ASYMMETRIC SYNTHESIS--STRUCTURE, STEREOCHEMISTRY AND NMR

不对称合成——结构、立体化学和核磁共振

• 批准号: 6105198
• 负责人: Herman Ziffer
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6105198
• 关键词: antimalarial agents; autoradiography; chemical structure function; chemical substitution; drug design /synthesis /production; drug interactions; molecular asymmetry; nerve /myelin protein; neurotoxicology; nuclear magnetic resonance spectroscopy; sesquiterpenes; stereochemistry

A series of N-substitutited 11-azaartemisinins were synthesized and several members were found to be four to fives times more active in vitro against drug resistant strains of malaria than the lead compound artemisinin, 1. An in vivo study of the 2'ethanal derivative confirmed the in vitro results. In an effort to increase further the activity of this series an SAR study was undertaken. For this purpose a new synthetic route from 11-azaartemisinin was devised and employed to prepare approximately a dozen additional compounds which contained polar groups on the 3'-carbon. The most active derivative in latter series was also four to five times more active in vitro than 1. Additional attempts to prepare more active derivatives are in progress.In addition, a program utilizing an N-substituted 11-azaartemisinin for the preparation of an affinity chromatographic column has been initiated. The column will be employed to identiy proteins from P. falciparum which bind or react with artemisinin derivatives. Our review on "Artemisinin: An Endoperoxidic Antimalarial from Artemisia annua L." appeared in "Progress in the Chemistry of Organic Natural Products" published by Springer-Verlag in 1997.

一系列N-取代的11-氮杂青蒿素 合成后发现有几个成员是四到五个 体外对抗疟疾耐药菌株的活性增强数倍 与先导化合物青蒿素相比，1. 青蒿素的体内研究 2'乙醛衍生物证实了体外结果。为了 SAR 研究进一步增加了该系列的活动 进行。为此，一条新的合成路线 11-氮杂青蒿素被设计并用于制备 大约十几种含有极性的其他化合物 3'-碳上的基团。后系列中最活跃的衍生品 体外活性也比 1 高四到五倍。 制备更多活性衍生物的尝试正在进行中。 另外，利用N-取代的11-氮杂青蒿素的程序 亲和色谱柱的制备 发起。该柱将用于鉴定 P. 恶性疟原虫与青蒿素衍生物结合或反应。我们的 “青蒿素：一种内过氧化抗疟药”的评论 青蒿”发表于《青蒿化学进展》 有机天然产品”由 Springer-Verlag 于 1997 年出版。