双磷酸伯氨喹啉的合成

隣苯二甲醯亚胺钾与1.4-二溴戊烷制成的4-溴-1-隣苯二甲醯亚氨基戊烷,与6-甲氧基-8-氨基喹啉共熔后,再行水解得伯氨喹啉。双磷酸伯氨喹啉总产率按所用隣苯二甲醯亚胺钾计算为42.5—48.4%。     

喹啉及其相关杂环类抗疟药研究进展

喹啉结构骨架广泛存在于多种具有药理活性的天然产物及合成药物中。这类化合物(如氯喹、奎宁、阿莫地喹、哌喹、伯氨喹和甲氟喹等)在抗疟领域具有重要地位。然而,随着耐药性的迅速增加,其疗效已大打折扣,故对其结构修饰,以克服耐药性并实现对疟疾的有效治疗与控制势在必行。本文对近十年来喹啉及其结构类似物(4-氨基喹啉、4-苯胺基喹啉、8-氨基喹啉、天然产物、喹诺酮、异喹啉和四氢喹啉、环修饰物等)在抗疟方面的研究进展进行了较全面的综述。     

一起集体性氯化喹啉急性中毒的报告

氯化喹啉中毒偶有报道,目前尚无特效解毒剂,为杜绝此类事件的发生,现将一起集体性氯化喹啉急性中毒,报告于后,供同道参考.一、中毒情况云南省墨江县景星区××小学,属疟疾高发区.为了预防疟疾,该校一教师于1984年4月19日上午9时半左右,将抗疟药(氯化喹啉、伯氨喹啉)发给学生服用.由于该     

抗疟药的研究 Ⅶ.α-(烷氨甲基)-2-苯基-4-喹唑啉甲醇类化合物的合成

Martin等报道α-(二丁氨甲基)-6,8-二氯-2-(3,4-二氯苯基)-4-喹啉甲醇(WR 30090)对抗药性恶性疟疗效较高,光敏副作用小;这类化合物中的喹啉核用吡啶、菲、芴等其它芳环核取代所合成的化合物都具有一定的抗疟作用,α-(烷氨甲基)-2,7-二氯-4-芴甲醇就是一例。因此,作者等用喹唑啉核取代喹啉核合成了通式为I的化合物14个,I_(a～n)(表1),以期找到更有效的抗疟药。     

降血糖药喹啉-8-羰酰氨烷基-苯磺酰胺衍生物

从口服抗糖尿药优降糖(Glybenclamid,HB419)出发,制备和试验过一系列的酰氨基-苯磺酰脲、酰氨基-苯磺酰氨基脲和酰氨基-苯磺酰氨基杂环化合物,改变酰氨烷基可增强或延长药效。本文以喹啉-8-羧酸等为酰化取代基制备了酰氨烷基-苯磺酰脲(Ⅰ,Ⅱ)酰氮烷基-苯磺酰氨基脲(Ⅲ)和酰氨烷     

竞争性AMPA受体拮抗剂SPD502的合成

5-溴异喹啉经硝化、甲基化和还原得到8-氨基-5-溴-2-甲基-1,2,3,4-四氢异喹啉(4),再经Sandmeyer靛红合成、Suzuki偶合得关键中间体N,N-二甲基-4-(8-甲基-2,3-二氧-2,3,6,7,8,9-六氢-1H-吡咯并[3,2-h]异喹啉-5-基)苯磺酰胺(8).最后与2-氨氧基-1,4-γ-丁内酯盐酸盐缩合并经碱性开环制得竞争性AMPA受体拮抗剂SPD 502,总收率约10%.     

