Chemical syntheses and in vitro antibacterial activity of two desferrioxamine B-ciprofloxacin conjugates with potential esterase and phosphatase triggered drug release linkers

Abstract

Two desferrioxamine B-ciprofloxacin conjugates with 'trimethyl-lock' based linkers that are designed to release the antibiotic after esterase or phosphatase-mediated hydrolysis were synthesized. The potential esterase-sensitive conjugate 13 displayed moderate to good antibacterial activities against selected ferrioxamine-utilizing bacteria, although the activities were lower than the parent drug ciprofloxacin. However, the potential phophatase-sensitive conjugate 23 was inactive against the same panel of organisms tested. These properties appeared to be related to the activating efficiency of the linker by the enzyme and to the outer membrane protein recognition of the chemically modified siderophore used in the conjugate.

Figure 1

Antibiotic resistance in bacteria and iron-transport mediated drug delivery (the “Trojan Horse” strategy).

Scheme 1

General siderophore drug conjugates and two naturally occurring examples.

Scheme 2

“Trimethyl lock” derived siderophore-antibiotic conjugates.

Scheme 3

Structures of desferrioxamine B (DFO) and Ciprofloxacin (Cip).

Scheme 4

Synthesis of the potential esterase triggered desferrioxamine-ciprofloxacin conjugate 13. Reagents and conditions: (a) Monobenzyl succinate, DCC, DMAP, CH₂Cl₂, rt (ca. 23 °C), 77%; (b) AcOH:THF:H₂O=3:3:1, rt, 97%; (c) PCC, CH₂Cl₂, rt, 82%; (d) NaClO₂, H₂O₂, NaH₂PO₄, CH₃CN/H₂O, 0 °C-rt, 97%; (e) EDC, HOBt, O-benzyl ciprofloxacin, Et₃N, DMAP, CH₂Cl₂, rt, 70%; (f) Pd/C, H₂ balloon, rt, 86%; (g) EDC, NHS, DMF then DFO mesylate, Et₃N, 47%.

Scheme 5

Synthesis of the potential phosphatase triggered desferrioxamine-ciprofloxacin conjugate 23. Reagents and conditions: (a) TBDMSCl, DBU, CH₂Cl₂, 90%; (b) LiAlH₄, THF, rt-reflux, 51%; (c) NaH, tetrabenzyl pyrophosphate, THF-DMF, 0 °C-rt, 53%; (d) PCC, CH₂Cl₂, rt, 78%; (e) NaClO₂, H₂O₂, NaH₂PO₄, CH₃CN/H₂O, 0°C-rt, 99%; (f) EDC, HOBt, O-benzyl ciprofloxacin, Et₃N, DMAP, CH₂Cl₂, rt, 59%; (g) KF, DMF-H₂O, rt, 74%; (h) EDC, O-benzyl desferri- oxamine succinic acid 24, DMF, rt, 45%; (i) Pd/C, H₂ balloon, THF-H₂O, 35%.

Scheme 6

Synthesis of the desferrioxamine-ciprofloxacin conjugate 26 with a stable linker. Reagents and conditions: (a) EDC, HOBt, O-benzyl ciprofloxacin, Et₃N, DMAP, CH₂Cl₂, rt, 75%; (b) Pd/C, H₂ balloon, MeOH, 82%.