Facile construction of structurally diverse thiazolidinedione-derived compounds via divergent stereoselective cascade organocatalysis and their biological exploratory studies

Article abstract of DOI:10.1021/co400022r

In this article, we present a new approach by merging two powerful synthetic tactics, divergent synthesis and cascade organocatalysis, to create a divergent cascade organocatalysis strategy for the facile construction of new privileged substructure-based DOS (pDOS) library. As demonstrated, notably 5 distinct molecular architectures are produced facilely from readily available simple synthons thiazolidinedione and its analogues and α,β-unsaturated aldehydes in 1-3 steps with the powerful strategy. The beauty of the chemistry is highlighted by the efficient formation of structurally new and diverse products from structurally close reactants under the similar reaction conditions. Notably, structurally diverse spiro-thiazolidinediones and -rhodanines are produced from organocatalytic enantioselective 3-component Michael-Michael-aldol cascade reactions of respective thiazolidinediones and rhodanines with enals. Nevertheless, under the similar reaction conditions, reactions of isorhodanine via a Michael-cyclization cascade lead to structurally different fused thiopyranoid scaffolds. This strategy significantly minimizes time- and cost-consuming synthetic works. Furthermore, these molecules possess high structural complexity and functional, stereochemical, and skeletal diversity with similarity to natural scaffolds. In the preliminary biological studies of these molecules, compounds 4f, 8a, and 10a exhibit inhibitory activity against the human breast cancer cells, while compounds 8a, 9a, and 9b display good antifungal activities against Candida albicans and Cryptococcus neoformans. Notably, their structures are different from clinically used triazole antifungal drugs. Therefore, they could serve as good lead compounds for the development of new generation of antifungal agents.

Full text of DOI:10.1021/co400022r

Research Article
pubs.acs.org/acscombsci
Facile Construction of Structurally Diverse Thiazolidinedione-Derived
Compounds via Divergent Stereoselective Cascade Organocatalysis
and Their Biological Exploratory Studies
Yongqiang Zhang,† Shengzheng Wang,† Shanchao Wu,† Shiping Zhu,† Guoqiang Dong,†
Zhenyuan Miao,† Jianzhong Yao,† Wannian Zhang,*,† Chunquan Sheng,*,† and Wei Wang*,‡,§
†Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433,
P. R. China
‡Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
§School of Pharmacy, East China University of Science and Technology, Shanghai 200237, P. R. China
S
* Supporting Information
ABSTRACT: In this article, we present a new approach by
merging two powerful synthetic tactics, divergent synthesis and
cascade organocatalysis, to create a divergent cascade organo-
catalysis strategy for the facile construction of new “privileged”
substructure-based DOS (pDOS) library. As demonstrated,
notably 5 distinct molecular architectures are produced facilely
from readily available simple synthons thiazolidinedione and
its analogues and α,β-unsaturated aldehydes in 1−3 steps with
the powerful strategy. The beauty of the chemistry is
highlighted by the efficient formation of structurally new and
diverse products from structurally close reactants under the similar reaction conditions. Notably, structurally diverse spiro-
thiazolidinediones and -rhodanines are produced from organocatalytic enantioselective 3-component Michael−Michael−aldol
cascade reactions of respective thiazolidinediones and rhodanines with enals. Nevertheless, under the similar reaction conditions,
reactions of isorhodanine via a Michael−cyclization cascade lead to structurally different fused thiopyranoid scaffolds. This
strategy significantly minimizes time- and cost-consuming synthetic works. Furthermore, these molecules possess high structural
complexity and functional, stereochemical, and skeletal diversity with similarity to natural scaffolds. In the preliminary biological
studies of these molecules, compounds 4f, 8a, and 10a exhibit inhibitory activity against the human breast cancer cells, while
compounds 8a, 9a, and 9b display good antifungal activities against Candida albicans and Cryptococcus neoformans. Notably, their
structures are different from clinically used triazole antifungal drugs. Therefore, they could serve as good lead compounds for the
development of new generation of antifungal agents.
KEYWORDS: divergent cascade organocatalysis, thiazolidinedione derivatives, structural diversity, anticancer, antifungal
program aimed at incorporating cascade organocatalysis into
DOS.10 A new divergent organocatalytic cascade approach was
introduced into DOS11 by merging two powerful synthetic
strategies, divergent synthesis and cascade catalysis.12 In
divergent synthesis, the power of the strategy is fueled by the
use of similar reactants under the same reaction conditions or
the different reactants under the same/similar reaction
conditions to generate different products. It is expected that
incorporation of organocatalytic enantioselective cascade
reactions into the strategy allows for the generation of
compounds with functional, stereochemical, and skeletal
diversity. Therefore, this new strategy could significantly save
cost and improve synthetic efficiency. Moreover, the use of
INTRODUCTION
■
The diversification of “privileged” structures1 using diversity-
oriented synthesis (DOS),2 defined as rational DOS or
privileged substructure-based DOS (pDOS) strategy,2c,3 has
proven to be a fruitful tool to rapidly discover biologically active
lead compounds.4 However, one of the important challenges in
the construction of pDOS libraries is to identify or develop
efficient synthetic methods to creatively and facilely construct
diverse molecular architectures embedded with privileged
substructures.5
Organocatalytic cascade reactions have been demonstrated as
powerful tools for the facile assembly of diverse and complex
frameworks in “one-pot” operations with high enantio- and
diastereoselectivity.6 Moreover, these processes have been
utilized in target-oriented synthesis.7 Nevertheless, their
applications in DOS is limited.8,9 Driven by our research
interest in DOS and drug discovery, we recently have initiated a
Received: February 18, 2013
Revised: April 15, 2013
© XXXX American Chemical Society
A
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Research Article
such an approach to building privileged substructure derived
libraries with structural diversity can delivers drug like
molecules and thereby offers the great possibility of identifying
novel modulators for biological targets.
Scheme 1. Construction of Functional, Stereochemical, and
Skeletal Diversified Thiazolidinedione-Derived Library via
Divergent Organocatalytic Cascades
For the construction of pDOS libraries, it is crucial to
identify a privileged substructure with the potential for
synthetic transformations toward novel skeletons via the
proposed divergent organocatalytic cascade approach
(DOCA). It is recognized that heterocyclic thiazolidinedione,
rhodanine and isorhodanine moieties units are featured in a
number of molecules displaying a broad spectrum of biological
activities, including antitumor, antibacterial, antiviral effect, etc.
