Synthesis and antifungal evaluation of novel dicyanoderivatives of rhodanine

Article abstract of DOI:10.1002/jhet.565

This work describes the synthesis and antifungal evaluation of 5-arylidene-(Z)-2-(1,1-dicyanomethylene)-1,3-thiazol-4-ones 5 obtained from the reaction of 2-(1,1-dicyanomethylene)-1,3-thiazol-4-one 3 and benzaldehydes 4. The starting material 3 was synthe

Full text of DOI:10.1002/jhet.565

March 2011
Synthesis and Antifungal Evaluation of Novel
Dicyanoderivatives of Rhodanine
347
Braulio Insuasty,a* Alberto Insuasty,a Alexis Tigreros,a Jairo Quiroga,a
Rodrigo Abonia,a Manuel Nogueras,b* Justo Cobo,b Marcos Derita,c
and Susana Zacchinoc
a
´ ´ ´
Grupo de Investigacion de Compuestos Heterocıclicos, Departamento de Quımica, Universidad
del Valle, A.A. 25360 Cali, Colombia
b
´
Departamento de Quımica Inorganica y Organica, Universidad de Jaen, 23071 Jaen, Spain
Farmacognosia, Facultad de Ciencias Bioquımicas y Farmaceuticas, Universidad Nacional de
´
´
´
´
c
´
´
Rosario, Suipacha 531, (2000), Rosario, Argentina
*E-mail: brainsu@univalle.edu.co or mmontiel@ujaen.es
Received March 15, 2010
DOI 10.1002/jhet.565
Published online 16 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
This work describes the synthesis and antifungal evaluation of 5-arylidene-(Z)-2-(1,1-dicyanomethy-
lene)-1,3-thiazol-4-ones 5 obtained from the reaction of 2-(1,1-dicyanomethylene)-1,3-thiazol-4-one 3
and benzaldehydes 4. The starting material 3 was synthesized by a condensation reaction of rhodanine 1
and malononitrile 2. The structures of the obtained products were established by IR, NMR, mass spec-
trometry, and elemental analysis.
J. Heterocyclic Chem., 48, 347 (2011).
INTRODUCTION
amounts of 2-(1,1-dicyanomethylene)-1,3-thiazol-4-one
3 and benzaldehydes 4a–i and aqueous 20% sodium hy-
droxide (0.3 mL) and ethanol (10 mL) was stirred at
room temperature during 12–20 h (Scheme 1, Table 1).
The starting material 3 was prepared previously by the
reaction of rhodanine 1, malononitrile 2, and sodium ac-
etate in absolute ethanol.
Rhodanine (2-thioxo-1,3-thiazolidin-4-one, 1) has given
place to a very important group of heterocyclic compounds
for drug discovery programs. Arylidene derivatives of rho-
danine have attracted great interest for the synthetic or-
ganic chemists because of the broad biological activities
shown by these compounds, with demonstrated antiviral
[1], antimicrobial [2], cardiac [3], anti-inflammatory [4],
and antifungal activities [5]. Additionally, rhodanine deriv-
atives can potentially be used in the treatment of diabetes,
obesity, Alzheimer’s disease, cystic fibrosis, thrombocyto-
penia, cancer, sleep, mood, and central nervous system dis-
orders as well as chronic inflammation [6]. We have
previously prepared some of these compounds to deter-
mine their antifungal activity [5(a)], and most recently
[5(b)], arylidene derivatives containing the a,b-unsaturated
carbonyl moiety have been used as bielectrophiles in
cyclocondensation reactions with heterocyclic amines [7].
As an ongoing work, here we provide a simple and effi-
cient method for the synthesis of new arylidene derivatives
of rhodanine 5a–i, by converting rhodanine into its dicya-
noderivative 3 and its subsequent condensation reaction
with aromatic aldehydes 4a–i (Scheme 1).
The formation of compounds 5 as the unique reaction
products was confirmed from the thin layer chromatog-
raphy (TLC) monitoring and by their spectroscopic data
(IR, 1D- and 2D NMR, high-resolution mass spectrome-
try, and elemental analysis).
Previously it has been reported that although arylalky-
lidenerhodanines may exist in both Z and E isomeric
forms, the thermodynamically more stable Z isomer is
the preferred [8–11]. In such reports, configuration on
the exocyclic double bond was determined on the basis
1
of NMR spectra. The H-NMR signals of the methine-
group hydrogens appeared in the range of 7.30–7.70
ppm for Z isomers and 6.60–7.10 ppm for E isomers.
