1-(1 H-1, 2, 4-三唑-1-基)-2-(2, 4-二氟苯基)-3-[N-异丙基-N-(4-取代苄基)]-2-丙醇的合成及抗真菌活性

目的研究具有异丙基结构的氮唑类化合物的抗真菌活性。方法引入4位羧酸酯取代的苄基侧链结构,合成一系列目标化合物,所有化合物结构均经MS、1H-NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果合成了14个未见文献报道的目标化合物;所有化合物对所选真菌均表现出了一定的抑菌活性,其中化合物(1)和(2)对除薰烟曲霉菌外的7种菌都表现出了较好的抑菌活性。结论 4位羧酸酯取代的苄基侧链结构的引入对目标化合物的抗菌活性有一定的影响,侧链越短,抑菌活性越好。     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-(N-异丙基-N-取代氨基)-2-丙醇的合成及抗真菌活性

目的：以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法：引入异丙基及取代氨基侧链结构,合成一系列目标化合物,所有化合物结构均经MS、^1H—NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果：合成了15个目标化合物;所有化合物对所选真菌均表现出了一定的抑菌活性,其中化合物（6c）,（6d）,（6e）,（6f）和（6g）对除薰烟曲霉菌外的7种菌株都表现出了较好的抑菌活性。结论：取代氨基侧链结构的引入对目标化合物的抗菌活性有一定的影响,侧链为取代苄基活性较好,且取代苄基侧链越短,抑菌活性越好。     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-[N-环丙基-N-(4-取代苄基)]-2-丙醇的合成及抗真菌活性

目的：以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法：引入4位羧酸酯取代的苄基侧链结构,合成一系列目标化合物,所有化合物结构均经MS、^1H-NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果：合成了15个未见文献报道的目标化合物;所有化合物对所选真菌均表现出了一定的抑菌活性,其中化合物（1）,（2）和（3）对除薰烟曲霉菌外的7种菌都表现出了较好的抑菌活性。结论：4位羧酸酯取代的苄基侧链结构的引入对目标化合物的抗菌活性有一定的影响,侧链越短．抑菌活性越好.     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-[(4-取代)-哌嗪-1-基]-2-丙醇的合成及其抗真菌活性

目的研究不同取代哌嗪侧链的引入对三唑醇类化合物抗真菌活性的影响.方法设计合成了13个三唑醇类新化合物;选择8种真菌为实验菌株,进行体外抑菌活性测试.结果目标化合物对8种真菌特别是深部真菌均有一定的抑制活性,其中有8个化合物对白色念珠菌的MIC80值小于或等于0.125μg/mL,是氟康唑活性的4倍以上,与酮康唑活性相当.结论脂水分配系数和立体化学因素的改变对该类化合物体外抑菌活性有较大影响.     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-(N-环己基-N-取代氨基)-2-丙醇的合成及抗真菌活性

目的：以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法：引入环己基侧链结构,合成一系列目标化合物,所有化合物结构均经Ms、1H—NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性。结果：合成了11个未见文献报道的目标化合物,部分化合物对所选真菌均表现出了一定的抑菌活性。结论：引入环己基对抗真菌活性影响较大。     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-取代-2-丙醇类化合物的合成及其抗真菌活性

目的研究不同取代哌啶和环仲胺侧链的引入对三唑醇类化合物抗真菌活性的影响。方法以氟康唑为先导化合物,设计合成了9个三唑醇类新化合物,化合物的结构均通过核磁、红外光谱确证;选择8种真菌为实验菌株,根据美国国家临床实验室标准委员会(NCCLS)推荐的标准化抗真菌敏感性实验方法,进行体外抑菌活性测试。结果目标化合物对8种真菌特别是深部真菌均有一定的抑制作用,其中化合物4、5对白色念珠菌的MIC80值小于或等于0.125μg.mL-1,是氟康唑活性的4倍以上,与伊曲康唑活性相当。结论立体化学因素的改变对该类化合物体外抑菌活性有较大影响。     

