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）：开发新型药物来应对现有和新出现的病毒疾病，这仍然是一个优先级的领域。苯并三唑和三唑部分是药物化学中非常重要的实体，并从中得出了几种抗病毒化合物。该提案有5个具体目标。首先是使用一种新型的机械基础来描述一种新的方法，用于合成羟苯二唑唑醚，该基本基本上利用苯并三位唑部分作为电力剂而不是核粒。化学依赖于易于使用或准备好的酒精，并且可以轻松地将其应用于手性醇，而不会失去手性。此外，将合成使用合适的醇循环和环状核苷外观。从此出现的各种新的基于苯并三唑的化合物将进行抗病毒筛查。该提案的第二个目的是查询该反应的机制，这对于进一步利用苯并三唑环系的反应性很重要。第三个目的是探索Arynes和Azido Carbasugar类似物之间的环加成化学的使用来产生苯并二唑酯5'-NOR核苷类似物。第四个目的是探索一种金属催化方法，该方法结合了Pd催化的C-N键形成和氢化剂，以得出基于吲哚的核苷类似物。目前由三个特定目标产生的未知实体将用于抗病毒活性。最后的具体目的是利用对铜催化的叠氮 - 烯烃结扎化学的机械理解，以重新解释性地将氘原子引入三唑的C-5位置，以导致三唑环形成的同一步骤。这将完全规避其形成后三唑部分的金属化的需求。在重原子取代药物以及药理代谢研究的新出现的概念的背景下，这种方法很重要。由于C-H和C-D键强度的固有差异，将重原子引入药物剂可能会提供更有效的药物。总体而言，该提案旨在探索目前苯并唑和三唑化学中未知的途径，预计大多数发展将对新型抗病毒剂的开发和评估产生重大影响。 公共卫生相关性：不自然的核苷是新抗病毒药物打击疾病的无尽来源。该建议旨在探索导致新型杂环基于杂环的核苷类似物作为潜在药物的反应，以及在重大原子替代药物的新出现概念中很重要的标记程序。