(Figure 1).13 In particular, thiazolidinediones represent an
component Michael−Michael−aldol and Michael−cyclization
cascades with enals proceeds to give spiro-thiazolidinedione
and -rhodanine frameworks and fused thiopyranoids, respec-
tively, in a divergent manner.
RESULTS AND DISCUSSION
■
Organocatalytic Enantioselective 3-Component Mi-
chael−Michael−Aldol Cascade Reaction of Thiazolidi-
nedione with Enals: One-Pot Synthesis of Chiral Spiro-
thiazolidinediones. Inspired by impressive organocatalytic
asymmetric Michael−Michael−aldol cascade reaction in the
synthesis of spiro-oxindoles,15 we envisioned that such a
process could be applied in reaction of thiazolidinedione (3)
with enal 2 in a 3-component reaction (Table 1). Double
Michael reaction of thiazolidinedione (3) with enal 2 (2 equiv)
produces an adduct, which undergoes a subsequent intra-
molecular aldol reaction, leading to a spiro-thiazolidinedione 4.
To probe the feasibility, we initiated the study by reaction of
thiazolidinedione (3) with trans-cinnamaldehyde (2a) catalyzed
by 1a (20 mol %)16 at rt (Table 1). To our delight, by
performing the reaction in CH2Cl2, we were able to isolate
desired product 4a in 87% yield with excellent enantioselec-
tivity and moderate diastereoselectivity (entry 1). The yield was
dropped when 10 mol % 1a was used (entry 2). Lower
diastereoselectivity was observed in other solvents (entries 2−
8) and additives (entries 9−12) screened. Then catalysts 1b−d
were examined (entries 13−15). Improved diastereoselectivity,
but with lower yields, was obtained when a larger side chain
moiety was introduced (1b, dr, 9:1, yield, 59%; 1c, dr, 10:1,
yield, 46%). Enhancing reaction concentration by using 1b led
to a better yield (entries 16−17). Finally, the optimal reaction
condition was established in the presence of catalyst 1b without
an acid additive (entry 16) in terms of yield, diastereoselec-
tivity, and enantioselectivity. It should be noted that our study
is inconsistent with the previous report, in which, no desired
product was obtained without acid as additive.15b,c The absolute
configuration was determined by X-ray crystal structure analysis
Figure 1. Representative structures of pharmaceutically relevant
thiazolidinedione or rhodanine derivatives.
important class of antidiabetic agents, such as rosiglitazone,
troglitazone, and epalrestat (Figure 1).14 In the construction of
the privileged substructure based libraries using the DOCA, the
reactants should be simple and readily available or easily
prepared. Furthermore, they should be able to participate in
organocatalytic cascade reactions in a divergent fashion. This is
a formidable challenging task. To our knowledge, thiazolidine-
dione-based diversity oriented synthesis and the constitution of
their corresponding DOS libraries with skeletal and stereo-
chemical diversity is a largely untapped field.
Herein, we wish to report the results of the investigation of
the divergent, organocatalytic, enantioselective, cascade reac-
tions between thiazolidinedione analogues and α,β-unsaturated
aldehydes to yield diverse polyheterocyclic scaffolds with
excellent stereoselectivity and to illustrate their efficiency in
the generation of structural complexity and diversity of libraries
(Scheme 1). Remarkably, by manipulation of the functional
group reactivities in thiazolidinedione and rhodanine, and
isorhodanine, respective organocatalytic enantioselective 3-
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Table 1. Exploration and Optimization of Organocatalytic
Table 2. Substrate Scope in the Organocatalytic Cascade
Michael−Michael−Aldol Cascade Reaction of
Reaction of Thiazolidinedione 3a with α,β-Unsaturated
a
a
Thiazolidinedione 3a with trans-Cinnamaldehyde 2a
Aldehydes 2
b
c
d
entry
R1
t (h)
4
yield (%)
dr
ee (%)
1
C6H5
36
36
24
24
36
24
24
36
36
36
5
4a
4b
4c
4d
4e
4f
73
83
8.4:1
6.6:1
7.3:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
2
p-BrC5H4
3
p-MeOC5H4
p-Me2NC5H4
p-NO2C5H4
2-furyl
75
4
89
>30:1
b
c
d
5
64
12.4:1
22.3:1
8.9:1
8.4:1
2.4:1
3:1
entry
cat
solvent
DCM
additive yield (%)
dr
ee (%)
6
90
1
1a
none
none
none
none
none
none
none
none
87
30
37
<5
55
64
73
73
83
64
60
64
59
45
77
73
67
6.7:1
f
>99
>99
>99
7
2-thienyl
4g
4h
4i
98
e
2
1a
DCM
nd
8
2-naphthyl
o-NO2C5H4
o-MeOC5H4
n-propyl
86
f
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1b
1b
toluene
THF
nd
9
80
f
f
4
nd
nd
10
11
4j
79
5
EtOH
MeCN
CHCl3
Cl(CH2)2Cl
DCM
2.6:1
5.5:1
3.7:1
6.1:1
2.4:1
2.5:1
4.0:1
4.2:1
9.0:1
10.0:1
6.4:1
8.4:1
9.7:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
e
e
4k
trace
nd
nd
6
a
b
Unless otherwise specified, see the Experimental Section. Isolated
7
c
d
yields. Determined by 1HNMR analysis. The ee value of major
8
diastereomer, determined by chiral HPLC (see the Supporting
g
9
BA
e
Information). Not determined.
10
11
12
13
14
15
16
17
DCM
PNBA
AcOH
AcOK
none
DCM
outstanding ee values were retained. Moreover, no spiro-
thiazolidinedione product was detected for alkyl-substituted
enals (entry 11). Notably, the process proceeded smoothly at a
larger scale (1.5 mmol) with the similar results when 4f was
used an example. When N-benzyl-thiazolidinedione was reacted
with compound 2a, no desired product was obtained (data not
shown), even with a base (e.g., DBU, K2CO3) as additive. It is
suggested that thiazolidinedione can convert to an aromatic
system to activate the methylene, whereas it is difficult for N-
substituted thiazolidinedione to conduct this tautomerization
(Scheme 2).
