Discovery of Oxaboroles as New Antimalarial Agents

发现氧杂硼杂环戊烯作为新型抗疟药

• 批准号: 9036317
• 负责人: Philip Jon Rosenthal
• 金额: $ 51.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036317
• 关键词: Amino Acyl-tRNA Synthetases; Antimalarials; Antiparasitic Agents; Artemisinins; Award; Back; Blood; Boron; Budgets; California; Chemistry; Child; Collaborations; Cytochrome P450; Development; Dose; Drug Kinetics; Drug resistance; Falciparum Malaria; Funding; Goals; Human; In Vitro; Knowledge; Lead; Libraries; Malaria; Medicine; Metabolism; Microbe; Modeling; Morphology; Mus; Outcome; Parasites; Pathway interactions; Pharmaceutical Preparations; Plasmodium falciparum; Pregnant Women; Preparation; Proteome; Research; Resistance; Safety; San Francisco; Solubility; Specificity; Staging; Structure-Activity Relationship; Testing; Time; Toxicology; United States National Institutes of Health; Universities; artemisinine; base; chemical synthesis; cost effective; cytotoxicity; design; drug discovery; drug metabolism; efficacy evaluation; experience; improved; in vivo; insight; leucine-tRNA; meetings; metabolic abnormality assessment; nanomolar; novel; novel therapeutics; pre-clinical; programs; resistance mechanism; safety study; scaffold; screening; small molecule; transcriptome

DESCRIPTION (provided by applicant): New drugs for malaria are greatly needed. This program is directed toward the development of new boron-containing small molecules as antimalarial drugs. Our preliminary results suggest that novel boron-containing small molecules (oxaboroles) have potent antimalarial activity and, importantly, are likely to meet standard pharmacokinetic and safety criteria for new drugs and also the unique requirements for antimalarials. We hypothesize that a systematic drug discovery program will identify optimized oxaboroles that are relatively simple to produce and meet established criteria for new antimalarial agents. Further, we will use a systematic approach to identify a specific antimalarial mechanism of action for oxaboroles. Appreciation of the mechanism of action will aid in drug optimization and in the understanding of drug resistance. Specifically, we will test the hypothesis that antimalarial oxaboroles inhibit a plasmodial leucyl tRNA synthetase (LeuRS). This hypothesis is based on specific activity of other oxaboroles against fungal or bacterial LeuRS. In addition, we will assess mechanisms of resistance. Our program will entail continued collaboration between Anacor, the world leader in boron chemistry and a malaria research group at the University of California, San Francisco with nearly two decades experience in antimalarial drug discovery. Specific aims of our program will be 1) hit-to-lead discovery of oxaborole antimalarials, 2) lead optimization of oxaborole antimalarials, and 3) characterization of the mechanisms of action and resistance for lead oxaboroles. We anticipate that, within the time-frame of this project, we will identify a candidate oxaborole antimalarial for development and that we will gain important insights into the antimalarial mechanisms of action of these compounds.

描述（申请人提供）：目前急需治疗疟疾的新药。该项目旨在开发新的含硼小分子抗疟疾药物。我们的初步结果表明，新型含硼小分子（oxaboroles）具有强大的抗疟活性，重要的是，它可能满足新药的药代动力学和安全性标准，也可能满足抗疟药物的独特要求。我们假设，一个系统的药物发现计划将确定优化的oxaboroles，相对简单的生产和满足新的抗疟疾药物的既定标准。此外，我们将采用一种系统的方法来确定一种特定的抗疟疾药物

项目成果

Benzoxaborole antimalarial agents. Part 4. Discovery of potent 6-(2-(alkoxycarbonyl)pyrazinyl-5-oxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles.

苯唑替洛尔抗疟药。第4部分。发现有效的6-（2-（2-（AlkoxyCarbonyl）吡唑）-5-oxy）-1,3-二氢-1-羟基-2,1-苯并oxoxaboroles。

• DOI: 10.1021/acs.jmedchem.5b00678
• 发表时间: 2015-07-09
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhang YK;Plattner JJ;Easom EE;Jacobs RT;Guo D;Sanders V;Freund YR;Campo B;Rosenthal PJ;Bu W;Gamo FJ;Sanz LM;Ge M;Li L;Ding J;Yang Y
• 通讯作者: Yang Y

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

• DOI: 10.1038/ncomms14574
• 发表时间: 2017-03-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Sonoiki E;Ng CL;Lee MC;Guo D;Zhang YK;Zhou Y;Alley MR;Ahyong V;Sanz LM;Lafuente-Monasterio MJ;Dong C;Schupp PG;Gut J;Legac J;Cooper RA;Gamo FJ;DeRisi J;Freund YR;Fidock DA;Rosenthal PJ
• 通讯作者: Rosenthal PJ