芳基哒嗪酮酸姜黄素酯的合成

目的:合成芳基哒嗪酮酸姜黄素酯。方法:以5-甲基-2-(3-氯-4-氟苯基)-2-氧代哒嗪酸(化合物1)和姜黄素为原料,在N,N-二环己基碳二酰亚胺(DCC)/4-二甲氨基吡啶(DMAP)催化下,姜黄素两侧酚羟基与哒嗪酮6位羧基双侧成酯。经柱层析分离,得到目标产物,质谱和核磁表征其结构,并单因素考察原料配比、反应温度、反应时间、催化剂对反应的影响。结果:经表征,目标产物即芳基哒嗪酮酸姜黄素酯,产率为56.3%(以姜黄素计),高效液相色谱法测得含量为98.1%。最优反应条件为姜黄素-化合物1的配比为1∶3,反应温度为50℃,反应时间为10 h,催化剂为DCC/DMAP。结论:成功合成芳基哒嗪酮酸姜黄素酯,且工艺稳定。     

对氰基苯代二氢哒嗪酮的设计,合成及抗惊活性的研究

在ＣｏＭＦＡ３Ｄ－ＱＳＡＲ研究的基础上设计并合成了对氰基苯代二氢哒嗪酮。对溴苯甲醛与吗啉、氰化钾反应得α－ｐ－溴苯基－４－吗啉基乙腈，再与丙烯腈反应得３－（ｐ－溴代苯基）丙酸。对溴基被氰基取代后与肼反应得目标化合物。其抗惊活性属中等强度，与ＣｏＭＦＡ方法预计值相差较大。     

苯基哒嗪酮及其GABA衍生物的合成、抗惊活性及构效关系的研究

本文报道了14个6－芳基－4，5－二氢－3（2H）哒嗪酮，15个6－芳基－3（2H）哒嗪酮和17个6－芳基哒嗪的3位GABA衍生物的合成及其抗电惊活性。活性最强的是2′，4′－二氯苯基－3（2H）哒嗪酮（ED50＝10.15mg/kg）。对芳基哒嗪酮类的构效分析表明，苯环上的取代基对化合物的抗惊活性有明显影响，吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

3,4,5-三甲氧基肉桂酰胺类化合物的合成及其抗惊活性

为寻找新的抗癫痫药物,合成了6个(E)-3,4,5-三甲氧基肉桂酰胺(1a～f)和4个α-溴代衍生物(12a,b)。以~1H-NMR 证实了它们的构型。药理试验表明,化合物1b 具有比1a 稍弱的抗惊活性。     

桂皮酰胺类化合物分子扭角与抗惊活性的关系

本文应用分子力学方法计算了２６个桂皮酰胺类化合物分子的扭角θ１和θ２，讨论了顺反异构体药物分子对抗惊活性的影响，分析了分子扭角与抗惊活性的关系，并探讨了药物分子抗惊作用机制。结果表明：由于顺反异构体的分子扭角相差较大，从而对抗惊活性的影响也较大；分子扭色与抗惊活性关系表明：有抗惊活性和无抗惊活性的药物分子在θ１～θ２图中存在明显的分界线，分子处于一定的扭角范围才有活性，扭角的最佳范围是θ１＝３２～３５°，θ２＝３７～３９°。在探讨药物分子的作用机制时，我们推测药物分子的活性部位应该是羰基或α位取代的含有π电子的基团，这一活性部位只有在分子处于一定角度时，才能与受体结合，从而显示出抗惊活性。     

氮唑类化合物的合成及其抗真菌活性评价

本文设计并合成了１０个新的三唑及苯并三唑类化合物，其化学结构均经过有关光谱数据证实，对合成的所有化合物经体外抗真菌试验表明：对所试验的常见真菌均有不同程度的抗菌活性。     

二氢哒嗪酮类化合物的合成及其抗血小板聚集活性研究

目的：合成新的哒嗪酮类化合物，并研究其抗血小板聚集活性。方法：在6-（4-氯乙酰氨基苯基）-4，5-二氢-3（2H）-哒嗪酮侧链引入不同取代的哌嗪，合成了一系列化合物，采用^1H-NMR、IR及元素分析等方法确证其结构。采用Born比浊法进行体外抗血小板聚集药理实验。结杲：合成的10个化合物都具有一定的抗血小板凝集的活性，其中化合物4的抗血小板聚集活性明显优于先导化合物MCI-154。结论：4-位取代哌嗪环基的引入对哒嗪酮类化合物抗血小板聚集的活性有显著影响。     

6-芳基-3-(4-取代哌嗪)哒嗪类化合物的合成及抗惊厥活性

由芳香醛与吗啉、氰化钾反应形成的α-芳基-α-(4-吗啉)乙腈,可对α、β-不饱和腈或酯进行1,4-加成,生成1,4-酮酸型化合物。此物与肼缩合,再经芳构化即得6-芳基-3-哒嗪酮。后者再经氯化及氨解可得3-氨基-6-芳基哒嗪。应用此法合成了10个3-取代哌嗪-6-取代苯基哒嗪类化合物,并初步测验了它们的抗惊厥(MES)活性。     

