Iron transport-mediated drug delivery: practical syntheses and in vitro antibacterial studies of tris-catecholate siderophore-aminopenicillin conjugates reveals selectively potent antipseudomonal activity

Abstract

An artificial tris-catecolate siderophore with a tripodal backbone and its conjugates with ampicillin and amoxicillin were synthesized. Both conjugates exhibited significantly enhanced in vitro antibacterial activities against Gram-negative species compared to the parent drugs, especially against Pseudomonas aeruginosa . The conjugates appeared to be assimilated by an induced bacterial iron transport process as their activities were inversely related to iron concentration. The easily synthesized tris-catecolate siderophore has great potential for future development of various drug conjugates to target antibiotic-resistant Gram-negative bacteria.

Figure 1

Structures of enterobactin 1 and triscatecholate siderophore 2.

Scheme 1. Syntheses of the tris -catecholate siderophore and its aminopenicillin conjugates 10 and 11

Reagents and conditions: (a) 1. BH₃-THF, THF, reflux; 2. Boc₂O, Et₃N, MeOH, reflux, 83% for 2 steps; (b) NiCl₂, NaBH₄, MeOH, sonication, rt, 92%; (c) Methyl succinyl chloride, Et₃N, CH₂Cl₂, 0 °C to rt, 75%; (d) 6 N HCl, reflux, 100%; (e) 2,3-Diacyloxybenzoyl chloride 8, aqueous NaHCO₃/THF, 0 °C to rt, 57%; (f) 1. Isobutyl chloroformate, N-methyl morpholine, THF, 0 °C; 2. ampicillin or amoxicillin, Et₃N, THF/H₂O, 0 °C to rt, 55% (for 10), 50% (for 11).