Our experimental NMR data showed the methine pro-
tons in the range 7.44–7.60 ppm, confirming that our
compounds 5 were obtained in the single Z isomeric
form.
The main vibration bands in the IR spectra for com-
pounds 5a–i correspond to: NH at 3401–3459 cmꢀ1
RESULTS AND DISCUSSION
,
CBN (only one band) at 2211–2220 cmꢀ1, and C¼¼O at
To prepare the 5-arylidene-(Z)-2-(1,1-dicyanomethy-
lene)-1,3-thiazol-4-ones 5a–i, a mixture of equimolar
1639–1671 cmꢀ1
.
C
V
2010 HeteroCorporation

348
B. Insuasty, A. Insuasty, A. Tigreros, J. Quiroga, R. Abonia, M. Nogueras, J. Cobo, M. Derita, and Vol 48
S. Zacchino
Scheme 1. Synthesis of dicyanoarylidenerhodanine derivatives 5.
Figure 2. Structures of dicyanorhodanines 5 and rhodanines 6.
tophytes, being the clinically relevant C. albicans and
C. neoformans particularly sensitive toward compounds
6b and 6c [5(a)]. Contrary to the observed above, any of
the analog compounds 5a–d displayed antifungal activity
below of 250 lg/mL. This finding clearly indicates that
the dicyano substituent in C-2 led to a loss of the antifun-
gal activity of arylidenerhodanines.
The H- and 13C-NMR spectra of products show that
the number of protons and carbon atoms agrees with the
1
CONCLUSIONS
proposed structures 5. The NH signal is not observed in
1
the H-NMR spectra of all compounds 5. For example,
In conclusion, we have developed a novel procedure
to synthesize new dicyanoarylidenerhodanine deriva-
tives, which were evaluated for antifungal properties
against a panel of human opportunistic and pathogenic
fungi with standardized procedures. Results demon-
strated the versatility and high regioselectivity of the
process and added interesting data for the SAR study on
the arylidenerhodanine derivatives.
1
in the H-NMR spectrum of compound 5c (Fig. 1), it is
observed a singlet at 7.50 ppm (1H) assigned to H-50,
and it is also observed two doblets at 7.61 and 7.57
ppm (2H) assigned to Hm and Ho, respectively, whereas
the most relevant signals in the 13C-NMR spectra corre-
spond to the two CN groups at 116.8 and 118.2 ppm,
the C-50 carbon atom at 126.8 ppm, and the C¼¼O func-
tion at 180.8 ppm. Moreover, the unambiguous assign-
ment of the above signals was performed through
HSQC and HMBC experiments.
EXPERIMENTAL
General procedures. Melting points were taken in open
capillaries on a Thomas Hoover melting point apparatus
(Thomas Hoover Capillary Apparatus, Philadelphia, PA) and
On the other hand, compounds 5a–i were tested for
antifungal properties with the microdilution technique
following the guidelines of Clinical and Laboratory Stand-
ards Institute against a panel of yeasts (Candida albicans,
Saccharomyces cerevisiae, and Cryptococcus neoformans),
Aspergillus spp. (A. niger, A. fumigatus, and A. flavus)
and dermatophytes in a similar way as previously reported
for some other rhodanine derivatives [5(a)].
1
are uncorrected. The H- and 13C-NMR spectra were run on a
Bruker DPX 400 spectrometer operating at 400 and 100 MHz,
respectively, using dimethyl sulfoxide-d6 as solvent and TMS
as internal standard (Bruker BioSpin GmbH, Rheinstetten, Ger-
many). High-resolution mass spectra (HRMS) were recorded
in a Waters Micromass Auto-Spec NT spectrometer (Waters,
´
Manchester, UK) (STIUJA, Servicios Tecnicos de Investiga-
´
Results showed that any of compounds 5 assayed dis-
played antifungal activity below of 250 lg/mL. These
findings constitute an important data for our current pur-
poses of structure–activity relationship (SAR) study on
the antifungal properties of arylidenerhodanines. In fact,
as we have reported previously, [5(a)] compounds 6a–d
(Fig. 2, Table 2) showed moderate to strong antifungal
activity against yeasts, Aspergillus spp. as well as derma-
´
cion de la Universidad de Jaen).
Experimental procedures.
Synthesis of 2-(1,1-dicyano-
methylene)-1,3-thiazol-4-one (3) [12]. A mixture of rhodanine
1 (1 mmol), malononitrile 2 (1.2 mmol), sodium acetate (1.2
mmol), and absolute ethanol (15 mL) was refluxed for 12 h.
