'On water' assisted synthesis and biological evaluation of nitrogen and sulfur containing hetero-1,4-naphthoquinones as potent antifungal and antibacterial agents

Article abstract of DOI:10.1016/j.ejmech.2010.02.023

2-Chloro-3-(4-methylpiperazin-1-yl)naphthalene-1,4-dione (3a), 2-chloro-3-(pyrrolidin-1-yl)naphthalene-1,4-dione (3b), 2-chloro-3-(piperidin-1-yl)naphthalene-1,4-dione (3c), 2-chloro-3-morpholinonaphthalene-1,4-dione (3d), 2-chloro-3-(2-phenylhydrazinyl)n

Full text of DOI:10.1016/j.ejmech.2010.02.023

European Journal of Medicinal Chemistry 45 (2010) 2418e2426
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
‘On water’ assisted synthesis and biological evaluation of nitrogen and sulfur
containing hetero-1,4-naphthoquinones as potent antifungal and
antibacterial agents
,
a
a
b
b
Vishnu K. Tandon a , Hardesh K. Maurya , Manoj K. Verma , Rohitashw Kumar , Praveen K. Shukla
*
a Department of Chemistry, University of Lucknow, Lucknow 226007, India
b Division of Fermentation Technology, Central Drug Research Institute, Lucknow 226001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Chloro-3-(4-methylpiperazin-1-yl)naphthalene-1,4-dione (3a), 2-chloro-3-(pyrrolidin-1-yl)naphtha-
lene-1,4-dione (3b), 2-chloro-3-(piperidin-1-yl)naphthalene-1,4-dione (3c), 2-chloro-3-morpholinonaph-
thalene-1,4-dione (3d), 2-chloro-3-(2-phenylhydrazinyl)naphthalene-1,4-dione (3e), 2-(allylamino)
-3-chloronaphthalene-1,4-dione (3f), 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)acetic acid
(3g), 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)succinic acid (3h), methyl 2-(3-chloro-1,4-
dioxo-1,4-dihydronaphthalen-2-ylthio)acetate (3i), 2-chloro-3-(2-mercaptoethylthio)naphthalene-1,4-
dione (3j), 3-hydroxy-4-methyl-4H-naphtho[2,3-b][1,4]thiazine-5,10-dione (3k) and compounds 3leq have
been synthesized bya green methodologyapproachusing wateras solvent and evaluated fortheirantifungal
and antibacterial activity. The antifungal profile of 3aen indicated that compounds 3aed, 3j, 3e and 3k have
potent antifungal activity. Amongst the most promising antifungal compounds, 3aeg, 3j, 3k showed better
antifungal activity than clinically prevalent antifungal drugs Fluconazole and Amphotericin-B against Tri-
chophyton mentagraphytes and compounds 3j and 3k have been found to be lead antifungal bicyclic and
tricyclic 1,4-naphthoquinones. Compound 3k also exhibited pronounced antibacterial activity.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 29 October 2009
Received in revised form
6 February 2010
Accepted 8 February 2010
Available online 13 February 2010
Keywords:
On water
Green chemistry
2,3-Dichloro-1,4-naphthoquinone
Quinone
Antifungal
Antibacterial
Fluconazole
1. Introduction
[9], cancer [10,26,31], bacterial and fungal diseases [11e16,27e30],
due to their redox potentials [5].
During last one decade, green chemistry has attracted the major
scientific discipline due to the application of green chemistry prin-
ciples which has led to the development of cleaner and more effi-
cient chemical synthesis [1] and water has contributed as an
important tool in green chemistry being the most versatile solvent
[2]. It has motivated us to develop a green methodology to synthe-
size medicinally important novel heterocyclic quinone derivatives
using water as an economic solvent having environmental safety
and societal implications.
The incidence of fungal and bacterial infections still remains an
important and challenging problem due to combination of factors
including emerging infectious diseases and also due to increase of
multi-drug resistant microbial pathogens [3]. The resistance of
wide spectrum antifungal and antibacterial agents prompted us to
discover and develop new antifungal and antibacterial drugs [4].
The hetero-1,4-naphthoquinones have shown potent biological
affinity towards viral [6], molluscidal [7], malarial [8], leishmanial
We have earlier reported the synthesis of novel hetero-1,4-
naphthoquinoes as potent antiviral, anticancer, antiproliferative,
antibacterial and antifungal agent [10e18]. The profound antifungal
activity exhibited by compounds IeIII (Fig. 1) [14,16,17] prompted
us to envisage ‘on water’ assisted synthesis of new hetero-1,4-
naphthoquinones containing nitrogen and sulfur atoms at 2- and
3-positions of 1,4-naphthoquinone and study their biological
activity. We report herein a green methodology concept in quinone
chemistry to carryout ‘on water’ assisted synthesis and biological
evaluation of some potent antifungal and antibacterial agents.
2. Results and discussion
2.1. Chemistry
It is well known that the reaction of 2,3-dichloro-1,4-naph-
thoquinonewith nucleophilesproceeds bynucleophilicsubstitution
whereas nucleophilic addition reactions of 1,4-naphthoquinones is
augmented by oxidative addition pathway [18]. Based on reactivity
and biological activity of 2,3-dichloro-1,4-naphthoquinones and
* Corresponding author. Tel.: þ919415066847; fax: þ91 522 26848.
E-mail address: vishnutandon@yahoo.co.in (V.K. Tandon).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.02.023

V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
2419
O
O
R
O
O
O
H
N
S
Z
O
Z
Z
O
O
HS
COOR1
X
Y
S
R
2a-d
HN
O
Cl
OH
S
COOR1
H2O
O
Y
Z
O
3g: Z=R=R1=H, Y=Cl
III
1a:
X=Y=Cl, Z=H
I
II
3h: Z=R1=H, R=CH2CO2H, Y=Cl
3i: Z=R=H, R1=Me, Y=Cl
1b: X=Z=H, Y=OH
OMe
O
O
O
O
HS
1
HS
3o:
Z=R=H, R =Et, Y=Cl
Cl
S
S
Ph
2l
S
SH
3p: Z=H, R=Me, R1=Et, Y=Cl
2j
H2O
H2O
Cl
S
O
O
Z
Z
O
Z
Z
O
V [14]
IV[14]
S
S
SH
Fig. 1. Lead antifungal agents I [14], II [17] and III [16].
