A Convergent Approach for the Syntheses of Sideromycins: Mycobactin T and Gallioxamine B Conjugates

Siderophores are extremely versatile molecules synthesized by a variety of organisms with the objective of gathering iron, an essential element for most of living forms. These molecules have been isolated, characterized and studied providing valuable information about their nature and role in metabolism. In the case of pathogenic bacteria, the importance of iron-acquisition has resulted in the ability to recognize and utilize exogenous siderophores, which in turn has been met with the generation of drug-conjugates to combat siderophore-mediated iron-thievery. The identification of these molecules has sparked the interest of many laboratories to use siderophores as carriers to deliver antibiotics and other molecules of interest, inside bacteriaBecause in many cases, siderophores are exclusively recognized and acquired by a specific microorganism, the possibility of designing bacteria-specific antibiotics makes the study and synthesis of these molecules an exciting area of research. In this work we explored the synthesis of a modified aryl-oxazoline component (4-NH2 substituted) present in mycobactin T, the siderophore secreted by Mycobacterium tuberculosis (Mtb), and explored the incorporation of a linker for derivatization. We then synthesized a series of mycobactin T analogs while pursuing a versatile maleimide-containing platform for the synthesis of novel drug-conjugates (sideromycins). Satisfactorily the synthetic mycobactins were found to be potent and selective inhibitors of Mtb H37Rv.We also developed a route for the functionalization of antibiotics in order to obtain thiol-containing precursors and synthesized sideromycins using maleimide-containing desferrioxamine B as the corresponding Ga3+-complex (gallioxamine B), our conjugates displayed selective and potent growth inhibition of Gram-positive bacteria. The application of this methodology allowed the synthesis of a mycobactin sideromycin and our preliminary findings are also described in this work.