β-Lactam antibiotics are one of the most important antibacterial drug classes worldwide. This work will present the first prototype on-DNA β-lactam combinatorial library with novel structures and chemical space properties that would be significant for phenotypic screening to identify the next generation of antibiotics to combat the pervasive problem of bacterial resistance.

Organophosphonic compounds are distinctive among natural products in terms of stability and mimicry. Numerous synthetic organophosphonic compounds, including pamidronic acid, fosmidromycin, and zoledronic acid, are approved drugs. DNA encoded library technology (DELT) is a wellestablished platform for identifying small molecule recognition to target protein of interest (POI). Therefore, it is imperative to create an efficient procedure for the on-DNA synthesis of α-hydroxy phosphonates for DEL builds.

A novel on-DNA oxidative disulfide formation method has been developed. Under ambient conditions, the methodology showcased wide applicability and swift implementation in routine DNA-encoded library synthesis to access pharmaceutically relevant motifs.

Thiophene and its substituted derivatives are a highly important class of heterocyclic compounds, with noteworthy applications in pharmaceutical ingredients. In this study, we leverage the unique reactivity of alkynes to generate thiophenes on-DNA, using a cascade iodination, Cadiot-Chodkiewicz coupling and heterocyclization. This approach, tackling on-DNA thiophene synthesis for the first time, generates diverse, and unprecedented structural and chemical features, which could be significant motifs in DEL screening as molecular recognition agents for drug discovery.