DCM
DCM
DCM
none
DCM
none
h
DCM
none
i
DCM
none
a
Reaction conditions were as follows: 2a (0.9 mmol), 3a (0.3 mmol),
b
and catalyst 1 (0.06 mmol) in solvent (3 mL) at rt to give 4a. Isolated
c
d
yields. Determined by 1H NMR analysis. Determined by chiral
e
HPLC (see the Supporting Information). cat (10 mol %) was used.
f
g
Not determined. BA, benzoic acid; PNBA, p-nitrobenzoic acid.
h
i
Reaction was conducted with a concentration of 0.3 M. Reaction was
conducted with a concentration of 0.6 M.
Scheme 2. Tautomerization of Thiazolidinediones
of the product (4a) as (5S,6R,10S),17 when S-chiral secondary
amine (1b) was used as catalyst (Figure 2).
Organocatalytic Enantioselective Michael−Michael−
Aldol Cascade Reaction of Rhodanine with Enals: One-
Pot Synthesis of Chiral Spiro-rhodanines. Having
developed a powerful 1b-catalyzed Michael−Michael−aldol
cascade reaction with thiazolidinediones, we questioned
whether this strategy could be extended to rhodanines. New
chiral spiro-rhodanines would be produced. To our delight,
under the same reaction conditions, the cascade reactions
between rhodanines and α, β-unsaturated aldehydes proceeded
in even shorter reaction times (1−8 h) with good
diastereoselectivity (3.9:1 to >30:1) and excellent enantiose-
lectivities (>99% ee for all cases) despite relatively low yields
(35−95%) (Table 3). The steric demand in rhodanine led to
better diastereoselectivity (entries 1−10). In addition to
aromatic enals, linear alkyl, furan and ester substituted enals
can be tolerated (entries 11−16). Notably, as compared with
the aryl-substituted enals, better drs were observed for these
Figure 2. X-ray crystal structure of compound 4a.
With the optimal reaction conditions in hand, the scope of
the reaction of thiazolidinedione with α,β-unsaturated
aldehydes 2 was explored next. As summarized in Table 2,
excellent diastereo and enantioselectivities were obtained for
enals bearing p-substituted aromatics and heterocyclics (entries
2−8). The diastereocontrol was less satisfying for substrates
with o-substituted aryl groups (entries 9 and 10) although
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strategy for isorhodanine 7 (Table 4). Unexpectedly, under the
similar reaction conditions, reactions of isorhodanine with enals
underwent a Michael−cyclization cascade. A new structurally
different fused thiopyranoid scaffold 8 with good enantiose-
lectivity and stereoselectivity was constructed instead. It is
noted that the reactions with isorhodanine were somewhat
complicated. Only a small amount of desired product was
observed under the reaction conditions (data not shown).
Therefore, we took effort to further optimize the reaction
conditions. Better ee values (up to 89%) were obtained when
more bulky catalyst 1e was used in toluene (entries 1−5).
Lowering the temperature to −20 °C did not improve the
stereoselectivity of the reaction but led to a lower yield (entries
3 and 5). It is noteworthy that the product can be purified
through a simple washing and filtrating process due to the bad
solubility of 8a in hexane (see Experimental Section). The
process served as a general approach to the thiopyranoids 8
under the optimized reactions. Generally good yields and
enantioselectivities were attained with various enals bearing
electron-neutral (entry 3), -withdrawing (entries 8 and 9), and
-donating (entry 10) substituents. Furthermore, heterocyclic
substituted enals were able to participate in the process. The
steric effect is also limited (entry 10). A single crystal of the
product (8a) obtained for X-ray crystallographic analysis
allowed to determine its absolute configuration with (5S,7S)
(Figure 3).18
Synthetic Elaboration of Chiral Spiro-thiazolidine-
diones and -rhodanines and Fused Thiopyranoids:
Facile Construction of Natural-Product-like Complex
Molecular Architectures through Simple Operation. We
have shown the divergent organocatalytic cascade strategy as a
powerful approach to construct structurally diverse, chiral
privileged substructures from simple achiral substances in one-
pot operation. The resulting products have complex structures
containing multiple stereogenic centers and functionalities.
They are expected to serve as good starting point for further
synthetic elaboration to assemble more complex natural
product-like molecules. Here we chose the products 4f, 6l,
and 8a as examples to produce new scaffolds with higher
structural complexity and diversity (Scheme 3). Notably,
Table 3. Scope for the Reactions between Rhodanine and Its
Derivatives 5 and α,β-Unsaturated Aldehydes 2
a
b
d
yield
ee
c
entry
R1/R4
t (h)
6
(%)
dr
(%)
1
2
C6H5/H
8
6a
6b
6c
6d
6e
6f
96
56
88
60
57
63
70
61
60
73
3.9:1
7.5:1
3.7:1
8.6:1
4.7:1
5.7:1
5.6:1
7.8:1
8.5:1
9.4:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
n-propyl/H
1.5
6
3
C6H5/Me
4
C6H5/n-butyl
C6H5/allyl
6
5
6
6
C6H5/Bn
6
7
C6H5/p-NO2C6H4CH2
C6H5/o-FC6H4CH2
C6H5/m-ClC6H4CH2
6
6g
6h
6i
8
6
9
6
10
C6H5/naphthalen-2-
methyl
6
6j
11
12
2-furyl/Bn
CO2Et/Bn
CO2Et/Bn
methyl/Bn
n-propyl/Bn
n-hexyl/Bn
6
1
2
1
1
1
6k
6l
68
95
80
44
67
72
11:1
>30:1
>30:1
>30:1
>30:1
>30:1
>99
>99
>99
>99
>99
>99
e
13
6l
14
15
16
6m
6n
6o
a
b
Unless otherwise specified, see the Experimental Section. Product
c
d
isolated. Determined by 1HNMR analysis. The ee value of the major
diastereomer, determined by chiral HPLC (see Supporting Informa-
e
tion). At 1.6 mmol scale.
enals. Again, the reaction proceeded smoothly at a larger scale
as well (1.6 mmol) with 2l (entry 13).
