Hydroamination of Dehydroalanine With Deuterium Incorporation to Access Unnatural 2- and 4-Pyridonyl α-Amino Acids: Evaluation of Their Antibacterial, Antifungal, and Immunomodulatory Activities.

A novel and facile method for the synthesis of unnatural β-pyridonyl α-amino acid derivatives via hydroamination of dehydroalanine (Dha) with 2- and 4-hydroxypyridine was described. The reaction of N,N-diprotected Dha with 2- and 4-hydroxypyrdine proceeded smoothly at room temperature to afford a variety of 2- and 4-pyridonyl amino acids, whereas the reaction of mono N-protected Dha with 2- and 4-hydroxypyridine reacted at 80 °C heating to give corresponding pyridonyl amino acid derivatives. Further, a new family of deuterated β-pyridonyl α-amino acid derivatives has been synthesized using D2O as cosolvent. The hydroamination method has been extented to Dha-containing small peptides. The antimicrobial evaluation of the synthesized compounds demonstrated moderate inhibitory activity against Escherichia coli, Staphylococcus aureus, Micrococcus luteus, and Klebsiella pneumoniae, along with antifungal activity against Candida albicans. Further, in vitro evaluation revealed that the six synthesized compounds exhibit notable anti-inflammatory potential in murine macrophages, as evidenced by high production of the anti-inflammatory cytokine (IL-10) and minimal release of pro-inflammatory cytokines (IL-1β and TNF-α). Overall, this strategy provides a straightforward approach to structurally diverse pyridonyl amino acids with promising applications in drug discovery, particularly for inflammatory disorders.