Halogenated Xanthones as Antimalarial Agents

描述(由申请人提供)：我们已经发表了我们的发现，xanthone具有强大的抗疟疾活性，甚至对恶性疟原虫的多药耐药株也是如此。基于我们对xanthone作用机理的了解，我们开发了第二代xanthone，3，6-双omega-二乙氨基淀粉氧基xanthone(C5)。C5的效力与氯喹大致相同，但对一组耐药菌株的活性相同。在此，我们建议开发第三代xanthone抗疟疾药物，并着眼于临床试验。实现这一目标的步骤包括： 。评估现有的xanthone类似物的体内疗效。 这将在P.v.vinckei疟疾小鼠模型中进行研究。将在未感染的小鼠身上调查xanthone的急性毒性的可能性。 。用微粒体法评价C5的体外代谢。这将在人类和小鼠来源的微粒体中进行研究。 。从C5开始优化药物结构，以确保安全性和抗疟疾效力。这将在体外和体内测试、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与评价。这些第三代xanthone的标志将是提高安全性和抗疟疾效力.第三代化合物将生产成本低廉，化学和代谢稳定，并可口服生物利用。 这些基于口山酮的抗疟疾药物的作用方式是通过与血红素的络合来抑制血球蛋白的形成。由于血红素是一种不变的生物分子，很难想象会有任何简单的突变导致抗药性。

DESCRIPTION (provided by the applicant): We have already published our discovery that xanthones exhibit potent antimalarial activity, even against multi-drug resistant strains of Plasmodium falciparum. Based on our understanding of xanthone mode of action, we have developed a 2nd generation xanthone, 3,6-bis-omega-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 anti-malarials, 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 3rd 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.