Synthetic Methodology to Access Novel Antivirals

获取新型抗病毒药物的合成方法

• 批准号: 8090198
• 负责人: MAHESH K LAKSHMAN
• 金额: $ 21.52万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090198
• 关键词: Alcohols; Alkynes; Amination; Amino Alcohols; Anthranilic Acids; Antiviral Agents; Area; Azides; Belgium; Carbon; Catalysis; Chemistry; Collaborations; Copper; Cyclopentenes; Deuterium; Development; Disease; Ethers; Evaluation; Health; Human; Indoles; Institutes; Isotopes; Label; Lactams; Ligation; Literature; Medical Research; Metals; Methodology; Methods; Nucleosides; One-Step dentin bonding system; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phenols; Positioning Attribute; Procedures; Property; Protocols documentation; Reaction; Route; Screening procedure; Skeleton; Source; System; Testing; Triazoles; Virus Diseases; Work; amino group; analog; base; benzotriazole; combat; comparative; cycloaddition; interest; metabolic abnormality assessment; novel; nucleoside analog; operation; pharmacophore; sugar

DESCRIPTION (provided by applicant): Development of novel agents to combat existing and newly emerging viral diseases continues to be an area of high priority. The benzotriazole and triazole moieties are very important entities in medicinal chemistry and several antiviral compounds are derived from them. There are 5 specific aims of this proposal. The first is to delineate a novel method for the synthesis of hydroxybenzotriazole ethers using a novel mechanistic basis that essentially utilizes the benzotriazole moiety as an electrophile rather than as a nucleophile. The chemistry relies on easily available or prepared alcohols and can be readily applied to chiral alcohols without loss of chirality. In addition, using suitable alcohols acyclic and cyclic nucleoside look-alikes will be synthesized. The wide range of new benzotriazole-based compounds emerging from this will be subjected to antiviral screening. The second aim of the proposal queries the mechanism of this reaction, which is important in order to further exploit the reactivity of the benzotriazole ring system. The third aim is to explore the use of cycloaddition chemistry between arynes and an azido carbasugar analogue to generate benzotriazolyl 5'-nor nucleoside analogues. The fourth aim is to explore a metal catalysis approach that incorporates Pd-catalyzed C-N bond formation and hydroamination, to derive indole-based nucleoside analogues. The currently unknown entities resulting from three of the specific aims will be tested for antiviral activity. The last specific aim is to utilize the mechanistic understanding of copper-catalyzed azide- alkyne ligation chemistry to regiospecifically introduce a deuterium atom at the C-5 position of triazoles in the same step that leads to the formation of the triazole ring. This will completely circumvent the need for metalation of the triazole moiety subsequent to its formation. This methodology is important in the context of the newly emerging concept of heavy atom substituted pharmaceuticals as well as for metabolic studies of pharmacophores. Introduction of a heavy atom into a pharmaceutical agent can potentially provide more efficacious agents due to the inherent differences in the C-H and C-D bond strengths. Overall, the proposal aims to explore currently unknown avenues in the chemistry of benzotriazoles and triazoles, and most developments are expected to have a significant impact in the development and assessment of novel antiviral agents. PUBLIC HEALTH RELEVANCE: Unnatural nucleosides are an endless source for new antiviral agents to combat diseases. This proposal aims to explore reactions leading to novel, facile approaches to new heterocycle-based nucleoside analogues as potential pharmaceutical agents, as well as labeling procedures that are important in the newly emerging concept of heavy-atom substituted pharmaceutical agents.

描述（由申请人提供）：开发对抗现有和新出现的病毒性疾病的新型药物仍然是一个高度优先的领域。苯并三唑和三唑部分是药物化学中非常重要的实体，多种抗病毒化合物均源自它们。该提案有 5 个具体目标。第一个是描述一种使用新机制基础合成羟基苯并三唑醚的新方法，该方法基本上利用苯并三唑部分作为亲电子试剂而不是亲核试剂。该化学依赖于容易获得或制备的醇，并且可以很容易地应用于手性醇而不损失手性。此外，使用合适的醇将合成无环和环状核苷类似物。由此出现的各种新型苯并三唑化合物将接受抗病毒筛选。该提案的第二个目标是探究该反应的机理，这对于进一步开发苯并三唑环系统的反应性非常重要。第三个目标是探索使用芳炔和叠氮卡巴糖类似物之间的环加成化学来生成苯并三唑基5'-去甲核苷类似物。第四个目标是探索一种金属催化方法，结合 Pd 催化的 C-N 键形成和加氢胺化，以衍生基于吲哚的核苷类似物。由三个具体目标产生的目前未知的实体将进行抗病毒活性测试。最后一个具体目标是利用对铜催化叠氮-炔连接化学的机理理解，在导致三唑环形成的同一步骤中，在三唑的 C-5 位上区域特异性地引入氘原子。这将完全避免三唑部分形成后金属化的需要。这种方法对于重原子取代药物的新概念以及药效团的代谢研究非常重要。由于 C-H 和 C-D 键强度的固有差异，将重原子引入药剂中可能会提供更有效的药剂。总体而言，该提案旨在探索苯并三唑和三唑化学中目前未知的途径，预计大多数进展将对新型抗病毒药物的开发和评估产生重大影响。 公共卫生相关性：非天然核苷是对抗疾病的新型抗病毒药物的无尽来源。该提案旨在探索导致新的、简便的方法的反应，以将新的基于杂环的核苷类似物作为潜在的药剂，以及在重原子取代的药剂的新概念中重要的标记程序。