抗HIV活性香豆素类化合物的研究进展

香豆素类化合物作为新型抗HW药物，对HIV逆转录酶、蛋白酶及整合酶具有一定的抑制作用。本文对具有抗HW活性的香豆素类化合物的来源、作用机制及结构改造进行综述，为开发研制抗艾滋病药物提供依据。     

香豆素类化合物的抗疟疾活性

疟疾仍是目前严重威胁人类健康的全球性公共卫生问题,每年近百万人因此丧命.不幸的是,随着耐药性的出现,一线抗疟疾药物的临床疗效逐年下降.因此,对新型抗疟药的研发刻不容缓.香豆素类化合物具有广泛的生物活性,且某些香豆素类化合物己在临床上用于治疗各种疾病.近年来的研究表明,香豆素类化合物具有潜在的体外抗恶性疟原虫和体内抗疟疾活性,引起了药物化学家的广泛关注.本文将归纳近年来香豆素类化合物在抗疟疾领域的研究进展,并讨论这类化合物的构-效关系,为更合理的设计这类抗疟新药提供理论支持.     

抗HIV活性香豆素类化合物的研究进展

目的：综述近年来抗HIV活性香豆素类化合物的研究进展。方法：以实例说明。结果：以天然抗HIV活性香豆素类化合物为先导物,筛选到多显著抑制HIV的衍生物。结论：为研制抗爱滋病药物提供了一个新的途径。     

香豆素衍生物及其抗结核活性

香豆素类化合物是一类极其重要的天然产物,广泛存在于自然界中.香豆素及其衍生物具有抗肿瘤、抗病毒、抗炎、抗氧化、抗菌和抗结核(TB)等多种生物活性,众多基于香豆素结构的药物在临床上广泛使用.近年来,香豆素及其衍生物在抗TB领域的研究引起了药物化学家的极大兴趣.药物化学家从天然产物中分离和设计合成了成千上万的香豆素衍生物,目前已从中筛选出了若干有潜力的化合物.特别值得一提的是,吡喃型香豆素类化合物(+)-Calanolide A不仅是抗HIV热点先导物,而且对药敏性和耐药性结核分枝杆菌(MTB)均显示出良好的体内外活性,无疑可用于治疗MTB/HIV双重感染患者.本文将着重探讨香豆素衍生物抗TB的构-效关系,为寻找疗效更高、毒副作用更小的香豆素类抗TB新药提供理论依据.     

香豆素类化合物药理和毒理作用的研究进展

香豆素类化合物是自然界重要的一类天然有机化合物,存在于不同种属的植物中,具有广泛的用途。实验研究发现香豆素具有抗HIV、抗肿瘤、抗氧化、抗炎等多种药理活性,在临床上广泛用于抗凝血和淋巴管性水肿的治疗。近年来的研究发现,香豆素类化合物在啮齿类动物中存在着明显的毒性作用,且具有种属和位点特异性,这与其代谢途径和CYP2A6酶的多态性有关。另外,毒性作用还与给药剂量和给药途径密切相关,口服和高剂量给药更容易产生毒性反应。该文综述了近年来有关香豆素及其衍生物在药理和毒理方面的研究进展,以期为香豆素类化合物的研发和临床应用提供帮助。     

香豆素类化合物的药理作用研究进展

香豆素(coumarins)是一类广泛存在于自然界中的天然化合物,具有广泛的药理作用,如抗肿瘤、抗人类免疫缺陷病毒(HIV)、抗氧化、抗菌、抗凝血、光敏等。同时已有研究证实,其药理作用与化学结构密切相关,因此可进一步研究开发更多的香豆素类化合物,从中寻找有效的先导化合物和活性基团,通过结构修饰和筛选,开发出高效低毒的临床药物。该文就近年来香豆素类化合物在肿瘤、艾滋病等治疗领域的研究作一综述。     