Y
Y
O
O
1,4-naphthoquinones [10e18], we studied its reactions with
different amines (Scheme 1), thiols (Scheme 2) and intramolecular
nucleophilic additioneelimination and cyclization (Scheme 3) 2aen
in the presence or absence of a base using water as solvent as
reported in Table 1 according to our ‘on water’ assisted synthetic
methodology [18] and evaluated their antifungal and antibacterial
activity.
When 2,3-dichloro-1,4-naphthoquinone (1a) was stirred with
different secondary heterocyclic amines (1.1 equivalent) viz.
1-methylpiperazine (2a), pyrrolidine (2b), piperidine (2c) and
morpholine (2d) [18] at room temperature/50 ꢀC using water as
solvent, mono substituted products; 2-chloro-3-(4-methylpiper-
azin-1-yl)naphthalene-1,4-dione (3a), 2-chloro-3-(pyrrolidin-1-yl)
naphthalene-1,4-dione (3b) [18], 2-chloro-3-(piperidin-1-yl)naph-
thalene-1,4-dione (3c) [18] and 2-chloro-3-morpholinonaph-
thalene-1,4-dione (3d) [18] were obtained respectively in 98e100%
yield as reported in Table 1 (Scheme 1). In order to study the
structureeactivity relationship (SAR) with compounds II (Fig. 1)
and 3aed, 5,8-dihydroxy-2-(4-methylpiperazin-1-yl)naphthalene-
1,4-dione (3m) and 5,8-dihydroxy-2-(pyrrolidin-1-yl)naphthalene-
1,4-dione (3n) were synthesized by the reaction of naphthazarine
(1c) with sec heterocyclic amines (2a,b) respectively as shown in
Scheme 1. The reaction of 1a with phenylhydrazine (2e) led to the
formation of 2-chloro-3-(2-phenylhydrazinyl)naphthalene-1,4-
3j: Z=H, Y=Cl
3l: Z=H, Y=OH
Scheme 2. Reaction of 1,4-naphthoquinones with sulfur nucleophiles in aqueous
medium (For reagents and conditions refer to Table 1).
dione (3e) in 96% yield whereas reaction of 1a with 4-nitro-
phenylhydrazine and 2,4-dinitrophenylhydrazine do not occur in
water due to electron withdrawing inductive effect of nitro group.
The reaction of 1a with prop-2-en-1-amine (2f) resulted in the
formation of 2-(allylamino)-3-chloronaphthalene-1,4-dione (3f) in
100% yield within 15 min in water (Scheme 1). It is pertinent to note
that only mono substituted products are formed as coloured solids
in water when compared with other organic solvents [18].
The reaction of 1a with 2-mercaptoacetic acid (2g) and 2-mer-
captosuccinic acid (2h), have been studied and the products 2-(3-
chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)acetic acid (3g)
and
2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)suc-
cinic acid (3h) respectively were obtained using water as solvent as
reported in Scheme 2 (Table 1) whereas the reaction of 1a with
methyl 2-mercaptoacetate (2i), ethyl 2-mercaptoacetate (2m) and
ethyl 2-mercaptopropionate (2n) in aqueous medium produced
methyl
2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)
acetate (3i), ethyl 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-
ylthio)acetate (3o) and ethyl 2-(3-chloro-1,4-dioxo-1,4-dihy-
dronaphthalen-2-ylthio)propanoate (3p) in excellent yields (Table
1). The reaction of 2,3-dichloro-1,4-naphthoquinone (1a) with
ethane-1,2-dithiol (2j) in water resulted in the formation of
Z
O
Z
O
HN
X
Y
N
Y
2a-d
2-chloro-3-(2-mercaptoethylthio)naphthalene-1,4-dione
(3j)
instead of an expected mixture of 2,3-dihydronaphtho[2,3-b][1,4]
dithiine-5,10-dione (IV) and 3,30-(ethane-1,2-diylbis(sulfanediyl))
bis(2-chloronaphthalene-1,4-dione) (V) [14] (Fig. 1).
Compounds 3i and 3p undergo further intramolecular nucleo-
philic addition-elimination and cyclization with methyl amine 2k
in water to yield 3-hydroxy-4-methyl-4H-naphtho[2,3-b][1,4]
H2O
Z
O
Z
O
3a-d & 3m-n
1a: X=Y=Cl, Z=H
1c:
X=Y=H, Z=OH
H2N
N
H2N
2e
H2O
H
2f
O
H2O
O
S
MeNH2
2k
R
O
S
R
Z
O
O
Z
O
H
N
N
H
H
N
O
N
OH
water
Cl
O
Y
O
Me
R1
Y
3k: R=H
3q: R=Me
Z
1
Z
O
3i:
R=R =H
3p: R=R1=Me
3e: Z=H, Y=Cl
3f : Z=H, Y=Cl
Scheme 1. Reaction of 1,4-naphthoquinones with nitrogen nucleophiles in aqueous
medium (For reagents and conditions refer to Table 1).
Scheme 3. Intramolecular nucleophilic addition-elimination and cyclization of 3i and
3p in aqueous medium (For reagents and conditions refer to Table 1).

2420
V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
Table 1
Reaction conditions of water assisted synthesis of hetero-1,4-naphthoquinone (3aeq).