1,4-双-[ω-(2,4-二氨基喹唑啉-6-取代氨基)烷基]哌嗪及其类似物的合成和生物活性

2,4-二氨基-6-取代氨甲基喹唑啉类化合物具有较强的抗疟作用,而在4-氨基喹啉类化合物中引入哌嗪基如喹哌(1)可增强药物与肝、肾等组织的亲和力,减缓从肝实质细胞和枯     

喹啉酸诱发实验性癫痫作用机制的初步研究

喹啉酸是一种内源性的兴奋性氨基酸,给小鼠每只icv10μl(1g·L~(-1)),可引起典型的实验性癫痫。ip异鹅羔胺激动GABA_A型受体;或ip GABA降解酶抑制剂氨氧乙酸,从而增加CNS中的GABA含量;或ip甲基三唑安定以增强GABA受体的亲和力来高脑中GABA能神经系统的功能,均能减弱或对抗喹啉酸的致惊作用。相反,sc GABA_A型受体拮抗剂荷包牡丹碱;或sc GABA合成和释放抑制剂3-巯基丙酸来降低中枢GABA能神经系统的功能,则能促进喹啉酸的致惊作用.所有这些结果提示.CNS中GABA系统的功能在喹啉酸的致惊机制中可能起调控作用。     

5-(8-喹啉氧甲基)-4-烯丙基(苯基)-3-巯基-4H-1,2,4-三唑衍生物的合成及其抗丝虫作用

许多喹啉类抗疟药物具有抗丝虫及血吸虫作用,已知氨酚喹(Ⅰ)、氯喹(Ⅱ)对丝虫微丝蚴有杀灭作用,RD 12869(Ⅲ)对实验小白鼠有抗曼氏血吸虫活性,UK 3883(Ⅳ)用于临床     

贵州省恶性疟原虫对氯喹敏感性的调查及抗氯喹恶性疟原虫株地区防治效果的观察

试验区概况荔波县水庆大队辖3个自然村,5华里内未与外村相邻,总人口918人,水族,务农。1982年9月,居民普查血检平均原虫率为22.7％,恶性疟占原虫组成的67.5％(表1),雷氏按蚊嗜人亚种为主要传疟媒介。同月,用体外微量测定法对该地15例恶性疟现症患者测试结果,有6例对氯喹有抗性。同年9月对发热患者血检查获的75例疟原虫阳性者,由当地卫生员发给氯喹1.5克(基质)加伯氨喹啉150毫克(儿童酌减)自服;12月上旬再由当地卫生员发给氯喹1.2克加伯氨喹啉112.5毫克(5天分服)进行全民服药。     

In vitro and in vivo evaluation of a primaquine prodrug without red blood cell membrane destabilization property

Primaquine is an important therapeutic resource for malaria treatment and it has wide activity against several pathogens. The haematotoxicity of primaquine is the major problem for its therapeutic application. This effect is aggravated by repeated use at high doses and by the wide fluctuation of plasma levels after administration. The primaquine prodrug (Phe‐Ala‐PQ) was planned in order to modify the pharmacokinetics and toxicity of primaquine. The in vitro conversion of Phe‐Ala‐PQ to primaquine, and the primaquine pharmacokinetics were evaluated in four groups of rats: two groups that received a single dose of Phe‐Ala‐PQ, one by intravenous and the other by gavage route, and two other groups that received primaquine diphosphate, by intravenous and gavage routes. In addition, the erythrocyte osmotic fragility was compared in two groups of rats that received multiple doses of primaquine diphosphate or Phe‐Ala‐PQ, as a parameter of haematotoxicity. The in vitro conversion of Phe‐Ala‐PQ to primaquine by plasma enzyme action was observed. The pharmacokinetic profile of primaquine from Phe‐Ala‐PQ was more favourable due to the lower fluctuation of plasma concentrations. Haematotoxicity was not evidenced in the prodrug administration. The results reinforce the need for further studies with this prodrug, promising an alternative in the therapeutic use of primaquine. Copyright © 2012 John Wiley & Sons, Ltd.     