香豆素类化合物对胃蛋白酶活性的影响研究

目的：基于香豆素类化合物与胃蛋白酶相互作用的研究，探讨香豆素类化合物对胃蛋白酶活性的影响，可能与胃部疾病治疗存在潜在的关系。方法：采用紫外-可见光谱法及福林酚法，以牛血红蛋白为底物，分别用香豆素、4-羟基香豆素、7-羟基香豆素、7-羟基-4-甲基香豆素作为干扰剂与胃蛋白酶混合，测定胃蛋白酶在540 nm处的吸光度值，计算胃蛋白酶表观酶活；在香豆素类化合物-胃蛋白酶体系中添加抗坏血酸，研究抗坏血酸对各体系中胃蛋白酶活性的影响；同时采用紫外-可见光谱法对香豆素类化合物与牛血红蛋白的相互作用光谱特征进行测定。结果：随着香豆素类化合物浓度增加，胃蛋白酶表观酶活呈降低趋势，但趋势略有不同。4-羟基香豆素、7-羟基香豆素、7-羟基-4-甲基香豆素、香豆素对胃蛋白酶的抑制率分别为10.15%～35.92%、7.27%～12.14%、10.58%～29.29%、13.88%～47.13%。添加抗坏血酸的4-羟基香豆素、7-羟基香豆素和7-羟基-4-甲基香豆素体系与未添加抗坏血酸的香豆素类化合物-胃蛋白酶体系相比，胃蛋白酶表观酶活进一步降低，而添加抗坏血酸的香豆素-胃蛋白酶体系与未添加抗坏血酸的香豆素-...     

香豆素苯并三唑的合成、抗微生物活性及其与氯霉素和氟康唑协同作用研究

以间苯二酚为起始原料,经过环化、醚化、N-烷化等多步反应合成了一系列新型香豆素苯并三唑类化合物,其结构经1H NMR、IR、MS和元素分析证实。体外考察了合成的香豆素类化合物抗革兰阳性菌、革兰阴性菌及真菌活性。结果表明香豆素苯并三唑能有效抑制细菌和真菌的生长,其中化合物11a～11e和13a～13c抗普通变形杆菌ATCC 6896活性强于氯霉素(chloromycin)。化合物11a和11b抑制金葡菌ATCC 25923和藤黄微球菌ATCC 4698的生长能力与氯霉素相当。化合物11a～11d抗烟曲霉菌ATCC 96918活性优于氟康唑(fluconazole)。此外,氯霉素或氟康唑与香豆素苯并三唑联用后,不仅减少了用药剂量,还拓宽了抗微生物谱,尤其增强了抑制耐甲氧西林的金葡菌N 315和氟康唑不敏感的烟曲霉菌的生长能力。     

抗日本血吸虫病药物研究——Ⅱ.溴乙酸及碘乙酸香豆素酯的合成

溴乙酸醇酯、酚酯类化合物作为抗日本血吸虫病药物的研究,前已报道。鉴于在筛选中发现4-甲基-7-羟基香豆素的溴乙酸酯具有明显的杀血吸虫作用,而文献报道香豆素衍生物具有广泛的生理活性,因此又合成了一系列羟基香豆素的溴(或碘)乙酸酯类化合物,以     

香豆素类化合物抗肿瘤机制的研究进展

香豆素类化合物是传统的中草药成分,在自然界中普遍存在.近年来,其抗肿瘤作用得到了广泛的关注.研究表明,香豆素类化合物可通过诱导肿瘤细胞凋亡、阻滞细胞分裂周期、抑制肿瘤血管生成及肿瘤细胞迁移和侵袭、抗氧化以及调控多种蛋白和酶的活性等机制发挥抗肿瘤作用.本文综述了近年来香豆素类化合物抗肿瘤机制的研究进展,以期为香豆素类化合物的进一步研究和开发提供理论基础和依据.     

Identification of natural coumarin compounds that rescue defective DeltaF508-CFTR chloride channel gating

1. Deletion of phenylalanine at position 508 (DeltaF508) of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the most common mutation causing cystic fibrosis (CF). Effective pharmacological therapy of CF caused by the DeltaF508-CFTR mutation requires the rescue of both intracellular processing and channel gating defects. 2. We identified a class of natural coumarin compounds that can correct the defective DeltaF508-CFTR chloride channel gating by screening a collection of 386 single natural compounds from Chinese medicinal herbs. Screening was performed with an iodide influx assay in Fischer rat thyroid epithelial cells coexpressing DeltaF508-CFTR and an iodide-sensitive fluorescent indicator (YFP-H148Q/I152L). 3. Dose-dependent potentiation of defective DeltaF508-CFTR chloride channel gating by five coumarin compounds was demonstrated by the fluorescent iodide influx assay and confirmed by an Ussing chamber short-circuit current assay. Activation was fully abolished by the specific CFTR inhibitor CFTR(inh)-172. Two potent compounds, namely imperatorin and osthole, have activation K(d) values of approximately 10 micromol/L, as determined by the short-circuit current assay. The active coumarin compounds do not elevate intracellular cAMP levels. Activation of DeltaF508-CFTR by the coumarin compounds requires cAMP agonist, suggesting direct interaction with the mutant CFTR molecule. Kinetics analysis indicated rapid activation of DeltaF508-CFTR by the coumarin compounds, with half-maximal activation of < 5 min. The activating effect was fully reversed for all five active compounds 45 min after washout. 4. In conclusion, the natural coumarin DeltaF508-CFTR activators may represent a new class of natural lead compounds for the development of pharmacological therapies for CF caused by the DeltaF508 mutation.     

