Micelles catalyzed chemoselective synthesis 'in water' and biological evaluation of oxygen containing hetero-1,4-naphthoquinones as potential antifungal agents

Article abstract of DOI:10.1016/j.bmcl.2011.08.095

Various oxygen containing 1,4-naphthoquinone derivatives have been synthesized chemoselectively by an economical, viable green methodology approach using water as solvent with or without surfactants such as Triton X-100, SDS, LD (laundry detergent), and T

Full text of DOI:10.1016/j.bmcl.2011.08.095

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6398–6403
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Micelles catalyzed chemoselective synthesis ‘in water’ and biological
evaluation of oxygen containing hetero-1,4-naphthoquinones as potential
antifungal agents
Vishnu K. Tandon a, , Hardesh K. Maurya a, Nripendra N. Mishra b, Praveen K. Shukla b
⇑
a Department of Chemistry, University of Lucknow, Lucknow 226 007, India
b Division of Fermentation Technology, Central Drug Research Institute, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Various oxygen containing 1,4-naphthoquinone derivatives have been synthesized chemoselectively by
an economical, viable green methodology approach using water as solvent with or without surfactants
such as Triton X-100, SDS, LD (laundry detergent), and TBAB, a phase transfer catalyst and evaluated
for their in vitro antifungal and antibacterial activity. The antifungal profile of 3, 4a, 4b, and 6 indicated
that compounds 3a, 3b, 4b, 6a, and 6c have potent antifungal activity compared to clinically prevalent
antifungal drugs Fluconazole and Amphotericin-B against Sporothrix schenckii, Trichophyton
mentagraphytes, and Candida parapsilosis and compound 3b has been found to be a lead antifungal agent
for further study.
Received 7 May 2011
Revised 6 August 2011
Accepted 24 August 2011
Available online 31 August 2011
Keywords:
Antifungal
Antibacterial
Surfactant
Ó 2011 Elsevier Ltd. All rights reserved.
Sodium dodecyl sulfate (SDS)
2,3-Dichloro-1,4-naphthoquinone
Green chemistry
Phenol
Water
Green chemistry has been currently receiving considerable
attention by major scientific discipline1 and water is a universal
solvent for various syntheses with respect to green chemistry prin-
ciples.2 This has motivated us to develop a green methodology to
synthesize potent biologically active oxygen containing heterocy-
clic 1,4-naphthoquinones using water as an economic solvent hav-
ing environmental safety and societal implications.
exhibited by naturally occurring newbouldiaquinone A (I)9 and
compounds II–IV14,20,21 (Fig. 1), prompted us to explore water as-
sisted syntheses of oxygen containing hetero-1,4-naphthoqui-
nones and study their antimicrobial activity which have not yet
been studied. We report herein a green methodology concept in
quinone chemistry to carry out micelles catalyzed synthesis ‘in
The incidence of fungal and bacterial infections still remains an
important and challenging problem due to combination of factors
including emerging infectious diseases and increase of multi-drug
resistant microbial pathogens.3 The resistance of wide spectrum
antifungal and antibacterial agents prompted us to discover and
develop potent and effective antifungal and antibacterial drugs.4
Due to their redox potentials,5 the various hetero-1,4-naphthoqui-
nones have been found to possess potent antiviral,6 antimolluscid-
al,7 antimalarial,8,9 antileishmanial,10 anticancer,11–14 antibacterial,
and antifungal14–22 activity
O
O
O
O
O
S
HO
Cl
O
O
Newbouldiaquinone A (I) [9]
II
(Natural Product)
O
O
O
We have earlier synthesized various hetero-1,4-naphthoqui-
noes as potent antiviral, anticancer, antiproliferative, antibacterial,
and antifungal agents.14–22 The profound antimicrobial activity
H
N
S
Cl
OH
O
⇑
Corresponding author. Tel.: +91 9415066847; fax: +91 522 2684388.
E-mail addresses: vishnutandon@yahoo.co.in, vishnutandon@rediffmail.com
IV
III
(V.K. Tandon).
