Development of new furanyl anti-tuberculosis inhibitors

新型呋喃类抗结核抑制剂的研制

• 批准号: 7054110
• 负责人: Richard E. Lee
• 金额: $ 49.83万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-20 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054110
• 关键词: AIDS therapy; HIV infections; Mycobacterium; amides; antiAIDS agent; antibacterial agents; chemical synthesis; comorbidity; cytotoxicity; drug design /synthesis /production; drug resistance; laboratory mouse; microarray technology; opportunistic infections; pharmacokinetics; protein binding; spectrometry; therapy design /development; tuberculosis; two dimensional gel electrophoresis

DESCRIPTION (provided by applicant): Tuberculosis is the leading AIDS associated opportunistic infection found in non-industrialized nations of the world. There is an urgent need to develop new, potent, fast acting anti-tuberculosis drugs that can be used in conjunction with drugs used to treat HIV infections. Towards these ends we propose to explore and develop a novel class of nitrofuranyl amides as new anti-tuberculosis agents. This series of compounds is particularly attractive for TB drug development because of its ease of synthesis allowing for rapid synthesis of analogs in this proposal and could ultimately lead to an inexpensive drug. The goals of this proposal are to enhance the activity of the series in vitro and in vivo and to produce viable preclinical drug candidates. Computational drug design methods and modern medicinal chemistry synthesis techniques will be used to design and synthesize further compound generations. A complete microbiological and biochemical assessment of the nitrofuranyl series will be performed. MIC and MBC determinations for the new generations of compounds will be determined against various M. tuberculosis strains including H37Rv and multidrug resistant tuberculosis. The resistance frequency of M. tuberculosis to the lead compounds will be examined and cross resistance to other anti-tuberculosis drugs will be investigated. Synergy tests will be performed with other anti-tuberculosis drugs and the cytotoxicity of the compounds determined. The mechanism of action of these inhibitors will be studied. The effectiveness of the leads against latent tuberculosis will be evaluated using an in vitro assay of M. tuberculosis grown under low oxygen conditions. Maximum tolerated dose assays and basic bioavailability assays will be performed on the lead compounds. Compounds with good pharmacological profiles will then be tested using a rapid in vivo model. The in vivo activity is then confirmed using the standard TB mouse model. The basic pharmacokinetic and biopharmaceutic properties of leads will be characterized in vivo.

描述（由申请人提供）：结核病是世界非工业化国家中发现的主要艾滋病。迫切需要开发新的，有效的快速作用抗结核药物，这些药物可与用于治疗HIV感染的药物一起使用。在这些目的方面，我们建议探索和开发一种新型的硝化呋喃基酰胺，作为新的抗结核药。这一系列化合物对于结核病药物的开发特别有吸引力，因为它易于合成，可以在该提案中快速合成类似物，并最终可能导致廉价的药物。该建议的目标是增强该系列在体外和体内的活性，并生产可行的临床前药物。计算药物设计方法和现代药物化学合成技术将用于设计和合成进一步的复合代。将对硝基呋喃基系列进行完整的微生物和生化评估。新一代化合物的MIC和MBC测定将针对包括H37RV（H37RV和多药耐药性结核病）的各种结核分枝杆菌确定。将检查结核分枝杆菌对铅化合物的耐药性频率，并将研究其他抗结核药物的交叉耐药性。将使用其他抗结核药物和确定化合物的细胞毒性进行协同测试。将研究这些抑制剂的作用机理。将使用在低氧气条件下生长的结核分枝杆菌的体外测定法评估铅针对潜在结核病的有效性。将在铅化合物上执行最大耐受剂量测定和基本的生物利用度测定。然后，将使用快速的体内模型对具有良好药理特征的化合物进行测试。然后使用标准TB小鼠模型确认体内活性。铅的基本药代动力学和生物药物特性将在体内表征。