疟疾防治药物的研究——Ⅵ.2,4-二氨基-6-取代氨基-磺酰基喹唑啉衍生物的合成及其抗疟作用

磺胺是对氨基苯甲酸拮抗剂,有较强的广谱抗菌作用,细菌代谢与疟原虫代谢有许多相似之处,早在1937年Hill等就用百浪多息(Prontosil,Ⅰ)治疗疟疾病人,以后发现多种磺胺可以抑制疟原虫的生长与繁殖。2,4-二氨基-6-取代氨基喹唑啉衍生物(Ⅱ)对伯氏鼠疟原     

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.     

疟疾防治药物的研究——Ⅰ.2,4-二氨基-5-取代氨基嘧啶和2,4-二氨基-6-甲基-5-取代氨基嘧啶衍生物的合成及其抗疟作用

本文报道2,4-二氨基-5-取代氨基嘧啶和2,4-二氨基-6-甲基-5-取代氨基嘧啶衍生物的合成及其抗疟活性的研究。这类化合物的合成是分别以2,4,5-三氨基嘧啶或2,4,5-三氨基-6-甲基嘧啶与相应的取代的苯甲醛缩合成席夫氏碱,然后经还原,亚硝化或甲酰化制得。经鼠疟原虫-斯氏按蚊系统的病因性预防初筛,发现有12个化合物有效,其中2,4-二氨基5-[(3′,4′-二氯代苯亚甲基)-氨基]嘧啶(化合物V₃)和2,4-二氨基-5-[(4′-溴代苄基)-N-亚硝基-氨基]嘧啶(化合物Ⅶ₄)效果最好,口服10 mg/kg共三天,可使小白鼠得到保护,血中未查见原虫。     

Tricyclic 2,4-diaminopyrimidines with broad antifolate activity and the ability to inhibit Pneumocystis carinii growth in cultured human lung fibroblasts in the presence of leucovorin

A selected number of 1,3-diaminobenzo[f]quinazolines and 1,3-diamino-5,6-dihydrobenzo[f]quinazolines, which may be viewed as tricyclic analogues of the lipid-soluble antifolates pyrimethamine (PM), metoprine (DDMP), and etoprine (DDEP), were tested as inhibitors of purified dihydrofolate reductase (DHFR) from WI-L2 lymphoblasts, and as inhibitors of the growth of Streptococcus faecium ATCC 8043 and L1210 murine leukemia cells in culture. In addition, these tricyclic compounds were tested for antimalarial activity against Plasmodium berghei in mice, and for the ability to inhibit the growth of Pneumocystis carinii trophozoites in WI-38 human lung fibroblast cultures in the presence of leucovorin (LV). The most potent analogues were those with chlorine substitution in the ring distal to the 2,4-diaminopyrimidine moiety. Fully aromatic compounds tended to be more active than those in which the 5,6-bond was reduced, suggesting that planarity favors binding to the DHFR active site and may be favorable for cellular uptake. Several of the 2,4-diaminopyrimidine analogues showed greater potency than PM, DDMP or DDEP, and were more nearly comparable to the bicyclic 2,4-diaminopyrimidine antifolates trimetrexate (TMQ) or piritrexim (BW301U), which are known to be selectively toxic to P. carinii in the presence of LV. Two of the tricyclic compounds, 1,3-diamino-8-chlorobenzo[f]quinazoline and 1,3-diamino-9-chlorobenzo[f]quinazoline, proved to have activity similar to TMQ and BW301U in this system.     

2,4-二氨基-6-(N-甲基-取代苄氨基)喹唑啉类化合物的合成和抗疟以及抗肿瘤活性

用两条不同路线合成了16个2,4-二氨基-6-(N-甲基-取代苄氨基)喹唑啉衍生物,其中13个未见报道。有4个化合物剂量5mg/kg对小鼠体内伯氏疟原虫(Plasmodium berghei)的抑制率达100%,2.5mg/kg的抑制率大于99%;有8个化合物对培养的L1210白血病细胞株的增殖抑制作用相当或优于阳性对照药物甲氨噗呤(MTX)。     

Folate antagonists. 12. Antimalarial and antibacterial effects of 2,4-diamino-6-[(aralkyl and alicyclid)thio-, sulfinyl-, and sulfonyl]quinazolines.

