N-Aminoimidazole-2-ones peptide mimics

α-Amino lactam (Agl) units have served as conformational constraints in peptide-based drug discovery since the pioneering studies of Freidinger and Veber [1]. In peptides, Agl residues have been shown to adopt the i + 1 position of β-turn secondary structure which play privileged roles in molecular recognition. N-Aminoimidazolone (Nai) residues offer similar means for constraining peptide backbone geometry in β- and γ-turn conformers and are apt for functionalization with substituents to study side chain orientation [2].

Our presentation discusses a general organocatalytic method for the synthesis of 4-, 5- and 4,5-substituted Nai dipeptides [3,4]. The synthesis and application of substituted Nai dipeptides will be showcased in structure-activity relationship studies of cluster of differentiation-36 receptor ligands that act as modulator of inflammation [3,4].

1. Freidinger, R. M. Design and Synthesis of Novel Bioactive Peptides and Peptidomimetics Med. Chem. 2003, 46, 5553- 5566.

2. St-Cyr D.J., García-Ramos Y., Doan N.D., Lubell W.D. Peptidomimetics I. Springer; Cham, Switzerland: 2017. Aminolactam, N-Aminoimidazolone, and N-Aminoimdazolidinone Peptide Mimics; pp. 125–175.

3. Hamdane, Y.; Poupart, J.; Lubell, W. D. Synthesis, 2022, 54 (6), 1518–1526.

4. Hamdane, Y.; Chauhan, S. P.; Vutla, S.; Mulumba, D.; Ong, H.; Lubell, W. D. Lett. 2021, 23 (9), 3491–3495.