Discovery of a Novel Cyclobutanol Scaffold With Anti‐Inflammatory Activity and Its Modular Synthesis

ABSTRACT The discovery of novel molecular scaffolds broadens chemical space and supports innovative therapeutics. We identified the underexplored scaffold N ‐((3‐hydroxycyclobutyl)(piperidin‐4‐yl)methyl)amide from the ChemBridge database using the similarity ensemble approach (SEA). Seven commercial analogs displayed modest cytotoxicity against prostate (PC‐3, LNCaP) and pancreatic (PANC‐1) cancer cells but significantly inhibited LPS‐induced ROS and nitrite production in RAW 264.7 macrophages, suggesting anti‐inflammatory potential. To expand this scaffold, we developed a modular synthesis. A Ni‐catalyzed reductive coupling of a tosyl‐protected iodopiperidine with 3‐(benzyloxy)cyclobutane‐1‐carboxylic acid successfully provided a key ketone intermediate. Reductive amination and acylation yielded amide derivatives, demonstrating synthetic feasibility. Sodium naphthalenide enabled concurrent O ‐benzyl and N ‐tosyl deprotection, streamlining the sequence to six steps from simple starting materials. This modular route permits late‐stage incorporation of diverse acyl fragments for analog diversification. Overall, N ‐((3‐hydroxycyclobutyl)(piperidin‐4‐yl)methyl)amide is a synthetically accessible scaffold with promising anti‐inflammatory activity, offering a foundation for further optimization and therapeutic development.