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.

疟疾仍然折磨着世界上大约一半的人口，造成大约50万人死亡

项目成果

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

• DOI: 10.1021/acs.jmedchem.0c00858
• 发表时间: 2020-10-22
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Huang G;Murillo Solano C;Melendez J;Shaw J;Collins J;Banks R;Arshadi AK;Boonhok R;Min H;Miao J;Chakrabarti D;Yuan Y
• 通讯作者: Yuan Y

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

通过通过铜叠叠叠式叠氮化物环载体来分析吡啶基乙烯基素氨酸化学空间，从而发现快速作用的双阶段抗疟药剂。

• 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