Pronounced differences in inhibition potency of lactone and non-lactone compounds for mouse and human coumarin 7-hydroxylases (CYP2A5 and CYP2A6)

1. The structural requirements for a compound to be a potent inhibitor for mouse CYP2A5 and human CYP2A6 enzymes catalysing coumarin 7-hydroxylase activity have been studied. 2. The IC50 of 28 compounds for the pyrazole-treated male DBA/2 mouse and human liver microsomal coumarin 7-hydroxylation were determined at 10 microm coumarin concentration 15 times over Km of coumarin. 3. The three most potent inhibitors for CYP2A5 were gamma-nonanoic lactone, gamma-decanolactone and gamma-phenyl-gamma-butyrolactone with an IC50 = 1.9+/-0.4, 2.1+/-0.2 and 2.4+/-0.3 microM and for CYP2A67-methylcoumarin, butylcyclohexane and indan with an IC50. = 30+/-3.2, 43+/-9 and 50+/-11 microM. 4. Among the 28 compounds studied, only 2-benzoxazolinone, 2-indanone and gamma-valerolactone showed similar inhibitory activity in both species. Indan had a lower IC50 for human than for mouse coumarin 7-hydroxylation, whereas the IC50 of 24 other compounds was higher for human than for mouse coumarin 7-hydroxylation. 5. The largest difference in IC50 between mouse and human activity was observed with 5-substituted phenyl, pentyl, hexyl, heptyl or octyl gamma-lactones or 6-substituted delta-lactones. IC50 of gamma-undecanolactone and gamma-decanolactone was 500 times lower for mouse than human coumarin 7-hydroxylation. 6. The difference in the IC50 between human and mouse coumarin 7-hydroxylation decreased substantially with the corresponding compounds without the lactone ring. 7. It is concluded that certain 5- or 6-position substituted gamma- and delta-lactones are potent inhibitors for mouse CYP2A5 but not for the orthologous human CYP2A6 and that the active site of CYP2A6 could be smaller than the active site of CYP2A5.     

抗癌及癌化学预防药物的研究:3-α-酮醛香豆素衍生物的合成及其抗致突活性与结构间的关系

α-酮醛及其衍生物在抗病毒、抗肿瘤方面有一定活性。我们合成了18个新的3-α-酮醛香豆素衍生物,研究该类化合物的质谱裂解方式与氢核磁共振谱的特征峰。体外药理筛选发现其中部分化合物有不同程度的抗致突活性,对其构效关系进行了分析,并提出了这类化合物产生抗致突活性的可能亚结构。     

Pronounced differences in inhibition potency of lactone and non-lactone compounds for mouse and human coumarin 7-hydroxylases (CYP2A5 and CYP2A6)

1. The structural requirements for a compound to be a potent inhibitor for mouse CYP2A5 and human CYP2A6 enzymes catalysing coumarin 7-hydroxylase activity have been studied. 2. The IC₅₀ of 28 compounds for the pyrazole-treated male DBA/2 mouse and human liver microsomal coumarin 7-hydroxylation were determined at 10 muM coumarin concentration 15 times over K_m of coumarin. 3. The three most potent inhibitors for CYP2A5 were gamma-nonanoic lactone, gamma-decanolactone and gamma-phenyl-gamma-butyrolactone with an IC₅₀=1.9 +/- 0.4, 2.1 +/- 0.2 and 2.4 +/- 0.3 muM and for CYP2A6 7-methylcoumarin, butylcyclohexane and indan with an IC₅₀=30 +/- 3.2, 43 +/- 9 and 50 +/- 11 muM. 4. Among the 28 compounds studied, only 2-benzoxazolinone, 2-indanone and gamma- valerolactone showed similar inhibitory activity in both species. Indan had a lower IC₅₀ for human than for mouse coumarin 7-hydroxylation, whereas the IC₅₀ of 24 other compounds was higher for human than for mouse coumarin 7-hydroxylation. 5. The largest difference in IC₅₀ between mouse and human activity was observed with 5-substituted phenyl, pentyl, hexyl, heptyl or octyl gamma-lactones or 6-substituted delta-lactones. IC₅₀ of gamma-undecanolactone and gamma-decanolactone was 500 times lower for mouse than human coumarin 7-hydroxylation. 6. The difference in the IC₅₀ between human and mouse coumarin 7-hydroxylation decreased substantially with the corresponding compounds without the lactone ring. 7. It is concluded that certain 5- or 6-position substituted gamma- and delta -lactones are potent inhibitors for mouse CYP2A5 but not for the orthologous human CYP2A6 and that the active site of CYP2A6 could be smaller than the active site of CYP2A5.     