Figure 1. Lead antifungal agents I,9 II,14 III,20 and IV.21
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.095

V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6398–6403
6399
Table 1
Reaction of 2,3-dichloro-1,4-naphthoquinone (1) with phenols (2)35
Compounds Base36 Timeb36 Temp
Yields (%)36
in water
using
Yields (%)
Yields (%) in
water using
TBABe
Yields (%) in water using
surfactant Triton X-100e
Mp
(°C)
Yields % (reaction conditions
reported in organic solvent)
°Cb36
‘on water’e
surfactant
LD36 SDS36
3a
3b
3c
3d
3e
3f
3g
4a
4b
6a
6b
6c
Et3Na
N
N
N
Et3N
N
2 h
60
60
60
60
60
60
60
70
70
94
99
84
90
92
92
89
35
40
90
95
75
93
97
83
91
93
90
87
36
42
91
94
73
00
50
45
20
02
40
45
10
11
80
86
60
60
74
71
79
20
81
79
24
26
90
92
78
80
98
86
94
60
92
89
38
43
94
96
79
136
148
112
132
202
108
100
290
182
102
114
154
93 (CsCO3, THF, rt, 76 h)37
30 min
1.5 h
2 h
6 h
5 h
95 (CsCO3, THF, rt, 76 h)37
92 (CsCO3, THF, rt, 76 h)37
d
d
d
d
N
5 h
K2CO3 1 h
K2CO3 1 h
N
N
N
69 (Pyridine, N2, 100 °C, 5-6 h)30
d
d
d
d
30 minc 50
30 minc 50
1 hc
50
a
b
c
1 equiv Et3N used, N = no base used.
Optimized time and temperature by monitoring TLC.
Step 2.
Literature in organic solvents not found.
Reaction condition: base-Et3N, time and temperature as reported in Table 1.
d
e
water’ and biological evaluation of some new potent antifungal
and antibacterial agents.
uct (3) in high yield (Scheme 1 and Table 1) as compared with
other procedures reported26–34 in the organic solvent such as RONa
in EtOH,26,27 MF and Al2O3,28 RONa and ArONa in THF,29a Na2CO3 in
DMSO,29b phenols in pyridine,30,31 alcohols in potassium carbon-
ate,32 phenols and alcohols without solvent.33,34 It is noteworthy
that only 0.5 mol % of surfactant is used which is reusable for fur-
ther reaction and single products are obtained in high yields.
In continuation of our previous work, ‘on water’ assisted syn-
thesis of nitrogen and sulfur containing potent biologically active
hetero-1,4-naphthoquinones.22,23 We earlier carried out reaction
of 2,3-dichloro-1,4-naphthoquinone (1) with oxygen nucleophiles
(2) ‘in water’ using only SDS and LD24 micelles as catalyst.36 Our
previous results ‘on water’ assisted reaction of oxygen nucleophiles
(2) with 2,3-dichloro-1,4-naphthoquinone were disappointing and
it is pertinent to note that unlike nucleophilic substitution reac-
tions with nitrogen and sulfur nucleophiles ‘on water’,21 the nucle-
ophilic substitution reactions with various oxygen nucleophiles did
not proceed in satisfactory yields. In the search of water assisted
syntheses with oxygen nucleophiles, we further explored, the var-
ious reactions of oxygen nucleophiles with 2,3-dichloro-1,4-naph-
thoquinone (1) ‘on water’ with base Et3N and ‘in water’ using
surfactant Triton X-100 in addition to SDS and LD24 as micelles
as well as tetrabutyl ammonium bromide (TBAB, a phase transfer
catalyst). Among the three surfactants employed, laundry deter-
gent (LD24; washing powder) has low cost and is economically
most viable24 as compared to traditional expensive surfactants em-
ployed for various synthetic reactions25 (Table 1). The nucleophilic
substitution reaction in presence of surfactants is highly chemose-
lective leading to formation of exclusively monosubstituted prod-
O
O
O
O
Cl
Cl
Cl
Cl
Ar-OH
HO-Ar
O
O
OAr
Cl
O
Ar
Cl
Cl
OH
O
Aqueous micelles
Atmosphere
Figure 2. Mechanism of nucleophilic substitution of 2,3-dichloro-1,4-naphthoqui-
none (1) with oxygen nucleophiles (2) in aqueous micelles.
R1
O
O
R1
HO
R2
R3
Cl
Cl
0.5 mole% Surfactant
H2O; 60 o
O
R2
R3
O
O
C
Cl
HO
H2O
O
O
Cl
R4
+
O
O
R4
Cl HO
3
2
1
O
1 eq
2h
O
4a
1
2
3
4
3a
: R =R =R =R =H
1
2
3
4
1
2a
: R =R =R =R =H
3b: R1=R2=R4=H; R3=Me
3c: R1=R2=R4=H; R3=OMe
3d: R1=R3=H; R2=R4=Me
2b: R1=R2=R4=H; R3=Me
2c: R1=R2=R4=H; R3=OMe
2d: R1=R3=H; R2=R4=Me
O
Cl
O
1
2
4
3
3e.
R =R =R =H; R =Cl
1
2
4
3
O
O
2e
: R =R =R =H; R =Cl
3f: R3=R4=H; R1=R2=
2f: R3=R4=H; R1=R2=
3g: R1=R4=H; R2=R3=
2g: R1=R4=H; R2=R3=
O
Cl
O
4b
Scheme 1. Chemoselective synthesis of 2-phenoxy-3-chloro-1,4-naphthoquinones
(3): reaction of 2,3-dichloro-1,4-naphthoquinone (1) with phenols (2) ‘on water’
and in water with TBAB and surfactant such as SDS/(LD),36 Triton X-100 (Table 1).
