Modular Synthesisof Desferrioxamine B and Its MethotrexateConjugate as a Selective Trojan Horse Antibiotic That Targets <i>Streptococcus pneumoniae</i>

A modular synthetic route for desferrioxamine B (DFOB) and its methotrexate (Mtx) conjugate is presented. This route employs acid-sensitive <i>p-</i>methoxybenzyl groups to protect the hydroxamic acid oxygen, and DFOB was obtained in the 11 longest linear steps with an overall 22% yield. Resulting DFOB–Mtx conjugate <b>2</b> exhibits antibacterial activity specifically against <i>Streptococcus pneumoniae</i> with a minimum inhibitory concentration of 3.9 nM while possessing 6449-fold reduced human cytotoxicity. The DFOB–Mtx conjugate currently represents the most potent DFOB antibacterial conjugate against <i>S. pneumoniae</i>.