Synthetic Methodology to Access Novel Antivirals

获取新型抗病毒药物的合成方法

• 批准号: 8306740
• 负责人: MAHESH K LAKSHMAN
• 金额: $ 19.02万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306740
• 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.

描述（由申请人提供）：开发新的药物来对抗现有的和新出现的病毒性疾病仍然是一个高度优先的领域。苯并三氮唑和三氮唑类化合物是药物化学中非常重要的结构单元，由它们衍生出许多抗病毒化合物。该提案有五个具体目标。第一个是描绘一种新的方法，用于羟基苯并三唑醚的合成使用一种新的机械基础，基本上利用苯并三唑部分作为亲电体，而不是作为亲核试剂。该化学依赖于容易获得或制备的醇，并且可以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。由此产生的各种新的苯并三唑化合物将进行抗病毒筛选。该提案的第二个目的是质疑该反应的机理，这对于进一步开发苯并三唑环系统的反应性是重要的。第三个目标是探索利用芳基和叠氮碳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的方法，结合钯催化的C-N键形成和氢胺化，以获得基于吲哚的核苷类似物。将检测由三个特定目标产生的目前未知的实体的抗病毒活性。最后一个具体目标是利用对铜催化的叠氮化物-炔连接化学的机理理解，在导致形成三唑环的同一步骤中在三唑的C-5位区域特异性地引入氘原子。这将完全避免三唑部分在其形成之后金属化的需要。这种方法对于新出现的重原子取代药物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以潜在地提供更有效的药剂。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。