diketopiperazine

2,5-Diketopiperazine (DKP) is a heterocyclic compound arising when two amino acids condense to form a cyclic dipeptide. The core ring is a six-membered piperazinedione, bearing two amide carbonyl groups at positions 2 and 5 and two nitrogens that can bear side-chain substituents derived from the parent amino acids. The ring is relatively rigid and often serves as a privileged scaffold in medicinal chemistry.

DKPs can be formed chemically by cyclization of dipeptides through dehydration, typically using coupling agents or high-temperature conditions, or by cyclodehydration with reagents such as diethyl azodicarboxylate (DEAD) or phosphorus-based methods. In nature, certain bacteria and fungi produce DKPs via cyclodipeptide synthases that join aminoacyl-tRNAs or through nonribosomal peptide pathways, yielding various cyclodipeptides that can become DKPs upon further modification.

DKPs occur widely as natural products. Simple DKP cores are found as components of microbial metabolites and some plant-derived compounds. Many DKPs exhibit biological activities, including antimicrobial, antitumor, immunomodulatory, or enzyme-inhibitory effects, though activity is highly dependent on substituents on the nitrogens and/or ring.

In medicinal chemistry, DKPs are valued as rigid, peptide-like scaffolds that mimic dipeptide segments while offering conformational constraint. They are used in combinatorial libraries and as starting points for the development of protease inhibitors, antimicrobial agents, and other bioactive molecules. N-substitution and side-chain variation allow tuning of pharmacokinetic properties and receptor interactions.

Examples include simple cyclo(Gly-Phe) and related natural products; many other DKP derivatives have been described. DKPs are usually studied within organic chemistry or natural product chemistry contexts.