Entry
1
2
Time
1 h
b
T
Product 3
Mp
Yield%
98%
c
W
A
Me
O
O
N
N
Cl
Cl
HN
N Me
1
N
rt
168
100
Cl
O
O
1a
O
2a
3a
O
Cl
Cl
N
HN
2b
2
10 min
N
rt
80
99%
100
A
Cl
O
1a
O
O
3b [18]
O
Cl
Cl
N
HN
2c
3
10 min
N
rt
150
98%
100
A
Cl
O
O
1a
3c [18]
O
O
O
O
Cl
Cl
N
HN
2d
O
4
20 min
N
50 ꢀC
110
100%
100
A
Cl
O
1a
3d [18]
O
O
O
Cl
Cl
NH NH
H2NHN
2e
5
6
7
4 h
N
50 ꢀC
190
100
98
96%
100
89%
95
100
91
C
A
D
Cl
O
1a
3e [18]
O
O
H
N
Cl
Cl
H2N
30
N
rt
Cl
O
O
2f
1a
3f
O
O
Cl
Cl
S
COOH
HS
HS
COOH
2h
Et3N
50 ꢀC
Cl
2g
O
O
1a
3g
O
O
COOH
COOH
Cl
Cl
S
COOH
COOH
8
9
2 h
Et3N
50 ꢀC
>280
89%
98%
90
D
Cl
O
O
2h
1a
3h
O
O
Cl
Cl
S
COOMe
HS
COOMe
1 h
N
rt
115
100
A
Cl
2i
O
O
1a
3i

V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
2421
W
Table 1 (continued)
Entry
1
2
Time
b
T
Product 3
Mp
Yield%
98%
c
O
O
Cl
Cl
S
SH
SH
HS
10
15 min
N
rt
196
100
A
C
A
Cl
2j
O
O
1a
3j [18]
O
O
S
S
H2NeCH3
70 ꢀC
170
20%
50
COOMe
11
24 h
Et3N
N
OH
Cl
2k
O
CH3
O
3k# [18]
3i
O
O
S
Cl
HS
12
4 h
N
50 ꢀC
160
98
100
OH
OH
O
2l
O
1b
OH
3l [18]
Me
O
OH
OH
O
N
N
HN
N Me
13
3 h
N
rt
>260
68%
100
C
OH
1c
O
O
2a
O
3m
OH
OH
O
N
HN
14
15
16
17
15 min
N
rt
180
98%
100%
93%
100
100
100
45
A
A
A
C
2b
OH
O
OH
O
O
1c
3n [18]
O
Cl
Cl
S
COOEt
COOEt
HS
HS
COOEt
2 h
N
50 ꢀC
96
Cl
2m
O
O
1a
3o [18]
O
O
Cl
Cl
S
COOEt
Me
50 ꢀ
C
83
Me
2h
N
Cl
O
O
2n
1c
3p
O
O
O
S
Me
OH
S
Me
H2NeCH3
50 ꢀC
186
20%
COOEt
24 h
K2CO3
N
Cl
2k
O
CH3
3q# [11]
3p
b: base, N: not required, #other product was not isolated, c: conversion% of 1, W: workup process, A: product directly filtered, B: product filtered as ppt 3, C: product filtered
and purified by column chromatography, D: water was evaporated or extracted with suitable solvent and purified by column chromatography using silica gel in hexane and
ethyl acetate.
thiazine-5,10-dione (3k) and 3-hydroxy-2,4-dimethyl-4H-naphtho
[2,3-b][1,4]thiazine-5,10-dione (3q) as exhibited in Scheme 1.
The structure of 3q has been confirmed by X-ray crystallography
(Fig. 2) [25].
2.2. Antifungal activity
Our laboratory during last five years has been engaged [10e18]
to discover new methodologies for the synthesis of potent

2422
V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
80
60
40
20
0
MCZ, Compounds and Pathogens
MCZ (C. albicance)
3c (C. albicance)
3a (C. albicance)
3j (C. albicance)
3b (C. albicance)
3k (C. albicance)
3e (C. neoformans)
MCZ (A. fumigates)
MCZ (C. neoformans)
3j (C. neoformans)
3k (A. fumigates)
Fig. 2. Crystal structure of 3-Hydroxy-2,4-dimethyl-4H-Naphtho[2,3-b][1,4]-thiazine-
5,10-dione 3q (No. CCDC765321) [25].
Fig. 3. Comparative antifungal study plot with Miconazole (MCZ), compounds and
Pathogens.
antifungal agents containing quinone chromophore [10e18] and in
our new endeavors, we have synthesized different heterocyclic
naphthoquinones containing compounds 3aen using water as
solvent 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 NCCLS
[23,24] protocol with a view to develop therapeutic agents having
broad spectrum of antifungal activity [10e18]. These studies have
led to the identification of potent antifungal agents as lead mole-
cules containing quinone chromophore. Subsequently on the basis
of structureeactivity relationship of antifungal activity of the lead
heterocyclic quinone derivatives, we further synthesized and
screened antifungal assay of 3aen as shown in Table 2.
Comparison ofantifungalactivityofcompounds 3aenwith thatof
antifungal drug Miconazole (MIC50 ¼ 60.08 mmol/mL), showed that
compound 3k (MIC50 ¼ 3.00 mmol/mL), 3a (MIC50 ¼ 5.38 mmol/mL),
3c (MIC50 ¼ 5.66 mmol/mL), 3e (MIC50 ¼ 10.45 mmol/mL), 3j
(MIC50 ¼ 10.96 mmol/mL), 3b (MIC50 ¼ 11.90 mmol/mL), 3d
(MIC50 ¼ 45.04 mmol/mL) and 3f (MIC50 ¼ 50.00 mmol/mL) had
better antifungal activity against C. albicans. Compounds 3e
(MIC50 ¼ 10.45 mmol/mL), 3j (MIC50 ¼ 10.96 mmol/mL), 3k
(MIC50 ¼ 10.96 mmol/mL) and 3aed (MIC50 ¼ 21.5e22.6 mmol/mL)
exhibited better antifungal activity when compared with Miconazole
(MIC50 ¼ 30.04 mmol/mL) against C. neoformans. Compounds 3aec,
3e, 3j and 3k had shown potent antifungal activity when compared
with Miconazole against T. mentagraphytes. Compound 3k
(MIC50
¼
24.10 mmol/mL) had shown promising antifungal
profiles on comparison with antifungal drug Miconazole
(MIC50 ¼ 30.04 mmol/mL) against A. fumigatus; (Table 2) as exhibited
in Fig. 3.
