吡唑杂合体的抗疟疾活性

疟疾是由按蚊叮咬或输入携带疟原虫血液引起的一类高传染性疾病,其临床症状包括发热、头痛、呕吐等,如不及时治疗可能危及生命。尽管临床上使用的抗疟疾药物对疟疾的防控不可或缺,但随着长期广泛使用甚至滥用,恶性疟原虫对抗疟药物产生了不同程度的耐药性。为克服耐药性,研发新型抗疟疾药物势在必行。吡唑类化合物具有包括抗疟疾在内的多种生物活性,且某些吡唑类药物已广泛用于临床,故这类化合物引起了药物化学家的持续关注。本文将归纳吡唑杂合体在抗疟疾领域的最新研究进展,并讨论此类化合物的构-效关系。     

喹啉杂合体的抗疟疾活性

随着耐药性的广泛传播,耐药疟疾业已成为临床医师所必须经常面对的棘手问题.因此,研发新的抗疟药势在必行.近年来,药物化学家对喹啉类杂合体进行了广泛的研究,发现了若干有苗头的化合物.本文着重探讨近年来喹啉类杂合体在抗疟疾领域的研究进展,为研发对敏感型和耐药型疟疾均有效的新型抗疟药提供理论支持.     

过氧化物-喹啉杂合体的抗疟疾活性

以青蒿素(ART)为主的联合疗法(ACT)是目前治疗疟疾最有效的途径,是WHO推荐的抗疟疾标准疗法.然而,ART存在生物利用度低、复发率高、溶解性差、价格昂贵等缺点,且耐ART疟原虫已然出现,故研发新的抗疟药势在必行.喹啉类药物具有优秀的抗疟疾活性,是目前临床上应用最为广泛的抗疟药.研究显示,内过氧化物单元是ART及其衍生物具有抗疟疾活性所必需的药效团,故将过氧化物与喹啉杂合或许可得到活性更高的抗疟疾候选物.药物化学家有针对性的设计合成并筛选了众多过氧化物-喹啉杂合体的体外抗疟原虫和体内抗疟疾活性,并得到了若干有苗头的候选物.本文将介绍近年来过氧化物-喹啉杂合体在抗疟疾领域的研究进展,并讨论此类化合物的构-效关系,以期为更合理的设计抗疟新药提供支持.     

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.     

四氮唑杂合体在抗疟疾领域的研究进展

疟疾主要是由恶性疟原虫引起的一类可致命传染性疾病,与艾滋病、结核病一起被认为是全球最重要的三大公共卫生问题。临床上使用的抗疟疾药物如喹啉类和青蒿素类尽管对药敏型疟疾依然高度有效,但随着耐药疟疾的不断涌现和广泛传播,现有抗疟疾药物的疗效呈逐年下降之势。因此,亟需开发新型抗疟疾药物。四氮唑作为羧基的生物电子等排体可用来取代药物中的羧基以提高药物分子的脂溶性、增加药物的生物利用度和降低毒副作用,故四氮唑被认为是最具发展前景的一类化合物。本文将着重介绍近年来四氮唑杂合体在抗疟疾领域的研究进展,并讨论此类化合物的构-效关系。     

具有优秀抗肿瘤活性的香豆素杂合体

香豆素结构片段广泛存在于自然界中,其可修饰的位点较多,在新药研发领域有着广泛的应用。研究表明,香豆素类化合物可通过多种作用机制发挥抗肿瘤活性,故此类化合物具有良好的广谱体内外抗肿瘤活性。其中,Irosustat (STX64)具有良好的抗乳腺癌活性,目前正处于临床评价阶段,有望于不久的将来为人类健康服务。本文将介绍近年来所发现的具有优秀体内外抗肿瘤活性(半抑制浓度或50%生长抑制所需的药物浓度<10 μmol/L或具有体内活性)的香豆素杂合体的最新研究进展,并总结了构-效关系和作用机制,为进一步研究提供理论支持。     

喹啉杂合体的抗结核活性

结核病主要由结核分枝杆菌引起,具有高发病率和死亡率等特点,是全球最具传染性的致命疾病之一。一线抗结核药物在结核患者的治疗中发挥着至关重要的作用,但结核分枝杆菌可通过内在性和获得性机制快速产生耐药性,降低了这些药物的疗效。因此,开发新型抗结核药物势在必行。喹啉类化合物可与结核分枝杆菌的多个作用靶点相结合,具有潜在的抗结核活性。喹啉母核可能是寻找新型抗结核药物的优秀骨架。特别值得一提的是,喹啉类抗结核药物贝达喹啉是继利福平之后50多年来首次问世的抗结核新药,2016年被中国国家食品药品监督管理总局批准用来联合治疗成人耐多药肺结核,这也是我国首次上市治疗耐多药肺结核新药。其中,喹啉杂合体可同时作用于结核分枝杆菌的多个结合靶点,对药敏型和耐药结核均显示出潜在的活性,引起了药物化学家的普遍关注。本文探讨了喹啉杂合体的抗结核活性及构—效关系,为进一步研究提供参考。     