叔丁基三唑衍生物的合成及抗真菌活性研究

目的研究具有叔丁基结构的三唑醇类化合物的抗真菌活性以及各种4-(4-烷氧基苯基)哌嗪侧链的引入对抗真菌活性的影响.方法以一氯频那酮、三氮唑为原料,经多步反应合成目标化合物,化合物结构经IR、1H-NMR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定其体外抗真菌活性.结果设计合成了10个新化合物.10个目标化合物对8种真菌均具有一定的抑制活性,其中,有4个化合物对白色念珠菌的MIC80值小于或等于0.125 mg·L-1,是氟康唑的4倍以上,与伊曲康唑相当.结论可以通过引入更多的疏水基团设计三唑醇类化合物,立体化学因素对该类化合物的体外抑菌活性有较大影响.     

新型三唑醇类化合物的合成及抗真菌活性研究

目的以氟康唑为先导化合物,设计合成新的三唑醇类化合物,并研究其抗真菌活性。方法引入较大基团的N,N-二取代侧链结构,合成一系列目标化合物,所有化合物结构均经MS、1H NMR等谱确证;选择8种真菌为实验菌株,测定其体外抗真菌活性,、结果合成了18个未见文献报道的目标化合物,化合物对所选真菌均表现出厂一定的抑菌活性,结论引入较大幕团的N,N-二取代侧链结构对抗真菌活性影响较大。     

叔丁基三唑醇类衍生物的合成及其抗真菌活性

目的设计合成具有叔丁基结构的三唑醇类化合物并研究其体外抗真菌活性。方法以一氯频那酮、三氮唑为原料,经多步反应合成目标化合物,化合物结构经IR、^1H-NMR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定其体外抗真菌活性。结果设计合成了10个新化合物,所有化合物对8种真菌均有一定的抑制活性。结论立体化学因素对该类化合物的体外抑菌活性有较大影响。     

含哌嗪环的三唑醇类化合物的合成及体外抗真菌活性

目的设计合成含哌嗪环侧链的三唑醇类化合物并研究其体外抗真菌活性。方法以2-氯-2′,4′-二氟苯乙酮为起始原料经多步反应合成目标化合物，化合物结构经IR、^1H-NMR谱确证；选择8种真菌为实验菌株，按国际标准抗真菌敏感性实验方法测定体外抑菌活性。结果设计合成了11个新化合物。所有目标化合物对8种真菌均具有一定的抑制作用。结论多个目标化合物的抗真菌活性明显高于阳性对照药氟康唑，其中化合物11具有广谱、高活性的优点，其体外抗真菌活性与对照药伊曲康唑相当，有进一步研究开发的价值。     

Transporter-mediated actions of R-(-)-1-(benzofuran-2-yl)-2-propylaminopentane

R-(-)-1-(Benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP] is a catecholaminergic and serotonergic activity enhancer that increases impulse-evoked catecholamine and serotonin release from nerve terminals, and is a candidate for symptomatic treatment of early Parkinson's disease. We now report the catecholamine and serotonin transporter-mediated actions of (-)-BPAP. The effects of (-)-BPAP on inhibition of neurotransmitter uptake and radioligand binding were assessed using human embryonic kidney 293 cells (HEK 293 cells) expressing cDNA for the human dopamine transporter (hDAT), norepinephrine transporter (hNET), and serotonin transporter (hSERT). The IC(50) values for the effects of (-)-BPAP on [3H]dopamine, [3H]norepinephrine, and [3H]serotonin uptake were 42+/-9, 52+/-19, and 640+/-120 nM, respectively. The IC(50) values for the effects of (-)-BPAP on [125I]3 beta-(4-iodophenyl)tropane-2 beta-carboxylic acid methyl ester ([125I]RTI-55) binding to hDAT, hNET, and hSERT were 16+/-2, 211+/-61, and 638+/-63 nM, respectively. The effects of (-)-BPAP on spontaneous and tyramine-induced norepinephrine and dopamine release from rat brain synaptosomes using a superfusion system were also assessed. Tyramine but not (-)-BPAP potentiated norepinephrine release. Furthermore, (-)-BPAP inhibited tyramine-induced norepinephrine release. Thus, (-)-BPAP may block tyramine-induced adverse effects such as hypertensive crisis. The actions of (-)-BPAP on the spontaneous and tyramine-induced dopamine release resembled its effects on norepinephrine release. We conclude that (-)-BPAP is not only catecholaminergic and serotonergic activity enhancer, but also a norepinephrine and dopamine uptake inhibitor and a weak serotonin uptake inhibitor that does not possess a tyramine-like action on catecholamine release, and is an inhibitor of tyramine-induced release of norepinephrine.     

Discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone as a potent and selective I(Kur) inhibitor

Previously disclosed dihydropyrazolopyrimidines are potent and selective blockers of I(Kur) current. A potential liability with this chemotype is the formation of a reactive metabolite which demonstrated covalent binding to protein in vitro. When substituted at the 2 or 3 position, this template yielded potent I(Kur) inhibitors, with selectivity over hERG which did not form reactive metabolites. Subsequent optimization for potency and PK properties lead to the discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)methanone (13j), with an acceptable PK profile in preclinical species and potent efficacy in the preclinical rabbit atrial effective refractory period (AERP) model.     

Pharmacological properties of 1-(4-methoxybutylamino)-2-(1-4-benzodioxan-2-yl)-ethane (2802 IS)

Summary The pharmacological properties of 1-(4-methoxybutylamino)-2-hydroxy-2-(1,4-benzodioxan-2-yl) ethane (2802 IS) are described. 2802 IS when administered by vein to anesthetized dogs and cats in doses of 0.025-0.05 mg/kg lowered the blood pressure. In an instrumental reward discrimination exercise in rabbits the depressant effects of the compound were demonstrated at 0.25-0.5 mg/kg i.v. 2802 IS provokes significant changes of the cortical and subcortical electrical activity of the unanaesthesized rabbit and a dampening of the arterial pressure response to the electrical stimulation of the hypothalamus. The site of action of the central effect of the compound is discussed.This work has been supported in part by a Grant from the National Institute of Mental Health, U.S.A. (MH-07093).     

Synthesis and biological evaluation of 1-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-3-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl)urea derivatives

A new series of eleven novel 1-(3-chloro-2-oxo-4-phenylazetidin-1yl)-3-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl)urea derivatives were synthesized by cyclocondensation of various Schiff bases of phenothiazine with chloroacetyl chloride in the presence of triethylamine. Various Schiff bases of phenothiazine were synthesized by condensation of 4-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl semicarbazide with various aryl aldehydes. The synthesized compounds were characterized by IR, MASS and ¹H NMR spectral data and evaluated for in vitro antimicrobial, antitubercular, antioxidant and anticancer activities by disc diffusion method, MIC method, REMA, DPPH, FRAP and MTT assay method, respectively. All synthesized compounds showed moderate-to-significant anti-bacterial and anti-fungal activity and compound 4d, 4g, 4h and 4k showed good antioxidant activity with EC₅₀ value of 55, 57, 56 and 47 μg/ml tested by DPPH method. The compounds 4j at a concentration of 10 μg/ml showed inhibition against the growth of Mycobacterium tuberculosis and 4f showed significant activity against human cervical cancer cell line with IC₅₀ values of 18.26 μM.     

Synthesis of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydrochloride, a novel, orally active antifungal agent

The preparation, determination of isomeric configuration, and antifungal properties of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydrochloride (1) are described. In vitro, compound 1 has been shown to have activity against Candida albicans comparable with miconazole. When administered orally to animals with experimentally induced vaginal candidiasis or systemic candidiasis, compound 1 produced results approaching those produced by ketoconazole. In addition, topical administration of compound 1 to rats with vaginal candidiasis produced results comparable with those produced by similar administration of clotrimazole. Unlike ketoconazole, which is active by a mechanism that is essentially fungistatic, compound 1 shares with miconazole a mode of action that is fungicidal. However, unlike miconazole, compound 1 exhibits activity following oral administration. Compound 1 has been found to be negative in the Ames test.