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0011 Pri
0011 Pri
113
Abstract Quinones are important naturally occurring pigments widely distributed in nature and are well known to
demonstrate various physiological activities as antimicrobial and anticancer compounds. This review will focus on the
preparation, therapeutic application, and administration of several benzoquinones, naphthoquinones, and anthraquinones
having anti-infective, e.g. antiviral and antibacterial activities, in recent patents.
Keywords: Benzoquinone, naphthoquinone, anthraquinone, anti-infective, antiviral activity, antibacterial activity, antimalarial
activity, patent.
INTRODUCTION
Infectious diseases have not yet been overcome. The
worldwide death toll is 52 million people a year according to
the estimate by WHO, and a third of them, 17 million
people, die from infectious diseases. It is reported that most
infections around the world are the diarrhea syndrome and 4
billion patients occur every year, those who are infected with
malaria amount to 500 million, and pneumonia attacks 400
million. Considering that the earths population is 6 billion,
such infections are a threat to human. The viruses related to
hepatitis, such as HEV and HCV, and the new infectious
diseases, such as the Ebola virus, Legionella pneumophila,
and human immunodeficiency virus (HIV), have been
discovered in the past 20 years. Furthermore, the appearance
of a multidrug-resistant strain by antibacterial medicine use
is a big factor.
One of the more significant achievements of the 20th
century has been the discovery and commercial development
of numerous therapeutic agents that now provide reliably
effective treatments for many infectious diseases that had
previously caused extensive mortality, morbidity, and fear.
The search for suitable drugs effective for the cure of human
diseases is a continuing process. A number of methods can
be used to perform susceptibility tests with antibacterial
agents in a clinical laboratory setting or for research purpose,
such as assessing the activities of new antimicrobial agents.
These methods include the broth microdilution, disk
diffusion, antibiotic gradient (epsilometer-test), and
automated-instrument methods.
For the antibacterial agents often used, quinone
compounds are tetracyclines, new quinolones, anthraciclines, and mitomycins. More than 2000 naturally occurring
quinones, for example - anthraquinones, naphthoquinones,
and benzoquinones (Fig. 1), are now known and widely
distributed in nature as pigments and as intermediates in
cellular respiration and photosynthesis [1, 2]. Some quinones
have important roles in the biochemistry of energy
*Address correspondence to this author at the Faculty of Pharmaceutical
Sciences, Kobe Pharmaceutical University, Higashinada-ku, Kobe 6588558, Japan; Tel: +81-441-7549; Fax: +81-441-7550;
E-mail: j-koyama@kobepharma-u.ac.jp
1574-891X/06 $100.00+.00
114
Junko Koyama
(1) anthraquinone
(3) 1,4-benzoquinone
(2) 1,4-naphthoquinone
NAD(P)H + H+
NAD(P)
O2
O2
H2O2
O-
115
O
R
R1
O
(5) methyljuglone: R= OH, R1= CH3
R1
O
[Formula B]
116
Junko Koyama
This invention provides antibacterial agents for drugresistant bacteria and antichlamydia agents comprising, as
the effective component, the furanonaphthoquinone derivative (Fig. 4 wherein each R may be the same or different
representing any one of the following a) to e)). These various
compounds may be produced by a variety of known methods
of chemical synthesis [25] or by methods such as the
extraction of naphthoquinones as natural products. For
example, 8-hydroxy-2-methylnaphtho[2,3-b]furan-4,9-dione
(6, FNQ13) was tested for 14 strains of MRSA and 12 strains
of MSSA as the control, and six fluconazole-resistant
Candida albicans (FRCA) and fluconazole-sensitive
Candida albicans (FSCA) as the control. It was found that
the MIC of MRSA was 5.36 g/ml, and MSSA 11.98 g/ml,
indicating that FNQ13 exhibits a stronger antimicrobial
activity against MRSA. FNQ13 exhibits the same degree of
antibacterial activity against the FRCA of Candida albicans
as that against FSCA. Furthermore, antibiotics by
concomitant use with a low concentration of FNQ13
decreases the resistance of MRSA against antibiotics such as
ampicilin, cefaclor, vancomycin, etc., from 1/2 to 1/4.
O
R
R
R
R1
a)
b)
c)
d)
e)
R= -R '
R = -OR '
R= -C OR '
R = -OC OR '
R= -S R'
O
O
R
(6) FN Q 13: R= CH 3, R 1= OH
(7) FN Q 3: R= CH 3, R 1= H
OH
X1
X3
X2
117
X4
X5
A
C
B
H
R1
Y3
Y1
H
R2
Y2
Y5
Y4
H
R3
(10)
(9)
(8)
Y6
OH
OH
Br
(11)
(13)
(12)
OH
Br
OH
Br
Br
O
(14)
(15)
compound
MIC (g/mL)
VRE
MRSA
VanA
VanB
VanC
996
730
664
11
64
64
128
64
64
64
12
13
14
16
32
16
32
64
64
15
16
vancomycin
256
128
16
118
OH
H3CO
OH
O
H3CO
OH
OH
OH
(16) YM187781: R= OH
(17) YM187787: R= H
Junko Koyama
119
Cs2 CO3
CH3CN, rt
6-7 days
R1
OR3
+
R2
HO
O
R3
R1
R2
B
O
(19)
(18)
(20)
Scheme (1).
O
Y
R1
O
R2
R3
O
O-
O
R3
R1
R2
HO
R2
O
(22)
or
R2
O
(23)
(19)
O
X
O
R1
O-
R1
O
Y
or
Crown ether, 1-3 days
(21)
R1
O
R2
R3
O
O
R3
HO
O
(24)
Scheme (2).
120
Junko Koyama
OH
HO
OH
HO
(25) (+)-avarol
(26) (-)-avarol
O
HO
Ph
OH
H
O
N
Compound (29)
O
(27) (+)-avarone
(28) (-)-avarone
R1
O
R2
R7
O
R3
R6
R4
R5
Formula I
Compound (30): R1=R3= OH
R2
R9
R8
R3
R4
R7
R6
R5
Formura II
121
122
Q1
O
Z2
Z1
Junko Koyama
R2
Q2
R2
R1
Q3
R1
Q4
Z1
Z2
R1
R1 7
(31)
R2
R1 6
(32)
Q1
(33)
R 18
Q1
O
Q2
R2
Q3
R1
Q2
R2
Q3
R1
O
Q4 R
16 R17
(35)
(34)
Q1
R 18
O
R2
Q2
Q3
R1
Q3
Q4
R 17
Q1
Q2
O
R2
O
Q4
R1
O
(37)
(36)
Q2
Q1
Q10
Q9
O
Q3
N
Q4
Q8
Q7
O
O
Q5
Q6
(38)
R1
CONHCHCOX
HO
OH
O
R4
CH3
OH
OH
CH3
HO
R 3O
(39)
R2
R1
(CH2)n
Formula III
R2
OH
O
O
Cl
(40) atovaquone
OH
O
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