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DEVELOPMENT OF NOVEL PHARMACOPHORE WITH ANTI-TB ACTIVITY

具有抗结核活性的新型药效团的开发

基本信息

批准号：
6311243
负责人：
ZE-QI XU
金额：
$ 10万
依托单位：
MEDICHEM RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-03-06 至 2001-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6311243
关键词：
alpha benzopyrone antitubercular agents chemical structure function drug design /synthesis /production drug receptors drug resistance drug screening /evaluation plant extracts

项目摘要

DESCRIPTION (Adapted from the application):Through the TAACF screening program sponsored by NIAID, a naturally occurring pyranocoumarin compounds were identified to be active against Mycobacterium tuberculosis. Further evaluation of the leading compound, (+)-calanolide A. demonstrated that it was active against Mycobacterium tuberculosis strains resistant to isoniazid, rifampin, streptomycin, and ethambutol, respectively. (+)-Calanolide A was also able to kill tubercle bacilli intracellularly in a bone marrow-derived murine macrophage. Preliminary mechanistic studies suggest that its novel anti-TB properties may be involved with unique target(s). Clearly, (+)-calanolide A and its related pyranocomarins represent a novel and unique pharmacophore for anti-TB activity. It is the objective of this SBIR program to embark on design, synthesis and evaluation of certain focused libraries of pyanocoumarin analogues in order to further understand the structural features necessary for the anti-TB activity, with an ultimate goal of developing a novel anti-TB drug. A systematic approach will be taken to initially investigate 4 structural characteristics during the SBIR Phase I research. It is hopeful that at the end of the phase II program an ideal candidate can be selected for a full IND-directed precIinicaI studies, leading to an lND submission and initiation of clinical trials in the SBIR Phase Ill program. PROPOSED COMMERCIAL APPLICATION: TB is the world's #1 killer among the infectious diseases and the leading cause of death among women of reproductive age. One-third (@ 2 billion) of the world's population, including 15 million Americans, is infected with TB and about 1/3 of the HIV-infected people are also co-infected with TB. Resistance has emerged to the current available anti-TB drugs and no standard optimal therapy in AIDS patients with TB infection. New anti-TB agent are in great demand worldwide.

描述（改编自应用程序）：通过TAACF筛选程序由NIAID赞助，一种天然存在的吡喃香豆素化合物，被鉴定为对结核分枝杆菌有活性。进一步评价的先导化合物，（+）-calanesthetA。证明了它是活跃的针对对异烟肼，利福平，链霉素和乙胺丁醇。（+）-Calanadine A也能够骨髓源小鼠细胞内杀伤结核杆菌巨噬细胞初步的机制研究表明，其新型抗结核药物特性可能涉及唯一的目标。显然，（+）-calanetrin A和其相关的吡喃苦苷代表了一种新型且独特的药效团，抗结核活性。SBIR计划的目标是着手设计，某些焦库吡喃香豆素的合成和评价类似物，以进一步了解必要的结构特征，抗结核活性，最终目标是开发新型抗结核药物。将采取系统的方法初步调查4个结构在SBIR第一阶段研究期间的特征。希望最终第二阶段计划的理想候选人可以选择一个完整的 IND指导的临床前研究，导致IND提交和启动 SBIR III期项目的临床试验。拟定商业应用：结核病是世界上头号杀手的传染病和主要死因在育龄妇女中。世界人口的三分之一（20亿），包括1500万美国人，感染了结核病，约1/3的艾滋病毒感染者人们也同时感染结核病。对目前可用的艾滋病合并结核病感染者的抗结核药物缺乏，没有标准的最佳治疗方法。新抗结核药物在世界范围内需求量很大。