Synthetic studies and antimalarial activities of bastimolides and related polyketides

巴斯蒂莫内酯及相关聚酮化合物的合成研究和抗疟活性

• 批准号: 10667027
• 负责人: GREGORY K FRIESTAD
• 金额: $ 8.29万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667027
• 关键词: Address; Antimalarials; Artemisinins; Binding Proteins; Biological; Biotinylation; Catalysis; Cells; Cessation of life; Child; Chloroquine; Chloroquine resistance; Clinical; Clinical Trials; Combined Modality Therapy; Cyclization; Data; Development; Doxycycline; Drug resistance; Evaluation; Exploratory/Developmental Grant; Feedback; Funding; Geography; HepG2; Investigational Drugs; Isomerism; Lactones; Lead; Life Cycle Stages; Liver; Macrolides; Malaria; Measurement; Methodology; Methods; Microsomes; Natural Products; Natural Products Chemistry; Natural Source; Parasites; Permeability; Pharmaceutical Chemistry; Phase; Plasma Proteins; Plasmodium falciparum; Primaquine; Property; Proteins; Quinine; Research Project Grants; Resistance; Signal Transduction; Solubility; Stereoisomer; Structure; Toxic effect; World Health Organization; analog; aqueous; artemether; chemoproteomics; clinical application; combat; complement C2a; drug candidate; drug discovery; drug resistance development; effective therapy; experience; functional group; improved; indexing; infectious disease treatment; innovation; member; novel; novel strategies; novel therapeutics; pathogen; pharmacologic; pharmacophore; polyketides; polyol; programs; resistant Plasmodium falciparum; resistant strain; screening program; tool

Project Summary/Abstract The World Health Organization estimated that 2016 and 2017 each saw an increase of 2–4 million cases of malaria worldwide, rising to a total of 241 million cases and 627,000 deaths by 2020, mostly among small children. These resurging numbers signal that the effective treatment of malaria is under threat from the development of drug resistance in Plasmodium falciparum and related malaria parasite species. Consequently, combatting resistance is a critical priority and requires continued effort in discovery and development of new antimalarial drug candidates with novel mechanisms of action. Natural product chemistry has had a dramatic impact in treatment of infectious disease. Bastimolide A is a recently discovered natural product that shows noteworthy activity (IC50 80–270nm) against resistant strains of P. falciparum, and its polyketide structure is unique among current clinical and investigational antimalarial drugs, suggesting a novel mechanism of action. If confirmed, this would strongly impact the field of antimalarial drug discovery, offering a new avenue to address the critical priority of combatting drug resistance. Our specific aims in this proposal are (a) to synthesize bastimolide A and analogs, including chemoproteomics probes, and (b) to evaluate their antiplasmodial potency, improve pharmacological properties, and identify protein(s) and lifecycle stage(s) targeted. The synthetic aims will exploit efficient new synthetic methods developed in the Friestad labs, including further development of a novel asymmetric catalysis approach to 1,2-difunctional compounds, and further expansion of a programmed synthesis approach to access 1,5- polyols with complete control of challenging remote stereochemical relationships. The biological evaluation of bastimolide A and analogs will employ resistant strains of P. falciparum, and for this aim, the extensive experience with assessment and development of novel antimalarial drug leads in the Chakrabarti labs is ideally suited. Measurement of EC50 versus chloroquine-resistant P. falciparum Dd2 will identify hits and verify activity of chemoproteomics probes; the latter will allow isolation and identification of a biological target for bastimolide A. Further screens of analogs will entail cross-resistance profiling versus geographical isolates and evaluation of pharmacological properties such as aqueous solubility, LogD, permeability (PAMPA), plasma protein binding and microsomal stability. A reiterative approach will be used, with feedback from initial analogs guiding the selection of higher-priority analogs to prepare during the second year of the proposed two-year funding period. The R03 funding requested will permit access to the preliminary results needed to assess the viability of a more extensive project that would be competitive for funding via R21 or R01 mechanism.

项目总结/摘要 世界卫生组织估计，2016年和2017年各增加了200万至400万例 到2020年，全球疟疾病例总数将上升至2.41亿例，死亡人数为62.7万人，其中大部分是小规模的 孩子这些重新出现的数字表明，疟疾的有效治疗正受到来自非洲的威胁。 恶性疟原虫和相关疟疾寄生虫物种的抗药性发展。 因此，打击耐药性是一个关键的优先事项，需要继续努力， 开发具有新作用机制的新抗疟候选药物。 天然产物化学在治疗传染病方面产生了巨大的影响。巴斯蒂安A是 最近发现的天然产物，对耐药菌株显示出显著的活性（IC 50 80- 270 nm） 它的聚酮结构在目前临床和研究的抗疟药中是独一无二的 药物，这表明了一种新的作用机制。如果得到证实，这将对该领域产生重大影响。 抗疟药物发现，为解决禁毒这一关键优先事项提供了新途径 阻力 我们在这项建议中的具体目标是（a）合成bastimetrin A及其类似物，包括化学蛋白质组学 探针，和（B）评价它们的抗疟原虫效力，改善药理学性质，和鉴定 蛋白质和生命周期阶段的目标。合成目标将探索有效的新合成方法 在Friestad实验室开发，包括进一步开发一种新的不对称催化方法， 1，2-双官能化合物，并进一步扩展了程序合成方法，以获得1，5- 多元醇具有挑战性的远程立体化学关系的完全控制。生物学评价 将使用恶性疟原虫的抗性菌株，为此，广泛的 Chakrabarti实验室评估和开发新型抗疟药物的经验， 非常合适测量抗氯喹恶性疟原虫Dd 2的EC 50将识别命中并验证 化学蛋白质组学探针的活性;后者将允许分离和鉴定生物靶标， 巴斯蒂姆河A.类似物的进一步筛选将需要与地理分离物的交叉抗性谱 以及评价药理学性质，例如水溶性、LogD、渗透性（PAMPA）， 血浆蛋白结合和微粒体稳定性。将使用迭代方法，并从初始 类似物指导选择更高优先级的类似物，以在拟议的第二年期间进行准备。 两年融资期。所要求的R 03资金将允许获得所需的初步结果， 评估通过R21或R 01获得资金的更广泛项目的可行性 机制