Scheme 2. Reaction of 2,3-dichloro-1,4-naphthoquinone (1) with catechol (2h) ‘on
water’ and in water with TBAB and surfactant such as SDS/laundry detergent (LD),36
Triton X-100.

6400
V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6398–6403
Me
stirring for 1 h in water with 0.5 mol % surfactants in separate
experiments led to isolation of mixture of products
benzo[b]dibenzo[b,e][1,4]dioxine-6,11-dione (4a) and 3,30-(1,2-
phenylenebis(oxy))bis(2-chloro naphthalene-1,4-dione) (4b) as
shown in Scheme 2.
In situ
O
O
O
Step 2
O
X
Cl
Cl
Step 1
i) Et3N, H2O,
0.5 mole% surfactant;
6h, 50oC
In order to further study, the reactivity of adjacent chlorine
atom in compound 3b towards nucleophilic substitution in water,
we explored reaction of 2,3-dichloro-1,4-naphthoquinone (1) first
with 4-methylphenol (2b) (step 1) and after completion, in situ
reaction with thiophenols or aniline (step 2) as shown in Scheme 3.
Thus 2,3-heterodisubstituted products of 1,4-naphthoquinone
can be synthesized in good to excellent yields in water (Table 1)
using laundry detergent (LD24; washing powder) as compared to
disubstituted products synthesized in the presence of excess meth-
anol/ethanol20 or DMSO11 in absence of water in two steps. On
comparison with other surfactants using Triton X-100 and Et3N
as a base leads to comparatively similar yields.
ii) 0.5 mole% surfactant;, H2O
HX
O
1
HO
R
(1 eq)
6
5
R
Me
2b (1 eq)
5a, 6a: X=S, R=H
5b, 6b: X=S, R=Me
5c, 6c: X=NH, R=H
Scheme 3. In situ one-pot synthesis of 6a–c: reaction of 2,3-dichloro-1,4-naph-
thoquinone (1) with 4-methylphenol (2b) and 5 (in situ) ‘on water’ and in water
with TBAB and surfactant such as SDS/laundry detergent (LD),36 Triton X-100
(Table 1).
During last 10 years, we are engaged14–23 discovering new
methodologies for the synthesis of potent antifungal agents con-
taining quinone pharmacophore9,14–23 and in our new endeavors,
we have synthesized various hetero-1,4-naphthoquinones contain-
ing oxygen atom viz 3, 4a, 4b, and 6 by economically viable and
eco-friendly methodology in aqueous micelles using various sur-
factants and evaluated their antifungal activity against a variety
of fungi viz Candida albicans, Cryptococcus neoformans, Sporothrix
schenckii, Trichophyton mentagraphytes, Aspergillus fumigatus, and
Candida parapsilosis by standard micro broth dilution as per
NCCLS38,39 protocol with a view to develop therapeutic agents hav-
ing broad spectrum of antifungal activity.9,14–23,41
However, in spite of the extensive literatures available about
the therapeutic potential of various naphthoquinones, their exact
mode of mechanism as antifungal agents remains obscure.18 Two
key mechanisms have been enunciated for the cytotoxic action of
quinones in various biological systems.41 In the first route, qui-
nones undergo one-electron reduction to semiquinone-free
radicals by electron-transferring flavin enzymes such as NADPH-
cytochrome P450 reductase and mitochondrial NADH-ubiquinone
oxidoreductase. These free radicals are oxidized back to quinones
The role of surfactant in these reactions is to lower the surface
tension of water and increase the collision rate of the reactants.
Surfactants are organic compounds that are amphiphilic in nature
which contain a tail called hydrophobic group and a head called
hydrophilic group. The hydrophobic tail sticks with reactants,
whereas insoluble heavy hydrophilic head settles down into the
water from surface and thus increases the collision of two reac-
tants and makes a favorable condition for reaction ‘in water’ as
compared to reaction ‘on water’ surface;36 Figure 2.
When 2,3-dichloro-1,4-naphthoquinone (1) was stirred with
various phenol derivatives (2) using water as solvent and laundry
detergent24 as surfactant, monosubstituted products were ob-
tained chemoselectively in 83–99% yields as reported in Table 1
(Scheme 1). The reactions carried out with SDS, LD,24 and Triton
X-100 as surfactants under identical conditions result in compara-
tively similar yields and we obtained moderate yields with TBAB, a
phase transfer catalyst. Low yields were obtained in absence of sur-
factant using Et3N as a base at various temperatures and different
duration of time as represented in Table 1.
