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Inhibitors and Inactivators of Aminoglycoside Modifying Enzymes

The synthesis of inhibitors or inactivators of aminoglycoside modifying enzimes is less common than the synthesis of compounds intrinsically active against resistant strains. Neamine has been modified by attaching the a-bromoacetyl group regioselectively at the amino group (Scheme 1) [1-2]. The binding mode of compounds 2-5 was not hampered by the incorporation of the a-bromoacetyl group, that inactivated the (APH(3 )-IIa) enzyme.

Scheme 1. Neamine based inactivators of aminoglycoside modifying enzymes

Another interesting design against APH(3 ) is 3 -ketokanamycin, 6 [3]. The keto group is  in equilibrium with its ketal form (Scheme 2). After phosphorylation catalyzed by APH(3 ), the phosphorylated ketal can be transformed into a keto form by eliminating a dibasic phosphate, and then it can further re-regenerate the ketal. Ketokanamycin modification of APH(3 ) is therefore reversible, in addition,
a molecule of ATP is consumed during the catalytic cycle. As a result, compound 6 may feature multiple antibacterial modes of actions, like binding to rRNA, inhibition of the APH(3 ), and depletion of ATP. The increased activity of 6 against resistant bacteria confirm the validity of this approach.

Scheme 2. Mode of action and antibacterial activity of ketokanamycin

The synthesis and inhibitory activity of 2-NO2 derivatives of neamine and kanamycin has been described (Scheme 3). The 2-NH2 group was selectively oxidized into 2-NO2, which increase the acidity of 2-H. Following phosphorylation at the 3-OH, elimination of phosphate lead to the formation of a nitroalkene intermediate, 14, that can function as a Michael acceptor and inactivate the APH(3 ) by trapping the nucleophilic residue in the aminoglycoside binding site (Scheme 4). Both 2'-nitrokanamycin 12, and 2'-nitroneamine 16, inactivated APH(3).

Scheme 3. Synthesis of 2'-nitrokanamycin

Scheme 4. Mode of action of 2'-nitrokanamycin

Other inhibitors were designed mimiking an ATP-aminoglycoside complex (Figure 1) [5].

Figure 1. ATP-aminoglycoside mimics.

 


1. Roestamadji, J.; Mobashery, S. Bioorg. Med. Chem. Lett. 1998, 8, 34833488.

2. Yang, Y.; Roestamadji, J.; Mobashery, S.; Orlando, R. Bioorg. Med. Chem. Lett. 1998, 8, 34893494.

3. Haddad, J.; Vakulenko, S.; Mobashery, S. J. Am. Chem. Soc. 1999, 121, 1192211923.

4. Roestamadji, J.; Grapsas, I.; Mobashery, S. J. Am. Chem. Soc. 1995, 117, 8084.

5. Liu, M.; Haddad, J.; Azucena, E.; Kotra, L. P.; Kirzhner, M.; Mobashery, S. J. Org. Chem. 2000, 65, 74227431.

 

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