The precipitate formed was filtered off and washed with water
and ice-cooled ethanol. The solid was purified by recrystalliza-
tion from ethanol, 74% yield; m.p. 225–227ꢁC; IR (KBr)
cmꢀ1, 3445 (NAH), 2212 and 2196 (2CBN), 1647 (C¼¼O);
1H-NMR (400 MHz, DMSO-d6, d) ppm, 3.79 (s, 2H, CH2);
13C-NMR (100 MHz, DMSO-d6, d) ppm, 39.2 (C-5), 46.4 (C-
20), 117.7 (CBN), 119.0 (CBN), 188.7 (C-2), 188.9 (C¼¼O);
HRMS (EI): C6H3N3OS requires: 164.9997. Found: 164.9998.
Anal. Calcd. for C6H3N3OS: C, 43.63; H, 1.83; N, 25.44.
Found: C, 43.71; H, 1.87; N, 25.35.
General procedure for the synthesis of 5-arylidene-(Z)-2-
(1,1-dicyanomethylene)-1,3-thiazol-4-ones 5a–i. A mixture of
2-(1,1-dicyanomethylene)-1,3-thiazol-4-one 3 (1 mmol), alde-
hyde 4 (1 mmol), ethanol (15 mL), and aqueous 20% sodium
Figure 1. Numbering of structure 5c.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2011
Synthesis and Antifungal Evaluation of Novel Dicyanoderivatives of Rhodanine
349
Table 1
Synthesis of dicyanoarylidenerhodanine analogs 5.
Entry
Compound
Ar
m.p. (ꢁC)
Yield (%)
r.t. (h)a
1
2
3
–
C6H5
225–227
334–336
323–325
341–343
>350
>350
342–343
>350
74
45
85
60
85
80
59
63
74
81
12
13
15
20
18
14
13
13
16
18
5a
5b
5c
5d
5e
5f
5g
5h
5i
3
4
4-FAC6H4
4-ClAC6H4
4-BrAC6H4
4-NO2AC6H4
4-CH3AC6H4
4-OCH3AC6H4
3,4,5-(CH3O)3AC6H2
3,4-(OCH2O)AC6H3
5
6
7
8
9
10
343–345
>350
a r.t.(h) refers to the reaction times in hours for the conversion of 3–5.
hydroxide (0.3 mL) was stirred at room temperature for 12–20
h. The precipitate formed was filtered off, washed with water
and ice-cooled ethanol. The solids were purified by recrystalli-
zation from ethanol.
Calcd. for C13H6FN3OS: C, 57.56; H, 2.23; N, 15.49. Found:
C, 57.65; H, 2.30; N, 15.40.
(Z)-5-(4-Chlorobenzylidene)-2-(1,1-dicyanomethylene)-1,3-
thiazol-4-one (5c). This compound was obtained according to
general procedure as a yellow powder, 60% yield; m.p. 341–
343ꢁC; IR (KBr) cmꢀ1, 3448 (NAH), 2215 (2CBN), 1648
(Z)-5-Benzylidene-2-(1,1-dicyanomethylene)-1,3-thiazol-4-
one (5a). This compound was obtained according to general
procedure as a yellow powder, 45% yield; m.p. 334–336ꢁC; IR
(KBr) cmꢀ1, 3459 (NAH), 2214 (2CBN), 1651 (C¼¼O); 1H-
NMR (400 MHz, DMSO-d6, d) ppm, 7.52 (s, 1H, ¼¼CH), 7.59
(d, 2H, J ¼ 7.63 Hz, Ho), 7.52 (dd, 2H, J ¼ 7.63, and 7.36
Hz, Hm), 7.41 (t, 1H, J ¼ 7.36 Hz, Hp); 13C-NMR (100 MHz,
DMSO-d6, d) ppm, 48.2 (C-20), 116.9 (CBN), 118.3 (CBN),
128.2 (C-50), 134.9 (C-5), 129.8 (Co), 130.0 (Ci), 129.5 (Cm),
129.6 (Cp), 180.0 (C-2), 181.0 (C¼¼O); HRMS (EI):
C13H7N3OS requires: 253.0310. Found: 253.0320. Anal. Calcd.
for C13H7N3OS: C, 61.65; H, 2.79; N, 16.59. Found: C, 61.78;
H, 2.84; N, 16.67.
