Discovery of Antimalarials with Novel Mechanism of Action

发现具有新颖作用机制的抗疟药

• 批准号: 10320854
• 负责人: DEBOPAM CHAKRABARTI
• 金额: $ 37.04万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320854
• 关键词: Antimalarials; Appearance; Area; Artemisinins; Biological Pharmacology; Blood; Cells; Cessation of life; Chemicals; Child; Collection; Data; Development; Disease; Drug Kinetics; Drug resistance; Economics; Effectiveness; Erythrocytes; Exhibits; Falciparum Malaria; Florida; In Vitro; Individual; Intervention; Laboratories; Lead; Libraries; Life Cycle Stages; Malaria; Mammalian Cell; Measures; Modeling; Molecular Target; Multi-Drug Resistance; Mus; Myanmar; Natural Products; Parasite resistance; Parasites; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Play; Population; Prevalence; Property; Proteomics; Publishing; Research; Resistance; Resistance development; Resistance profile; Resources; Rodent; Rodent Model; Role; Southeastern Asia; Speed; Structure; Testing; Therapeutic; Time; Toxicology; Universities; Vietnam; analog; asexual; base; cellular targeting; cheminformatics; design; efficacy evaluation; experience; genome sequencing; global health; improved; in vivo; in vivo evaluation; lead optimization; nanomolar; next generation; novel; novel therapeutics; resistance mechanism; scaffold; small molecule; transmission process; whole genome

Malaria still afflicts about half of the world population causing about 500,000 deaths, mostly children. The global economic toll of malaria is enormous. Most of the drugs that are currently utilized for malaria treatment are losing their effectiveness due to widespread emergence of drug resistance. Even artemisinin-based combination treatments (ACTs) that are the front-line therapies against falciparum malaria are showing signs of resistance in endemic regions of Southeast Asia. Therefore, it is urgent to identify new drug leads acting on novel targets for the development of next generation of therapies against malaria. We have screened cheminformatics-selected 2,115 unique scaffolds from a BioDesign library that incorporates privileged features of pharmacologically relevant natural products for antiplasmodial activities. This screen has identified two scaffolds that exhibit potent antiplasmodial activity, acting early on parasite's asexual life cycle, including invasion. One of the scaffold also possess stage V gametocyte activity. The proposed research seeks to establish and further develop these novel antimalarial chemotypes. We hypothesize that these chemotypes will be excellent platforms for hit-to-lead optimization studies that will yield effective antimalarial lead compounds targeting cellular mechanisms distinct from current malaria drugs. To accomplish the objective of developing new malaria therapeutics and prove our hypothesis, we plan to: (a) Design and synthesize early-acting lead compounds through structure-activity and structure-property relationship studies. (b) Determine stage-specific action, resistance profile, pharmacological properties, in vivo pharmacokinetics, toxicology, transmission blocking activity, and antimalarial efficacy. (c) Determine molecular targets of the scaffolds by whole genome sequencing of resistant lines and chemical proteomics. The proposed research is highly significant because at the end of the project we expect to have novel antimalarial lead compounds with defined mechanism of action.

疟疾仍然困扰着世界约一半人口，造成约 50 万人死亡，其中大部分是 孩子们。疟疾造成的全球经济损失是巨大的。目前大部分药物 由于疟疾的广泛出现，用于治疗疟疾的药物正在失去其有效性。 耐药性。即使是一线青蒿素联合治疗 (ACT) 恶性疟疾的治疗方法在流行地区显示出耐药迹象 东南亚。因此，迫切需要寻找作用于新靶点的新药物先导物 开发下一代抗疟疾疗法。我们已经筛选了 化学信息学从 BioDesign 库中选择了 2,115 个独特的支架，其中包含 具有抗疟原虫活性的药理学相关天然产物的独特特征。 该筛选已鉴定出两种表现出有效抗疟原虫活性的支架，它们可以在早期发挥作用 寄生虫的无性生命周期，包括入侵。其中一个支架也具有 V 阶段 配子体活性。拟议的研究旨在建立并进一步发展这些新颖的 抗疟化学型。我们假设这些化学型将成为优秀的平台 命中先导优化研究将产生有效的抗疟先导化合物靶向 细胞机制与目前的疟疾药物不同。为了实现以下目标 开发新的疟疾疗法并证明我们的假设，我们计划： (a) 设计和 通过结构-活性和结构-性质合成早效先导化合物 关系研究。 (b) 确定特定阶段的作用、耐药性、药理学 特性、体内药代动力学、毒理学、传播阻断活性和抗疟活性 功效。 (c) 通过全基因组测序确定支架的分子靶标 抗性株系和化学蛋白质组学。拟议的研究非常重要，因为 在该项目结束时，我们预计将获得具有明确定义的新型抗疟先导化合物 作用机制。

项目成果

Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines.

6-氯-2-芳基乙烯基喹啉的合成、构效关系和抗疟功效。

• 发表时间: 2020
• 影响因子: 7.3
• 作者: Huang, Guang;Murillo Solano, Claribel;Melendez, Joel;Shaw, Justin;Collins, Jennifer;Banks, Robert;Arshadi, Arash Keshavarzi;Boonhok, Rachasak;Min, Hui;Miao, Jun;Chakrabarti, Debopam;Yuan, Yu
• 通讯作者: Yuan, Yu

Microwave-assisted, rapid synthesis of 2-vinylquinolines and evaluation of their antimalarial activity.

微波辅助快速合成 2-乙烯基喹啉并评估其抗疟活性。

• DOI: 10.1016/j.tetlet.2019.05.054
• 发表时间: 2019-05-28
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Guang Huang;C. Solano;Yuxin Su;N. Ezzat;Shinobu Matsui;Liuyu Huang;D. Chakrabarti;Yu Yuan
• 通讯作者: Yu Yuan

Discovery of fast-acting dual-stage antimalarial agents by profiling pyridylvinylquinoline chemical space via copper catalyzed azide-alkyne cycloadditions.

通过铜催化叠氮-炔环加成分析吡啶乙烯基喹啉化学空间，发现快速作用的双级抗疟药。

• DOI: 10.1016/j.ejmech.2020.112889
• 发表时间: 2021-01-01
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: Huang G;Solano CM;Melendez J;Yu-Alfonzo S;Boonhok R;Min H;Miao J;Chakrabarti D;Yuan Y
• 通讯作者: Yuan Y