A series of 2,4-diamino-6-[(aralkyl and alicyclic)thio-, sulfinyl-, and sulfonyl]quinazolines was prepared via condensation of 5-chloro-2-nitrobenzonitrile or 5,6-dichloro-2-nitrobenzonitrile with the appropriate aralkyl or alicyclic thiopseudourea, reduction of the resulting 2-nitro-5-[(aralkyl or alicyclic)thio]benzonitrile with stannous chloride to the amine, and cyclization with chloroformamidine hydrochloride. Oxidation was effected with hydrogen peroxide or the bromine complex of 1,4-diazabicyclo[2.2.2]octane. These analogues when examined for suppressive activity against drug-sensitive lines of Plasmodium berghei in mice were not as active as 2,4-diamino-6-[3,4-dichlorobenzyl)amino]quinazoline (Ia).     

疟疾防治药物的研究——Ⅹ.2,4-二氨基-6-N1,N2-二取代肼基-喹唑啉类衍生物的合成及其抗疟作用

本文报道了2,4-二氨基-6-N¹,N²-二取代肼基-喹唑啉类衍生物的合成及其抗疟活性的研究。这类化合物的合成是以2,4-二氨基6-取代苄基氨基-喹唑啉为原料经亚硝化、还原成为2,4-二氨基6-(N¹-取代苄基)—肼基喹唑啉,再与相应的醛缩合而成。此类化合物经伯氏鼠疟原虫抑制性治疗初筛表明有少数具有一定的效果。有11个化合物经约氏鼠疟原虫—斯氏按蚊系统病因性初筛有效。其中化合物Ⅱ_1,7,8,11,15和Ⅲ₁口服2.5mg/kg,连续3天,可使受试小鼠全部得到保护。     

Synthesis and antimalarial and antitumor effects of 2-amino-4-(hydrazino and hydroxyamino)-6-[(aryl)thio]quinazolines

A variety of analogues of 2,4-diamino-6-[(aryl)thio]quinazolines with known antimalarial properties were prepared wherein the 4-amino group was replaced by hydrazino and hydroxyamino moieties. Such changes were found to reduce markedly the antimalarial and antitumor properties of this series.     

蒿甲醚对小鼠血清IgG及脾重的影响

青蒿素与青蒿酯钠的某些免疫作用已有报道。本文报道应用单向免疫扩散测定技术,测定了蒿甲醚对小鼠血清IgG含量的影响,还观察了蒿甲醚对脾脏重量的影响。动物用20～25g JCR纯种小鼠,按雌雄各半随机分组。蒿甲醚(桂林制药厂提供)与氯喹(重庆制药厂生产)均混悬于1％西黄蓍胶,供灌胃用。兔抗小鼠IgG抗血清及标准JCR小鼠血清抗原均为本实验室制备。     

2,4-二氨基-5-甲基-6-取代苄氨基喹唑啉衍生物的合成及其抗疟和抗肿瘤作用

本文报道2,4-二氨基-5-甲基-6-取代苄氨基喹唑啉衍生物的合成及其抗疟和抗肿瘤活性。这类化合物由5-甲基-2,4,6-三氨基喹唑啉与相应的取代苯甲醛缩合成Schiff碱,然后经还原,甲酰化或亚硝化制得。经对伯氏鼠疟原虫(Plasmodium berghei)抑制性治疗筛选,有三个化合物Ⅳ_(2,5,6)剂量5mg/kg×4d抑制率为100%;体外抗肿瘤活性以Ⅱ_7和Ⅳ_8最强,对L1210白血病细胞株的IC_(50)分别为3.910×10~(-3)μg/ml和6.172×10~(-3)μg/ml,与MTX相当。     

疟疾防治药物的研究——Ⅸ.2,4-二氨基-6-[N-(取代苄基)-N-(取代氨基甲基)氨基]-喹唑啉类衍生物的合成

In searching for new antimalarial agents ten new compounds of 2,4-diamino-6-[N-(substituted benzyl)-N-(substituted aminomethyl)-amino]-quinazoline have been synthesized. Preliminary screening results showed that only one (Ⅳ₆) of these compounds displayed a slight degree of antimalarial activity against plasmodium berghei in mice. The intermediate compound (Ⅰ₂) showed suppressive effect on plasmodium berghei in mice and prophylactic activity against plasmodium gallinaceum in chicken.     

