Pseudopteroxazole and Related Antitubercular Agents

拟蝶恶唑及相关抗结核药

• 批准号: 6863274
• 负责人: MICHAEL HARMATA
• 金额: $ 27.71万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6863274
• 关键词: antitubercular agents; biological products; cycloalkene; diterpenes; drug design /synthesis /production; oxazoles; stereochemistry; thiazines

DESCRIPTION (provided by applicant): The goals of this work are to develop syntheses of antitubercular agents based on natural product leads. This will involve the total synthesis of the natural products pseudopteroxazole, seco-pseudopteroxazole, erogorgiaene, ileabethin, elisapterosin B and elisabethin A. Testing of targets and intermediates will be performed by the Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF). A unifying methodology will be developed in pursuing these goals. This involves the synthesis of enantiomerically pure benzothiazines through the intramolecular, stereoselective addition of sulfoximine carbanions to unsaturated esters. The development of this methodology will be coupled with aspects of other new chemistry to achieve the synthetic goals. Of particular importance will be the development of a stereoselective, intramolecular radical ring closure reaction as a means of establishing a six-membered ring. Two approaches to this general type of process will be explored. Benzothiazine chemistry will be further developed, particularly in the context of the synthesis of elisabethin A, during which the study of benzothiazine carbanions as nucleophiles in Michael addition reactions will be undertaken. The compounds to be prepared in this study will contribute to the goal of developing chemotherapeutics for tuberculosis. Since the targets are related to pseudopterosins, compounds with potent analgesic and antiinflammatory properties, the work will have an impact in this area as well. More generally, the methodology to be developed should have extremely broad impact, as it can be applied to the generation of stereogenic centers in a large number of compounds of biological and medicinal interest.

描述（由申请人提供）：这项工作的目标是开发基于天然产物先导物的抗结核药物的合成。这将涉及天然产物伪teroxazole、开环伪teroxazole、erogorgiaene、ileabethin、elisapterosin B和elisabethin A的全合成。靶标和中间体的检测将由结核病抗菌药物采购和协调机构（TAACF）进行。 在实现这些目标时，将制定统一的方法。这涉及到合成对映体纯苯并噻嗪通过分子内，立体选择性加成亚砜亚胺碳负离子的不饱和酯。这种方法的发展将与其他新化学的方面相结合，以实现合成目标。特别重要的是发展立体选择性的分子内自由基闭环反应作为建立六元环的手段。将探讨这一一般类型过程的两种方法。苯并噻嗪化学将进一步发展，特别是在伊丽莎白辛A的合成的背景下，在此期间，将进行迈克尔加成反应中的亲核试剂的苯并噻嗪碳负离子的研究。 本研究中制备的化合物将有助于开发结核病化疗药物的目标。由于这些靶点与具有强效镇痛和抗炎特性的化合物假蝶呤有关，因此这项工作也将对这一领域产生影响。更一般地说，要开发的方法应该有非常广泛的影响，因为它可以应用于产生立体中心的大量化合物的生物和医学的利益。