Effect of nifedipine on Leishmania donovani infection in-vivo and in-vitro: chemiluminescence responses of peritoneal macrophages and neutrophils

Abstract— After peritoneal macrophages had been exposed to different concentrations of nifedipine (10–120 ng mL^?1) there was a significant increase (P < 0.001) in the percentage of Leishmania donovani infected macrophages compared with controls. Parasite load was also significantly increased (P < 0.001) in nifedipinetreated, L. donovani infected, BALB/c mice, compared with untreated, infected mice, post-inoculation. Peak chemiluminescence responses were significantly depressed (P < 0.001) in nifedipinetreated infected mice compared with untreated mice post-inoculation. It is suggested that availability of intracellular calcium is a factor in the defense mechanism of inflammatory cells in L. donovani infections.     

Echinacea and trypanasomatid parasite interactions: Growth-inhibitory and anti-inflammatory effects of Echinacea

Context/objective: Herbal preparations derived from various species and parts of Echinacea (Asteraceae) have been advocated for various medical applications, as a result of the many antimicrobial and immunomodulatory activities attributed to them.

Materials and methods: In order to investigate their effects on parasites, four preparations of Echinacea, with distinct chemical compositions, were evaluated for growth inhibition of three species of trypanosomatids: Leishmania donovani, Leishmania major, and Trypanosoma brucei. In addition one Echinacea preparation was tested for anti-inflammatory activity in cell culture models designed to measure pro-inflammatory cytokines induced by L. donovani.

Results and discussion: All Echinacea preparations inhibited growth of the organisms, though with different relative potencies, and in some cases morphological changes were observed. However, there was no obvious correlation with the composition of the marker compounds, alkylamides, caffeic acid derivatives, and polysaccharides. L. donovani stimulated the production of the pro-inflammatory cytokines IL-6 and IL-8 in human bronchial epithelial cells and in human skin fibroblasts, but in both cases the standardized ethanol extract of E. purpurea (L.) Moench (Echinaforce^®) abolished the stimulation, indicating anti-inflammatory activity of this extract.

Conclusions: Thus various Echinacea extracts can inhibit the proliferation of these parasites and at least one can reverse the pro-inflammatory activity of Leishmania donovani.     

Evaluation of the antileishmanial potency,toxicity and phytochemical constituents of methanol bark extract of Sterculia villosa

Context: Visceral leishmaniasis is a protozoan disease caused by Leishmania donovani parasite. The genus Sterculia (Malvaceae) possesses ethnobotanical potential against this protozoan infection.

Objective: Determining the potential role of methanol bark extracts from Sterculia villosa Roxb (SVE) and its phytoconstituents against Leishmania donovani promastigotes.

Materials and methods: SVE was analysed by TLC, UV–Vis, IR spectroscopy and biochemical assays. Antileishmanial potential of SVE (0.5–130?μg/mL for 72?h) was characterized by MTT assay. Fluorescent microscopy was performed to validate the IC₅₀ dose. To determine the effect of SVE on promastigotes, reactive oxygen species (ROS) and superoxide generation, lipid peroxidation and DNA fragmentation assays were performed. Molecular aggregation of compounds was determined by atomic force microscopy (AFM). Extent of cytotoxicity of SVE at IC₅₀ dose was determined against RAW 264.7 macrophages, peritoneal macrophages and murine RBCs. In vivo cytotoxicity of SVE was evaluated in BALB/c mice.

Result: SVE exhibited reverse dose dependent antileishmanial activity when 130–0?μg/mL doses were tested against promastigotes. The IC₅₀ and IC₇₀ values were found to be 17.5 and 10?μg/mL, respectively. SVE at IC₅₀ dose demonstrated elevated level of ROS, superoxide, lipid peroxidation and DNA fragmentation against promastigotes with no cytotoxicity. AFM analysis suggested increasing size of molecular aggregation (31.3?nm Discussion and conclusions: The study elucidates the antileishmanial potential of SVE against Leishmania donovani promastigotes by exerting oxidative stress and DNA damage. In sum, SVE can be explored as an immunotherapeutic candidate against leishmaniasis and other infectious diseases.     

