Medicinal Chemistry Optimisation of Novel Heterocyclic Anti-infective Agents

新型杂环抗感染药物的药物化学优化

• 批准号: 2599532
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2599532
• 关键词: Medicinal; Chemistry; Optimisation; Novel; Heterocyclic

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.

疟疾是一种通过蚊子传播的传染病，由于经济欠发达国家的高死亡率，它对全球卫生构成了重大挑战。目前以青蒿素为基础的联合疗法(ACTs)为治疗提供了有效的一线疗法；然而，ACT耐药株的出现优先于确定能够针对耐药疟疾株的新药物，而不影响青蒿素的药代动力学和快速作用。2017年，确定了含有氨基恶二唑的抗疟疾药物的新分类。这些药物具有与青蒿素类似的良好的抗寄生虫谱，但I期代谢被认为会产生有毒的联氨代谢物，阻碍了它们作为抗疟疾药物的应用。最近的研究已经检测了氨基恶二唑的生物异构体，特别是氨基取代的杂环类似物，目的是避免不利的联氨代谢物的产生。这些结构对抗药性恶性疟原虫菌株表现出良好的纳米分子活性。此外，它们还表现出良好的水溶性和适度的代谢稳定性。该项目的范围将建立在这些发现的基础上，通过进一步优化合适的生物等价物替代支架，目标是开发具有更好的类药物特性的快速有效的抗疟疾候选药物。