Organocatalytic Enantioselective Michael−Cycliza-
tion Cascade Reaction of Isorhodanine with Enals:
One-Pot Synthesis of Fused Thiopyranoids. Having
demonstrated the high efficiency in the synthesis of structurally
diverse spiro-thiazolidinediones using the divergent organo-
catalytic Michael−Michael−aldol cascade reactions with
thiazolidinediones and rhodanines, we further explored the
a
Table 4. Scope for the Reactions between Isorhodanine and α,β-Unsaturated Aldehydes
b
c
d
entry
cat.
R1
C6H5
solvent
t (h)
8
yield (%)
dr
ee (%)
1
2
1a
1b
1e
1e
toluene
toluene
toluene
DCM
10
10
10
10
16
10
10
10
10
10
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
87
84
82
54
50
87
90
56
87
66
5.6:1
3.0:1
5.5:1
5.5:1
5.3:1
5.5:1
4.5:1
5.4:1
4.3:1
5.9:1
55
79
89
79
90
56
78
79
89
73
C6H5
3
C6H5
4
C6H5
e
5
1e
C6H5
toluene
toluene
toluene
toluene
toluene
toluene
6
1e
1e
1e
1e
1e
2-furyl
7
2-thienyl
p-NO2C6H4
p-BrC6H4
o-MeOC6H4
8
9
10
a
b
c
d
Unless otherwise specified, see Experimental Section. Isolated yields. Determined by 1HNMR analysis. The ee value of the major diastereomer,
determined by chiral-phase HPLC analysis of hydroxyl TBS-derived product (with TBSCl/imidazole/DMF) of 8 (see the Supporting Information).
e
The reaction was conducted at −20 °C.
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scaffolds are also reported to possess anticancer activity.21 The
hetero-Diels−Alder cycloaddition of 6l to ethylvinylether
(EVE) was carried out to create a new framework 10a in
excellent yield (99%) and stereoselectivity. Further treatment
with morpholine and o-aminobenzoic acid gave new poly-
heterocyclic ring systems 10b22 and 10c.23 The absolute
configurations of new scaffolds 9a and 10a were further
assigned to be (5aS,5′S,7S,9S) and (3S,4aS,5′S,6S,8S) accord-
ing to NOESY and 1H NMR spectra (see Supporting
Information) (Figure 4) on the basis of X-ray crystallographic
Figure 3. X-ray crystal structure of compound 8a.
straightforward reactions involving only 1−2 steps enabled to
create polyheterocyclic structures.
Figure 4. NOESY effects of compound 10a and 9a.
Scheme 3. Generation of Diverse and Complex Ring Systems
from the Products of Divergent Organocatalytic Cascade
Reactions
analysis of 8a. Finally, new functionalities 11a and 11b were
constructed by the simple Witting reactions of 8a with high
enantioselectivity (up to 99% ee).
Screening of the pDOS Library for Biological Studies.
With the methodologies for the synthesis of spirothiazolidine-
dione, spiro-rhodanine and fused thiopyranoid libraries were
completed, these compounds were screened for their antitumor
and antifungal activities. In probe of anticancer properties, their
inhibitory activity against three human cancer cell-lines, A549
(lung cancer), ZR-75-30 (breast cancer), and HCT116 (colon
cancer), were determined using MTT assay.24 As shown in
Table 5, several compounds 4f, 8a, and 10a showed inhibitory
Table 5. In Vitro Antitumor Activities of Thiazolidinedione-
Derived Compounds
ZR-75-30
(IC50 μM)
A549
(IC50 μM)
HCT116
c
a
b
entry compounds
(IC50 μM)
1
2
3
4
5
6
7
8
9
4f
77.4
22.0
>100
>100
>100
>100
>100
>100
>100
>100
53.5
>100
>100
>100
>100
>100
94.5
d
ent-4f
8a
19.1
9a
40.1
9b
>100
14.7
10a
10b
10c
>100
>100
10.7
>100
>100
irinotecan
17.3
a
b
c
ZR-75-30: Breast cancer cells. A549: Lung cancer cell. HCT116:
d
Colon cancer cell. Generated with R-1b as catalyst.
activity against the ZR-75-30 cancer cell line. Among them,
compound 10a showed the best activity with an IC50 value of
14.7 μM, which can be used as a lead for the development of
new antitumor agents.
Moreover, the compounds were assayed for their antifungal
activities.25 In vitro antifungal activity of each compound was
expressed as the minimal inhibitory concentration (MIC) that
achieved 80% inhibition of the tested fungi (Table 6). The
results revealed that compounds 9a, 9b, and 8a showed
inhibitory activities against Candida albicans and Cryptococcus
neoformans, which are leading causes of life-threatening fungal
infections. Moreover, compounds 11a and 11b were only active
against Cryptococcus neoformans. The most active antifungal
In the light of the pyran moiety being widely distributed in
natural and biological active compounds,19 L-proline catalyzed
3,3′-dipolar cycloaddition reactions of 4f with 1,3-dicarbonyls
were developed to form pyran and 2H-pyran rings (Scheme
3).20 Fused pyrans 9a and b incorporated into spiro-
thiazolidinedione and spiro-rhodanine frameworks were
successfully installed in high yields and with good enantiose-
lectivity (ee up to >99%) and moderate diastereoselectivity (4:1
dr). It is noted that the fused thiopyranecycle and thiazolidine
E
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solid. The pure product is used to determine ee by chiral HPLC
analysis and for structural characterization (see Supporting
Information for detail).
Table 6. Antifungal in Vitro Activities of Thiazolidinedione-
Derived Compounds (MIC, μg/mL)
a
b
entry
compounds
Candida albicans
Cryptococcus neoformans
General Procedure for Reactions of 2 with 5 (Table 3,
6a as Example). The catalyst 1b (17.0 mg, 0.05 mmol, 0.2
equiv) was added to a solution of α,β-unsaturated aldehyde 2a
(100 mg, 0.8 mmol, 3 equiv) and rhodanine 5a (35 mg, 0.3
mmol, 1 equiv) in DCM (1 mL). The resulted solution was
stirred for 8 h at room temperature. After evaporation of the
solvent, the product was purified though column chromatog-
raphy over silica gel with hexane/EtOAc (10:1−8:1) as the
eluent to yield 6a (94.0 mg, 95% yield) as white solid. The pure
product is used to determine ee by chiral HPLC analysis and for
structural characterization (see Supporting Information for
detail).