Anti-inflammatory new coumarin from the Ammi majus L

ABSTRACT: Investigation of the aerial parts of the Egyptian medicinal plant Ammi majus L. led to isolation of new coumarin, 6-hydroxy-7-methoxy-4 methyl coumarin (2) and 6-hydroxy-7-methoxy coumarin (3); this is the first time they have been isolated from this plant. The structures of the compounds (2 &3) were elucidated by spectroscopic data interpretation and showed anti-inflammatory and anti-viral activity. GRAPHICAL ABSTRACT: An efficient, one-new coumarin (2) was isolated from the aerial parts of the A. Majus L. was evaluated for their anti-viral and anti-inflammatory activities.     

Coumarin congeners as antidepressants.

3-Carboethyl coumarin (I) was converted to coumarin 3-acid hydrazide (II). This on reaction with appropriate aldehyde yielded 3-arylidino amino coumarin (III). Compound III on diazotisation and reaction with ferric chloride yielded the corresponding formazans viz. 3-substituted phenyl azoarylidino, amido coumarins (IVa1-a10) and oxadiazoles viz. 2-aryl-5-(3-coumarinyl)-1,3,4-oxadiazoles (Va1-a3), respectively. Simultaneously 3-carboethyl coumarin on hydrolysis gave 3-carboxy coumarin (VI) which on reaction with aryl amine in methylene chloride yielded 3-(N-aryl)amido coumarin (VIIa1-a3). The compounds were screened for their antidepressant activity against a tricyclic antidepressant (imipramine). Compounds IVa4, IVa5 and IVa9 exhibited activity better than imipramine with no toxicity (ALD50 greater than 1000 mg/kg) but IVa5 showed some side effects.     

Discovering the structure–activity relationships of different O-prenylated coumarin derivatives as effective anticancer agents in human cervical cancer cells

Cervical cancer remains one of the greatest life threatening diseases for women worldwide. Although chemotherapy is considered as a standard treatment for advanced cervical cancers, there are still some drawbacks in this procedure including side effects and acquired drug resistance, which necessitate further research on development of more effective agents with less side effects. Among natural compounds, coumarin derivatives have shown anticancer properties on various cancerous cells and coumarin ring has proven to have a paramount role in development of anticancer drugs.Here, we aimed to establish the structure-activity relationships of eighteen O-prenylated coumarin derivatives and determined their anticancer properties on HeLa cervical cancer and HDF normal cells by MTT assay. Moreover, the mechanism of cell death induced by these compounds and their effects on cell cycle were studied using flow cytometry. MTT results indicated that twelve O-prenylated coumarin derivatives exhibited selective toxicity on HeLa cells, while they had no significant toxic effects on normal cells. Besides, flow cytometric analyses, showed that the selected compounds induced apoptosis in HeLa cells, and could also result to G₁ cell cycle arrest.In conclusion, analyzing structural–activity relationships revealed that a prenylation substitution at position 6 of the coumarin ring greatly improved anticancer properties of these agents. As these derivatives exerted their cytotoxic effects via apoptosis and were not toxic on normal cells, they can be considered as effective anticancer agents for further preclinical experiments.     

Synthesis and antifungal activity of novel 7-<Emphasis Type="Italic">O</Emphasis>-substituted pyridyl-4-methyl coumarin derivatives

A new series of 7-O-substituted pyridyl-4-methyl coumarin derivatives were synthesized and characterized based on their spectral data. All the target compounds were evaluated for their in vitro antifungal activity against eight important fungal pathogens. This study showed that the introduction of the substituted pyridyl moiety at the 7-hydroxy position of coumarin could enhance the antifungal activities. It also indicated that a bulky substituent was not beneficial to the antifungal activity of those coumarin derivatives.     

Synthesis, biopharmaceutical characterization, and antimicrobial study of novel azo dyes of 7-hydroxy-4-methylcoumarin

Herein, we report the synthesis and biopharmaceutical characterization of coumarin based azo compounds. The novel coumarin based azo compounds were obtained by the coupling of bis-coumarin (2Z,2′Z)-2,2′-[ethane-1,2-diylbis(azan-1-yl-1-ylidene)]bis(4-methylchroman-7-ol) with diazotized aromatic amines. The compounds were fully characterized using spectroscopic analytical method and tested for their antibacterial and antifungal activity. A correlation of structure and activities relationship of these compounds with respect to molecular modeling, Lipinski rule of five, drug-likeness, toxicity profiles, and other physico-chemical properties of drugs are described and verified experimentally.