Medicinal Chemistry Optimisation of Novel Heterocyclic Anti-infective Agents

疟疾是一种蚊媒传染病，由于在经济欠发达国家的高死亡率，对全球健康构成重大挑战。目前基于青蒿素的联合疗法（ACT）提供了有效的一线治疗方法;然而，ACT耐药株的出现优先鉴定能够靶向耐药疟疾株而不影响青蒿素的药代动力学和快速作用的新型药物。2017年，确定了含氨基恶二唑的抗疟药物的新分类。这些药物具有很好的抗寄生虫作用，与青蒿素相当，但I期代谢被认为会产生有毒的肼代谢物，阻碍其作为抗疟药的应用。最近的研究已经检查了氨基恶二唑，特别是氨基取代的杂环类似物的生物电子等排体，旨在避免肼代谢物的不利产生。这些结构显示出良好的抗耐药恶性疟原虫菌株的纳摩尔活性。此外，它们表现出良好的水溶性和中等的代谢稳定性。该项目的范围将建立在这些发现的基础上，进一步优化合适的生物电子等排体替代支架，目标是开发具有改善药物样特性的快速作用的抗疟候选药物。

Malaria, a mosquito-borne infectious disease, poses a significant challenge for global health due to high mortality rates in less economically developed countries. Current artemisinin-based combination therapies (ACTs) provide effective first-line therapies for the treatment; however, the appearance of ACT resistant strains has prioritised the identification of novel agents capable of targeting resistant malarial strains without compromising the pharmacokinetics and fast action of artemisinin. In 2017 a new classification of antimalarial aminooxadiazole containing agents were identified. These agents possessed promising antiparasitic profiles, comparable with artemisinin, however phase I metabolism was recognised to generate toxic hydrazine metabolites hindering their application as antimalarials. Recent investigations have examined bio-isosteres of the aminooxadiazoles, especially amino-substituted heterocyclic analogues, aiming to evade the unfavourable generation of hydrazine metabolites. These structures display good nanomolar activity against resistant plasmodium falciparum strains. Furthermore, they demonstrate good aqueous solubility and moderate metabolic stability. The scope of this project will build upon these findings by further optimisation of suitable bioisostere replacement scaffolds with the goal of developing fast acting antimalarial candidates with improved drug-like properties.