General Procedure for Reactions of 2 with 7 (Table 4,
8a as Example). The catalyst 1e (22.0 mg, 0.04 mmol, 0.1
equiv) was added to a solution of α, β-unsaturated aldehyde 2a
(74.0 mg, 0.6 mmol, 1.5 equiv) and isorhodanine 7 (50.0 mg,
0.4 mmol, 1 equiv) in toluene (1 mL). The mixture was stirred
for 10h, then the resulting thick solution was diluted with
hexane (10 mL), and stirred for another 30 min at room
temperature, filtrated and washed with hexane to give the
desired product 8a (82.0 mg, 82% yield) as white solid. The
pure product is used for characterization (see Supporting
Information for detail). It was further converted to more stable
hydroxyl TBS-derived product to determine the corresponding
ee value.
(5aS,5′S,7S,9S)-7,9-Di(furan-2-yl)-3-methyl-6,7-dihy-
dro-1H-spiro[pyrano[4,3-b]chromene-8,5′-thiazolidine]-
1,2′,4′(5aH,9H)-trione (9a). A solution of 4f (50.0 mg, 0.15
mmol, 1.0 equiv), 4-hydroxy-6-methyl-2-pyrone (190.0 mg,
0.15 mmol, 1.0 equiv), and L-proline (86.0 mg, 0.075 mmol, 0.5
equiv) in 5 mL of ethyl acetate was heated at 70 °C under an
argon atmosphere for 24 h. The mixture was cooled to room
temperature, diluted with 50 mL of ethyl acetate, washed twice
with 30 mL of brine, dried (Na2SO4), filtered, and
concentrated. Column chromatography on silica gel of the
crude product using a gradient mixture of ethyl acetate/hexane
(1:5−1:3) as eluent gave 59.0 mg (87% yield) of 9a.
1
4f
>64
>64
>64
64
>64
>64
>64
32
c
2
ent-4f
3
6l
4
8a
5
9a
16
8
6
9b
32
32
7
10a
>64
>64
>64
>64
>64
>64
2
>64
>64
>64
8
8
10b
9
10c
10
11
12
13
trans-11a
cis-11a
11b
64
64
fluconazole
2
a
b
c
Strain number: SC5314. Strain number: 32609. Generated with R-
1b as catalyst.
compound is 9a and its structure is completely different from
traditional antifungal drugs, which provides a novel scaffold for
further antifungal drug discovery. Interestingly, 9a and 9b
displayed inhibitory activity against pathogenic fungi, while 4f
and 10a showed better activity against human cancer cell line.
These results show the importance of core skeletons embedded
with privileged thiazolone motif.
CONCLUSION
■
In conclusion, motivated by the broadly application of pDOS in
generating biologically active molecules and the lack of efficient
synthetic methods to facilely assemble structurally diverse
complex molecular architectures, we have developed a new
powerful divergent organocatalytic cascade reactions of
thiazolidinedione analogies to α,β-unsaturated aldehydes to
generate diverse scaffolds with high stereoselectivity and
synthetic efficiency. As demonstrated in this study, the power
of the divergent organocatalytic cascade strategies has been
fueled by its high synthetic efficiency to create functional,
stereochemical and skeletal diversified thiazolidinedione-
derived privileged substructure library compounds. The
collection of these natural product-like polyheterocycles has
been subjected to antifungal and antitumor bioassays to
generate new promising leads for further development. In
particular, compounds 8a, 9a, and 9b exhibit strong antifungal
activities against Candida albicans and Cryptococcus neoformans,
while their structures are different from triazole antifungal
drugs. Therefore, they could serve as good lead compounds for
the development of new generation antifungal agents.
Furthermore, the application of the synthetic strategy in the
construction of new pDOS libraries is being actively pursued in
our laboratories.
1H NMR (600 MHz, CDCl3) δ = 8.06 (br s, 1H), 7.37−7.38
(m, 1H), 7.32−7.33 (m, 1H), 6.38−6.39 (m, 1H), 6.32−6.33
(m, 2H), 6.29 (d, J = 3.3 Hz, 1H), 6.25 (d, J = 3.3 Hz, 1H),
5.76 (s, 1H), 5.66 (dd, J = 5.8, 11.2 Hz, 1H), 4.26 (s, 1H), 4.00
(dd, J = 4.1, 13.7 Hz, 1H), 3.15 (q, J = 12.8 Hz, 1H), 2.45 (dt, J
= 4.3, 12.9 Hz, 1H), 2.20 (s, 3H); 13CNMR (150 MHz,
CDCl3) δ =173.1, 168.6, 164.0, 163.0, 162.4, 152.5, 151.7,
142.7, 142.5, 126.1, 114.8, 111.0, 110.7, 109.6, 109.5, 97.8, 97.6,
75.5, 66.2, 50.0, 41.2, 34.6, 20.3; HRMS (ESI) calcd for
C23H17NO7S (M + H+) 452.0804, found 452.0792; HPLC
(Chiralpak OD, 0.46 cm I.D. × 10 cm L × 5 um, ethanol/
hexane =20/80, 35 °C, flow rate 1.0 mL/min, λ = 230 nm)
tmajor = 6.4 min, tminor = 10.5 min, ee > 99%; [α]2D5 = 47.2 (c =
0.2 in EtOAc).