查耳酮类化合物合成及抗乳腺癌活性研究

目的 设计、合成并筛选具有抗乳腺癌活性的查耳酮类化合物。方法 利用Claisen-Schmidt 羟醛缩合反应,合成了一系列的查耳酮类化合物,并通过MTT法测试化合物抗乳腺癌活性。结果 合成了36个查耳酮类化合物,其结构均通过¹H-NMR和¹³C-NMR进行了表征。初步生物活性结果表明大部分目标分子查耳酮对MCF-7有较强的抑制活性,对MDA-MB-231也展现出了中等的抑制活性,其中化合物27(IC₅₀=11.3 μmol·L^-1)对MCF-7的抑制活性是他莫昔芬的1.5倍,同时这些查尔酮类化合物对正常细胞均没有毒性。结论 本研究为开发具有抗乳腺癌活性的查耳酮类化合物提供了参考和依据。     

Synthesis and Anticonvulsant Activity of New N‐(Alkyl/Sub‐stituted aryl)‐N′‐[4‐(5‐cyclohexylamino)‐1,3,4‐thiadiazole‐2‐yl)phenyl]thioureas

A series of novel thiourea derivatives carrying the 5‐cylohexylamino‐1,3,4‐thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, ¹H‐NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10 , 11 , 13 , and 14 carrying 2‐methylphenyl, 4‐chlorophenyl, allyl, and 4‐methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED₅₀ values of the active compounds 10 , 11 , 13 , and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.     

Anticonvulsant action of thiabendazole

Thiabendazole was found to be specifically effective against maximal electroshock seizures in albino rats. It produced a significant dose-dependent decrease in the duration of the tonic extensor phase of hind legs. The ED50 was similar for oral or s.c. administration. PTZ-induced convulsions were unaffected by lower doses but aggravated by the higher dose studied.     

Synthesis and Anticonvulsant Activity of N‐(2‐Hydroxy‐ethyl)amide Derivatives

A series novel of N‐(2‐hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N‐(2‐hydroxyethyl)decanamide 1g , N‐(2‐hydroxyethyl)palmitamide 1l , and N‐(2‐hydroxyeth‐yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti‐epileptic drug valproate. In the anti‐MES potency test, these compounds exhibited median effective doses (ED₅₀) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD₅₀) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti‐epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g , 1l , and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3‐mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.     

Synthesis and Evaluation of 3‐[(2,4‐Dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile Derivatives as Potential Anticonvulsants

New 3‐[(2,4‐dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile derivatives 8 – 37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure–activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11 , 18 , 31 , and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two‐electron donor.     

Synthesis and Anticonvulsant Activity Evaluation of 5‐Phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amines

In the present study we describe the syntheses and anticonvulsant activity evaluation of 5‐phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amine derivatives. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of these compounds, the most promising was compound 8h , which showed an ED₅₀ value of 27.4 mg/kg and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED₅₀ and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti‐MES efficacy, the potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide were also established, with the results suggesting that the GABAergic system‐mediated mechanisms might be involved in its anticonvulsant activity.     

Synthesis and Anticonvulsant Activity of 5‐Phenyl‐[1,2,4]‐triazolo[4,3‐a]quinolines

A series of novel 5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline derivatives was synthesized by the cyclization of 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene with formohydrazide. The starting material 2‐chloro‐4‐phenyl‐1,2‐dihydronaphthalene was synthesized from ethyl‐3‐oxo‐3‐phenylpropanoate and substituted aniline. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The maximal electroshock test showed that 7‐hexyloxy‐5‐phenyl‐[1,2,4]‐triazolo[4,3‐a]quinoline 4f was found to be the most potent compound with an ED₅₀ value of 6.5 mg/kg and a protective index (PI = ED₅₀ / TD₅₀) value of 35.1, which was much higher than the PI of the reference drug phenytoin.     

Design,Synthesis, and Anticonvulsant Activity Evaluation of 4‐(3‐Alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones

A series of 4‐(3‐alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones were synthesized using the appropriate synthetic route and evaluated experimentally in the maximal electroshock test; their neurotoxicities were evaluated by the rotarod neurotoxicity test. The structures of these compounds were confirmed by IR, MS, ¹H‐NMR, and elementary analysis. All target compounds exhibited anticonvulsant activity to varying degrees in the maximal electroshock test. 4‐(3‐Benzyloxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐one ( 4i ) was the most promising compound with an ED₅₀ value of 30.5 mg/kg and a protective index (PI) of 18.63, showing a higher safety than the standard carbamazepine (PI = 6.45). In addition, the potency of compound 4i against seizures induced by pentylenetetrazole and 3‐mercaptopropionic acid suggested its broad‐spectrum activity, and the mechanisms of action including inhibition of voltage‐gated ion channels and modulation of GABAergic activity might be involved in its anticonvulsant activity.     

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).