Design/Syntheses/Studies/Novel Antituberculosis Agents

描述（由申请人提供）：提出了基于生物学必需的分枝杆菌铁螯合过程的新型抗结核药物的设计、合成和研究。铁的吸收对大多数生物体来说是必不可少的。因此，包括结核分枝杆菌在内的微生物已经进化出非常有选择性和特异性的方法来螯合生理必需的铁。该提议的一般假设是，结核分枝杆菌利用的铁螯合过程可以被开发为用于开发新型抗结核药物的“阿喀琉斯之踵”。虽然这个概念已经被考虑过，但以前没有实验室能够合成相关化合物进行相关研究。具体目标如下。 1.设计、合成和研究了M.结核病，以确定类似物是否可以抑制铁的获取，从而诱导微生物选择性铁饥饿和微生物死亡（“斯诺假说”的确认）。类似物的设计将建立在我们的初步发现，选择性的结构变化的分枝杆菌产生新的抗结核药物。因此，先导化合物的实际规模合成之后将进行集中的结构修饰。合成工作将通过对样品进行全面的化学和物理表征来补充，包括测定分枝杆菌素类似物和缀合物的铁结合亲和力以及它们从介质中结合铁的能力。2.合成和研究一组集中和有限的分枝杆菌素（铁载体）-抗生素缀合物，能够选择性微生物细胞转运和药物输送。所有缀合物都可以从我们已经合成的先导化合物以简单的方式（一到三个步骤）制备。3.将对样品进行体外和体内生物学评价，以确定具有抗结核活性的新化合物的作用模式，包括抗结核活性、抑制或促进其他选定分枝杆菌生长以及相关研究（包括总体毒性）。 总之，这些研究将确定开发新的抗结核药物的可行性，这些药物具有与分枝杆菌（包括M.结核

DESCRIPTION (provided by applicant): Design, syntheses and studies of novel anti-tuberculosis agents based on biologically essential mycobacterial iron sequestration processes are proposed. Assimilation of iron is essential for most living organisms. Thus, microbes, including Mycobacterium tuberculosis, have evolved very selective and specific methods to sequester physiologically essential iron. The general hypothesis of this proposal is that the iron sequestration process utilized by Mycobacterium tuberculosis can be exploited as an "Achilles' heel" for the development of novel antituberculosis agents. Though this concept has been considered, no laboratory has previously been able to synthetically access the relevant compounds for related studies. The specific aims are the following. 1. Design, syntheses and studies of focused sets of analogs of natural iron chelators (mycobactins) used by M. tuberculosis to determine if analogs can inhibit iron acquisition, thus, inducing microbe selective iron starvation and microbe death (confirmation of "Snow's Hypothesis"). The analog design will build on our preliminary findings that selective structural variation of mycobactins does produce novel antiTB agents. Thus, practical scale syntheses of lead compounds will be followed by focused structural modification. The synthetic work will be complemented by full chemical and physical characterization of samples, including determination of the iron binding affinity of the mycobactin analogs and conjugates as well as their ability to bind iron from media. 2. Syntheses and studies of a focused and limited set of mycobactin (siderophore)- antibiotic conjugates capable of selective microbe cell transport and drug delivery. All conjugates can be prepared in straightforward fashion (one to three steps) from our already synthesized lead compounds. 3. In Vitro and in vivo biological evaluation of samples for antituberculosis activity, growth inhibition or promotion of other selected mycobacteria and related studies, including gross toxicity, will be performed to determine the mode of action of new compounds with anti-TB activity. Taken together, these studies will determine the feasibility of developing new antituberculosis agents with a novel mode of action related to the required iron uptake processes needed by mycobacteria, including M. tuberculosis.