萘酚喹衍生物的筛选与药效评价

发布时间：2018-03-05 04:09

  本文选题：萘酚喹　切入点：抗疟药　出处：《大理学院》2013年硕士论文　论文类型：学位论文

【摘要】：疟疾严重危害着人类的生命健康,世界卫生组织(The world health organization,简称WHO)把它被列为全球三大公共卫生问题之一。疟疾的病原体是疟原虫,属于虫媒传染病,其发病率、死亡率在世界上最高,是地球上流行范围最广、危害程度最大的寄生虫病,主要在东南亚、中南美洲及非洲等热带国家流行,其中非洲国家最严重,集中在撒哈拉沙漠以南的大部分国家。2010年WHO发表的世界疟疾报告显示,目前疟疾在108个国家和地区流行,大约33亿人受到威胁,每年近似2亿病例,大约80万人死亡,绝大部分是五岁以下的儿童。 在我国,疟疾也危害着人民的身体健康与生命安全。疟疾曾经在我国80%的县市流行,居传染病之首。疟疾的防治工作自建国以来取得了很大的成绩,并且在全国建立了检测机构和防治机构,开展了许多有效的疟疾防治工作,取得了很大的成绩,发病率大幅度的降低。 萘酚喹是我国研发的新型4-氨基喹啉类抗疟药,对各种疟原虫红内期无性体有杀灭作用,具有治愈率高,杀虫彻底、复燃率低等特点,同时具有较长半衰期,可以作为一个很好的治疗或预防药物。但缺点是起效慢。为了发掘和合理地应用萘酚喹,有必要对其衍生物做一研究。 研究目的： 1建立伯氏疟原虫K173株鼠疟模型,对常用抗疟药氯喹、青蒿素和萘酚喹进行测试,证明鼠疟模型对它们敏感。说明此模型可用于新化合物的评价。 2用鼠疟模型对抗疟药萘酚喹衍生物的药效进行评价。 3培养研究生的科研能力和科研思维。 4学会处理实验过程中遇到问题的解决能力。 研究方法： Peters4天抑制试验法。采供血鼠的尾巴血,然后按照所需的比例进行稀释,接种到实验鼠体内(含1×107个感染红细胞)。腹腔注射0.2ml药物,连续4天给药,依次为D0,D1,D2,D3,第5天处理结果。给药物分多个浓度,每个浓度和空白各5只小鼠。2h以后灌胃给药,连给4天,第5天采尾血进行涂片,甲醇固定,吉姆萨染色后油镜下观察3个区域各200个红细胞以上,计算感染率。 疟原虫寄生率=感染的红细胞数(IRBC)÷红细胞总数(RBC)×100% 结果： 1昆明系小鼠对K173株较敏感,且青蒿素对伯氏疟原虫K173株的ED50和ED9o值分别为18.86mg/kg和54.83mg/kg,氯喹对K173株的ED50和ED90值分别为2.32mg/kg和21.88mg/kg,萘酚喹对K173株的ED50和ED90的值分别为0.42mg/kg和1.08mg/kg。图形的拟合度高,即得出的ED50和ED90值准确度高,所建鼠疟模型可用于抗疟药的药效评价。 2化合物1、2、3、5、6、7、8、9、12、13、21、23、24号萘酚喹衍生物对对K173株的抑制作用和萘酚喹相近。24个化合物中的化合物1和化合物13对伯氏疟原虫K173株的抑制作用最强；化合物1(ED50=0.40mg/kg；ED90=1.01mg/kg)和衍生物13(ED50=0.38mg/kg;ED90=0.61mg/kg)的ED50,和ED90与萘酚喹的ED50和ED90相近,图形曲线的模拟度高,有研究的价值。化合物4、10、11、14、15、16、17、18、19、20、22号的药效学显示,和萘酚喹的ED50和ED90有差别,但可以做进一步的研究。 结论： 14天抑制实验法是抗疟药筛选的标准测试,通常也用于药物的筛选。此次实验得出的数据说明伯氏疟原虫K173株对传统的抗疟药的敏感性是高的,模型是可用的。可用于萘酚喹衍生物的药效评价。 2伯氏疟原虫K173株对萘酚喹衍生物的敏感性不完全相同。军事医学科学院微生物流行病研究所新合成的24种萘酚喹衍生物中,有2种与萘酚喹的ED50和ED90与萘酚喹的ED50和ED90相近。具有进一步研究的价值；有11种与萘酚喹的ED50和ED90值有差别,但可以做进一步的调节研究。这对我们进一步研究萘酚喹衍生物奠定了一定的基础。
[Abstract]:Malaria serious harm to human life and health, WHO (The World Health Organization, referred to as WHO) it is listed as one of the world's three major public health problems. The causative agent of malaria is a parasite, belonging to insect borne infectious diseases, the incidence rate, mortality was highest in the world, the earth is the most popular, the biggest harm degree parasitic disease, mainly popular in Southeast Asia, Latin America and Africa tropical countries, including African countries most seriously, on display in the Sahara desert to the south of.2010 in most of the World Malaria Report published by WHO, popular in 108 countries and regions of the malaria, about 3 billion 300 million people are threatened, approximately 200 million cases annually, about the death of 800 thousand people, mostly children under the age of five.
In our country, malaria also do harm to people's health and safety. Malaria in China was 80% of the counties in the epidemic of infectious diseases, the first. The prevention and treatment of malaria has made great achievements since the founding of new China, and the establishment of the detection mechanism and prevention and control institutions in the country, to carry out a number of effective malaria prevention and control work that has made great achievements, the incidence rate decreased greatly.
Naphthoquine is China's developed a new type of 4- aminoquinolines antimalarial drugs, killing effect on various Plasmodium asexual erythrocytic stages, with high cure rate, low recurrence rate of insecticide thoroughly, at the same time, has a longer half-life, can serve as a good therapeutic or preventive drugs. But the disadvantage is slow. In order to explore and rational application of naphthoquine, it is necessary to do a research on its derivatives.
The purpose of the study is:
1, we established the rat malaria model of K173 strain of Plasmodium bergi, and tested the commonly used antimalarial drugs, such as chloroquine, artemisinin and naphthoquine, which showed that the rat malaria model is sensitive to them. This model can be used for the evaluation of new compounds.
2 the efficacy of the antimalarial model was evaluated against the efficacy of the naphthol quinoline derivatives.
3 training graduate students' scientific research ability and scientific research thinking.
4 learn how to deal with problems in the process of the experiment.
Research methods:
Peters4 inhibition test. Blood rat tail blood was diluted and then according to the required proportion, were inoculated into mice (containing 1 x 107 infected red blood cells). The intraperitoneal injection of 0.2ml drugs, administered for 4 consecutive days, followed by D0, D1, D2, D3, fifth days of treatment results. For multiple drug concentration, concentration of each blank and 5 mice of each.2h after intragastric administration for 4 days, even fifth days, blood samples were smeared, fixed with methanol, after Giemsa staining under microscope observation of the above 3 areas of the 200 red blood cells, calculate the infection rate.
Plasmodium parasitism rate = infected red blood cells (IRBC), red blood cell count (RBC) * 100%
Result锛，

本文编号：1568666