(1′S,2′S,3′S,4a′S)-1′,3′-Di(furan-2-yl)-4′,4a′,6′,7′-
tetrahydrospiro[thiazolidine-5,2′-xanthene]-
2,4,8′(1′H,3′H,5′H)-trione (9b). A solution of 4g (50.0 mg,
0.15 mmol, 1 equiv), 1,3-dimedone (320.0 mg, 0.30 mmol, 2
equiv), and L-proline (170.0 mg, 0.15 mmol, 1 equiv) in 5 mL
of ethyl acetate was heated at 70 °C under an argon atmosphere
for 12 h. The mixture was cooled to room temperature, diluted
with 50 mL of ethyl acetate, washed twice with 30 mL of brine,
dried (Na2SO4), filtered, and concentrated. Column chroma-
EXPERIMENTAL PROCEDURES
■
General Procedure for Reactions of 2 with 3 (Table 2,
4a as Example). The catalyst 1b (22.0 mg, 0.06 mmol, 0.2
equiv) was added to a solution of α,β-unsaturated aldehyde 2a
(120.0 mg, 0.9 mmol, 3 equiv) and thiazolidinedione 3 (35.0
mg, 0.3 mmol, 1 equiv) in DCM (1 mL). The resulted solution
was stirred for 36 h at room temperature. After evaporation of
the solvent, the product was purified though column
chromatography over silica gel with hexane/EtOAc (10:1−
8:1) as the eluent to yield 4a (79.6 mg, 73% yield) as white
F
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ACS Combinatorial Science
Research Article
tography on silica gel of the crude product using a gradient
mixture of ethyl acetate/hexane (1:5−1:3) as eluent gave 57.0
mg (88% yield) of 9b.
t
major = 8.7 min, tminor = 29.7 min, ee > 99%; [α]2D5 = −53.7 (c =
1.2 in EtOAc).
(2′S,3S,4aS,6S,8S)-Diethyl-3-ethoxy-7′-methoxy-3′,5′-
dioxo-3,3′,4,4a,5,5′,6,8-octahydrospiro[isochromene-
7,2′-thiazolo[2,3-b]quinazoline]-6,8-dicarboxylate (10c).
A solution of 10a (25.0 mg, 0.047 mmol, 1.0 equiv) and 2-
amino-5-methoxybenzoic acid (15.0 mg, 0.094 mmol, 2.0
equiv) in glacial acetic acid (2 mL) was heated to gentle reflux
for 2.5 h, then cooled to room temperature. The pH was
adjusted to 7 with saturated NaHCO3 (aq), extracted with ethyl
acetate (20 mL × 3), dried over Na2SO4, concentrated to give
the crude product. It was purified through column chromatog-
raphy on silica gel (ethyl acetate/hexanes =10:1−8:1), 17.0 mg
(65% yield) of pure 10c was obtained as amorphous solid.
1H NMR (600 MHz, CDCl3) δ = 7.67 (d, J = 3.0 Hz, 1H),
7.48 (d, J = 8.9 Hz, 1H), 7.31 (dd, J = 3.0, 8.8 Hz, 1H), 6.20 (s,
1H), 5.05 (t, J = 3.0 Hz, 1H), 4.75 (s, 1H), 4.10−4.27 (m, 4H),
3.90 (s, 3H), 3.84 (dq, J = 7.3, 9.5 Hz, 1H), 3.54 (dq, J = 7.2,
9.3 Hz, 1H), 3.03−3.09 (m, 1H), 3.00−3.03 (m, 1H), 2.29 (dt,
J = 5.5, 14.1 Hz, 1H), 2.16 (ddd, J = 2.3, 7.7, 14.2 Hz, 1H), 1.92
(dd, J = 4.7, 14.0 Hz, 1H), 1.71 (dt, J = 3.6, 14.1 Hz, 1H),
1.27−1.31 (m, 6H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (15025
MHz, CDCl3) δ = 171.6, 171.3, 169.5, 158.5, 158.4, 152.5,
141.6, 138.1, 127.9, 125.4, 120.8, 111.1, 108.4, 96.8, 64.2, 63.8,
61.9, 61.9, 56.0, 50.8, 48.6, 32.8, 32.3, 29.8, 26.8, 15.5, 14.1;
HRMS (ESI) calcd for C27H30N2O9S (M + H+) 559.1750,
found 559.1757; HPLC (Chiralpak AD, Φ 0.46 × 25 cm, 25
°C, ethanol/hexane = 20/80, flow rate 1.0 mL/min, λ = 254
1H NMR (600 MHz, CDCl3) δ = 8.42 (br s, 1H), 7.34−7.36
(m, 1H), 7.30−7.31 (m, 1H), 6.35−6.36 (m, 2H), 6.31 (dd, J =
1.9, 3.2 Hz, 1H), 6.25 (d, J = 3.2 Hz, 1H), 6.23 (d, J = 3.3 Hz,
1H), 5.57 (ddd, J = 1.7, 5.9, 11.1 Hz, 1H), 4.22 (s, 1H), 3.97
(dd, J = 4.0, 13.7 Hz, 1H), 3.11 (q, J = 12.8 Hz, 1H), 2.33−2.45
(m, 5H), 1.92−1.99 (m, 2H); 13C NMR (150 MHz, CDCl3) δ
= 195.0, 174.6, 172.8, 168.6, 153.0, 151.9, 142.5, 142.4, 124.0,
114.5, 111.0, 110.7, 110.2, 109.4, 109.0, 75.4, 66.3, 50.0, 41.2,
36.3, 34.6, 29.8, 28.2; HRMS (ESI) calcd for C23H19NO6S (M
+ H+) 438.1011, found 438.1003; HPLC (Chiralpak OD, Φ
0.46 × 25 cm, ethanol/hexane = 20/80, 35 °C, flow rate 1.0
mL/min, λ = 230 nm): tmajor = 3.5 min, tminor = 8.5 min, ee >
99%; [α]2D5 = −21.9 (c = 0.2 in EtOAc).
(3S,4aS,5′S,6S,8S)-Diethyl-2′-(benzylthio)-3-ethoxy-
4′-oxo-3,4,4a,5,6,8-hexahydro-4′H-spiro[isochromene-
7,5′-thiazole]-6,8-dicarboxylate (10a). To a solution of 6l
(50.0 mg, 0.11 mmol) in ethyl vinyl ether (2 mL) was added
Yb(fod)3 (10 mg, 20% w/w). The mixture was stirred three
days under argon and after this time ethyl vinyl ether was
evaporated under reduced pressure. Flash chromatography on
silica gel (ethyl acetate/hexanes =15:1−10:1) afforded 58.0 mg
(99% yield) of pure 10a as amorphous solid.