The reaction of 2,3-dichloro-1,4-naphthoquinone (1) with cate-
chol (2h) (1 equiv) in the presence of K2CO3 (1 equiv) at 70 °C by
Table 2
Structures and in vitro antifungal activity for compounds 3, 4a, 4b, and 6
Compounds
MIC:
lg/mL
C. albicans
C. neoformans
S. schenckii
T. mentagraphytes
A. fumigatus
C. parapsilosis
3a
3b
3c
3d
3e
3f
3g
4a
12.50
6.25b
12.50
12.50
12.50
12.50
>50.00
6.25b
50.00
25.00
25.00
12.50
4.88
6.25
3.12b,c
0.78b,c
1.56b,c
1.56b,c
1.56b,c
1.56b,c
>50.00
0.78b,c
25.00
1.56b,c
3.12b,c
1.56b,c
a
1.56
1.56
a
a
13.20
2.00
a
0.78b,c
1.56b,c
1.56b,c
1.56b,c
1.56b,c
1.56b,c
50.00
1.56b,c
50.00
0.78b,c
1.56b,c
0.78b,c
a
50.00
25.00
50.00
50.00
>50.00
>50.00
50.00
25.00
>50.00
>50.00
>50.00
50.00
a
12.50
3.12c
6.25
3.12c
6.25
12.50
>50.00
3.12c
50.00
12.5
25.00
12.50
a
12.50
12.50
12.50
12.50
25.00
>50.00
12.50
>50.00
12.50
12.50
12.50
a
6.25
0.78
1.56
12.50
3.50
4b
6a
6b
6c
I32,d
II14,d
6.25
1.56
12.5
25.00
7.80
1.56
1.56
0.78
<0.78
a
12.5
3.12
25.00
12.50
a
6.25
6.25
a
a
a
III20,d
IV21,d
Miconazole17
Nystatin17
Fluconazole17
Amphotericin-B17
1.00
0.39
0.50
0.78
1.56
1.56
2.00
a
1.00
a
a
b
c
Activity not reported.
Entries in bold font indicate better activity than reference drug Nystatin.17
Entries in bold font indicate better activity than reference drugs Fluconazole17 and Amphotericin-B.17
See Fig. 1
d

V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6398–6403
6401
activity when compared with Miconazole (MIC50 = 12.50
lg/mL)
against C. neoformans. Compounds 3a, 6a, and 6c (MIC50
=
0.78 g/mL) had shown potent antifungal activity when compared
l
with Miconazole against T. mentagraphytes (Table 2) as exhibited in
Figure 3.
On comparison of antifungal activity with that of antifungal
drug Nystatin (MIC50 = 7.80
(MIC50 = 6.25 g/mL) were found to exhibit better activity against
C. albicans. Compounds 3b, 4a (MIC50 = 0.78 g/mL), 3c–f, 6a, 6c
(MIC50 = 1.56 g/mL), and 3a, 6b (MIC50 = 3.12 g/mL) had better
antifungal profile against S. schenckii on comparison with Nystatin
(MIC50 = 13.20 g/mL) as exhibited in Figure 4.
Compounds 3b, 4a (MIC50 = 0.78 g/mL), and 3c–f, 6a, 6c
(MIC50 = 1.25 g/mL) exhibited extremely potent antifungal activ-
ity when compared with clinically prevalent antifungal drug Fluco-
lg/mL), compounds 3b and 4a
l
l
l
l
l
l
l
Figure 3. Comparative antifungal study plot with Miconazole (MCZ), compounds
and pathogens.
nazole (MIC50 = 2.00
6a, 6c (MIC50 = 0.78
4a, 6b (MIC50 = 1.56
l
l
l
g/mL) against S. schenckii. Compounds 3a,
g/mL) exhibited twofold better and 3b–f,
g/mL) exhibited similar antifungal activity
when compared with clinically prevalent antifungal drugs
Fluconazole (MIC50 = 1.56 g/mL) and Amphotericin-B
(MIC50 = 1.56 mmol/mL) against T. mentagraphytes (Fig. 5).
Compounds 3b, 3d, and 4a (MIC50 = 3.12 g/mL) also exhibited
l
l
twofold better antifungal activity as compared with previously
synthesized antifungal agents II and III (Fig. 1) against C. parapsilo-
sis (MIC50 = 6.25 lg/mL).
