DEVELOPMENT OF NOVEL PHARMACOPHORE WITH ANTI-TB ACTIVITY

描述(改编自应用程序)：通过TAACF筛选计划 在NIAID的赞助下，一种自然产生的吡喃香豆素化合物 经鉴定对抗结核分枝杆菌有积极作用。进一步评估 在先导化合物(+)-Calanolide A中，证明了它的活性。 抗结核分枝杆菌对异烟肼、利福平、 链霉素和乙胺丁醇。(+)-Calanolide A也能够 骨髓来源的小鼠细胞内杀伤结核杆菌的实验研究 巨噬细胞。初步的机制研究表明，它的新型抗结核作用 物业可能涉及的唯一对象(S)。显然，(+)-Calanolide A和 其相关的焦菊素代表了一种新的和独特的药效团 抗结核活性。这个SBIR项目的目标是着手设计， 某些吡喃香豆素焦点文库的合成与鉴定 类似物，以进一步了解 抗结核活性，最终目标是开发一种新的抗结核病药物。 将采取系统的方法对4个结构进行初步调查 在SBIR第一阶段研究期间的特点。希望到了最后， 在第二阶段的计划中，可以选择一名理想的候选人 IND指导的临床研究，导致LND提交和发起 在SBIR阶段Ill计划中的临床试验。 建议的商业应用： 结核病是世界上传染病中的头号杀手，也是主要的死亡原因 在育龄妇女中。世界人口的三分之一(@20亿) 其中包括1500万美国人，是结核病感染者和约三分之一的艾滋病毒感染者 人们也同时感染了结核病。已经出现了对目前可用的 抗结核药物和没有标准的最佳治疗方案使艾滋病患者感染结核病。新的 抗结核药物在世界范围内需求量很大。

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.