Halogenated Xanthones as Antimalarial Agents

超出所提供的空间。我们已经发表了我们的发现，氧杂蒽酮表现出有效的抗疟活性，甚至对恶性疟原虫的多药耐药菌株。基于我们对氧杂蒽酮作用机制的理解，我们开发了第二代氧杂蒽酮，3，6-双-co-二乙基氨基戊氧基氧杂蒽酮（C5）。C5与氯喹的效力大致相同，但对一组耐药菌株具有相同的活性。在此，我们建议开发第三代氧杂蒽酮抗疟药，并将其长期用于临床试验。实现这一目标的步骤是：评估现有氧杂蒽酮类似物的体内功效。 这将在疟疾的P. v. v. vinckei鼠模型中进行研究。 将在未感染小鼠中研究氧杂蒽酮急性毒性的可能性。通过微粒体评价C5的体外代谢。 将使用人和鼠源性微粒体对此进行研究。从C5开始优化药物结构，以确保安全性和抗疟效力。 这将在体外和体内试验、分子建模、药代动力学和光谱证据之间的迭代过程中完成。第三代化合物的合成和评价。 这些第三代氧杂蒽酮的特点将是提高安全性和抗疟效力. 第三代化合物生产成本低，化学和代谢稳定，口服生物利用度高.这些基于氧杂蒽酮的抗疟药的作用方式是通过血红素的复合来抑制疟原虫色素的形成。由于血红素是一种不可变的生物分子，很难想象任何简单的突变都可能导致耐药性。性能现场=

EXCEED THE SPACE PROVIDED. We have already published our discovery that xanthones exhibit potent antimalarial activity, even against multidrug resistant strains of Plasmodium falciparum. Based on our understanding of xanthone mode of action, we have developed a 2 nd generation xanthone, 3,6-bis-co-diethylaminoamyloxyxanthone (C5). C5 is approximately as potent as chloroquine, yet with equal activity against a panel of drug resistant strains. Herein, we propose to develop the 3 rd generation of xanthone antimalarials, with a long-term view toward clinical trials. The steps toward this goal are: ¿ Evaluate the in vivo efficacy of existing xanthone analogs. This will be investigated in the P. v. vinckei murine model of malaria. The possibility for acute toxicity of xanthones will be investigated in uninfected mice. ¿ Evaluate the in vitro metabolism of C5 by microsomes. This will be investigated with both human and murine derived microsomes. ¿ Optimize the drug structure beginning with C5 for both safety and antimalarial potency. This will be done in a process iterative between in vitro and in vivo testing, molecular modeling, pharmacokinetics, and spectroscopic evidence. ¿ Synthesis and evaluation of 3r_generation compounds. The hallmark of these 3 rd generation xanthones will be improved safety and antimalarial potency. The 3 rd generation compounds will be inexpensive to produce, chemically and metabolically stable, and orally bioavailable. The mode of action of these xanthone-based antimalarial agents is inhibition of hemozoin formation via complexation of heme. Since heme is an immutable biomolecule, it is difficult to envision any simple mutation that could lead to resistance. PERFORMANCE SITE ========================================Section End===========================================