和170.4mg·kg-1.结论 E型异构体较Z型异构体具有较好的抗惊厥活性,其构效关系和药理作用机制值得进一步研究.     

1-[2-(取代苯基甲硫基)-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物的合成及抗真菌活性

设计合成了21个1-[2-(取代苯基甲硫基)-2-(2,4-二氟苯基)乙基]-1H-1,2,4-三唑类化合物,其中19个为首次报道。体外抑菌试验表明:所有目标化合物对8种试验真菌均有不同程度的抗菌活性,其中化合物1,2,5对絮状表皮癣菌的活性为硫康唑的512倍以上;化合物5对白色念株菌的活性为硫康唑的32倍;化合物2对申克孢子丝菌的活性为硫康唑的32倍;化合物2,14对新型隐球菌的活性分别为硫康唑的64倍,32倍;化合物1,5对熏烟色曲菌的活性分别为硫康唑的16倍以上。     

3,5-二亚苄基哌啶-4-酮类化合物的合成及其体外抗肿瘤活性

目的 合成3,5-二亚苄基哌啶-4-酮类化合物,并对其体外抗肿瘤活性进行初步评价。方法 以芳香醛、4-哌啶酮为原料,通过Claisen-Schmidt缩合制备目标化合物。采用MTT法测试目标化合物对人慢性粒细胞白血病急变细胞株K562增殖的抑制活性,考察部分化合物对多种肿瘤细胞株的抑制活性。结果与结论 合成了7个未见报道的3,5-二亚苄基哌啶-4-酮类化合物,其结构经¹H-NMR和MS谱确证;5个目标化合物的体外抗肿瘤活性明显强于姜黄素。     

1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成及抗真菌活性

报道了29个新的1-(1-取代苯基)-2-(1H-1,2,4-三唑或苯并三唑基)-O-(取代苄基)乙酮肟醚类化合物的合成与体外抗菌试验。结果表明,大多数化合物对大部分真菌有抑菌活性,化合物T₁,T₄,T₆,T₁₁,T₁₂,B₁,B₃,B₄和B₆对部分真菌抑菌活性优于或相当于奥昔康唑。     

Synthesis and anticonvulsant activity evaluation of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinoline derivatives

Two series of 8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinolines and 8-alkoxy-5-(2H-1,2,4-triazol-3-one-4-yl)quinolines were synthesized. The anticonvulsant activity of these compounds was evaluated with maximal electroshock seizure test and rotarod test. Among the synthesized compounds, 8-octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (4g) was the most active compound with ED₅₀ of 8.80 mg/kg, TD₅₀ of 176.03 mg/kg and protective index of 20.0. Its neurotoxicity was lower than all other synthesized compounds and also markedly lower than that of the reference drug carbamazepine. In addition, the potency of compound 4g against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline suggested its broad spectrum activity, and the mechanisms of action including inhibition of voltage-gated ion channels and modulation of GABAergic activity might involve in its anticonvulsant activity.     

2,4-Dihydro-3H-1,2,4-triazol-3-ones as anticonvulsant agents

A series of 5-aryl-2,4-dihydro-3H-1,2,4-triazol-3-ones was evaluated for anticonvulsant activity. In general the members of this series were prepared by the alkaline cyclization of 1-aroyl-4-alkylsemicarbazides. The resulting 2-unsubstituted 3H-1,2,4-triazol-3-ones were then alkylated, yielding 2,4-dialkyl-3H-1,2,4-triazol-3-ones. Approximately one-third of the compounds examined exhibited activity against both maximal electroshock- and pentylenetetrazole-induced seizures in mice. Receptor-binding studies suggest that this activity was not a consequence of activity at either benzodiazepine or NMDA-type glutamate receptors. From this series, compound 45 was selected for further evaluation where it was also found to be active against 3-mercaptopropionic acid, bicuculline, and quinolinic acid induced seizures in mice. In addition, 45 also protected gerbils from hippocampal neuronal degeneration produced by either hypoxia or intrastriatal quinolinic acid injection.     

Synthesis and antimicrobial evaluation of 4,5-diaryl-2-[4-(t-amino)-2-butynyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones

A series of 4,5-diaryl-2-[4-(t-amino)-2-butynyl]-2,4-dihydro-3H-1,2,4-triazol-3-ones were synthesized and characterized by infrared spectrum (IR), ¹H-NMR spectra and elemental analyses. Investigation of their antimicrobial activity was performed. Antimicrobial activity profile of the title compounds were evaluated against Gram- positive bacteria, Gram-negative bacteria and fungi. The synthesized compounds displayed different degrees of antimicrobial activities as shown in Table?3. Compound 12 was the most active one. This may be attributed to 4,5-diphenylsubstituent on the triazoline-3-one ring and the nature of the amino groups at terminal acetylenic moiety.     

