Research Article
Library Synthesis and Antibacterial Investigation of Cationic
Anthraquinone Analogs
Marina Y. Fosso, Ka Yee Chan, Rylee Gregory, and Cheng-Wei Tom Chang*
Department of Chemistry and Biochemistry, Utah State University, 0300 Old Main Hill, Logan, Utah 84322-0300, United States
*
S Supporting Information
ABSTRACT: We report the parallel synthesis of a series of
novel 4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-
ium chloride salts, which are analogs to cationic anthraquinones.
Three synthetic protocols were examined leading to a convenient
and facile library synthesis of the cationic anthraquinone analogs
that contain double alkyl chains of various lengths (C −C ) at
2
12
N-1 and N-3 positions. The antibacterial activities of these
compounds were evaluated against Gram-positive bacterium Staphylococcus aureus and Gram-negative bacterium Escherichia coli.
The antibacterial activities of these compounds were expected to be associated with the structural features of naphthoquinone,
cation and lypophilic alkyl chain and, interestingly, they showed much higher levels of antibacterial activities against G+ than G−
bacteria. In addition, when the total number of carbon atoms of the alkyl groups at both N-1 and N-3 positions lies between 9
and 18, the bactericidal activity against S. aureus increased with increasing alkyl chain length at both N-atoms with MIC ≤ 1 μg/
mL.
KEYWORDS: anthraquinone analogs, Staphylococcus aureus, Escherichia coli, antibacterial activity
INTRODUCTION
recently discovered that a thermodynamically controlled
cycloaddition of 1,4-naphthoquinone (or simply naphthoqui-
none), 1, with azido compounds, followed with an oxidation
using excess naphthoquinone, affords 1-alkyl-1H-naphtho[2,3-
■
The alarming prevalence of drug-resistant bacteria, combined
with the continuous emergence of infectious diseases, has
triggered a considerable increase in the scope of antibacterial
7
1
−3
d][1,2,3]triazole-4,9-diones (Scheme 1). This simple but
research.
Numerous efforts have been devoted to the
versatile reaction can provide structurally diverse molecules
depending on the order of the addition of the different reagents
or the reaction conditions.
For example, when naphthoquinone 1, sodium azide 2, and
alkyl bromides 3{1}/3{3−5} were allowed to react in DMF in
a one-pot/one-step [3 + 2] cycloaddition, compounds 4{1}/
development of new antibacterial agents and nature often
provides leads that help to guide the discovery of new
antibiotics. Naphthoquinones and anthraquinones are com-
monly found compounds that display a vast range of biological
4
−6
activities.
As part of our research program on the synthesis
of these biologically active molecules, our group has developed
the naphthoquinone derivatives 1-alkyl-1H-naphtho[2,3-d]-
1,2,3]triazole-4,9-diones. The insolubility of these naphtho-
quinone derivatives in aqueous media and thus their non-
availability for biological testing have led us to the discovery of
4
{3−5} were obtained. This method also afforded the
7
byproducts 2-alkyl-2H-naphtho[2,3-d][1,2,3]triazole-4,9-diones
5
provided a one-pot divergent synthesis of both compounds in a
unique and simple fashion, difficulty in separating them arose as
[
7
{1}/5{3−5}(Scheme 1, Method A). Although this protocol
8
a class of cationic anthraquinone analogs. The profound
they displayed almost identical R values on TLC plate and was
antibacterial activity exhibited by some members of this class of
compounds, notably against G+ bacteria, has therefore
prompted us to improve on the preparation of its precursor
f
therefore a major drawback in scaling up this protocol.
To circumvent this problem, we decided to approach the
synthesis of 1-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dio-
nes 4{1−5} in a one-pot/two-step fashion, whereby alkyl
azides 6{1−5} were first prepared in situ by reaction of sodium
azide 2 and alkyl bromides 3{1−5} before being allowed to
react with naphthoquinone 1 (Scheme 1, Method B). To our
surprise, this also gave rise to the byproducts 2-(alkylamino)-
naphthalene-1,4-diones 7{1−5}. It should be noted that several
compounds of chemset 7 have been extensively studied for
1
-alkyl-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione and develop
a parallel synthesis for the library of 1,3-dialkyl-4,9-dioxo-4,9-
dihydro-1H-naphtho[2,3-d][1,2,3]triazol-3-ium chloride salts.
Through the study of the antibacterial activity resulting from
the incorporation of various alkyl groups at the N-1 and N-3
positions, detailed structure−activity relationship can be
elucidated.
RESULTS AND DISCUSSION
,4-Naphthoquinones are unique reagents in organic chemistry,
but the syntheses of their derivatives usually impose the need
for multiple steps and various starting materials. We have
■
1
Received: December 12, 2011
Revised: January 24, 2012
Published: February 10, 2012
9
©
2012 American Chemical Society
231
dx.doi.org/10.1021/co2002075 | ACS Comb. Sci. 2012, 14, 231−235