Hydroxamates as carboxylate substitutes in cephalosporins, penicillins
MW Majewski et al
5
Table 3 Spectrum of activity for select compounds against select
S. aureus strains
functionalization of the ionizable position of these important anti-
biotics might be of value in development of much needed alternative
forms of antibiotics.
Zones of growth inhibition (mm)
and MIC (μM, in bold)
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Entry
Compound
SG 511
ISR-001
ISR-002
1
2
1
0.2
6
6
22
ACKNOWLEDGEMENTS
2a
1.6–3
28
We acknowledge the University of Notre Dame, and partial funding from the
NIH (NIH-2R01-AI054193-05A2) for support of this work. We acknowledge
Nonka Sevova (Mass Spectrometry and Proteomics Facility, UND) for mass
spectroscopic analyses and Viktor Krchnak (UND) for LC/MS analysis.
MWM acknowledges an ECK Global Health Fellowship (2014–2015, UND).
6
.0
6.0
3
4
2b
3
3
28
24
1
2.5
12.5
23
1.6
25
2
5
25
5
6
Cloxicillin (Parent Compound)
0.2
o0.1
29
o0.1
29
11
0.4–0.8
0
.4
27
.4
0.4–1.6
28
1
2
Page, M. I. & Jaws, A. P. The chemical reactivity of β-lactams, β-sultams and
β-phospholactams. Tetrahedron 56, 5631–5638 (2000).
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Miller, M. J., DeBons, F. E. & Loudon, G. M. The chemistry of a method for the
determination of carboxyl-terminal residues in peptides. J. Org. Chem. 42, 1750–1762
7
13
1.6
0
0.4–1.6
100
32
8
9
Carbenicillin (Parent Compound)
0.8
100
14
1.6–3
28
3
3
–6
6–12.5
6.25–25
50
1
1
1
1
0
1
2
3
Methicillin
Ampicillin
Cefaclor
3
6.25
25
(
1977).
0.4
6
4
5
6
Brown, L. D., Zygmunt, W. A. & Stavely, H. E. Active derivatives of penicillin. App.
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50
50
Ciprofloxacin
0.2
0.471
43.8
330181119670131.
Lewis, B. A., Sassiver, L. M. & Shepherd, R. G. (American Cyanamid Company)
7-(Phenylacetylamino) Cephalosporin Carboxamides and 7-(Thiophene-2-Acetylamino)
Cephalosporin Carboxamides. US Patent 3641015A19720208.
For diffusion assays, all zones represent 100% inhibition. All wells are not subtracted from
reported zones. Ciprofloxicin tested at a concentration of 1.66 μg ml
−
1
.
7
8
Desikan, P. & Amberg, C. H. Catalytic hydrodesulfurization of thiophene. V. hydro-
thiophenes. selective poisoning and acidity of the catalyst surface. Can. J. Chem. 42,
exhibited MICs in the range of 1.6–6 μM against all three strains, while
the parent compound was seen to be inactive against strains ISR-001
and ISR-002.
To close, we have synthesized a focused set of cephalosporins and
penicillins with hydroxamate replacement of the classical carboxyl
groups. Preliminary biological assessments indicated that several of the
hydroxamates retained broad spectrum activity against Gram-positive
8
43–850 (1964).
Woulfe, S. R.
[3(S)-(acylamino)-2-oxo-1-azetidinyl]oxy] acetic acids. a new class of heteroatom-
&
Miller, M. J. Synthesis and biological activity of substituted
[
activated β-lactam antibiotics. J. Med. Chem. 28, 1447–1453 (1985).
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α-amino acid hydroxamate derivatives. J. Org. Chem 46, 5438–5441 (1981).
0 Sharma, S. K., Miller, M. J. & Payne, S. M. Spermexatin and spermexatol: new
synthetic spermidine-based siderophore analogues. J. Med. Chem 32, 357–367
(1989).
9
1
1
1 Afonin, S. et al. 4-fluorophenylglycine as a label for 19F NMR structure analysis of
membrane-associated peptides. Chem. Bio.Chem 4, 1151–1163 (2003).
2 Murray, P. R., Baron, E. J., Pfaller, M. A., Tenover, F. C. & Yolken, R. H. Manual of
Clinical Microbiology (American Society for Microbiology, Washington, DC, USA, 1999).
(including select MRSA strains) and Gram-negative pathogens.
Further, removal of the acidic proton of the hydroxamate portion
diminished both level of and the spectrum of activity. Thus, further
1
The Journal of Antibiotics