On comparison of antifungal activity with that of antifungal
drug Nystatin (MIC50
¼
8.42 mmol/mL), compound 3k
(MIC50
¼ 3.00 mmol/mL), 3a (MIC50 ¼ 5.38 mmol/mL), 3c
(MIC50 ¼ 5.66 mmol/mL) were found to exhibit better activity
against C. albicans. Compounds 3j (MIC50 ¼ 2.74 mmol/mL), 3e
(MIC50 ¼ 10.45 mmol/mL) and 3a (MIC50 ¼ 10.75 mmol/mL) had
better antifungal profile against S. schenckii on comparison with
Nystatin (MIC50 ¼ 14.25 mmol/mL) as exhibited in Fig. 4.
Table 2
Structures and in vitro antifungal activity for compounds 3aeq.
Compounds
MIC: mmol/mL
C. albicans
C. neoformans
S. schenckii
T. mentagraphytes
A. fumigatus
C. parapsilosis
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o [11]
3p [11]
5.38b
11.90b
5.66b
21.54
23.85
22.69
22.52
10.45b
50.50
88.50
146.74
168.50
10.96b
24.10
>177.11
>73.43
>192.86
40.22
38.49
11.42
30.04
3.78
10.75b
23.85
22.69
1.34b,c
1.49b,c
1.42b,c
2.81b,c
1.31b,c
3.15b,c
5.52b
43.09
95.39
90.74
90.09
41.88
101.01
176.99
146.74
168.50
87.79
21.54
23.85
11.32b
22.52
45.04
22.52
10.45b
50.50
10.45b
50.50
20.94
50.50
88.50
88.50
88.50
73.37
>146.74
>168.50
10.96b
3.00b
177.11
>173.43
>192.86
>160.90
>153.95
22.87
36.68
42.12
146.74
168.50
43.89
168.50
2.74b,c
24.10
>177.11
173.43
>192.86
80.45
1.37b,c
3.00b,c
177.11
>173.43
96.43
24.10
6.02b
>177.11
173.43
>192.86
>160.90
>153.95
22.87
>177.11
173.43
>192.86
>160.90
>153.95
>160.90
>153.95
5.71
76.98
3q [11]
11.42
45.74
a
a
Miconazole [13]
Nystatin [13]
Fluconazole [13]
Amphotericin-B [13]
60.08
8.42
3.26
0.42
<1.87
30.04
a
a
a
14.25
1.63
0.84
6.53
5.09
1.69
6.53
3.26
a
a
a
a
Activity not reported.
b
Entries in bold font indicate better activity than reference drugs Miconazole [13] and/ or Nystatin [13].
Entries in bold font indicate better activity than reference drugs Fluconazole [13] and Amphotericin-B [13].
c

V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
2423
Table 3
Structures and in vitro antibacterial activity for compounds 3aeq.
15
10
5
Compounds
MIC: mmol/mL
E. coli
S. aureus
K. pneumoniae
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o [11]
3p [11]
43.09
47.69
43.37
45.04
83.75
101.01
44.25
36.68
42.12
87.79
24.10
88.56
173.43
192.86
40.22
38.49
5.71
43.09
95.39
90.74
180.18
83.75
101.01
44.25
146.74
42.12
43.89
3.00
177.11
173.43
192.86
40.22
38.49
11.42
4.13
21.54
95.39
90.74
22.52
83.75
25.25
22.12
4.58
0
NYS, Compounds and Pathogens
3a (C. albicans)
NYS (C. albicans)
3c (C. albicans)
NYS (S. schenckii)
3j (S. schenckii)
42.12
21.95
3.00
3k (C.albicans)
3a (S. schenckii)
3e (S. schenckii)
177.11
173.43
192.86
160.90
153.95
11.42
66.05
1.71
Fig. 4. Comparative antifungal study plot with Nystatin (NYS), compounds and
Pathogens.
3q [11]
Kanamycin [13]
Amikacin [13]
Tobramycin [13]
Gentamicin [13]
33.02
1.71
1.07
Compounds 3aef, 3j, 3k (MIC50 ¼ 1.32e3.15 mmol/mL) had
27.32
0.53
1.63
2.14
0.82
exhibited extremely potent antifungal activity compared with
0.38
clinically
(MIC50
prevalent
antifungal
drugs
Fluconazole
¼
5.09 mmol/mL) and compounds 3aec, 3e, 3j
(MIC50 ¼ 1.32e1.49 mmol/mL) compared with Amphotericin-B
(MIC50 ¼ 1.69 mmol/mL) against T. mentagraphytes. Compounds 3k
had also exhibited better activity than clinically prevalent anti-
fungal drug Fluconazole against C. albicans and S. schenckii
respectively (Fig. 5).
3aen was elucidated against Escherichia coli, Staphylococcus aureus
(ATCC25923), Klebsiella Pneumoniae (ATCC 27736) and Pseudo-
monas aeruginosa parapsilosis by standard micro broth dilution as
per NCCLS [23,24] protocol as shown in Table 3.
Comparison of antibacterial activity with that of antibacterial
Compounds 3k and 3c were also shown to posses pronounced
antifungal activity MIC50 ¼ 6.02 mmol/mL and MIC50 ¼ 11.32 mmol/
mL against C. parapsilosis respectively.
drug Kanamycin (MIC50
¼
33.02 mmol/mL) showed that
compounds 3k (MIC50 ¼ 24.10 mmol/mL) had better activity
against E. coli. Compound 3k (MIC50 ¼ 3.00 mmol/mL) exhibited
Structure activity relationship of 3aen revealed that mono
substituted secondary heterocyclic amines 3aed, ethane-1,2-
dithiol derivative 3j and cyclic analogs 3k of 1,4-naphthoquinone
possess potent antifungal activity when compared with aliphatic
acids 3g, 3h, ester 3i aryl thiol 3l. Comparative results have shown
that free thiol group in 3j is an important factor to exhibit potent
antifungal activity. The withdrawals of alkylating group in cyclic
analog 3q (Scheme 3 & Table 2) [11] results in slight increase of
antifungal activity of compound 3k.
better
activity
when
compared
with
Kanamycin
(MIC50 ¼ 4.13 mmol/mL) against S. aureus (ATCC25923). Compound
3k (MIC50 ¼ 3.00 mmol/mL), 3h (MIC50 ¼ 4.58 mmol/mL), 3a, 3d,
3f, 3g, 3j and 3i also exhibited better activity than Kanamycin
againest Klebsiella Pneumoniae (ATCC 27736).
