抗疟药的非抗疟作用

抗疟药指喹啉类化合物 (如氯喹 )、羟氯喹及吖啶化合物(如阿的平 ) ,不包括其他类抗疟药。 17世纪以来 ,长期大量研究证明 ,抗疟药除传统抗疟作用外 ,还有多方面药理作用被广泛应用于临床 ,现概述如下。1　抗疟药的药理作用1.1　免疫抑制作用　抗疟药影响免疫过程的多个环节。氯喹和羟氯喹为弱碱性 ,能提高细胞外液pH值 ,减少细胞表面自身抗体数量。细胞内的酸性环境是处理抗原蛋白 ,是与白细胞介素 (IL)类主要组织相容性复合体 (MHC)的α和 β链结合的必要条件 ,氯喹和羟氯喹通过脂质细胞膜 ,在酸性胞质囊泡中聚集 ,使细胞内pH值提高 ,因此抑制了抗原肽 MHC蛋白复合物的形成和转运。抗疟药还能抑制自然杀伤细胞活性 ,抑制植物血凝素的激活及丝裂原诱导的外周血单个核细胞产生免疫球蛋白。氯喹和羟氯喹通过喹啉环与DNA结合 ,竞争性地抑制DNA与抗DNA抗体反应 ;抑制免疫复合物形成。阿的平可抑制狼疮细胞的形成。抗疟药可抑制补体活性 ,干扰补体依赖性抗原抗体反应 ;抑制淋巴细胞转化、增殖。氯喹和羟氯喹能干扰单核细胞释放IL 1,抑制巨噬细胞产生肿瘤坏死因子 ;抑制类风湿滑膜细胞 (CD 4 ,CD 8)产生...     

去甲丙咪嗪逆转疟原虫对氯喹抗性

疟原虫对氯喹等抗疟药物的抗性是疟疾治疗的一大难题。举世医药界除了不断寻找疟原虫尚未产生抗性的新药(如青蒿素)以外,也在探索抗性的机埋。前几年揭晓癌细胞对药物抗性原理(见本刊1987,(1):55)启发下,研究者发现氯喹在抗性虫株的蓄积量比在敏感虫株的蓄积量更少,其原因可能由于抗性寄生虫能将药物迅速排出虫体,从而不受药物作用。钙通道阻滞剂维拉帕米(异搏定)抑制寄     

氯喹、硝喹、乙胺嘧啶对巨噬细胞释出TNF的影响

目的观测3种抗疟药对疟原虫诱导的大鼠腹腔巨噬细胞释放肿瘤坏死因子（TNF）的影响。方法：以酶联免疫法检测细胞培养液中TNF的含量。结果：感染约氏疟原虫的红细胞可诱导大鼠腹腔巨噬细胞释放TNF，12h时释出量达高锋。氯喹、硝喹明显抑制TNF的释放，乙胺嘧啶作用不明显。结论：氯喹、硝喹抑制TNF释放可能是其抗疟作用机制之一。     

氯喹,硝基,乙胺嘧啶对巨噬细胞释出TNF的影响

目的：观察３种抗疟药对疟原虫诱导的大鼠腹腔巨噬细胞释放肿瘤坏死因子（ＴＮＦ）的影响。方法：在酶联免疫法检测细胞培养液中ＴＮＦ的含量。结果：感染约氏疟原虫的红细胞可诱导大鼠腹腔巨噬细胞释放ＴＮＦ，１２ｈ时释出时达高峰。氯喹、硝喹明显抑制ＴＮＦ的释放，乙胺嘧啶作用不明显。结果：氯喹、硝喹抑制ＴＮＦ释放可能是其抗疟作用机制之一。     

抗疟药甲氟喹的研究进展

本世纪60年代以来,东南亚、南美洲及印度抗氯喹恶性疟的蔓延形成非常严重的问题。据报告,东南亚有的地方90%恶性疟原虫是抗氯喹的,这就迫切需要寻找治疗抗氯喹或多重抗药性恶性疟原虫有效的药物。甲氟喹即为目前唯一有效的新抗疟药。甲氟喹(Mefloquine)是70年代美国(Wal-     

新抗疟药的研究进展

第二次世界大战前后是抗疟药研究的兴旺时期,并取得了重大突破。氯喹、伯喹、乙胺嘧啶都是当时的研究成果。尽管这些抗疟药还存在一些不足之处,但到五十年代,疾疟化疗问题似乎已经解决,以致放松了抗疟药的研究。到六十年代初期,由于疟原虫产生了抗药牲,特别是抗氯喹恶性疟的出现和蔓延,再度引起人们对寻找新的疟疾化疗剂的重视。20年来,国内外作了广泛深入的研究。据美国报导,至     

抗疟药双咯喹及其类似物的合成

报道了双咯喹(4)和同类抗疟药阿莫地喹(1)、环喹(2)、阿莫吡喹(3)及衍生物5～14的合成,均用烷基胺与4-(4-羟基苯胺基)-7-氯喹啉进行Mannich反应而得。对鼠伯氏疟原虫的作用,以4及3最强;毒性均低于氯喹;与氯喹的交叉抗性指数分别为4及5。4治疗间日疟病人的疗效与氯喹相当。1,2,3,7,8还具有抗小鼠日本血吸虫的作用。     

氯喹、氨苯砜、乙氨嘧啶在人乳中的排泄

在疟疾流行地区,对疟疾有自然免疫力的妇女在怀孕期间和产后直至6周内应该服用抗疟预防药,这是因为她们在这一时期的免疫系统功能下降。在疟疾流行区域无免疫力的妇女在怀孕期间及哺乳期应劝告服用抗疟预防药。但缺乏抗疟药物向人乳中排泄的报道。一项研究在同时服用氯喹和氨苯砜及乙胺嘧啶复合剂后检测了氯喹、氨苯砜和乙胺嘧啶向人乳中的排泄。这种合并治疗法被推荐为这一地区的抗疟预防措施,在这地区中流行着对多种药物抵抗的恶性疟原虫和间日疟原虫株。     

抗疟药物

本文综述了近十年来抗疟药物研究的某些新进展。 1.氯喹的抗性 1·1抗性分布五十年代末期,由于按蚊对灭蚊剂以及恶性疟原虫对氯喹产生抗性而使根治疟疾的希望完全破灭。1986年,氯喹抗性的分布已从原先的东南亚和南美洲扩展到全世界有恶性疟原虫存在的地方。 1·2.感染抗氯喹恶性疟原虫的治疗由于R1和R2抗性的疟原虫对奎宁仍很敏感,故奎宁广泛用于治疗抗氯喹的感染。一般治疗方案是:每天服3次,每次600mg,连服7天(总剂量12.6 g)。在对奎宁出现抗性的地方,加服四环素类药物,如强力霉素每天1～2 g,可消除原虫和病症。氯林可霉素也可用以代替四环素类药物,但它可引起假膜     

青蒿酯钠在体外对六株恶性疟原虫的作用

在体外测定青蒿酯钠对恶性疟原虫6个分离虫株的作用,结果表明6个虫株(包括抗氯喹株)对该药均敏感,各株之间无明显差异。与氯喹和喹哌等5种常用抗疟药比较,青蒿酯钠的有效浓度最低。完全抑制恶性疟原虫裂殖体成熟的浓度在0.018μM,完全杀灭浓度为0.O63μM;半数抑制浓度(IC_(50))为0.0013-0.0029μM,90％抑制浓度(IC_(90))为0.0071-0.0098μM。     

Folate antagonists. 13. 2,4-Diamino-6-](alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline and related 2,4-diamino-6-[(phenyl- and naphthyl)thio]quinazolines, a unique class of antimetabolites with extraordinary antimalarial and antibacterial effects.

An array of nonclassical thioquinazoline analogues (VIII) of methotrexate was prepared by cyclization of the requisite 2-amino-5-(arylthio)benzonitrile with chloroformamidine hydrochloride (28--79%). The aminonitrile precursors were obtained by SnCl2-HCl reduction (28--99%) of the corresponding 2-nitro-5-(arylthio)benzonitriles, which were synthesized by the condensation of the appropriate 5-chloro-2-nitrobenzonitriles with various arylthiols (36--83%). Many of the thioquinazolines (VIII) showed suppressive antimalarial activity comparable with or superior to chloroquine, cycloguanil, and pyrimethamine against drug-sensitive lines of Plasmodium berghei in mice and Plasmodium gallinaceum in chicks, and several displayed potent prophylactic activity with P. gallinaceum. Moreover, the thioquinazolines retained potent antimalarial effects against chloroquine-, cycloguanil-, pyrimethamine- and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of Plasmodium falciparum in owl monkeys. The most active compound, namely, 2,4-diamino-6-[alpha,alpha,alpha-trifluoro-m-tolyl)thio]quinazoline, was designated for preclinical toxicological studies. Numerous substances exhibited in vitro activity against a broad spectrum of pathogenic bacteria at concentrations of less than 0.25 microgram/mL. The thioquinazolines also prove to be potent folate antagonists, causing 50% inhibition of Streptococcus faecalis R (ATCC 8043) at drug concentrations ranging from 0.2 to 2.0 ng/mL. Structure--activity relationships are discussed.     

