Asymetric Synthesis of 3,6- Disubstituted Dioxopiperazines with Potential Siderophore Properties

Antibiotic resistance is an emerging disease and a real problem of health. Resistance of Gram negative bacteria such as Acinetobacter baumannii and Escherichia coli to conventional antibiotics lead to therapeutic failure and require new antibiotherapies. The use of the iron transport systems is one of the most promising strategies to overcome this resistance phenomenon. These specific routes of entry, essential for the survival of the microorganisms, allow ferric siderophore complexes to carry iron within the bacteria.

These systems allow the introduction of antibacterial agents (conjugates antibiotic-siderophore) or toxic complexes (gallium complexes) into the bacteria to kill them. Rhodotorulic acid (RA) is a siderophore transported by TonBox dependant Fhu receptors. These kinds of receptors are expressed by Acinetobacter baumannii and Escherichia coli. RA is dioxopiperazine iron chélater with hydroxamate as iron ligands and two asymmetric centers (S,S configuration). This spatial orientation is essential for the Fhu receptors recognition.

We have previously reported the asymmetric synthesis of 3-substituted 2-oxopiperazines. Herein, we present an original and a convergent strategy to synthesize RA and corresponding 3,6-disubstituted analogues. Siderophore-like test and measurement of the complexing strength of these compounds will be carried out.