Compound 3k (MIC50 ¼ 3.00 mmol/mL) had better activity than
antibacterial drug Amikacin against S. aureus (ATCC25923).
Compound 3aen were also screened against Pseudomonas aerugi-
nosa at MIC50 ¼ 50.0
mg/mL but did not exhibit significant anti-
bacterial activity (Fig. 6).
2.3. Antibacterial activity
Structure activity relationship of 3aen revealed that cyclic
analog 3k has better antibacterial activity as compared to acyclic
mono substituted amino and thiols derivatives of quinone (3aej, 3l)
Based on mechanism of the antibacterial action of quinones
[19e21] and our previous work [10e17], antibacterial activity of
8
6
4
2
70
60
50
40
30
20
10
0
FLU, AMP, Compounds and Pathogens
FLU (C. albicans)
3k (C. albicans)
0
KAN, AMI, TOB, Compounds and Pathogens
FLU (S. Schenckii)
3j (S. Schenckii)
FLU (T. mentagraphytes)
3b (T. mentagraphytes)
3e (T. mentagraphytes)
3k (T. mentagraphytes)
AMP (T. mentagraphytes)
3c (T. mentagraphytes)
3f (T. mentagraphytes)
3a (T. mentagraphytes)
3d (T. mentagraphytes)
3j (T. mentagraphytes)
KAN (E. coli)
3k (E. coli)
KAN (S. aureus)
AMI (S. aureus)
KAN (K. pneumoniae)
3k (S. aureus)
3h (K. pneumoniae)
3k (K. pneumoniae)
Fig. 5. Comparative antifungal study plot with compounds and Fluconazole (MCZ),
Fig. 6. Comparative antibacterial study plot with Kanamycin (KAN), Amikacin (AMI),
Amphotericin-B (AMP), compounds and Pathogens.
Tobramycin (TOB), compounds and pathogens.

2424
V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
3. Conclusion
(Mþ, 100%), 263.09 (Mþ þ 1, 25%), 264.09 (Mþ þ 2, 33%); Anal. Calcd
C14H12ClNO2: C, 64.25; H, 4.62; N, 5.35. Found: C, 64.16; H, 4.56; N,
5.31; Beilstein test [22]: Cl positive.
In conclusion, we are the first to synthesize amino and thiol
derivatives of 1,4-naphthoquinone 3aeq by a green methodology
approach using water as solvent. The derivatives 3aen have been
evaluated for their antifungal activity. The antifungal profile of
3aen indicated that compounds 3aed, 3j, 3e and 3k have potent
antifungal activity. Amongst the most promising antifungal
compounds, 3aeg, 3j, 3k exhibited better antifungal activity than
clinically prevalent antifungal drugs, Fluconazole and Amphoter-
icin-B against T. mentagraphytes. Compound 3j is lead compound as
potent antifungal agent and compound 3k exhibited promising
antibacterial activity. Compounds 3j and 3k are the lead drug
candidates and further work is being carryout at Central Drug
Research Institute, Lucknow, India concerning its toxicological
evaluation. Efforts are paving way to synthesize more potent bio-
logically active derivatives containing quinone chromophore using
a green methodology approach.
4.2.3. 2-Chloro-3-(piperidin-1-yl)naphthalene-1,4-dione (3c)
Orange powder; IR (KBr): 1585 and 1642 (pC]O of quinone)
cmꢁ1 1H NMR (300 MHz, CDCl3): 1.59 (m, 6H, CH2CH2CH2), 2.96
;
(m, 4H, NCH2), 7.88 (m, 2H, C5eH and C8eH), 8.05 (m, 2H, C6eH and
C7eH); Mass (ESI): 275.01 (Mþ); Anal. Calcd C15H14ClNO2: C, 65.34;
H, 5.12; N, 5.08. Found: C, 65.22; H, 5.05; N, 5.03; Beilstein test [22]:
Cl positive.
4.2.4. 2-Chloro-3-morpholinonaphthalene-1,4-dione (3d)
Orange powder; IR (KBr,): 1581 and 1649 (pC]O of quinone)
cmꢁ1; 1H NMR (300 MHz, CDCl3): 3.62 (t, 4H, J ¼ 4.8 Hz, NCH2), 3.82
(t, 4H, J ¼ 4.8 Hz, OCH2), 7.68e7.73 (m, 2H, C5eH and C8eH), 8.01
(dd, 1H, J ¼ 8.2 and 1.8 Hz, C7), 8.11 (dd, 1H, J ¼ 8.2 and 1.8 Hz, C6);
Mass (ESI): 277.05 (Mþ); Anal. Calcd (C14H12ClNO3): C 60.55, H 4.36,
N 5.04. Found: C 60.32, H 4.49, N 5.16; Beilstein test [22]: Cl
positive.
4. Experimental
4.1. Materials and methods
4.2.5. 2-Chloro-3-(2-phenylhydrazinyl)naphthalene-1,4-dione (3e)
Red powder; IR (KBr): 3442 and 3388 (NH),1660 and 1585 (pC]
The reagents and the solvents used in this study were of
analytical grade and were used without further purification. The
melting points were determined on an electrically heated Townson
Mercer melting point apparatus and are uncorrected. IR spectra
were recorded on FTIR 8201 PC, Schimadzu Spectrophotometers on
KBr discs. Nuclear Magnetic Resonance (NMR) spectra were recor-
ded on PerkineElmer model R.32 spectrometers using TMS as an
internal reference. All compounds showed satisfactory elemental
analysis for C, H, N and S. Progress of reactions and purity of
compounds were monitored by thin layer chromatography (TLC),
which was performed on silica gel G and compounds were detected
with UV Chamber, where required. Spectra facilities and elemental
micro-analyses were carried out by SAIF division of Central Drug
Research Institute, Lucknow, India. Most reagents were purchased
from Lancaster, SigmaeAldrich and Merck.