Synthesis and anticonvulsant evaluation of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazoles

A series of 3-substituted-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole derivatives (3a-s) were synthesized as open-chain analogues of 7-hexyloxyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines (1c) using 4-hexyloxyaniline, acyl hydrazines, and dimethoxy-N,N-dimethylmethanamine as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES test) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). MES test showed that all open-chain compounds exhibited strong anticonvulsant activity and lower neurotoxicity, and that some possessed obviously stronger activity than compound 1c. Compound 3d, 3-propyl-4-(4-hexyloxyphenyl)-4H-1,2,4-triazole was found to be the most potent with an ED₅₀ value of 5.7 mg/kg and protective index (PI = TD₅₀/ED₅₀) value of 11.5, which was much greater than that of the prototype drug phenytoin (PI = 6.9).     

Synthesis of 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles as potential anticonvulsant agents

A series of 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test, subcutaneous pentylenetetrazole (Sc-PTZ), and rotarod tests in intraperitoneally injected mice. Among the synthesized compounds, compound 2-phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3a) could be considered the potentially most useful and safe therapeutic compound, with ED₅₀ = 29.6 mg/kg, TD₅₀ = 285 mg/kg, and PI = 9.7. Its neurotoxicity was the lowest of all the synthesized compounds and was also markedly lower than that of the reference drug carbamazepine with PI value of 6.4.     

Synthesis and anticonvulsant activity of 3-carbamoyl-4-aryl-isoquinolin-1(2H)-ones]

The syntheses of nineteen 3-carbamoyl-4-aryl-isoquinoline-1(2H)-ones are described. The compounds show anticonvulsant activity in maximal electroshock test (i.p. administration). A representative substance is 3-carbamoyl-2-isopropyl-4-(4-chlorophenyl)-isoquinoline-1(2H)-one, ED50 = 2.1 x 10(-4) mol/kg. This agent shows 20% of the activity of phenytoin (ED50 = 0.44 x 10(-4) mol/kg).     

Synthesis of some 3-(arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazole derivatives and their anticonvulsant activity

A series of novel 3-[[(substituted phenyl)methyl]thio]-4-alkyl/aryl-5-(4-aminophenyl)-4H-1,2,4-triazoles 11-20 and several related Schiff's bases, 3-[[(substituted phenyl)-methyl]thio]-4-alkyl/aryl-5-[[[(substituted phenyl/5-nitro-2-furyl)methylene]amino]-phenyl]-4H-1,2,4-triazoles 21-31 were synthesized for evaluation of their biological properties. Structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and neurotoxicity (NT) screens. A number of triazole derivatives, exhibited protection after intraperitoneal administration at the dose of 100 and 300 mg/kg in one or both models employed. Compounds 12, 13 and 14 were subjected to oral MES screening in rats at 30 mg/kg and were observed to protect 50% of the animals employed in the experiment. Antimicrobial and antituberculosis activity of these compounds 11-31 were also screened. Some of the tested compounds showed marginal activity against M. tuberculosis H37 Rv.     

Potential antihypertensives. Synthesis of 6-substituted-N-(4H-1,2,4-triazol-4-yl)-3-pyridazinamines and 3-substituted-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazines

A series of 6-substituted-N-(4H-1,2,4-triazol-4-yl)-3-pyridazinamines [(II), Scheme 1] and 3-substituted-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl) pyridazines [(XII), Scheme 3-5] were synthesized. The compounds were evaluated for their oral antihypertensive activity in rats (SHR) and only some compounds of structure (XII) induced a moderate decrease in systolic blood pressure.     

Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones

In this paper, we describe the synthesis of a series of novel substituted 4-aryl-6,7-methylenedioxyphthalazin-1(2H)-ones. The anticonvulsant activity of these compounds against audiogenic seizures was evaluated in DBA/2 mice after intraperitoneal (ip) injection. Most of these derivatives are more active than 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (1, GYKI 52466), a well-known noncompetitive AMPA receptor antagonist. As deduced by the rotarod test, all the compounds exhibit a toxicity lower than that of 1. Within the series of derivatives submitted to investigation, 4-(4-aminophenyl)-2-butylcarbamoyl-6,7-methylenedioxyphthalazin -1(2H)-one (21) proved to be the most active compound and is 11-fold more potent than 1 (i.e., ED50 3.25 micromol/kg for 21 versus ED50 35.8 micromol/kg for 1). When compared to 1, compound 21 as well as its analogue 4-(4-aminophenyl)-6,7-methylenedioxyphthalazin-1(2H)-one (16) show a longer lasting anticonvulsant activity. Compound 21 also effectively suppresses seizures induced in Swiss mice by maximal electroshock (MES) and pentylenetetrazole (PTZ). Furthermore, it antagonizes in vivo seizures induced by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA), 2-amino-3-(3-hydroxy-5-tert-butyl-isoxazol-4-yl)propionic acid (ATPA), and kainate (KA), and its anticonvulsant activity is reversed by pretreatment with aniracetam. Using the patch-clamp technique, the capability of derivatives 16 and 21 to antagonize KA-evoked currents in primary cultures of granule neurons was tested. They behaved as antagonists, but they proved to be less effective than 1 and 1-(4-aminophenyl)-3,4-dihydro-4-methyl-3-N-methylcarbamoyl-7,8-met hylenedioxy-5H-2,3-benzodiazepine (2, GYKI 53655) to reduce the KA-evoked currents.