Novel piperazine tethered thiazole compounds as antimalarials

作为抗疟药的新型哌嗪系噻唑化合物

• 批准号: 8978667
• 负责人: Heather Ann Michaels
• 金额: $ 22.5万
• 依托单位: SMART BIOMOLECULES, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-07 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8978667
• 关键词: Address; Antimalarials; Appearance; Area; Artemisinins; Biological Factors; Blood; Cells; Cessation of life; Chemicals; Child; Collection; Combined Modality Therapy; Country; Data; Development; Disease; Drug resistance; Exhibits; Falciparum Malaria; Florida; Future; Goals; In Vitro; Individual; Institutes; Institution; Lead; Libraries; Malaria; Mammalian Cell; Measures; Medicine; Modeling; Molecular; Molecular Medicine; Mus; Myanmar; Oral Administration; Parasite resistance; Parasites; Pharmaceutical Preparations; Phase; Piperazines; Play; Population; Property; Reporting; Research; Research Project Grants; Resistance; Resistance development; Resources; Risk; Role; Scanning; Series; Severities; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Source; Southeastern Asia; Staging; Structure; Testing; Therapeutic; Thiazoles; Time; Tropical Disease; Universities; Vietnam; Work; artemisinine; base; cellular targeting; chemotherapy; combinatorial; density; disorder control; high throughput screening; in vivo; killings; novel; novel therapeutic intervention; pharmacophore; phase 1 study; public health relevance; scaffold; screening; southeast Asian; therapeutic development

 DESCRIPTION (provided by applicant): In spite of all the advances in molecular medicine, malaria still afflicts about 300 million people worldwide and half of the world population is at rik. The disease causes nearly million deaths each year, mostly children. Unfortunately, the prospects for control of malaria by chemotherapy have been seriously compromised by the emergence of resistance to all available drugs. Most of the current malaria therapeutics was developed more than 30 years ago and many are derived from older chemotypes. Given the severity of the global malaria situation, it is extremely urgent to identify potent and safe chemicl entities with antimalarial activity that are structurally distinct from existing antimalarials. The proposed phase I STTR research project, which is a partnership between Smart Biomolecules Inc., and the University of Central Florida, seeks to discover and further develop novel antimalarial scaffolds through screening of the Torrey Pines Institute for Molecular Studies (TPIMS) proprietary high-density combinatorial libraries containing of over 30 million compounds. Because the TPIMS compound libraries occupy underrepresented areas of chemical space and have large degree of molecular complexity, we hypothesize that the proposed studies will identify novel pharmacophores, thus contributing significantly to the malaria elimination campaign. Arrangement of the libraries in the scaffold ranking and positional scanning formats will enable us to screen the entire collection very rapidly. Our preliminary work has identified novel scaffolds from the piperazine-tethered thiazole library to possess potent and selective anti-plasmodial activity. To accomplish our objective to identify leads for malaria therapy from this series of compounds, we propose to: (a) Deconvolute the piperazine-tethered thiazole library to identify selective lead compounds and (b) Determine development stage-specific action and resistance potential; (3) Evaluate the in vivo efficacy of piperazine-tethered thiazole lead compounds.

 描述（由申请人提供）：尽管分子医学取得了巨大的进步，但疟疾仍然困扰着全世界约 3 亿人，这种疾病每年导致近百万人死亡，其中大部分是儿童。由于对所有可用药物的耐药性的出现，通过化疗控制疟疾的前景受到严重影响，目前大多数疟疾治疗方法都是在 30 多年前开发的，并且考虑到疟疾的严重性，许多治疗方法都源自较旧的化学类型。鉴于全球疟疾形势，迫切需要确定具有抗疟活性且在结构上与现有抗疟药不同的有效且安全的化学实体。 拟议的第一阶段 STTR 研究项目是 Smart Biomolecules Inc. 和中佛罗里达大学之间的合作伙伴关系，旨在通过筛选托利松分子研究所 (TPIMS) 专有的高密度材料来发现和进一步开发新型抗疟支架由于 TPIMS 化合物库占据了化学空间中代表性不足的区域，并且具有很大程度的分子复杂性，因此我们认为所提出的研究将识别新的药效基团。支架排序和位置扫描格式的文库排列将使我们能够非常快速地筛选整个集合，这对消除疟疾运动做出了重大贡献。我们的初步工作已经从哌嗪系噻唑文库中鉴定出具有有效和选择性的新型支架。为了实现从这一系列化合物中鉴定疟疾治疗先导化合物的目标，我们建议：（a）对哌嗪系噻唑库进行解卷积以鉴定选择性先导化合物。 (b) 确定特定发育阶段的作用和耐药潜力； (3) 评估哌嗪系噻唑先导化合物的体内功效。

项目成果

Parallel Synthesis of Piperazine Tethered Thiazole Compounds with Antiplasmodial Activity.

具有抗疟原虫活性的哌嗪系噻唑化合物的平行合成。

• 发表时间: 2023-12-12
• 影响因子: 5.6
• 作者: Rayala, Ramanjaneyulu;Chaudhari, Prakash;Bunnell, Ashley;Roberts, Bracken;Chakrabarti, Debopam;Nefzi, Adel
• 通讯作者: Nefzi, Adel

Identification of Bis-Cyclic Guanidines as Antiplasmodial Compounds from Positional Scanning Mixture-Based Libraries.

从基于位置扫描混合物的文库鉴定双环胍作为抗疟原虫化合物。

• 发表时间: 2019-03-20
• 作者: Perry Jr, David L;Roberts, Bracken F;Debevec, Ginamarie;Michaels, Heather A;Chakrabarti, Debopam;Nefzi, Adel
• 通讯作者: Nefzi, Adel