Tunable Bioactive Glycine-Based Peptoids: Support-Free Scalable Synthesis of Sequence-Defined Oligomers/Dendrimers...

Sequence-defined polymers have emerged as a unique class of macromolecules with precisely controlled monomer sequences. Despite advances, precise sequence control in synthetic oligomers remains elusive. In the present study, we report a novel approach for the efficient production of sequence-defined peptoid oligomers (SDO) without support for the first time. The proposed strategy provides several advantages, including efficient, iterative, scalable, support-free, and protection-deprotection-free synthesis of glycine-based peptoids. It also provides a facile postsynthetic modification that enables the design of a novel SDO framework incorporating diverse amine groups, yielding versatile platforms with broad applications. This approach is based on a tunable comonomer, chloroacetyl chloride, utilizing a commercially available reactive amine derivative, forming a chloro-terminal amide scaffold, which can be employed for the synthesis of oligomers without chromatographic purification. This viable approach enabled us to perform high-speed synthesis of sequence-defined peptoid oligomers with five monomer sequences in 9 h. As a proof-of-concept method, we incorporated various alkyl and aryl moieties into sequence-defined oligomers at precise sites. Our SDO platform has achieved two key developments: (i) innovative postsynthetic modification strategies and (ii) single-step chain length extension. The resulting compounds were comprehensively screened for potential bioactive properties, displaying promising biological properties, against both bacterial and fungal strains. Such findings highlight the strong potential of our platform to generate oligomeric structures with therapeutic relevance, particularly as next-generation antimicrobial and antifungal candidates. Further, SAR studies with in silico analysis on peptoids enable us to discover interesting findings on biological properties.