Structural Requirements for Ga³⁺ Coordination in Synthetic Analogues of the Siderophore Piscibactin Deduced by Chemical Synthesis and Density Functional Theory Calculations

Abstract

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 13S is 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 complete 1H and 13C 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 against Vibrio anguillarum agrees 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.