4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues as potential antimalarial agents

Five 4-substituted 5-[m-(trifluoromethyl)phenoxy]primaquine analogues were synthesized and tested for radical curative activity against Plasmodium cynomolgi in Rhesus monkeys and for blood schizonticidal antimalarial activity against Plasmodium berghei in mice. In addition, they were evaluated for causal prophylactic antimalarial activity against Plasmodium berghei yoelii in mice. One compound, 4-ethyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2b), showed radical curative activity equivalent to 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2a). A second compound showed radical curative activity slightly less than 2a and 2b; the remaining three compounds were not active against P. cynomolgi. All five compounds showed much higher blood schizonticidal activity and less toxicity than primaquine; however, none of the compounds were as active as 2a. Three of four compounds tested showed high activity against P. berghei yoelii.     

Synthesis of 4-alkyl and 4-(beta-alkylvinyl) derivatives of primaquine as potential antimalarials.

4(beta-Alkylvinyl)-6-methoxy-8-nitroquinolines (6) were prepared from 6-methoxy-8-nitroquinoline-4-carboxaldehyde (5) via a Wittig reaction. Stannous chloride reduction of 6 gave 4-(beta-alkylvinyl)-8-amino-6-methoxyquinolines (8), whereas catalytic reduction of 6 using Raney nickel catalyst gave 4-alkyl-8-amino-6-methoxyquinolines (7). Alkylation of 7 and 8 with 4-iodo-1-phthalimidopentane, followed by removal of the phthaloyl-protecting group with hydrazine, gave 4-alkyl and 4-(beta-alkylvinyl) derivatives of primiquine, respectively. These compounds were evaluated for antimalarial activity against P. berghei and P. berghei yoelii in mice and against P. cynomolgi in rhesus monkeys. Several of the compounds were active in the P. bergheii yoelii screen. None of the compounds showed significant activity in the other two screens.     

胍丁胺对伯氏疟原虫K173株的抗疟作用(英文)

AIM: To study the antimalarial effect of agmatine (Agm) on chloroquine-susceptible Plasmodium berghei K173strain (S strain) and the P berghei K173 resistant strain (R strain). METHODS: The antimalarial effects of Agm onP berghei K173 S strain and R strain were evaluated by Peters 4-d suppression test in mice. RESULTS: Agm(12.5-200 mg/kg,ig,daily) decreased the parasitemia for both P berghei K173 S strain (IC50=139 mg/kg) and Rstrain (IC50=126mg/kg) in mice. Subcutaneous injection (sc) of Agm (5-40mg/kg,tid) showed relatively strongerantimalarial effect than intragastric gavage (IC50=30 mg/kg) in P berghei K 173 S strain. Spermidine antagonized theantimalarial effect of Agm for P berghei K173 S strain and R strain. Agm did not reverse the chloroquine resistanceof P berghei K173 S strain, dl-α-Difluoromethylornithine (DFMO, sc) decreased the parasitemia of P BergheiK173 S strain and this effect was antagonized by spermidine. CONCLUSION: Agm has an antimalarial effect andthe mechanism is related to its inhibition of polyamine synthesis.     

Folate antagonists. 15. 2,3-Diamino-6-(2-naphthylsulfonyl)quinazoline and related 2,4-diamino-6-[(phenyl and naphthyl)sulfinyl and sulfonyl]quinazolines, a potent new class of antimetabolites with phenomenal antimalarial activity.

Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogues. A variety of these nonclassical analogues of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of one of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline (35), with sulfadiazine to monkeys infected with P. falciparum of P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.     

Antimalarial in-vivo activity of bis(9-amino-6-chloro-2-methoxyacridines)

In the fight against malaria, chemotherapy using bisacridines may represent an alternative method to overcoming chloroquine-resistance. Eight bis(9-amino-6-chloro-2-methoxyacridines), in which acridine moieties were linked by polyamines substituted with a side chain, were tested for their in-vivo activity upon mice infected by Plasmodium berghei. Three of the compounds revealed antimalarial activity but no relationship could be deduced from a comparison of in-vitro and in-vivo activities. N-alkylation of the central amino group generated toxicity and, therefore, only compounds N-acylated in this position can be selected as leads.     