1H NMR (600 MHz, CDCl3) δ = 7.30−7.39 (m, 5H), 6.12
(t, J = 1.5 Hz, 1H), 4.98 (dd, J = 2.6, 4.8 Hz, 1H), 4.60−4.62
(m, 3H), 4.13−4.16 (m, 4H), 3.80 (dq, J = 7.2, 9.6 Hz, 1H),
3.51 (dq, J = 7.2, 9.6 Hz, 1H), 3.03−3.10 (m, 1H), 2.87 (dd, J =
2.0, 4.7 Hz, 1H), 2.14 (ddd, J = 2.4, 7.7, 13.6 Hz, 1H), 2.02 (dt,
J = 5.2, 14.1 Hz, 1H), 1.96 (ddd, J = 1.8, 5.5, 14.1 Hz, 1H), 1.61
(dt, J = 4.7, 14.0 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.20−1.25
(m, 6H); 13C NMR (150 MHz, CDCl3) δ = 199.1, 188.1,
171.4, 169.4, 136.8, 134.7, 129.4, 129.0, 128.3, 113.1, 97.1, 73.3,
64.1, 61.5, 61.4, 50.2, 47.7, 38.3, 34.7, 33.1, 27.2, 15.4, 14.2,
14.1; HRMS (ESI) calcd for C26H31NO7S2 (M + H+) 534.2620,
found 534.2628; HPLC (Chiralpak AD, Φ 0.46 × 25 cm, 25
°C, ethanol/hexane = 20/80, flow rate 1.0 mL/min, λ = 254
nm) tminor = 14.7 min, tmajor = 22.3 min, ee > 99%; [α]2D5 = −97.3
(c = 3.1 in EtOAc).
(3S,4aS,5′S,6S,8S)-Diethyl-3-ethoxy-2′-morpholino-4′-
oxo-3,4,4a,5,6,8-hexahydro-4′H-spiro[isochromene-
7,5′-thiazole]-6,8-dicarboxylate (10b). A solution of 10a
(30.0 mg, 0.056 mmol, 1.0 equiv) and morpholine (24.0 mg,
0.28 mmol, 5.0 equiv) in acetonitrile (5 mL) was heated to 55
°C for 1 h, then cooled to room temperature, concentrated to
give the crude product. It was purified through column
chromatography on silica gel (ethyl acetate/hexanes = 5:1−
1:1), 23.5 mg (84% yield) of pure 10b was obtained as
amorphous solid.
nm): tminor = 11.0 min, tmajor = 16.5 min, ee > 99%; [α]D25
−120.0 (c = 0.3 in EtOAc).
=
(7S)-5-(2-Oxo-2-phenylethyl)-7-phenyl-3,5,6,7-tetra-
hydro-2H-thiopyrano[2,3-d]thiazol-2-one (11b). 8a (50.0
mg, 0.19 mmol, 1.0 equiv) and 1-phenyl-2-(triphenylphosphor-
anylidene) ethanone (140.0 mg, 0.38 mmol, 2.0 equiv) were
dissolved into DCM (5 mL). The resulting mixture was stirred
for 12 h at room temperature. After that time, the insoluble
solid was removing through filtrating, and the organic phase
was concentrated to give the crude product. It was purified
through column chromatography on silica gel (ethyl acetate/
hexanes =10:1−5:1), 59.5 mg (85% yield) of pure 11b (trans/
cis = 1:1) was obtained as white solid. Two diastereoisomers
were separated through further careful column chromatography
on silica gel.
1
11b (trans): H NMR (600 MHz, CDCl3) δ = 8.93 (br s,
1H), 7.93 (d, J = 7.3 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J
= 7.4 Hz, 2H), 7.35 (t, J = 7.4 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H),
7.23 (d, J = 7.4 Hz, 2H), 4.01−4.05 (m, 1H), 3.93 (dd, J = 5.8,
7.5 Hz, 1H), 3.52 (dd, J = 8.3, 17.6 Hz, 1H), 3.31 (dd, J = 5.4,
17.5 Hz, 1H), 2.34−2.42 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ = 196.6, 173.2, 142.5, 136.4, 133.8, 129.0, 128.9,
128.2, 128.0, 127.7, 120.1, 107.4, 43.2, 39.1, 38.7, 35.0; HRMS
(ESI) calcd for C20H17NO2S2 (M + H+) 368.0774, found
368.0782; HPLC (Chiralpak AD, Φ 0.46 × 25 cm, 25 °C, i-
propanol/hexane = 30/70, flow rate 0.8 mL/min, λ = 230 nm)
1H NMR (600 MHz, CDCl3) δ = 6.09 (s, 1H), 4.95−4.98
(m, 1H), 4.60 (s, 1H), 4.11−4.21 (m, 4H), 3.97−4.00 (m, 2H),
3.73−3.87 (m, 5H), 3.46−3.58 (m, 3H), 3.07−3.15 (m, 1H),
2.86 (d, J = 4.8 Hz, 1H), 2.15 (dd, J = 8.0, 13.6 Hz, 1H), 2.00
(dd, J = 5.2, 14.0 Hz, 1H), 1.92 (dt, J = 5.1, 13.4 Hz, 1H), 1.58
(dt J = 5.7, 13.4 Hz, 1H), 1.25−1.29 (m, 6H), 1.23 (t, J = 7.2
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ = 187.6, 179.3,
171.9, 169.7, 136.6, 113.5, 97.5, 73.8, 66.5, 66.2, 64.2, 61.2,
61.1, 50.9, 48.7, 48.2, 46.7, 35.0, 34.0, 27.4, 15.4, 14.2; HRMS
(ESI) calcd for C23H32N2O8S (M + H+) 497.1958, found
497.1959; HPLC (Chiralpak AD, Φ 0.46 × 25 cm, 25 °C,
ethanol/hexane =20/80, flow rate 1.0 mL/min, λ = 230 nm):
t
major = 13.7 min, tminor = 20.9 min, ee > 99%; [α]2D5 = 88.1 (c =
0.4 in EtOAc).