Structure–activity relationship of 3a, 3b, 4b, and 6a, 6c com-
pared with compounds II and III revealed that antifungal activity
of compound 3a, 3b, 4b, 6a, and 6c was enhanced by introduction
of oxygen atom in place of sulfur (II) or nitrogen (III) against
S. schenckii, T. mentagraphytes, and C. parapsilosis. Sulfur containing
compound (II and IV), however, had better activity as compared to
Figure. 4. Comparative antifungal study plot with Nystatin (NYS), compounds and
pathogens.
by transferring electrons to O2, generating superoxide anions and
hydrogen peroxide. This reduction and oxidation cycle of quinones
is defined as ‘redox cycling’. It may also lead to glutathione (GSH)
oxidation to GSSG by glutathione peroxidase. The second route is
based upon the action of quinones as potent electrophiles and able
to directly react with thiol groups of proteins and glutathione.
Interaction with GSH forms mono- and diglutathione–hydroqui-
none conjugates that can transfer electrons to O2 and produce
hydrogen peroxide and GSSG–quinone conjugates.41–43 While re-
dox cycling was identified as the main mode of action of plumba-
gin, as deduced by the stoichiometric conversion of GSH to GSSG,
the cytotoxicity of juglone could also be attributed to its nucleo-
philic conjugation with GSH. Similar free-radical-forming mecha-
nisms were also suggested for plumbagin and menadione in
Saccharomyces cerevisiae.41,43 In short the antifungal and antibacte-
rial activity has been shown due to the redox potential of
quinones.44
Figure 5. Comparative antifungal study plot with Fluconazole (FLU), Amphotericin-B
(AMP), compounds and pathogens.
These studies have led to the identification of potent antifungal
agents as lead molecules containing 1,4-quinone pharmacophore.
Subsequently on the basis of structure activity relationship of anti-
fungal activity of the lead oxygen containing hetero-1,4-naphtho-
quinone derivatives (Fig. 1), we further synthesized and screened
antifungal assay of various derivative of 3, 4a, 4b, and 6 as shown
in Table 2.
Comparison of antifungal activity of compounds 3, 4a, 4b, and 6
with that of antifungal drug Miconazole (MIC50 = 25.00
showed that compounds 3b and 4a (MIC50 = 6.25 g/mL) have
fourfold better and compounds 3a and 3c–f (MIC50 = 12.50
g/mL) twofold better antifungal activity against C. albicans. Com-
pound 3a (MIC50 = 6.25 g/mL) exhibited twofold better antifungal
lg/mL)
l
l
Figure 6. Comparative antifungal study plot of oxygen (3b), sulfur (II) and nitrogen
(III) containing compounds against antifungal pathogens.
l

6402
V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6398–6403
Table 3
Structures and in vitro antibacterial activity for compounds 3, 4a, 4b, and 6
Compounds
MIC: lg/mL
E. coli
S. aureus
P. aeruginosa
K. pneumonia
3a
3b
3c
3d
3e
3f
3g
4a
4b
6a
6b
6c
>50.00
25.00
>50.00
50.00
>50.00
50.00
>50.00
50.00
>50.00
>50.00
>50.00
50.00
16.00
1.00
50.00
12.50a
50.00
25.00
50.00
25.00
>50.00
25.00
>50.00
25.00
12.50a
50.00
2.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>128
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
>50.00
32
Kanamycin17
Amikacin17
Tobramycin17
Gentamicin17
16.00
0.25
0.78
2.0
4.0
0.78
1.0
1.0
0.39
0.50
0.18
a
Entries indicate better activity than reference drugs Amikacin.17
2. Li, C. J.; Chen, L. Chem. Soc. Rev. 2006, 35, 68.
oxygen containing compounds (3, 4a, 4b, and 6) against C. albicans,
C. neoformans, and A. fumigatus (Fig. 6).
3. (a) Rice, L. B. Biochem. Pharmacol. 2006, 71, 991; Todar’s online Textbook of
Bacteriology. http://www.textbookofbacteriology.net/; (c) Peara, S.; Patterson,
T. F. Clin. Infect. Dis. 2002, 35, 1073.
4. (a) Kauffman, C. A.; Malani, A. N.; Easley, C.; Kirkpatrick, P. In Nature Reviews
Drug Discovery; Kirkpatrick, P. C., Ed.; Nature Publishing Group: London, 2007;
Vol. 6, p 183; (b) Kresse, H.; Belsey, M. J.; Rouini, H. In Nature Reviews Drug
Discovery; Kirkpatrick, P. C., Ed.; Nature Publishing Group: London, 2007; Vol. 6,
p 19.
5. (a) Gutierrez, P. l. Free Radical Biol. Med. 1989, 6, 405; (b) Tudor, G.; Gutierrez,
P.; Aguilera-Gutierrez, A.; Ville, E. A. S. Bio. Chem. Pharmacol. 2003, 65, 1061.
6. Ganapaty, S.; Thomas, P. S.; Karagianis, G.; Waterman, P. G.; Brun, R.
Phytochemistry 2006, 67, 1950.
