Stereoselective total
synthesis of several analogues of piscibactin
(Pcb), the siderophore produced by different pathogenic Gram-negative
bacteria, was performed. The acid-sensitive α-methylthiazoline
moiety was replaced by a more stable thiazole ring, differing in the
configuration of the OH group at the C-13 position. The ability of
these Pcb analogues to form complexes with Ga3+as a mimic
of Fe3+showed that the configuration of the hydroxyl group
at C-13 as 13Sis crucial for the chelation of Ga3+to preserve the metal coordination, while the presence of
a thiazole ring instead of the α-methylthiazoline
moiety does not affect such coordination. A complete1H
and13C NMR chemical shift assignment of the diastereoisomer
mixtures around C9/C10 was done for diagnostic stereochemical disposition.
Additionally, density functional theory calculations were performed
not only for confirming the stereochemistry of the Ga3+complex among the six possible diastereoisomers but also for deducing
the ability of these to form octahedral coordination spheres with
gallium. Finally, the lack of antimicrobial activity of Pcb and Pcb
thiazole analogue Ga3+complexes againstVibrio anguillarumagrees with one of the roles of
siderophores in protecting pathogens from metal ion toxicity. The
efficient metal coordination shown by this scaffold suggests its possible
use as a starting point for the design of new chelating agents or
vectors for the development of new antibacterials that exploit the
“Trojan horse” strategy using the microbial iron uptake
mechanisms. The results obtained will be of great help in the development
of biotechnological applications for these types of compounds.