Antibiofilm Activity of a Diverse Oroidin Library
Generated through Reductive Acylation
T. Eric Ballard, Justin J. Richards, Arianexys Aquino,
Catherine S. Reed, and Christian Melander*
Department of Chemistry, North Carolina State UniVersity,
2620 Yarbrough DriVe, Raleigh, North Carolina 27695
FIGURE 1. Original synthesis of oroidin analogues.
ReceiVed October 10, 2008
for the development of novel small molecules that control
biofilm growth and maintenance (Figure 1).4,8-13
Numerous reports have been disclosed detailing the acylation
step toward the total synthesis of oroidin with yields ranging
from only 13% to 25%.14-17 Other groups have experienced
low yields on other oroidin family members incorporating the
similar architecture of dibrominated pyrrole carboxamide moi-
eties. Toward the synthesis of dimethylbromoageliferin by Ohta
et al., installation of the pyrrole carboxamide proceeded in only
21% even on a methylated 2-aminoimidazole (2-AI) scaffold.18
In the recent synthesis of preaxinellamine, Baran et al. obtained
a 45% yield of the pyrrole carboxamide coupled product.19
Additional syntheses have also suffered from the low-yielding
amide bond formation step.20-22
We envisioned the use of a reductive in situ acylation reaction
on the protected 2-AI azido scaffold 3 (Scheme 1) as a robust
method of constructing diverse molecules with amide bond
directionality identical with the natural products. Although
reductive approaches to acylate 2-AI derived compounds are
A diverse 20-compound library of analogues based on the
marine alkaloid oroidin were synthesized via a reductive
acylation strategy. The final target was then assayed for
inhibition and dispersion activity against common proteo-
bacteria known to form biofilms. This methodology repre-
sents a significant improvement over the generality of known
methods to acylate substrates containing 2-aminoimidazoles
and has the potential to have broad application to the
synthesis of more advanced oroidin family members and their
corresponding analogues.
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Cavanagh, J.; Wozniak, D. J.; Melander, C. Mol. BioSyst. 2008, 4, 614–621.
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Deora, R.; Melander, C. J. Am. Chem. Soc. 2007, 129, 6966–6967.
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J.; Melander, C. Chem. Commun. 2008, 1698–1700.
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Bacterial infections are now known to predominately exist
in a biofilm growth state that confers both enhanced virulence
and defensive properties to the bacterium.1 Biofilms are
responsible for upward of 75% of bacterial infections in the
body making remediation of these infections problematic.2
Bacteria that reside within the biofilm state also are inherently
more resistant to many antibiotics and biocides that would often
lead to their eradication.2,3 Given the breadth of biofilm mediated
infections, there is a significant need for new and potent
antibiofilm modulators.
Oroidin (1) has been previously documented to have moderate
biofilm inhibitory activity against PAO1 and PA14,4 two of the
most commonly studied strains of the γ-proteobacterium Pseudo-
monas aeruginosa. It was also shown that oroidin elicits its
effects through a nonmicrobicidal mechanism; however, the
exact mechanism of action is currently unknown and still under
active investigation. Since naturally occurring biofilm modula-
tors are scarce,5-7 it became a goal to use oroidin as a template
(16) Denanteuil, G.; Ahond, A.; Poupat, C.; Thoison, O.; Potier, P. Bull.
Soc. Chim. Fr. 1986, 813–816.
(17) Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63, 1248–
1253; oroidin was synthesized as reported and matched characterization data. .
(18) Kawasaki, I.; Sakaguchi, N.; Fukushima, N.; Fujioka, N.; Nikaido, F.;
Yamashita, M.; Ohta, S. Tetrahedron Lett. 2002, 43, 4377–4380.
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Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3578–3580.
(20) Foley, L. H.; Buchi, G. J. Am. Chem. Soc. 1982, 104, 1776–1777.
(21) Birman, V. B.; Jiang, X. T. Org. Lett. 2004, 6, 2369–2371.
(22) Baran, P. S.; Zografos, A. L.; O’Malley, D. P. J. Am. Chem. Soc. 2004,
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(4) Richards, J. J.; Ballard, T. E.; Huigens, R. W.; Melander, C. ChemBio-
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10.1021/jo802260t CCC: $40.75
Published on Web 01/08/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1755–1758 1755