7. Silva, T. M. S.; Camara, C. S.; Barbosa, T. P.; Soares, A. Z.; da Cunha, L. C.; Pinto, A.
C.; Vargas, M. D. Bioorg. Med. Chem. 2005, 13, 193.
Based on the antibacterial action of 1,4-naphthoquinones9 and
our previous work,14–22 antibacterial activity of 3, 4a, 4b, and 6
were elucidated against Escherichia coli, Staphylococcus aureus
(ATCC25923), Klebsiella pneumoniae (ATCC 27736), and Pseudomo-
nas aeruginosa by standard micro-broth dilution as per NCCLS38,39
protocol as shown in Table 3.
Comparison of antibacterial activity with that of antibacterial
drug Amikacin (MIC50 = 16.00
lg/mL) showed that compounds 3b
and 6b (MIC50 = 12.50 g/mL) had better antibacterial activity
l
against S. aureus (ATCC25923). Compound 3, 4a, 4b, and 6 were
also screened against P. aeruginosa and K. pneumoniae at
8. Biot, C.; Bauer, H.; Schirmer, R. H.; Davioud-Charret, E. J. Med. Chem. 2004, 47,
5972.
9. Eyong, K. O.; Folefoc, G. N.; Kuete, V.; Beng, V. P.; Krohn, K.; Hussain, H.;
Nkengfack, A. E.; Saeftel, M.; Sarite, S. R.; Hoerauf, A. Phytochemistry 2006, 67,
605.
10. Mantyla, A.; GarnierRautio, J. T.; Nevalainen, T.; Vepsalainen, J.; Koskinen, A.;
Croft, S. I.; Jarvinen, T. J. Med. Chem. 2004, 47, 188.
11. Miguel del Corral, J. M.; Castro, M. A.; Gordaliza, M.; Martín, M. L.; Gamito, A.
M.; Cuevas, C.; Feliciano, A. S. Bioorg. Med. Chem. 2006, 14, 2816.
12. Ryu, C.-K.; Jeong, H.-J.; Lee, S. K.; Kang, H.-Y.; Ko, K.-M.; Sun, Y.-J.; Song, E.-H.;
Hur, Y. H.; Lee, C.-O. Arch. Pharmacol. Res. 2000, 23, 554.
13. Ryu, C.-K.; Kang, H.-Y.; Lee, S.-K.; Nam, K. A.; Hong, C. Y.; Ko, W.-G.; Lee, B.-H.
Bioorg. Med. Chem. Lett. 2000, 10, 461.
14. Tandon, V. K.; Maurya, H. K.; Tripathi, A.; ShivaKesva, G. B.; Shukla, P. K.;
Srivastava, A.; Panda, D. Eur. J. Med. Chem. 2009, 44, 1086.
15. Tandon, V. K.; Maurya, H. K.; Yadav, D. B.; Tripathi, A.; Kumar, M.; Shukla, P. K.
Bioorg. Med. Chem. Lett. 2006, 16, 5883.
16. Tandon, V. K.; Yadav, D. B.; Maurya, H. K.; Chaturvedi, A. K.; Shukla, P. K. Bioorg.
Med. Chem. 2006, 14, 6120.
17. Tandon, V. K.; Yadav, D. B.; Singh, R. V.; Chaturvedi, A. K.; Shukla, P. K. Bioorg.
Med. Chem. Lett. 2005, 15, 5324.
18. Tandon, V. K.; Chhor, R. B.; Singh, R. V.; Rai, S.; Yadav, D. B. Bioorg. Med. Chem.
Lett. 2004, 14, 1079.
19. Tandon, V. K.; Yadav, D. B.; Singh, R. V.; Vaish, M.; Chaturvedi, A. K.; Shukla, P.
K. Bioorg. Med. Chem. Lett. 2005, 15, 3463.
MIC50 = 50.0 lg/mL but did not exhibit significant antibacterial
activity. Structure–activity relationship of 3, 4a, 4b, and 6 revealed
that methyl group containing analogs 3b and 6b had better anti-
bacterial activity.
In conclusion, we have synthesized a series of oxygen contain-
ing hetero-1,4-naphthoquinone 3, 4a, 4b, and 6 by a green method-
ology approach using water as
a solvent with or without
surfactants such as Triton X-100, SDS, LD, and TBAB, a phase trans-
fer catalyst. The derivatives 3, 4a, 4b, and 6 have been evaluated for
their antifungal activity. The antifungal profile of 3, 4a, 4b, and 6
indicated that compounds 3a–b, 4b, 6a, and 6c have potent anti-
fungal activity compared to clinically prevalent antifungal drugs
Fluconazole and Amphotericin-B against S. schenckii, T. mentagra-
phytes and C. parapsilosis. Compound 3b is a lead drug candidate
and further work is being carried out at Central Drug Research
Institute, Lucknow, India concerning its toxicological evaluation.
Our efforts have paved way to synthesize more potent and effec-
tive drug candidates containing oxygen atom in quinone pharma-
cophore using economical viable and green methodology
approach in aqueous micelles.
20. Tandon, V. K.; Maurya, H. K.; Mishra, N. N.; Shukla, P. K. Eur. J. Med. Chem. 2009,
44, 3130.
21. Tandon, V. K.; Singh, R. B.; Yadav, D. B. Bioorg. Med. Chem. Lett. 2004, 14, 2901.
22. Tandon, V. K.; Maurya, H. K.; Verma, M. K.; Kumar, R.; Shukla, P. K. Eur. J. Med.
Chem. 2010, 45, 2418.
Acknowledgments
23. Tandon, V. K.; Maurya, H. K. Tetrahedron Lett. 2009, 50, 5896.
24. LD is
a common laundry detergent (common washing powder used for
washing of cloths in home) which contains alkylbenzenesulfonates.40 It is
economical more viable than SDS, triton X-100 or other surfactants. Therefore,
in place of SDS or triton X-100 and other costly surfactant, we prefer to use LD
as surfactant. laundry detergent (LD, washing powder) used as surfactant is
Ariel, detergent product made in India by Proctor and Gramble Home Products
Ltd, Mumbai 400 099 (Tel.: +91 22 24942113, e-mail: intouch.lm@pg.com) No.:
4902430214933, MRP: Rs. 2.00, Packed 03/2009, net weight: 14 g. while the
cost of SDS is Rs. 1123.00 for 25 g in the catalog of Sigma–Aldrich (436143-
25G)-2008. In place of Ariel, other laundry detergent (washing powder) can
also used.36
We thank Director, SAIF of Central Drug Research Institute, Luc-
know, India for spectral and biological data reported in the manu-
script. H.K.M. thanks C.S.I.R. (Project No. 01(2280)/08/EMR-II), New
Delhi, India for award of research associate fellowship.
References and notes
1. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563; (b) Herrerias, C. I.;
Yao, X.; Li, Z.; Li, C.-J. Chem. Rev. 2007, 107, 2546.
25. Shiri, M.; Zolfigol, M. A. Tetrahedron 2009, 65, 587.

V. K. Tandon et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6398–6403
6403
26. Valderrama, J. A.; Gonzalez, M. F.; Torres, C. Heterocyles 2003, 60, 2343.
27. Sarhan, A. E.-W. A. O.; El-Dean, A. M. K.; Abdel-Monem, M. I. Monatshefte fuer
Chemie 1998, 129, 205.
28. Anufriev, V. P.; Novikov, V. L. Tetrahedron Lett. 1995, 36, 2515.
29. (a) Lien, J.-C.; Huang, L.-J.; Teng, C.-M.; Wang, J.-P.; Kuo, S.-C. Chem. Pharm. Bull.
2002, 50, 672; (b) Chang, H.-X.; Chou, T. C.; Savaraj, N.; Liu, L. F.; Yu, C.; Cheng,
C. C. J. Med. Chem. 1999, 42, 405.
30. Czekanski, T.; Hanack, M. J. Org. Chem. 1991, 56, 1569.
31. Ishikawa, S.; Hinoshita, H.; Tagaki, M.; Ueno, K. Nippon Kagaku Kaishi 1988, 5,
743.
32. Valderrama, J. A.; Leiva, H.; Rodriguez, J. A.; Theoduloz, C. G.; Schmeda-
Hirshmann Bioorg. Med. Chem. 2008, 16, 3687.
Calcd for C26H12Cl2O6: 391.0089 (M+H)+; found: 391.0071; Anal. Calcd for
26H12Cl2O6: C, 63.43; H, 2.66. Found: C, 63.24; H, 4.62; (c) Representative
C
procedure for synthesis of 6: 1 mmol phenol (2) was added to 5 mL aqueous
suspension of surfactant (0.5 mol %). After stirring for 5 min, 2,3-dichloro-1,4-
naphthoquinone 1 (1 mmol) was added and stirred at room temperature or at
temperatures shown in Table 1 and after monitoring TLC, added thiol or amine
(1 mmol) and stirred at room temperature or at temperatures shown in Table
1. Residue was filtered and dried followed by column chromatography (if
required) in hexane/EtOAc (30:1 ? 0:100) to yield products 6; 2-(p-tolyloxy)-
3-(p-tolylthio)naphthalene-1,4-dione (6b): red solid; IR (KBr): 1590 and 1666
(>C@O of quinone); 1H NMR (300 MHz, CDCl3): d 2.32 (s, 3H, Me), 2.33 (s, 3H,
Me), 6.90 (m, 2H, Ph), 6.98 (m, 1H, Ph), 7.11 (m, 3H, Ph), 7.30 (m, 2H, Ph), 7.65
(m, 1H, quinone), 7.77 (m, 1H, quinone), 7.96 (m, 1H, quinone), 8.03 (m, 2H,
quinone); ESI-MS: m/z: 387 (M+H)+; HRMS-ESI Calcd for C24H18O3S: 387.1055
(M+H)+; found: 387.1049; Anal. Calcd for C24H18O3S: C, 74.59; H, 4.69; S, 8.30.
