Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines

• Published in: Angewandte Chemie 2024-10, Vol.136 (40), p.n/a
• Main Authors: Wang, Sheng‐Cai, Zhou, Xiang, Li, Ying‐Xian, Zhang, Chun‐Yan, Zhang, Zi‐Yan, Xiong, Yan‐Shi, Lu, Gui, Dong, Jiajia, Weng, Jiang
• Format: Article
• Language: English
• Subjects: Amidation; Amides; Amines; Biological activity; Carboxylic acids; Chemical activity; Chemical compounds; Chemical reactions; Chemical synthesis; Chemistry; Combinatorial library synthesis; Double click reaction; Drug resistance; Fluorosulfuryl isocyanate; Isocyanates; Screening; SuFEx reaction; Sulfur
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202410699

High‐throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double‐click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur‐fluoride exchange) process. This method provides facile access to chemical libraries of N‐fluorosulfonyl amides (RCONHSO2F) and N‐acylsulfamides (RCONHSO2NR′R′′) in near‐quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96‐well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram‐positive bacterium S. aureus and drug‐resistant MRSA (MIC up to 6.25 μg ⋅ mL−1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high‐throughput medicinal chemistry. A double click strategy that enables the sequential ligation of carboxylic acids and amines with FSO2NCO has been developed. This method provides facile access to modular click chemistry library under simple conditions in tubes or on 96‐well microplates. Preliminary screening reveals that some compounds exhibit high antimicrobial activities against S. aureus and MRSA, highlighting the potency of this method in high‐throughput medicinal chemistry.