O of quinone) cmꢁ1; 1H NMR (CDCl3):
d 3.07 (bs, 1H, NH), 5.00 (bs,
1H, NH), 6.98e7.09 (m, 3H, phenyl), 7.47 (m, 2H, Phenyl), 7.86 (m,
2H, C5eH and C8eH), 8.05 (m, 2H, C6eH and C7eH); Mass (ESI):
298.05 (Mþ); Anal. Calcd for C16H11ClN2O2: C, 64.33; H, 3.71; N,
9.38. Found: C, 64.18; H, 3.68; N, 9.27; Beilstein test [22]: Cl positive.
4.2.6. 2-(Allylamino)-3-chloronaphthalene-1,4-dione (3f)
Red powder; IR (KBr): 3430 (NH), 1589 and 1665 (pC]O of
quinone) cmꢁ1; 1H NMR (300 MHz, CDCl3):
d
3.85 (d, J ¼ 4.8 Hz, 2H,
NCH2), 5.28e5.30 (m, 2H, CH2CH), 5.93 (m,1H, CH2CH), 6.06 (bs,1H,
NH); 7.98 (m, 2H, C5eH and C8eH), 8.17 (m, 2H, C6eH and C7eH);
Mass (ESI): 247.04 (Mþ); Anal. Calcd for C13H10ClNO2: C, 63.04; H,
4.07; N, 5.66; Found: C, 63.15; H, 4.10; N, 5.68; Beilstein test [22]: Cl
positive.
4.2.7. 2-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)
acetic acid (3g)
4.2. General procedure for the synthesis of hetero-1,4-
naphthoquinones (3aeq)
Red powder; IR (KBr): 3421 (OH), 2920 (SCH2), 2852 (SCH2),
1736 (pC]O of COOH), 1658 and 1466 (C]O of quinone) cmꢁ1; 1H
Suspension of quinone 1 (1.0 mmol) in water (6 mL) and sec
heterocyclic amines, aliphatic amines, hydrazines, thioacids or
thiols (solid, 1.0 mmol or liquid, 1.1 mmol) 2 was stirred at room
temperature or 50e70 ꢀC for 10 min to 24 h. and workup was fol-
lowed as shown in Table 1. Column chromatography (if required) of
the reaction mixture (hexane/EtOAc 50:1 / 15:1) gave 3aeq as
orange or red solid (Table 1).
NMR (300 MHz, CDCl3): d 4.02 (s, 2H, SCH2), 7.98 (m, 2H, C5eH and
C8eH), 8.17 (m, 2H, C6eH and C7eH), 12.78 (bs, 1H, OH); Mass (ESI):
281.98 (Mþ); Anal. Calcd for C12H7ClO4S: C, 50.98; H, 2.50; S, 11.34;
Found: C, 51.08; H, 2.53; S, 11.37; Beilstein test [22]: Cl positive.
4.2.8. 2-(3-Chloro-1,4-dioxo-1,4-dihydronaphthalen-2-ylthio)
succinic acid (3h)
Red powder; IR (KBr): 3441(OH), 3001(SCH2), 2986(SCH2), 1785
4.2.1. 2-Chloro-3-(4-methylpiperazin-1-yl)naphthalene-1,4-dione
(3a)
(pC]O of COOH), 1655 and 1662 (C]O of quinone) cmꢁ1; 1H NMR
(300 MHz, CDCl3):
d
3.25 (m, 2H, CH2CO); 3.79 (t, 1H, J ¼ 6.3, SCH),
Orange powder; IR (KBr): 1597 and 1675 (pC]O of quinone), 1H
7.94 (m, 2H, C5eH and C8eH), 8.12 (m, 2H, C6eH and C7eH), 12.40
(bs, 1H, NH), 12.78 (bs, 1H, NH); Mass (ESI): 339.99 (Mþ); Anal.
Calcd for C14H9ClO6S: C, 49.35; H, 2.66; S, 9.41; Found: C, 49.41; H,
2.70; S, 9.45; Beilstein test [22]: Cl positive.
NMR (300 MHz, CDCl3):
d
2.19 (t, J ¼ 4.8 Hz, 4H, CH2NMe), 2.31 (s,
3H, NCH3), 2.85 (t, J ¼ 4.8 Hz, 4H, NCH2CH2NMe), 7.92 (m, 2H, C5eH
and C8eH), 8.01 (m, 2H, C6eH and C7eH); Mass (ESI): 290.10 (Mþ,
33%), 291.11 (Mþ þ 1, 100%); Anal. Calcd for C15H15ClN2O2: C, 61.97;
H, 5.20; N, 9.64. Found: C, 62.09; H, 5.23; N, 9.68; Beilstein test [22]:
Cl positive.
4.2.9. Methyl 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-
ylthio)acetate (3i)
Orange powder; IR (KBr): 1588 and 1670 (pC]O of quinone),
4.2.2. 2-Chloro-3-(pyrrolidin-1-yl)naphthalene-1,4-dione (3b)
Orange powder; IR (KBr): 1572 and 1670 (pC]O of quinone)
1739 (pC]O of COOMe) cmꢁ1; 1H NMR (200 MHz, CDCl3):
d 3.63 (s,
3H, OCH3), 4.00 (s, 2H, SCH2), 7.63 (m, 2H, C5eH and C8eH), 8.18 (m,
2H, C6eH and C7eH); Mass (ESI): 296.00 (Mþ); Anal. Calcd
C13H9ClO4S: C, 52.62; H, 3.06; S, 10.81. Found: C, 52.48; H, 2.98; S,
10.74; Beilstein test [22]: Cl positive.