Found: C, 74.74; H, 4.67; S, 8.18.
33. Musso, H. Angew. Chem., Int. Ed. Engl. 1963, 2, 723.
34. Mueller, P.; Venakis, T.; Eugster, C. H. Helv. Chim. Acta. 1979, 62, 2350;
Knoevenagel, E.; Bueckel, C. Ber. Dtsch. Chem. Ges. 1901, 34, 3993.
35. (a) Representative procedure for synthesis of 3: 1 mmol phenol (2) was added to
5 mL aqueous suspension of surfactant (0.5 mol). After stirring for 5 min, 2,3-
36. Tandon, V. K.; Maurya, H. K. Tetrahedron Lett. 2010, 51, 3843.
37. Lee, D.-M.; Ko, J. H.; Lee, K. I. Monatshefte für Chemie 2007, 138, 741.
38. National Committee for Clinical Laboratory Standard. Reference method for
broth dilution antifungal susceptibility testing of yeast, approved standard.
Document M27-A. National Committee for Clinical Laboratory Standards,
Wayne, PA, USA, 1997.
39. National Committee for Clinical Laboratory Standard. Reference method for
broth dilution antifungal susceptibility testing of conidium forming
filamentous fungi: proposed standard. Document M38-P. National
Committee for Clinical Laboratory Standard, Wayne, PA, USA, 1998.
40. For detail refer to: http://en.wikipedia.org/wiki/Laundry_detergent.
41. Eilenberg, H.; Pnini-Cohen, S.; Rahamim, Y.; Sionov, E.; Segal, E.; Carmeli, S.;
Zilberstein, A. J. Exp. Bot. 2010, 61, 911.
dichloro-1,4-naphthoquinone
1 (1 mmol) was added and stirred at room
temperature or at temperatures shown in Table 1. Residue was filtered and
dried followed by column chromatography (if required) in hexane/EtOAc
(50:1 ? 0:100)
to
yield
products
3;
2-chloro-3-(3,5-
dimethylphenoxy)naphthalene-1,4-dione (3d) red solid; IR (KBr): 1587 and
1678 (>C@O of quinone); 1H NMR (300 MHz, CDCl3): d 2.30 (s, 6H, 2xMe), 6.64
(s, 2H, Ph), 6.79 (s, 1H, Ph), 7.82 (m, 2H, quinone), 8.21 (m, 2H, quinone); ESI-
MS: m/z: 313 (M+H)+; HRMS-ESI Calcd for C18H13ClO3: 313.0587 (M+H)+;
found: 313.0579; Anal. Calcd for C18H13ClO3: C, 69.13; H, 4.19. Found: C, 69.01;
H, 4.09; (b) Representative procedure for synthesis of 4a and 4b: the reaction of
2,3-dichloro-1,4-naphthoquinone (1) with catechol (2h) (1 equiv) in the
presence of K2CO3 (1 equiv) at 70 °C by stirring for 1 h in water with
0.5 mol % surfactant in separate experiments led to isolation of mixture of
products 4a and 4b; benzo[b]dibenzo[b,e][1,4]dioxine-6,11-dione (4a)30 and
3,30-(1,2-phenylenebis(oxy))bis(2-chloronaphthalene-1,4-dione) (4b): red
solid; 1589 and 1667 (>C@O of quinone); 1H NMR (300 MHz, DMSO-d6): d
7.91 (m, 6H), 8.17 (m, 4H), 8.36 (m, 2H); ESI-MS: m/z: 391 (M+H)+; HRMS-ESI
42. Inbaraj, J. J.; Chignell, C. F. Chem. Res. Toxicol. 2004, 17, 55.
43. Castro, F. A.; Mariani, D.; Panek, A. D.; Eleutherio, E. C.; Pereira, M. D. PLoS One
2008, 3, e3999.
44. (a) Gutierrez, P. l. Free Radical Biol. Med. 1989, 6, 405; (b) Tudor, G.; Gutierrez,
P.; Aguilera-Gutierrez, A.; Ville, E. A. S. Biochem. Pharmacol. 2003, 65, 1061.