先导化合物题库.ppt

* 合成的化合物数量越多，速度越快，发现活性化合物的概率就越大。过去20多年的新药创制的策略好发发发生的重大变革都反应了这样的要求：更多的发现的新靶标，快速合成大量化合物，尽快地进行筛选。 * 疟疾，俗称打摆子，是由疟原虫经蚊虫叮咬传播的传染病。目前是世界第二大传染病，也是流行最广、发病率和死亡率最高的热带寄生虫传染病。 　 20世纪70年代，中国的药物学家从黄花蒿中提取出了名为“青蒿素”的新化合物，由于它能在短时间内迅速消除疟原虫和退高热，因而成为致人死命最多的疾病——疟疾的克星。 青蒿素 :近期复燃率较高；制剂不够理想，难以溶于水或油，生物利用度低；杀虫不彻底，28天后复发率高达50％。 1976年，中科院上海药物所李英教授和课题组成员在合成数百个化合物的基础上，经过筛选比较，最终获得蒿甲醚。它是具有一个过氧基的倍半萜内酯的甲醚化合物，与传统抗疟药相比，具有全新的化学结构。其抗疟效果比青蒿素强5－14倍，具有特效、高效、速效、低毒以及可以多途径给药的优点。是治疗恶性疟、脑疟及抗氯喹疟等重症疟疾的首选药。但是它也存在作用时间短，复发率高等缺点。 * Nicotine(烟碱）是植物源农药，从烟草中提取，俗名尼古丁，很早就被人们 用作杀虫剂，但是对人类高毒，活性低，成本高，随后人们开发出nithiazin（含硝基的噻嗪环，但是硝基不稳定，见光分解，后来又结合烟碱和他，开发出新烟碱类。(吡虫啉）。 (2)-Nicotine and nicotinoids such as epibatidine 蛙皮素 have been tested as agents in insect control. In particular, nicotine, obtained from tobacco extracts has been used for centuries as an aphicide in the control of sucking insects, although it has a considerable low potency as insecticide, a narrow spectrum of application and a high toxicity to mammals. Furthermore, although the insecticidal activity of synthetic nicotinoids has been improved, it has never reached the degree required for commercialization. Subsequent research led to a novel class of synthetic compounds called neonicotinoids; this term was originally proposed by Yamamoto for compounds having a structural similarity to nicotine and a common mode of action. In general, neonicotinoids possess an electron-withdrawing group, either a nitroimino, cyanoimino or nitromethylene moiety. Classical nicotinoids (eg Fig 1, 1) have been used for insect control for many years. In the 1980s, nithiazin (2) was discovered by Shell1 and this finding resulted in the discovery of imidacloprid (3) by Bayer in 1991.2 These discoveries accelerated the research and development of this class of insecticide. Subsequent research resulted in the commercialization of several outstanding insecticides (Fig 1), such as nitenpyram (4) (Takeda, 1995),3 acetamiprid (5) (Nippon Soda, 1996),4 thiacloprid (6) (Bayer, 2000),5 thiamethoxam (