cmꢁ1 1H NMR (300 MHz, CDCl3): 1.82 (m, 4H, CH2), 2.80 (m, 4H,
;
NCH2), 7.69e7.76 (m, 2H, C5eH and C8eH), 8.02 (dd, 1H, J ¼ 8.2 and
1.8 Hz, C7), 8.10 (dd, 1H, J ¼ 8.2 and 1.8 Hz, C6); Mass (ESI): 262.09

V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
2425
4.2.10. 2-Chloro-3-(2-mercaptoethylthio)naphthalene-1,4-dione (3j)
Orange powder; IR (KBr): 1582 and 1662 (pC]O of quinone)
Anal. Calcd for C15H13ClO4S: C, 55.47; H, 4.03; S, 9.87. Found: C,
55.36; H, 3.98; S, 9.77.
cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 1.61 (bs, 1H, SH), 3.32 (m, 4H,
CH2CH2), 7.82 (m, 2H, C5eH and C8eH), 8.21 (m, 2H, C6eH and
4.2.17. 3-Hydroxy-2,4-dimethyl-4H-naphtho[2,3-b][1,4]-thiazine-
5,10-dione (3q) [11]
C7eH); 13CNMR (300 MHz, CDCl3 þ MeOH):
d 26.8, 33.1, 126.7,
127.6, 130.8, 131.4, 133.8, 134.7, 140.7, 143.4, 176.0, 178.6; Mass (ESI):
284.07 (Mþ, 100%), 285.07 (Mþ þ 1, 25%), 286.07 (Mþ þ 2, 33%);
Anal. Calcd. for C12H9ClO2S2: C, 50.61; H, 3.19; S, 22.52. Found: C,
50.48; H, 3.14; S, 22.49; Beilstein test [22]: Cl positive.
The general procedure was followed to give orange crystals after
crystallization with EtOH; IR (KBr): 3443 (OH),1654 and 1542 (pC]
O of quinone) cmꢁ1; 1H NMR (300 MHz, CDCl3):
d 1.57 (s, 3H, CH3),
1.59 (s, 1H, OH), 3.47 (s, 3H, NCH3), 7.59e7.74 (m, 2H, C5eH and
C8eH), 8.02e8.16 (m, 2H, C6eH and C7eH); 13CNMR (CDCl3):
4.2.11. 3-Hydroxy-4-methyl-4H-naphtho[2,3-b][1,4]thiazine-5,10-
dione (3k)
d 14.50, 35.00, 36.99, 99.98, 126.49, 127.16, 131.20, 131.96, 132.52,
134.03, 134.19, 141.54, 166.07, 180.63; Mass (ESI): 273 (Mþ); Anal.
Calcd for C14H11NO3S: C, 61.52; H, 4.06; N, 5.12; S, 11.73. Found: C,
61.68; H, 4.14; N, 5.30; S, 11.84.
Orange solid; IR (KBr): 1549 and 1658 (pC]O of quinone), 3446
(OH) cmꢁ1 1H NMR (200 MHz, CDCl3):
; d 1.69 (s, 1H, OH), 3.34 (s,
3H, NCH3), 5.92 (s, 1H, CH), 7.62 (m, 2H, C5eH and C8eH), 8.01 (m,
2H, C6eH and C7eH); Mass (ESI): 259.03 (Mþ); Anal. Calcd for
C13H9NO3S: C, 60.22; H, 3.50; N, 5.40; S, 12.37; Found: C, 60.02; H,
3.46; N, 5.38; S, 12.32.
4.3. Crystallographic data of 3-hydroxy-2,4-dimethyl-4H-Naphtho
[2,3-b][1,4]-thiazine-5,10-dione (3q) [11, 25]
ꢀ
Monoclinic, Space group P 21/n; a ¼ 10.6307(16) A, b ¼ 8.1826
ꢀ
ꢀ
a
4.2.12. 2-Hydroxy-3-(phenylthio)naphthalene-1,4-dione (3l)
Orange solid; IR (KBr): 3440 (OeH), 1584 and 1661 (pC]O of
(12) A, c ¼ 14.619(2) A,
¼ 90,
b
¼ 101.380(2), γ ¼ 90;
ꢀ
3
ꢀ
V ¼ 1246.62 A , Z ¼ 4, T ¼ 296 K,
l
¼ 0.71073 A, F(000) ¼ 544,
quinone) cmꢁ1
;
1H NMR (300 MHz, CDCl3):
d
7.27e757 (m, 5H,
Crystal size ¼ 0.44 ꢂ 0.31 ꢂ 0.25 mm3, Theta range for data
phenyl), 7.75 (m, 2H, C5eH and C8eH), 8.05 (m, 2H, C5eH and
C8eH), 10.06 (bs, 1H, OH); Mass (ESI): 283.04 (Mþ þ 1); Anal. Calcd
for C16H10O3S: C, 68.07; H, 3.57; S, 11.36. Found: C, 67.97; H, 3.58; S,
11.31.
collection ¼ 4.72e32.45ꢀ,Index ranges ¼ ꢁ23ꢃhꢃ21, ꢁ10ꢃkꢃ10,
ꢁ14ꢃlꢃ17, Reflections collected
¼
11 868, Independent
reflections
¼
2365 [R(int)
¼
0.0338], Completeness to
theta ¼ 25.00ꢀ, 99.0%, Absorption correction ¼ Semi-empirical
from equivalents, Max. and min. transmission ¼ 1.00000 and
0.84802, Refinement method ¼ Full-matrix least-squares on F2,
4.2.13. 5,8-Dihydroxy-2-(4-methylpiperazin-1-yl)naphthalene-1,4-
dione (3m)
Data/restraints/parameters
¼
2365/0/109, Goodness-of-fit on
Red solid, IR (KBr): 1598 and 1679 (pC]O of quinone), 3435
F2 ¼ 1.135, Final R indices [I > 2sigma(I)] R1 ¼0.0615, wR2 ¼ 0.2005,
R indices (all data), R1 ¼ 0.1158, wR2 ¼ 0.2349, Largest diff. peak
(OeH); 1H NMR (300 MHz, CDCl3):
d
2.22 (t, J ¼ 4.8 Hz, 4H,
3
ꢀ
CH2NMe), 2.35 (s, 3H, NCH3), 2.89 (t, J ¼ 4.8 Hz, 4H, NCH2), 6.59 (s,
1H, C3eH), 7.69 (d, 1H, J ¼ 8.2 Hz, C6eH), 7.71 (d, 1H, J ¼ 8.2 Hz,
C7eH), 12.05 (bh, 2H, OH); Mass (ESI): 289.12 (Mþ þ 1); Anal. Calcd
for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found: C, 62.59; H, 5.60;
N, 9.74.
and hole ¼ 0.592 and ꢁ0.411 e A Symmetry: a) x,y,z; b) 1/2ꢁx,1/
2 þ y,1/2ꢁz; c) ꢁx,ꢁy,ꢁz; d) 1/2 þ x,1/2ꢁy,1/2 þ z (For detail see
Supplementary data).