Terpenoidal constituents of Eucalyptus loxophleba ssp. lissophloia

Context: Eucalyptus has been a source of a number of biologically active compounds. The anti-leishmanial activity of terpenoids from Eucalyptus loxophleba (Benth.) ssp. lissophloia (Myrtaceae) has not yet been investigated.

Objective: Isolation of the terpenoidal constituents for evaluation of in vitro anti-leishmanial activity against the Leishmania donovani (Dd8 strain) promastigotes.

Materials and methods: The chloroform–methanol (8:2) extract of dried leaves of Eucalyptus loxophleba was used to isolate terpenoidal constituents employing solvent partitioning, column chromatography and preparative high performance liquid chromatography and characterized from spectral data. The anti-leishmanial activity of the isolated compounds was tested in vitro using an Alamar blue assay against a culture of L. donovani (Dd8 strain) promastigotes.

Results: Two new naturally occurring triterpenes, named loxanic acid and 3-acetyl loxanic acid together with four known ursane triterpenoids and one bis-monoterpene glycoside, cuniloside B isolated from the leaves showed anti-leishmanial activity (IC₅₀ 133 to 235 μM) against the promastigotes of the tested strain.

Conclusion: The terpenes isolated from the leaves of E. loxophleba showed moderate anti-leishmanial activity.     

Inhibition of growth of Leishmania donovani promastigotes by newly synthesized 1,3,4-thiadiazole analogs

Leishmania donovani, the causative agent of visceral leishmaniasis, is transmitted by sand flies and replicates intracellularly in their mammalian host cells. The emergence of drug-resistant strains has hampered efforts to control the spread of the disease worldwide. Forty-four 1,3,4-thiadiazole derivatives and related compounds were tested in vitro for possible anti-leishmanial activity against the promastigotes of L. donovani. Micromolar concentrations of these agents were used to study the inhibition of multiplication of L. donovani promastigotes. Seven compounds were identified with potential antigrowth agents of the parasite. Compound 4a was the most active at 50 μM followed by compound 3a. These compounds could prove useful as a future alternative for the control of visceral leishmaniasis.     

疟原虫组织期裂殖体杀灭剂的研究:5-三氟乙酰基伯氨喹及其衍生物的合成

伯氨喹与三氟乙酸酐作用,可制得相应的N-三氟乙酰基伯氨喹(2),也可形成双-(三氟乙酰基)伯氨喹(化合物6),后者再水解,生成5-三氟乙酰基伯氨喹,简称三氟乙酰伯氨喹(11)。化合物1,3～5以及7～10,均按上法分别制得。其中以化合物11杀灭鼠、猴疟原虫组织期裂殖体的作用最强,对小鼠的急性毒性比伯氨喹低2倍。是一种值得研究的疟原虫组织期裂殖体杀灭剂。     

Solid-Supported Parallel Synthesis of Hydroxybenzylamine Libraries Possessing Antileishmial Activity

A concise solid-supported parallel synthesis of 64 compounds is described. Starting with isovanillin, a two-step sequence involving reductive amination and N-benzylation was performed to provide the compounds in good purity. The library has been tested against Leishmania donovani and Plasmodium falciparum, with activity at the micromolar level.     

Design,synthesis, and antiprotozoal evaluation of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives

A series of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC₅₀ values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic‐to‐antiparasitic activities of 107 and 39 against a chloroquine‐sensitive and a chloroquine‐resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G‐quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.     

Synthesis and in vitro Screening of 29, 30-Dibromo-28-oxoallobetulin against Parasitic Protozoans,Leishmania donovani and Leishmania Major

A simple synthesis and in vitro antileishmanial activity of 29,30-dibromo-28-oxoallobetulin against the parasitic protozoans, Leishmania donovani and Leishmania major is described. The structure of the compound is established on the basis of spectral data (IR, NMR, MS). Both the antiproliferative effect and the cell cycle progression were studied.