11b (cis): 1H NMR (600 MHz, CDCl3) δ = 9.00 (br s, 1H),
7.90 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J =
7.4 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H),
7.24 (d, J = 7.4 Hz, 2H), 4.17−4.23 (m, 1H), 4.03 (dd, J = 5.5,
10.8 Hz, 1H), 3.29 (dd, J = 7.8, 17.5 Hz, 1H), 3.23 (dd, J = 5.8,
17.5 Hz, 1H), 2.60 (ddd, J = 1.9, 5.5, 13.7 Hz, 1H), 2.05 (dt, J =
11.0, 13.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ = 196.2,
G
dx.doi.org/10.1021/co400022r | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
173.3, 142.5, 136.3, 133.9, 129.0, 128.2, 128.0, 127.7, 119.8,
109.8, 43.2, 42.2, 41.7, 38.1; HRMS (ESI) calcd for
C20H17NO2S2 (M + H+) 368.0779, found 368.0772; HPLC
(Chiralpak AD, Φ 0.46 × 25 cm, 25 °C, i-propanol/hexane =
30:70, flow rate 0.8 mL/min, λ = 230 nm) tmajor = 17.5 min,
tminor = 42.0 min, ee > 99%; [α]2D5 =15 (c = 0.4 in CHCl3).
Ethyl-2-((7S)-2-oxo-7-phenyl-3,5,6,7-tetrahydro-2H-
thiopyrano[2,3-d]thiazol-5-yl)acetate (11a). To a solution
of 8a (50.0 mg, 0.19 mmol, 1.0 equiv) in DCM (5 mL), 1-
phenyl-2-(triphenylphosphoranylidene)ethanone (130.0 mg,
0.38 mmol, 2.0 equiv) was added, the resulting mixture was
stirred, and the solution was gradually clear (12h), concentrated
to give the crude product. It was purified through column
chromatography on silica gel (ethyl acetate/hexanes = 10:1−
5:1), 35.6 mg (56% yield) of pure 11a (trans/cis = 1:1) was
obtained as white solid.
were incubated at 35 °C, and the growth MIC was determined
at 24 h for Candida albicans and at 72 h for Cryptococcus.
neoformans.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures and H and 13C NMR, chiral HPLC
analysis data for products 4, 6, 8, 9, and 10 and X-ray data (CIF
files) of 4a and 8a. The antitumor inhibitory curve of
compound 10a. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*Tel./Fax: 86-21-81871243 (W.Z.); 86-21-81871243 (C.S.).
Phone: (505) 277-0756 (W.W.). Fax: (505) 277-2609 (W.W.).
E-mail: zhangwnk@hotmail.com (W.Z.); shengcq@hotmail.
com (C. S.); wwang@unm.edu (W.W.).
1
Compounds 11a (trans and cis). H NMR (600 MHz,
CDCl3) δ = 9.53 (br s, 1H), 9.49 (brs 1H), 7.20−7.36 (m,
10H), 4.11−4.18 (m, 4H), 3.96 (dd, J = 5.4, 11.1 Hz, 1H),
3.93−3.98 (m, 1H), 3.90 (dd, J = 5.7, 7.0 Hz, 1H), 3.74−3.79
(m, 1H), 2.76 (dd, J = 8.2, 16.0 Hz, 1H), 2.68 (dd, J = 8.2, 16.0
Hz, 1H), 2.60 (d, J = 7.1 Hz, 2H), 2.53 (ddd, J = 1.9, 5.5, 13.9
Hz, 1H), 2.26−2.35 (m, 2H), 2.00 (dt, J = 11.2, 13.7 Hz, 1H),
1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ = 173.8, 173.7, 170.4, 170.2, 142.6, 142.4,
129.0, 128.0, 127.9, 127.8, 127.6, 120.0, 119.9, 109.8, 107.4,
61.3, 61.2, 42.4, 41.6, 39.4, 38.9, 38.9, 38.5, 35.7, 14.3, 14.2;
HRMS (ESI) calcd for C16H17NO3S2 (M + H+) 336.0728
found 336.0730; HPLC (Chiralpak OZ, 0.46 cm I.D. × 25 cm
L × 5 mm, ethanol/hexane =20/80, 35 °C, flow rate 0.8 mL/
Author Contributions
Yongqiang Zhang and Shengzheng Wang contributed equally
to this article.
Funding
Financial support of this research by the National Natural
Science Foundation of China (Grant 81222044, C.-Q.S.), the
863 Hi-Tech Program of China (Grant 2012AA020302, C.-
Q.S.), Shanghai Rising-Star Program (grant 12QH1402600, C.-
Q.S.), the National Science Foundation (CHE-1057569, W.
W.), and East China University of Science & Technology
(W.W.) is gratefully acknowledged.
min, λ = 230 nm) t1minor = 11.1 min, t1major = 12.9 min/t2minor
=
Notes
17.6 min, t2major = 19.0 min, ee = 89%/88%; [α]2D5 = 4.3 (c = 2.2
in EtOAc).
The authors declare no competing financial interest.
In Vitro Antitumor Activity Assay. Cells were plated in
96-well microtiter plates at a density of 5 × 103/well and
incubated in a humidified atmosphere with 5% CO2 at 37 °C
for 24 h. Test compounds were added onto triplicate wells with
different concentrations and 0.1% DMSO for control. After
they had been incubated for 72 h, 20 μL of MTT [3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] solu-
tion (5 mg/mL) was added to each well and the plate was
incubated for an additional 4 h. The formazan was dissolved in
100 μL of DMSO. The absorbance (OD) was read on a
WellscanMK-2 microplate reader (Labsystems) at 570 nm. The
concentration causing 50% inhibition of cell growth (IC50) was
determined by the Logit method. Irinotecan, a clinically
available antitumor agent, was used as the positive control.
All experiments were performed three times.
In Vitro Antifungal Activity Assay. In vitro antifungal
activity was measured by means of the minimal inhibitory
concentrations (MIC) using the serial dilution method in 96-
well microtest plates. Test fungal strains were obtained from
the ATCC (American type culture collection). Fluconazole was
used as a positive control. The MIC determination was
performed according to the National Committee for Clinical
Laboratory Standards (NCCLS) recommendations with RPMI
1640 (Cell culture from Sigma) buffered with 0.165MMOPS
buffer [(3-N-morpholino)propanesulfonic acid, Sigma] as the
test medium. The MIC value was defined as the lowest
concentration of test compounds that resulted in a culture with
turbidity less than or equal to 80% inhibition when compared
with the growth of the control. Test compounds were dissolved
in DMSO serially diluted in growth medium. The fungal strains
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