Heterocyclic Assembly: An Underutilized Disconnection with Potential to Maximize High Fsp3 Chemical Space Exploration

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-28 DOI:10.1021/acsmedchemlett.4c0059110.1021/acsmedchemlett.4c00591

Brandon M. Taoka, Ning Qi, Zachary G. Brill, Anthony Donofrio, Tao Meng, Yiting Zheng, Bryan S. Matsuura*, Anilkumar G. Nair* and Rohan R. Merchant*,

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Abstract

From a retrosynthetic standpoint, functionalization or synthesis of heterocyclic cores are fundamental disconnections that chemists make. This manuscript highlights heterocycle synthesis as the strategic bond disconnection by leveraging ubiquitous building blocks, carboxylic acids and amines, for preparation of heterocyclic cores in a library-friendly format. This heterocyclic formation strategy allows medicinal chemists to access much wider chemical space, especially for analogs with higher Fsp³ vs state-of-the-art heterocycle functionalization methods. The direct impact on medicinal chemistry programs is underscored by adapting and miniaturizing the synthesis of N2-indazoles and C2-benzimidazoles to μ-scale parallel medicinal chemistry (PMC) libraries, affording a similar success rate (80%) as venerable Suzuki and Buchwald-Hartwig libraries.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.