4.4. In vitro antifungal and antibacterial evaluation by MIC assay
4.2.14. 5,8-Dihydroxy-2-(pyrrolidin-1-yl)naphthalene-1,4-dione
(3n)
The compounds 3aen were evaluated for their in vitro anti-
fungal activity against C. albicans, C. neoformans, S. schenckii,
T. mentagraphytes, A. fumigatus and C. parapsilosis (ATCC 22019) and
antibacterial activity against E. coli, S. aureus (ATCC25923), Klebsi-
ella pneumoniae (ATCC 27736) and P. aeruginosa at the Division of
Fermentation Technology of Central Drug Research Institute,
Lucknow, India. In this process minimum inhibitory concentration
of compounds 3aen was tested according to standard micro broth
dilution as per NCCLS [23,24] protocol. Briefly, testing was per-
formed in flat bottom 96 well tissue culture plates (CELLSTARÒ
Greiner bio-one GmbH, Germany) in RPMI 1640 medium buffered
with MOPS (3-[N-Morpholino]propane sulfonic acid) (Sigma chem.
Co. MO, USA) for fungal strains and in Muller Hinton broth (Titan
Biotech Ltd, India) for bacterial strains. Initial inoculums of fungal
and bacterial strain were maintained at 1e5 ꢂ 103 cells/mL. These
plates were incubated in a moist chamber at 35 ꢀC and absorbance
at 492 nm was recorded on Versa Max micro plate reader (Molec-
ular devices, Sunnyvale, USA) after 48 h for C. albicans and C. par-
apsilosis, 72 h for A. fumigatus, S. schenckii and C. neoformans and
96 h for T. mentagraphytes while bacterial strains were incubated
for 24 h. MIC was determined as 90% inhibition of growth with
respect to the growth control was observed by using SOFTmax Pro
4.3 Software (Molecular Devices, Sunnyvale, USA).
The general procedure was followed to give dark violet crystals
after crystallization with methanol; IR (KBr): 3427 (OeH), 1598 and
1649 (pC]O of quinone) cmꢁ1; 1H NMR (300 MHz, CDCl3): 1.78 (m,
4H, CH2), 2.69 (m, 4H, NCH2), 6.56 (s, 1H, C3eH), 7.60 (m, 2H, C6eH
and C7eH), 12.20 (bh, 2H, OeH); Mass (ESI): 269.09 (Mþ þ 1); Anal.
Calcd C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.78; H, 5.00;
N, 5.37.
4.2.15. Ethyl 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-
ylthio)acetate (3o) [11]
The general procedure was followed to give orange crystals on
crystallization with EtOH; IR (KBr): 1737 (pC]O of COOEt), 1669
and 1590 (pC]O of quinone) cmꢁ1 1H NMR (200 MHz, CDCl3):
;
d
1.19 (t, 3H, J ¼ 6.3 Hz, CH3), 3.64 (s, 2H, SCH2), 4.13 (q, 2H,
J ¼ 6.3 Hz, OCH2), 7.62 (m, 2H, C5eH and C8eH), 8.16 (m, 2H, C6eH
and C7eH); Mass (ESI): 310.01 (Mþ); Anal. Calcd for C14H11ClO4S: C,
54.11; H, 3.57; S, 10.32. Found: C, 54.28; H, 3.64; S, 10.48.
4.2.16. Ethyl 2-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-
ylthio)propanoate (3p) [11]
The general procedure was followed to give orange crystals after
crystallization with EtOH; IR (KBr): 1738 (pC]O of COOEt), 1669
and 1591 (pC]O of quinone) cmꢁ1
;
1H NMR (200 MHz, CDCl3):
Acknowledgements
d
1.09 (t, 3H, J ¼ 6.3 Hz, CH3),1.57 (d, 3H, J ¼ 7.2 Hz, CH3), 4.06 (q, 2H,
J ¼ 6.3 Hz, OCH2), 4.68 (q, 1H, J ¼ 7.2 Hz, SCH), 7.72 (m, 2H, C5eH
We thank Director, SAIF of Central Drug Research Institute,
Lucknow, India for spectral, micro analyses data reported in the
and C8eH), 8.05 (m, 2H, C6eH and C7eH); Mass (ESI): 324.02 (Mþ);

2426
V.K. Tandon et al. / European Journal of Medicinal Chemistry 45 (2010) 2418e2426
[13] V.K. Tandon, D.B. Yadav, R.V. Singh, A.K. Chaturvedi, P.K. Shukla, Bioorg. Med.
Chem. Lett. 15 (2005) 5324e5328.
[14] V.K. Tandon, D.B. Yadav, R.V. Singh, M. Vaish, A.K. Chaturvedi, P.K. Shukla,
Bioorg. Med. Chem. Lett. 15 (2005) 3463e3466.
[15] V.K. Tandon, R.B. Chhor, R.V. Singh, S. Rai, D.B. Yadav, Bioorg. Med. Chem. Lett.
14 (2004) 1079e1083.
manuscript. H.K.M. thanks C.S.I.R. (Project No. e 01(2280)/08/EMR-
II), New Delhi, India for award of S.R.F. (Extended).
Appendix. Supplementary data
[16] V.K. Tandon, R.B. Singh, D.B. Yadav, Bioorg. Med. Chem. Lett. 14 (2004)
2901e2904.
[17] V.K. Tandon, H.K. Maurya, N.N. Mishra, P.K. Shukla, Eur. J. Med. Chem. 44
(2009) 3130e3137.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2010.02.023.
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