Folate antagonists. 10. Synthesis and antimalarial effects of 6-[[(aryl and aralkyl)amino]methyl]-2,4-pteridinediamines and -pteridinediamine 8-oxides.

Various 6-[[(aryl and aralkyl)amino]methyl]-2,4-pteridinediamines and their 8-oxides have been synthesized for antimalarial evaluation. Condensation of 3-amino-6-(bromomethyl)-2-pyrazinecarbonitrile 4-oxide (V) with the appropriately substituted amine afforded a series of 3-amino-6-[[(aryl and aralkyl)amino]methyl]-2-pyrazinecarbonitrile 4-oxides VI. Deoxygenation gave the corresponding pyrazines VII. Cyclization of VI and VII with guanidine then produced the desired 6-(aminomethyl)-2,4-pteridinediamine N-oxides VIII and teridinediamines IX, respectively. Formylation of 6-[[(3,4-dichlorophenyl)amino]methyl]-2,4-pteridinediamine gave N-[(2,4-diamino-6-pteridinyl)-methyl]-N-(3,4-dichlorophenyl)formamide. The N-oxides VIII did not exhibit significant activity against Plasmodium berghei infections in mice. Activity among the 2,4-pteridinediamines IX was generally poor with the exception of the 3,4,5-trimethoxyphenyl and 1-naphthalenyl analogues which showed strong suppressive activity at doses ranging from 80 to 640 mg/kg. Furthermore, several of the 2,4-pteridinediamines exhibited potent prophylactic activity against Plasmodium gallinaceum infections in the chick and also showed strong antibacterial action against Streptococcus faecalis and Staphylococcus aureus.     

Synthesis and in vitro studies of novel pyrimidinyl peptidomimetics as potential antimalarial therapeutic agents

A class of new pyrimidinyl peptidomimetic agents (compounds 1-6) were synthesized, and their in vitro antimalarial activities against Plasmodium falciparum were evaluated. The core structure of the new agents consists of a substituted 5-aminopyrimidone ring and a Michael acceptor side chain methyl 2-hydroxymethyl-but-2-enoate. The synthesis of 1-6 featured a Baylis-Hillman reaction of various aldehydes with methyl acrylate catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) and a S(N)2' Mitsunobu reaction under the conditions of diethyl azadicarboxylate (DEAD), triphenylphosphine (Ph(3)P), and various acids. The new compounds exhibited potent in vitro growth inhibitory activity (IC (50) = 10-30 ng/mL) against both chloroquine sensitive (D-6) and chloroquine resistant (W-2) Plasmodium falciparum clones. Compound 6 (IC(50) = 6-8 ng/mL) is the most active compound of the class, the antimalarial efficacy of which is comparable to that of chloroquine. In general, this class of compound exhibited weak to moderate in vitro cytotoxicity against neuronal and macrophage cells with IC (50) in the range of 1-16 microg/mL and showed less toxicity in a colon cell line. Preliminary results indicated that compounds 3 and 6 are active against P. berghei, prolonged the life span of parasite-bearing mice from 6 days for untreated control to 16-24 days for drug-treated animals.     

Sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine as potential antimalarial agents

Two isomeric sulfur-interrupted 8-amino side chain analogues of 4-methyl-5-[m-(trifluoromethyl)phenoxy]primaquine (2) were prepared and tested for antimalarial activity. The compounds were evaluated for blood schizonticidal activity against Plasmodium berghei in mice and radical curative activity against Plasmodium cynomolgi in rhesus monkeys. In addition, they were evaluated for causal prophylactic activity against Plasmodium berghei yoelii in mice. Both compounds were more active and less toxic than primaquine in the P. berghei screen. One of the compounds showed radical curative activity similar to primaquine but was less active than 2. One of the compounds was active at 160 mg/kg in the P. berghei yoelii screen; the other was not active.     

Synthesis of quinoline-Mannich bases of possible antimalarial activity

For possible antimalarial activity, a series of some 4-substituted aminoquinoline Mannich bases (5a-e) was synthesized. The antimalarial evaluation showed that compound 5b was active against Plasmodium berghei in mice at a dose of 100 mg/kg.