Synthesis of 4′-aminopantetheine and derivatives to probe aminoglycoside N-6′-acetyltransferase

Abstract

A convenient synthesis of 4'-aminopantetheine from commercial D-pantethine is reported. The amino group was introduced by reductive amination in order to avoid substitution at a sterically congested position. Derivatives of 4'-aminopantetheine were also prepared to evaluate the effect of O-to-N substitution on inhibitors of the resistance-causing enzyme aminoglycoside N-6'-acetyltransferase. The biological results combined with docking studies indicate that in spite of its reported unusual flexibility and ability to adopt different folds, this enzyme is highly specific for AcCoA.

Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds

“…Synthesis of compound 12 d′ : Compound 12 d′ was prepared using a previously reported method with small modifications as detailed below. Boc‐ d ‐alaninol (5.71 mmol, 1 equiv) in wet CH 2 Cl 2 (10 mL) was added to DMP (2.86 mmol, 0.5 equiv).…”

“…Synthesis of compound 12 d':C ompound 12 d' was prepared using ap reviously reported [38] method with small modifications as detailed below.B oc-d-alaninol (5.71 mmol, 1equiv) in wet CH 2 Cl 2 (10 mL) was added to DMP (2.86 mmol, 0.5 equiv). The mixture was stirred at room temperature for 15 min, before another batch of DMP (2.86 mmol, 0.5 equiv) was added and the mixture was stirred for another 15 min.…”

Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

“…28A). 107 Compound 158 was subjected to reductive amination followed by reaction with diketene to yield 159 . The disulfide dimer was reduced in situ by using DTT, and the free thiol generated was subjected to nucleophilic substitution reaction with 160 to yield 161 .…”

Understanding and overcoming aminoglycoside resistance caused by N-6′-acetyltransferase

“…Even the addition of substituents expected to reach into potential hydrophobic binding pockets (see compounds 23a-c) was not sufficient to counter the negative effect of the amide bond. 111 These studies highlight the important contribution of the diphosphate moiety on AAC(6′) inhibition by bisubstrates. Attempts to replace the diphosphate with non-charged mimics have nevertheless produced active molecules, one of which (22a) is the first biologically active molecule in blocking aminoglycoside resistance caused by expression of AAC(6′) in cells.…”

“…Analogues containing mimics of the diphosphate moiety, such as compounds 21a-b, 22a-b and 23a-c were also reported ( Figure 4D). 108,111 It was found that although succinate (see 21b) was a poor mimic of the diphosphate group, malonate (see 21a) and acetoacetate (see 22a) proved to be very good replacements. Even though the in vitro AAC(6′)-Ii inhibition activity of the last two compounds is similar, their potentiation effect on the activity of kanamycin A against a resistant strain of E. faecium, differ largely, and only 22a was found to be biologically active.…”