一种新的三嗪类抗锥虫药:SIPI-1029及其类似物的合成和抗原虫作用

合成了1,2-二氢-2,2-二甲基-4,6-二氨基-1-(ω-卤代烷氧基)-s-三嗪类和O,O’-双(4,6-二氨基-1,2-二氢-2,2-二取付-s-三嗪-1-基)烷烃二醇两类化合物,它们大多有较好的体内抗疟原虫(Plasmodium berghei)作用,化合物IIc～e对用伊氏锥虫(Trypanosoma evansi)感染的小鼠,有较好的作用,经深入的药理、毒理和药代动力学以及疗效等研究,化合物IIe(SIPI-1029,T-46)被证明是一高效、低毒并有较长的血药半衰期的抗锥虫新药。     

Vitis vinifera L. grape skin extract activates the insulin-signalling cascade and reduces hyperglycaemia in alloxan-induced diabetic mice

Objectives This study examined the effect of Vitis vinifera grape skin extract (ACH09) on hyperglycaemia and the insulin‐signalling cascade in alloxan‐treated mice. Methods Glycaemia, serum insulin and Western blot analysis of insulin cascade proteins were evaluated in the gastrocnemius muscles of four groups of adult mice: control, ACH09 (200 mg/kg per day, p.o.), alloxan (300 mg/kg, i.p.) and alloxan + ACH09. Insulin secretion in isolated pancreatic islets was also studied. Key findings Glycaemia values in the alloxan + ACH09 and ACH09 groups were significantly lower than in the alloxan‐treated and control groups, respectively. Increased insulin resistance (HOMA index) was observed in the alloxan‐treated group but not in the alloxan + ACH09 group. Insulin receptor content and Akt phosphorylation were significantly greater in the alloxan + ACH09 group compared with the alloxan‐treated group. The glucose transporter (GLUT‐4) content was reduced in alloxan‐treated mice compared with the control group, while alloxan + ACH09 and ACH09‐treated mice showed a significant increase in GLUT‐4 content. ACH09 treatment did not change glucose‐induced insulin secretion in isolated pancreatic islets. Conclusions The results suggest that ACH09 has hypoglycaemic and antihyperglycaemic effects that are independent of an increase in insulin release but are probably dependent on an increase in insulin sensitivity resulting from an activation of the insulin‐signalling cascade in skeletal muscle.     

疟疾防治药物的研究——Ⅲ.2,4-二氨基-6-取代哌哔嗪基喹唑啉衍生物的合成及其抗疟作用

本文报道2,4-二氨基-6-取代哌哗嗪基喹唑啉衍生物的合成及其抗疟活性。这类化合物的合成是以间氯苯甲腈为原料,经硝化与哌哔嗪缩合,还原制得2-氨基-5-(哌哔嗪-1′)苯甲腈,再与各种卤代物反应,然后与二氰二胺环合;也可以2-硝基5-氯苯甲腈与取代的哌哔嗪缩合,经还原,然后与二氰二胺环合而得。经鼠疟抑制性治疗初筛,有4个化合物(X_1,2,3,8有效;经鼠疟病因性预防初筛,有3个化合物(X_1,8,10有效;经蚊模抑制孢子增殖初筛,当浓度0.01%时,有2个化合物(X_8,9)使70%蚊虫的孢子增殖受到抑制。     

