Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling

组合化学 药物发现 仿形(计算机编程) 化学 计算生物学 级联 纳米技术 生化工程 计算机科学 生物 材料科学 生物化学 工程类 色谱法 操作系统
作者
Ildar R. Iusupov,Evgeny R. Lukyanenko,Andrea Altieri,Alexander V. Kurkin
出处
期刊:ChemMedChem [Wiley]
卷期号:17 (24) 被引量:4
标识
DOI:10.1002/cmdc.202200394
摘要

Abstract Medicinal chemists are keen to explore tridimensional compounds, especially when it comes to small molecules. It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry. This is usually done by comparing the saturated carbon atoms in a molecule with the total number of its non‐hydrogen atoms (the Fsp3 value). While this aspect is clear, still there are not enough synthetic tools that support the realization of novel chemotypes that conform to these criteria. Herein we describe a diversity oriented synthesis (DOS) synthetic cascade technology that starts from two simple reagents, and generates highly enriched Fsp3 novel and diverse spiro‐scaffolds with pragmatic synthetic handles (points of diversity). The spiro nature of these scaffolds not only ensures high Fsp3 values but renders the compounds more rigid and therefore more effective in forming precise stereo‐interactions with their potential biological targets. These compounds were also profiled for their drug‐like properties and as potential modulators of the NNMT enzyme.
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