Modular Synthesis of Desferrioxamine B and Its Methotrexate Conjugate as a Selective Trojan Horse Antibiotic That Targets Streptococcus pneumoniae

A modular synthetic route for desferrioxamine B (DFOB) and its methotrexate (Mtx) conjugate is presented. This route employs acid-sensitive p-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 2 exhibits antibacterial activity specifically against Streptococcus pneumoniae 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 S. pneumoniae.