2,4-二氨基-6-取代氨基磺酰喹唑啉类化合物抗鼠疟作用的研究

用伯氏鼠疟模型筛选了17个2,4-二氨基-6-取代氨基磺酰喹唑啉类化合物。初步结果显示,化合物Ⅰ₄,Ⅰ₅,Ⅰ₁₀,Ⅰ₁₁和Ⅰ₁₂口服有较好抗疟作用,对正常敏感株(N)的SD₅₀为0.43～2.4mg/kg×4d,高度抗氯喹株(RC)为0.19～0.42mg/kg×4d,(NK₆₅)株为7.2～100mg/kg×4d,抗磺胺株(ORA)为11～76 mg/kg×4d。上述结果表明,该类化合物对(RC)株的疗效显著优于(N)株,但对(NK₆₅)株的疗效较差,与磺胺类药物有轻度交叉抗性。     

Antimitotic agents: synthesis of imidazo[4,5-c]pyridin-6-ylcarbamates and imidazo[4,5-b]pyridin-5-ylcarbamates

Cyclization of ethyl 5,6-diamino-4-hydrazinopyridin-2-ylcarbamate (10) with a mixture of CS2 and Et3N in dimethylacetamide gave mainly ethyl 1,4-diamino-2(3H)-thioxoimidazo[4,5-c]pyridin-6-ylcarbamate (15), whereas, in the absence of dimethylacetamide, a double cyclization gave mainly ethyl 5-amino-2(1H)-4-dithioxodiimidazo-[4,5-b:5,4-c]pyridin-7-ylcarb amate (16). Cyclization of the benzylidenehydrazino derivative (6) of 10 with either CS2-Et3N or (EtO)3CH-HCl gave 1-(benzylideneamino)imidazo[4,5-c]pyridines 11 and 7 as major products and 7-(benzylidenehydrazino)imidazo[4,5-b]pyridines 12 and 8 as minor products. Dethiolation of 11 to give 7 and of 12 to give 8 was effected with excess Raney nickel in refluxing ethanol. The benzylidene group of 11 was removed with hydrazine in ethanolic HCl to give 15. This key compound was condensed with benzaldehydes to give 1-benzylideneamino derivatives (20, 21) and alkylated with benzyl halides to give 2-benzylthio derivatives (24-26). In addition, cyclization of ethyl 5,6-diamino-4-(benzylidene-1-methylhydrazino)pyridin-2-ylcarbam ate (30) with (EtO)3CH provided a method for the synthesis of an imidazo[4,5-c]- and -[4,5-b]pyridines gave compounds that inhibited proliferation of growth and caused mitotic arrest against lymphoid leukemia L1210 at micromolar concentrations. However, the more active in vitro compounds (7, 8, 24-26) gave only borderline activity in mice against lymphocytic leukemia P388.     

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.     

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.     

鲨鱼肝活性肽S-8300的降血糖作用机制初探

目的：探讨鲨肝活性肽S-8300的降血糖作用机制。方法：观察S-8300对四氧嘧啶糖尿病小鼠的血浆总胆固醇（CHOL）,血浆甘油三酯（TG）,血浆游离脂肪酸（NEFA）,肝、肾组织中超氧化物歧化酶（SOD）活力,肝、肾组织中丙二醛（MDA）含量,心肌ATP酶活力的影响及红细胞在体外所发生的自氧化溶血和H2O2在体外对红细胞膜的损伤的影响。结果：S-8300显著降低四氧嘧啶糖尿病小鼠的血浆CHOL、TG、NEFA水平及肝、肾组织中MDA含量,提高肝、肾组织中SOD活力和心肌ATP酶活力,显著抵抗红细胞在体外所发生的自氧化溶血及H2O2在体外对红细胞膜的损伤。结论：降低糖尿病小鼠血浆中脂质,减轻自由基的氧化损伤可能是S-8300降血糖作用的机制之一。     

疟疾防治药物的研究——Ⅻ.2,4-二取代-6-取代氨基喹唑啉衍生物的合成及其抗疟作用

2,4-二氨基-6-取代苄氨基喹唑啉类化合物有较强的抗疟作用,其中2,4-二氨基-6-[(3,4-二氯苄基)-N-亚硝基-氨基]喹唑啉(Ⅰ,硝喹)经国内研究已用于临床,对抗氯喹恶性疟也有较好的作用。为了进一步探讨其构效关系,作者合成了一系列2,4-二氨基2-氨基-4-羟基和2,4-二羟基-6-取代氨基喹唑啉类化合物。