Chalcone hybrids and their antimalarial activity

Malaria, one of the most striking, re-emerging infectious diseases caused by the genus Plasmodium, places a huge burden on global healthcare systems. A major challenge in the control and eradication of malaria is the continuous emergence of increasingly widespread drug-resistant malaria, creating an urgent need to develop novel antimalarial agents. Chalcone derivatives are ubiquitous in nature and have become indispensable units in medicinal chemistry applications due to their diverse biological profiles. Many chalcone derivatives demonstrate potential in vitro and in vivo antimalarial activity, so chalcone could be a useful template for the development of novel antimalarial agents. This review covers the recent development of chalcone hybrids as antimalarial agents. The critical aspects of the design and structure–activity relationship of these compounds are also discussed.     

Antipyretic and antimalarial activities of Solenostemon monostachyus

Context: Solenostemon monostachyus P. Beauv (Lamiaceae) is an important herb used traditionally in the treatment of malaria, fever, and other diseases.

Objectives: Antiplasmodial and antipyretic activities of S. monostachyus aerial extract were evaluated to ascertain the folkloric claim of its antimalarial and antipyretic activities.

Materials and methods: The extract (75–225?mg/kg) and fractions (chloroform and aqueous; 150?mg/kg) of S. monostachyus were investigated for suppressive, prophylactic, and curative antiplasmodial activities against chloroquine-sensitive Plasmodium berghei infections in Swiss albino mice and for antipyretic activity against 2,4-dinitrophenol and yeast-induced pyrexia. Artesunate (5?mg/kg) and pyrimethamine (1.2?mg/kg) were used as positive controls for antiplasmodial models. Thin films made from tail blood of each mouse were used to assess the level of parasitaemia of the mice.

Results: The extract/fractions progressively reduced parasitaemia induced by chloroquine sensitive P. berghei infection in prophylactic (28.48–71.72%), suppressive (12.52–72.47%), and curative (22.4–82.34%) models in mice. These reductions were statistically significant (p?<?0.01–0.001). They also improved significantly (p?<?0.01–0.001) the mean survival time (MST) from 12.26 to 25.63?d relative to control (11.36?d). The activities of extract/fractions were incomparable with that of the standard drugs used (artesunate and pyrimethamine). The extract exerted prominent inhibition of pyrexia on dinitrophenol (87.33–90.11%, 5?h) and yeast (56.22–65.33, 5?h) induced pyrexia. Inhibition was significant (p?<?0.05–0.001) from 3 to 5?h post-administration of extract and in a dose-dependent fashion.

Conclusion: The plant may possess antiplasmodial and antipyretic effects which may in part be mediated through the chemical constituents of the plant.     

Central and Peripheral Catecholamine Levels after Pyrazole Treatment

Abstract: Pyrazole (50 to 300 mg/kg intraperitoneally) given to male rats produced a decrease in body weight. A dose dependent fall in the noradrenaline content of the brain was observed, but no changes occurred in the central levels of dopamine or 5-hydroxytryptamine. Even a single dose of pyrazole (100 mg/kg) decreased the noradrenaline content by 20 %. Successive doses had an additive effect which was maximal 24 hrs after the final dose. Recovery was quite rapid, but 3 days after the final administration the levels were still lower than in the controls. The noradrenaline content of the heart and spleen was also slightly reduced. The adrenaline content of the adrenals seemed unaffected by the treatment. It is concluded that pyrazole administration in the dose and time schedules used, markedly reduces the noradrenaline content of the central nervous system. This should be kept in mind when this substance is combined with ethanol in similar studies.     

Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids

Abstract  Synthesis and evaluation of the antimalarial activity of new pyridine quinoline hybrid molecules against a chloroquine-susceptible strain of Plasmodium falciparum and as inhibitors of β-hematin formation are described. Two novel pyridine quinoline hybrid molecules and one bisquinoline molecule were synthesized and purified by column chromatography and evaluated for antimalarial and haem polymerization inhibition (HPIA) activities. The molecules were found to be very good haem polymerization inhibitors but showed poor antimalarial activity. This was attributed to their low vacuole accumulation ratio (VAR) in comparison to chloroquine. These molecules can be used as templates for designing new antimalarials targeting haem detoxification pathway of malaria parasite. Graphical Abstract   Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids B.N Acharya, D. Thavaselvam^# and M.P Kaushik^* Discovery Centre, Process Technology Development Division Defence R & D Establishment, Jhansi Road, Gwalior-474002 (MP) INDIA ^#Division of Microbiology, Defence Research and Development Establishment,Gwalior-474002, India Synthesis and evaluation of antimalarial activity of new pyridine–quinoline hybrid molecules against a chloroquine-susceptible strain of Plasmodium falciparum and as inhibitors of β-hematin formation are described.     

有机磷农药诱变性的构效关系分析及分子机理

通过建立整体结构模式化多因素判别分析法(WSPMDA),对有机磷农药三种构份的亚型进行了有代表性的模式化,进而排列组合成36种整体模式,据有机磷农药诱变性测试资料,用该法推算出各整体模式在6种诱变试验中的预期阳性概率P(M~+),并分析每种构份的亚型模式与诱变性关系的密切程度.观察到三种构份均对有机磷的诱变性几乎在每种试验中都有影响,讨论了如何正确应用所得P(M~+)、还就分析结果结合诱变试验原理推测有机磷诱变分子机理存在三条不同途径。     

Coumarin-containing hybrids and their antibacterial activities

Infections caused by Gram-positive and -negative bacteria are one of the foremost causes of morbidity and mortality globally. Antibiotics are the mainstay of therapy for bacterial infections, but the emergence and wide spread of drug-resistant pathogens have already become a huge issue for public healthcare systems. The coumarin moiety, which is ubiquitous in nature, could bind to the B subunit of DNA gyrase in bacteria and inhibit DNA supercoiling by blocking the ATPase activity; hence, coumarin derivatives possess potential antibacterial activity. Several coumarin-containing hybrids such as coumermycin A1, clorobiocin, and novobiocin have already been used in clinical practice for the treatment of various bacterial infections; thus, it is conceivable that hybridization of the coumarin moiety with other antibacterial pharmacophores may provide opportunities for the development of novel antibiotics. This review outlines the advances in coumarin-containing hybrids with antibacterial potential in the recent 5 years and the structure–activity relationships are also discussed.     

Nobiletin and tangeretin (citrus polymethoxyflavones): an overview on their chemistry,pharmacology and cytotoxic activities against breast cancer

The fruit peel of Citrus species(Chenpi), particularly those of mandarin oranges, is a useful source of food and medicine in China. Flavonoids from the citrus fruit peel are mainly polymethoxyflavones(PMFs), of which nobiletin and tangeretin are the most abundant components. In the present review, we summarized the cytotoxic activities of these two PMFs to breast cancer cells. Studies have reported that these two compounds inhibit the growth of breast cancer cells by inducing apoptosis, cytostat...     

Pharmacological and Toxicological Properties of 4-Hydroxypyrazole,a Metabolite of Pyrazole

Abstract: The effects of 4-hydroxypyrazole (4-HP), a principal metabolite of pyrazole, were studied in mice. The compound was toxic, much more so than pyrazole with an LD50 of 1.1 mmol/kg (92 mg/kg) and doses greater than 1.5 mmol/kg (126 mg/kg) were almost invariably fatal. Toxicity seemed to be centred on the liver with microscopic evidence of centrolobular necrosis apparent. Mouse liver catalase was almost totally inhibited 1 hour after administration of 1 mmol/kg of 4-HP. Tryptophan pyrrolase was also inhibited. 4-HP seemed to penetrate into the brain as judged by inhibition of brain catalase activity. A slight increase in brain serotonin concentration was found but 4-HP hadno effect in the doses used(l.5 mmol/kgor4× 1.0 mmol/kg)on brain or heart noradrenaline. We conclude that the pyrazole-induced decrease in brain noradrenaline is not mediated via 4-HP. Furthermore, simultaneous treatment with methanol and pyrazole, which prevents the formation of 4-HP, did not prevent the decrease in brain noradrenaline levels. Since methanol prevented the pyrazole-induced decrease in brain catalase activity, we can also rule out the possibility that the decrease in brain noradrenaline is secondary to pyrazole-induced inhibition of brain catalase. It is concluded that though 4-HP is an active metabolite of pyrazole, causing, in particular, the hepatotoxicity of the parent molecule, it is not responsible for all the varied biological effects of pyrazole.