1
(C¼¼O); H-NMR (400 MHz, DMSO-d6, d) ppm, 7.50 (s, 1H,
¼¼CH), 7.61 (d, 2H, J ¼ 7.96 Hz, Hm), 7.57 (d, 2H, J ¼ 7.96
13
Hz, Ho); C-NMR (100 MHz, DMSO-d6, d) ppm, 49.4 (C-20),
116.8 (CBN), 118.2 (CBN), 126.8 (C-50), 134.1 (C-5), 129.7
(Co), 130.7 (Ci), 131.6 (Cm), 133.8 (Cp), 179.7 (C-2), 180.8
(C¼¼O); HRMS (EI): C13H6ClN3OS requires: 286.9920. Found:
286.9923. Anal. Calcd. for C13H6ClN3OS: C, 54.27; H, 2.10;
N, 14.60. Found: C, 54.20; H, 2.02; N, 14.52.
(Z)-5-(4-Bromobenzylidene)-2-(1,1-dicyanomethylene)-1,3-
thiazol-4-one (5d). This compound was obtained according to
general procedure as a yellow powder, 85% yield; m.p.
>350ꢁC; IR (KBr) cmꢀ1, 3446 (NAH), 2218 (2CBN), 1671
(Z)-2-(1,1-Dicyanomethylene)-5-(4-fluorobenzylidene)-1,3-
thiazol-4-one (5b). This compound was obtained according to
general procedure as a yellow powder, 85% yield; m.p. 323–
325ꢁC; IR (KBr) cmꢀ1, 3456 (NAH), 2214 (2CBN), 1656
1
(C¼¼O); H-NMR (400 MHz, DMSO-d6, d) ppm, 7.47 (s, 1H,
¼¼CH), 7.70 (d, 2H, J ¼ 8.54 Hz, Hm), 7.47 (d, 2H, J ¼ 8.54
13
Hz, Ho); C-NMR (100 MHz, DMSO-d6, d) ppm, 48.4 (C-20),
1
(C¼¼O); H-NMR (400 MHz, DMSO-d6, d) ppm, 7.51 (s, 1H,
116.8 (CBN), 118.2 (CBN), 126.8 (C-50), 130.9 (C-5), 131.7
(Co), 122.8 (Ci), 132.6 (Cm), 134.2 (Cp), 179.7 (C-2), 180.9
(C¼¼O); HRMS (EI): C13H6BrN3OS requires: 330.9415.
Found: 330.9458. Anal. Calcd. for C13H6BrN3OS: C, 47.01; H,
1.82; N, 12.65. Found: C, 47.10; H, 1.89; N, 12.58.
¼¼CH), 7.65 (dd, 2H, J ¼ 8.75, and 5.50 Hz, Ho), 7.35 (dd,
2H, J ¼ 8.75 Hz, and 7.35 Hz, Hm); 13C-NMR (100 MHz,
DMSO-d6, d) ppm, 48.2 (C-20), 116.9 (CBN), 118.3 (CBN),
3
127.1 (C-50), 131.5 (C-5), 132.2 (d, Co, JCAF ¼ 8.7 Hz),
2
129.7 (Ci), 116.7 (d, Cm, JCAF ¼ 21.9 Hz), 162.6 (d, Cp,
(Z)-2-(1,1-Dicyanomethylene)-5-(4-nitrobenzylidene)-1,3-
thiazol-4-one (5e). This compound was obtained according to
general procedure as a brown powder, 80% yield; m.p.
1JCAF ¼ 248.5 Hz), 179.9 (C-2), 181.0 (C¼¼O); HRMS (EI):
C13H6FN3OS requires: 271.0216. Found: 271.0208. Anal.
Table 2
Comparative antifungal activity (MICs in lg/mL) of compounds 6a–d from Ref. 5(a) with their current
dicyanoarylidenerhodanine analogs 5a–d.
MICsa (lg/mL) for compounds 6 [5a]
MICs (lg/mL) for compounds 5
Entry
Compound
R1
R2
R3
Yeasts
Aspergillus spp.
Dermatophytes
All fungi assayed
1
2
3
4
6a/5a
6b/5b
6c/5c
6d/5d
H
F
Cl
Br
H
H
H
H
H
H
H
H
62.5–125
7.8
15.6–250
62.5–(>250)
62.5–125
250
125–250
>250
3.9–7.8
7.8–32
62.5
>250
>250
>250
>250
>250
a Minimum inhibitory concentration.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

350
B. Insuasty, A. Insuasty, A. Tigreros, J. Quiroga, R. Abonia, M. Nogueras, J. Cobo, M. Derita, and Vol 48
S. Zacchino
>350ꢁC; IR (KBr) cmꢀ1, 3406 (NAH), 2214 (2CBN), 1661
(C¼¼O), 1498, 1286 (NO2); H-NMR (400 MHz, DMSO-d6, d)
Ho), 7.14 (dd, 1H, J ¼ 8.10 and 1.64 Hz, Ho0), 7.05 (d, 1H, J
¼ 8.10 Hz, Hm0); 13C-NMR (100 MHz, DMSO-d6, d) ppm,
47.7 (C-20), 102.2 (OCH2O), 117.0 (CBN), 118.5 (CBN),
128.3 (C-50), 127.9 (C-5), 109.3 (Co), 125.0 (Co0), 129.2 (Ci),
148.7 (Cm), 109.4 (Cm0), 148.5 (Cp), 179.8 (C-2), 181.1
(C¼¼O); HRMS (EI): C14H7N3O3S requires: 297.0208. Found:
297.0204. Anal. Calcd. for C14H7N3O3S: C, 56.56; H, 2.37; N,
14.13. Found: C, 56.49; H, 2.30; N, 14.21.
1
ppm, 7.60 (s, 1H, ¼¼CH), 8.33 (d, 2H, J ¼ 8.88 Hz, Hm), 7.84
(d, 2H, J ¼ 8.54 Hz, Ho); 13C-NMR (100 MHz, DMSO-d6, d)
ppm, 49.2 (C-20), 116.5 (CBN), 117.9 (CBN), 125.6 (C-50),
134.4 (C-5), 130.8 (Co), 141.5 (Ci), 124.7 (Cm), 147.2 (Cp),
179.4 (C-2), 180.5 (C¼¼O); HRMS (EI): C13H6N4O3S requires:
298.0161. Found: 298.0159. Anal. Calcd. for C13H6N4O3S: C,
52.35; H, 2.03; N, 18.78. Found: C, 52.26; H, 1.98; N, 18.86.
(Z)-2-(1,1-Dicyanomethylene)-5-(4-methylbenzylidene)-1,3-
thiazol-4-one (5f). This compound was obtained according to
general procedure as a yellow powder, 59% yield; m.p. 342–
343ꢁC; IR (KBr) cmꢀ1, 3441 (NAH), 2213 (2CBN), 1650
Acknowledgments. The authors thank the Departamento
´
Administrativo de Ciencia, Tecnologıa e Innovacion (COLCIEN-
CIAS); Universidad del Valle, Cali-Colombia; Agencia Nacional
´
´
´
´
de Promocion Cientıfica y Tecnologica de Argentina and
National University of Rosario (UNR) for financial support. M.
Derita acknowledges Consejo Nacional de Investigaciones Cien-
1
(C¼¼O); H-NMR (400 MHz, DMSO-d6, d) ppm, 2.34 (s, 3H,
CH3), 7.47 (s, 1H, ¼¼CH), 7.48 (d, 2H, J ¼ 8.04 Hz, Hm),
7.32 (d, 2H, J ¼ 8.04 Hz, Ho); 13C-NMR (100 MHz, DMSO-
d6, d) ppm, 21.5 (CH3), 47.9 (C-20), 117.0 (CBN), 118.5
(CBN), 128.3 (C-50), 128.7 (C-5), 130.2 (Co), 139.7 (Ci),
130.0 (Cm), 132.1 (Cp), 180.0 (C-2), 181.2 (C¼¼O); HRMS
(EI): C14H9N3OS requires: 267.0466. Found: 267.0461. Anal.
Calcd. for C14H9N3OS: C, 62.91; H, 3.39; N, 15.72. Found: C,
62.84; H, 3.31; N, 15.65.
´
tıficas y Tecnologicas (CONICET-Argentina) for a post-doctoral
fellowship and Universidad de Jaen, Jaen-Espan˜a.
´
´
´
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´
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D. C.; Lifer, S. L.; Berry, D.; Ray, J.; Little, S. P.; Liu, X.; Marshall,
W. S.; Panetta, J. A. Bioorg Med Chem Lett 1996, 6, 2157.
[12] Insuasty, A.; Ortiz, A.; Tigreros, A.; Solarte, E.; Insuasty,
(Z)-2-(1,1-Dicyanomethylene)-5-(3,4-methylendioxybenzylidene)-
1,3-thiazol-4-one (5i). This compound was obtained according
to general procedure as a yellow powder, 81% yield; m.p. >
350ꢁC; IR (KBr) cmꢀ1, 3421 (NAH), 2211 (2CBN), 1639
1
(C¼¼O); H-NMR (400 MHz, DMSO-d6, d) ppm, 6.10 (s, 2H,
´
B.; Martın, N. Dyes Pigments 2011, 88, 385.
AOCH2OA), 7.44 (s, 1H, ¼¼CH), 7.12 (d, 1H, J ¼ 1.64 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet