Facile synthesis of new N -sulfonamidyl-4-thiazolidinone derivatives and their biological evaluation

Article abstract of DOI:10.1039/c6nj00021e

The one-pot three-component syntheses of new N-sulfonamide-thiazolidin-4-one derivatives were carried out in excellent yield using [HDBU][HSO₄] as an ionic liquid under solvent-free conditions. The newly synthesized compounds were screened against fungal strains and a number of compounds were seen to display excellent antifungal activity. In addition, the synthesized compounds were screened for their scavenging activity of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and showed very good antioxidant activity. Finally, theoretical predictions derived from molecular docking studies against the potential target sterol 14α-demethylase (CYP51) helped establish a link between the observed biological activity and the binding affinity, thereby providing insights into the specific bonding and non-bonding interactions governing the activity.

Full text of DOI:10.1039/c6nj00021e

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Facile synthesis of new N-sulfonamidyl-4-
thiazolidinone derivatives and their biological
Cite this:DOI: 10.1039/c6nj00021e
evaluation†
Dnyaneshwar D. Subhedar,a Mubarak H. Shaikh,a Firoz A. Kalam Khan,b
Jaiprakash N. Sangshetti,b Vijay M. Khedkarcd and Bapurao B. Shingate*a
The one-pot three-component syntheses of new N-sulfonamide-thiazolidin-4-one derivatives were
carried out in excellent yield using [HDBU][HSO4] as an ionic liquid under solvent-free conditions. The
newly synthesized compounds were screened against fungal strains and a number of compounds were
seen to display excellent antifungal activity. In addition, the synthesized compounds were screened for
their scavenging activity of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and showed very good
antioxidant activity. Finally, theoretical predictions derived from molecular docking studies against the
potential target sterol 14a-demethylase (CYP51) helped establish a link between the observed biological
activity and the binding affinity, thereby providing insights into the specific bonding and non-bonding
interactions governing the activity.
Received (in Montpellier, France)
4th January 2016,
Accepted 18th January 2016
DOI: 10.1039/c6nj00021e
www.rsc.org/njc
furthermore, it is also able to cause superficial and/or invasive
infections in immune-compromised individuals.2,3 Therefore,
1. Introduction
The emergence over the past few decades of eukaryotic micro- it is necessary to find new and efficacious drugs to solve these
organism fungi highly resistant to current drugs is challenging problems.
research group’s the world over to design, synthesize, and
The human body has a complex system of natural enzymatic
evaluate new drug molecules.1 Fungi are vital opportunistic and non-enzymatic antioxidant defenses to counteract the
pathogens of humans and are becoming drug-resistant to many harmful effects of free radicals and other oxidants. Reactive
approved compounds, in particular Cryptococcus neoformans oxygen species (ROS) are essential for an organism’s essential
and the species of Candida and Aspergillus, with serious activities, such as the regulation of cell proliferation, intra-
potential consequences. Other factors that are contributing cellular signaling and the synthesis of biologically active com-
to drug resistance are the more frequent use of invasive pounds, and energy. However, the excessive production of ROS
medical procedures and excessive treatment with broad- causes oxidative stress and chronic diseases, such as cardio-
spectrum antibiotics. In many medical cases, for instance with vascular disease, Alzheimer’s disease, rheumatoid arthritis, aging,
AIDS or cancer, it is not the AIDS or cancer itself but the heart diseases, and cancer. ROS are known to directly interact
mycoses that are lethal to these patients. Many serious fungal with all types of biomolecules, including proteins, lipids, and
infections are caused by Candida albicans, Cryptococcus neo- DNA, resulting in oxidative cellular damage.4 Another impor-
formans and Aspergillus fumigates, with Candida albicans being tant aspect regarding the antioxidant activity is the lipophilicity
the most common agent of fungal blood stream infections; of the compounds. It is well established in the literature that
lipophilic compounds exhibit good antioxidant behavior in lipid
systems.5
a Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University,
The thiazolidin-4-one ring is one of the most intensively
investigated, and its derivatives have a variety of medicinal
Aurangabad, 431 004, India. E-mail: bapushingate@gmail.com;
Fax: +91-240-2403113; Tel: +91-240-2403311-12
b Department of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy,
applications, such as antimicrobial,6 antitubercular,7 anti-
inflammatory,8 HIV inhibitors,9 antihypertensive,10 anticonvulsant,11
antiproliferative,12 antitumor growth and metastasis,13 CNS-
penetrant,14 antiparasitic,15 anti-hyperglycemic,16 antibiofilm,17
monoamine oxidase A inhibitors,18 and antioxidant agents.19
Highly functionalized thiazolidinones (Fig. 1) display very good
antifungal activity.20
Aurangabad, 431 001, India
c Combichem-Bioresource Centre, National Chemical Laboratory, Pune 411 008,
India
d School of Health Sciences, University of KwaZulu Natal, Westville Campus,
Durban 4000, South Africa
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c6nj00021e
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2. Results and discussion
2.1 Chemistry
The synthetic strategy for new N-sulfonamido-thiazolidin-4-ones
4a–m via a one-pot, three-component reaction of various aryl
aldehyde 1a–m, 4-methylbenzenesulfonohydrazide 2, and thio-
glycolic acid 3 compounds using [HDBU][HSO4] as an efficient
catalyst is presented in Scheme 2. The required starting material
4-methylbenzenesulfonohydrazide 2 was prepared by the reac-
tion of 4-methylbenzene-1-sulfonyl chloride (tosyl chloride) with
hydrazine hydrate at 0 1C in THF.29 As per the literature survey,
till date, there have been no reports on the use of [HDBU][HSO4]
as a catalyst for carrying out cyclocondensation between various
aryl aldehyde, p-toluene sulphonyl hydrazide, and thioglycolic acid
compounds. In view of the unique properties of [HDBU][HSO4]
and its ability to act as a catalyst, herein we reveal [HDBU][HSO4]
as a potential catalyst for the synthesis of 4-methyl-N-(4-oxo-2-
phenylthiazolidin-3-yl)benzenesulfonamide derivatives.
In order to optimize the reaction conditions and to obtain the
best catalytic activity, the reaction of benzaldehyde 1a (1 mmol),
4-methylbenzenesulfonohydrazide 2 (1 mmol), and thioglycolic
acid 3 (1 mmol) was used as a model reaction, with the reaction
conducted under different reaction parameters, such as different
solvents and amount of catalyst (Scheme 1).
Initially, the model reaction was carried out in several solvents,
like EtOH, MeOH, H2O, CH3CN, THF, CH2Cl2, DMF, and toluene
under solvent-free conditions to investigate the efficiency of the
catalyst. In this study, it was found that conventional heating at
80 1C under solvent-free conditions was more efficient than using
organic solvents with respect to the reaction time and yield of the
desired 1,3-thiazolidin-4-one 4a (Table 1).
The effect of the amount of catalyst on the model reaction was
then subsequently tested for different concentrations, namely 5, 10,
15, 20 and 25 mol% (Table S1, entries 1–5, ESI†) of [HDBU][HSO4],
at 80 1C under solvent-free conditions. Using less than 20 mol%
of catalyst, moderate yields of the product (68–83%) were obtained
with extended reaction times. It is evident from (Table S1, entry 5,
ESI†) that 20 mol% of the [HDBU][HSO4] is adequate to gain the
optimum yield in the shortest reaction time (1 h), while with
an excess mol% of catalyst (25 mol%) there was no further
increase in the yield of the product, possibly due to saturation
of the [HDBU][HSO4]. The above results signify that 20 mol% of
[HDBU][HSO4] was the optimum catalyst loading in terms of
efficient yield and reduced reaction time.
Fig. 1 Thiazolidin-4-one derivatives that exhibit antifungal activity.
Ionic liquids (ILs) have emerged as promising homogeneous
catalysts21 because of their unique physicochemical properties,
including negligible vapor pressure, wide liquid range, high
ionic conductivity, and excellent solubility.22 Multi-component
reactions (MCRs) are powerful tools and have attracted much
attention from synthetic organic chemists because they allow
the efficient construction of highly complex molecules in a
single procedure step, thus avoiding complicated purification
operations and allowing savings to be made in the use of both
solvents and reagents.23 The synthesis of thiazolidin-4-one deri-
vatives has been achieved via the one-pot three-component
cyclocondensation of carbonyl, amines, and thioglycolic acid
using DCC,24a HBTU,24b Hunig’s base,24c activated fly ash,24d
ferrite,24e [bmim][PF6],24f [BmIm]OH,24g supported protic acid,24h
Bi(SCH2COOH)3,24i silica gel,24j and nano-Fe3O4@SiO2.24k However,
some of these methods suffer from at least one of the following
disadvantages: longer reaction time, corrosive nature, hazardous
reaction conditions, tedious work-up procedures, unsatisfactory
yields, and use of non-recyclable reagents. Therefore, it seems that
a major task of current research is to replace less efficient and
traditional catalysis procedures with more acceptable methods based
on improved yields, stability, and the recoverability and reusability of
catalysts. Bronsted acidic ionic liquids may be promising greener
alternatives to conventional reagents, and using Bronsted acids for
catalysis can help to overcome some of these drawbacks.25 Herein,
DBU-based26 (DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene) hydrogen
sulfate anion ionic liquid has been successfully applied to the
reaction of arylaldehydes, 4-methylbenzenesulfonohydrazide and
thioglycolic acid in solvent-free conditions to provide a series of
1,3-thiazolidin-4-one derivatives.
To determine the catalyst recyclability and reusability, the
[HDBU][HSO4] was reused as such for each subsequent experi-
ment under similar reaction conditions. After completion of
Considering the significance of thiazolidin-4-one scaffolds
and the utility of ionic liquids for organic transformation
and in continuation of our studies based on synthesis and bio-
evaluation,27 herein we report the synthesis of new thiazolidin-
4-one derivatives via a one-pot three-component reaction using
[HDBU][HSO4] as a catalyst under solvent-free heterocyclic
synthesis conditions in high yields.28 In addition to this, we
screened the synthesized compounds for their antifungal and
antioxidant properties. Moreover, we also performed a mole-
cular docking study for the synthesized compounds.
Scheme 1 Standard model reaction.
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Scheme 2 Synthesis of N-sulfonamido-thiazolidin-4-ones 4a–m.
Table 1 Screening of solvent
Table 2 Comparison of the efficiency of [HDBU][HSO4] for the synthesis
of (4a)
[HDBU][HSO4]
Entry Solvent
mol%
Time (h) Temp. (1C) Yielda (%)
Entry Catalyst
Reaction conditionsa Timeb/h Yieldc (%)
1
2
3
4
5
6
7
8
EtOH
MeOH
CH2Cl2
H2O
CH3CN
THF
DMF
Toluene
Solvent-free 20
Solvent-free 20
Solvent-free 20
Solvent-free 20
Solvent-free 20
20
20
20
20
20
20
20
20
1
1
1
1
1
1
1
1
1
1
1
1
1
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
50
60
80
100
110
60
55
62
Trace
50
55
57
61
58
69
90
90
86
1
2
3
4
5
6
7
8
HClO4
TFA
AcOH
[Et3NH][HSO4]
[Et3NH][H2PO4]
[Et3NH][CH3COO] Solvent-free/80 1C
—
[HDBU][HSO4]
Solvent-free/80 1C
Solvent-free/80 1C
Solvent-free/80 1C
Solvent-free/80 1C
Solvent-free/80 1C
5
64
53
36
84
6.4
8.2
1.5
2
3.5
24–48
1
79
72
PhMe/120 1C
Solvent-free/80 1C
87.330
90
9
a
Reaction conditions: 1a (1 mmol), 2 (1 mmol) and 3 (1 mmol),
10
11
12
13
b
different acid catalyst and ionic liquids (20 mol%). Reaction progress
monitored by TLC. Isolated yield of products.
c
Reaction conditions: 1a (1 mmol), 2 (1 mmol), 3 (1 mmol) and 20 mol%
[HDBU][HSO4]. Isolated yield.
and AcOH were employed as the catalyst, it resulted in a low
yield of product in a much greater reaction time (Table 2,
entries 1–3). We also studied a variety of other Bronsted acid
a
the reaction, the reaction mixture was poured on to ice water ionic liquid catalysts to probe the superiority of [HDBU][HSO4].
and the product was separated by filtration. It is apparent from (Table 2) that the catalytic activity was
The filtrate was subjected to evaporation of the water to strongly affected by the anionic part of the ionic liquids. In the
obtain a viscous liquid, which on cooling gave the ionic liquid. case of the [HSO4] anion, higher yields were obtained (Table 2,
Then, we reused the catalyst in at least four consecutive cycles entries 4). However, when [H2PO4] and [CH3COO] anions were
without much appreciable loss in its catalytic activity. The probed for their efficiency, lower yields (72–79%) were obtained
recyclability data demonstrated the high stability of the catalyst compared to the [HSO4] anion (84–90%), probably due to the
under the reaction conditions (ESI,† Table S2 and S3). Although weaker acidity of the phosphate and acetate anions in com-
the reaction rate decreased with the non-dried-recycled catalyst to parison to the [HSO4] anion. Our reaction results compare
give 70–52% yield of product (Table S3, entries 1–4, ESI†), when well with previously reported reaction. This reaction requires
we used the dried-recycled catalyst, we succeeded in obtaining 24–48 h in toluene (Table 2, entry 7). The results obtained in
the desired product 4a in a satisfactory 90–86% yield (Table S2, (Table 2) validate that the anions of the ionic liquid have a
entry 2, ESI†).
notable effect compared to the cations on the reaction rates.
In the next step, we examined the efficiency of the present As one can see, our results have better performance with other
method for the synthesis of 1,3-thiazolidin-4-ones, wherein Bronsted acid catalysts, ionic liquids, and previously reported
compound 4a was compared with a variety of other organic, data, when all the factors, including yields, reaction times, and
inorganic and Bronsted acid catalysts. When HClO4, TFA, reaction conditions are taken into account (Table 2, entry 8).
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These results imply that [HDBU][HSO4] is the best ionic liquid thiazolidinones 4b–m in high yields (Scheme 2). Therefore,
catalyst/promoter for the synthesis of the current 4-thiazol- the above results suggest that the one-pot three-component
idinone derivatives.
cyclocondensation reaction proceeded smoothly.
The structure of compound 4a was confirmed by FT-IR,
A plausible mechanism for the formation of 1,3-thiazolidin-
1H NMR, 13C NMR, and HRMS spectrometry. The IR spectra 4-one catalyzed by [HDBU][HSO4] as a ionic liquid is shown in
of the 4a synthesized compounds showed characteristic signals Scheme 3. It can be speculated that the [HSO4] of [HDBU][HSO4]
at 3230 cmÀ1 due to an N–H group, at 1719 cmÀ1 due to a favors interaction with an oxygen atom of the carbonyl group of
carbonyl group, and at 1330, 1171 cmÀ1 due to a N–SO2– group. the aldehyde, followed by nucleophilic attack of sulfonylhydrazide,
Similarly, in the 1H NMR spectra of compound 4a, the methylene leading to the formation of an imine intermediate VI. Then,
2À
protons of thiazolidin-4-one ring appear as two distinct parts of a free SO4 ions interact with the protons of thioglycolic acid
doublet, thereby indicating that both the protons are magneti- and the sulfur anions of thioglycolic acid attack the activated
cally non-equivalent. The C–H proton of the 4 thiazolidinone imine group of the intermediate VII, affording the intermediate
ring appeared as a singlet at d 6.88 ppm. The formation of the VIII. Next, the [HDBU][HSO4] again activates the intermediate
4-thiazolidinone ring was also proven by the appearance of the VIII, followed by removal of water from the intermediate IX,
peaks at around 35.8, 52.0, and 165.8 (CH, CH2, and CQO, resulting in the final product 4a, and then regeneration of the
respectively) ppm in the 13C NMR spectra. Furthermore, the catalyst takes place.
formation of compound 4a was confirmed by the HRMS spectrum
and the calculated [M + H]+ was 349.1864 compared to the
2.2 Biological activity
observed value at 349.1844.
2.2.1. Antifungal activity. All the synthesized compounds
After optimization of the reaction conditions, to delineate were screened for their in vitro antifungal activity. The anti-
this approach, the present methodology was evaluated with a fungal activity was evaluated against different fungal strains,
variety of substituted aryl aldehydes 1b–m in the presence of including C. albicans (NCIM 3471), Fusarium oxysporum (NCIM
[HDBU][HSO4] under similar conditions. The reaction conditions 1332), Aspergillus flavus (NCIM 539), Aspergillus niger (NCIM 1196),
worked well for the electron donating and electron withdrawing and C. neoformans (NCIM 576). Minimum inhibitory concentration
groups on aldehydes 1b–m, resulting in the corresponding (MIC, mg mLÀ1) values of all the compounds were determined
Scheme 3 Plausible mechanism for the synthesis of thiazolidin-4-ones by [HDBU][HSO4].
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Table 3 In vitro antifungal, antioxidant activities, and molecular docking analysis of compounds 4a–m MIC in (mg mLÀ1
)
Antifungal activity MIC (mg mLÀ1
)
DPPH IC50
Docking
score
Binding energy
Entry
R1
R2
R3
CA
FO
AF
AN
CN
(mg mLÀ1
)
(kcal molÀ1
)
4a
4b
4c
4d
4e
H
H
OMe
OMe
Cl
H
H
F
H
H
OH
H
H
—
—
—
H
H
H
H
H
Cl
H
H
NO2
H
H
H
H
—
—
—
H
Me
H
OMe
H
H
Cl
H
H
NO2
H
OH
NMe2
—
—
—
100
150
25
25
25
50
25
25
100
125
75
25
100
50
50
*
*
*
200
*
50
150
50
50
125
50
200
200
50
*
*
48.65
45.87
19.42
16.25
22.30
44.63
33.64
18.45
38.29
26.76
20.39
25.30
*
À6. 04
À6.03
À7. 31
À6.98
À7.04
À6.17
À6.84
À7.06
À8.70
À7.45
À7.02
À6.13
À6.00
NT
À28.98
À21.58
À50.44
À43.42
À46.21
À35.04
À41.49
À48.81
À21.08
À21.07
À45.81
À34.77
À21.23
NT
75
75
25
75
150
25
*
25
100
25
75
100
100
*
4f
4g
4h
4i
4j
4k
4l
4m
BHT
MA
FA
50
25
150
200
25
150
200
50
100
200
NT
25
*
*
50
25
*
NT
25
6.25
100
100
*
NT
25
12.5
50
100
NT
25
NT
25
6.25
16.47
NT
NT
NT
À7.34
NT
À52.92
6.25
6.25
CA, Candida albicans; FO, Fusarium oxysporum; AF, Aspergillus flavus; AN, Aspergillus niger and CN, Cryptococcus neoformans. BHT: butylated
hydroxytoluene; MA: micanazole, FA: fluconazole, NT: not tested, Note: * no activity was observed.
using the standard agar dilution method as per CLSI guidelines.31 which was measured using the 2,2 diphenyl-1-picrylhydrazyl
All the experiments were performed in triplicate and the mean (DPPH) radical scavenging assay.32 DPPH radical scavenging
reading was taken as the final reading. 5% DMSO was used as a activity is the most commonly used method for screening the
negative control, along with miconazole and fluconazole as the antioxidant activities of various natural as well as syn-
standard antifungal drugs (Table 3).
thetic antioxidants. A lower IC50 value indicates greater anti-
According to the antifungal activity data (Table 3), it can be oxidant activity. The IC50 (concentration required to scavenge
observed that many of the synthesized compounds display 50% of the radicals) values were calculated in order to evaluate
prominent antifungal activity. Some compounds were narrow- the potential antioxidant activities. Butylated hydroxytoluene
spectrum active against only one fungal strain, while some were (BHT) was used as the standard drug for the comparison of
found to have broad-spectrum activity against all fungal strains. antioxidant activity, and the observed results are summarized
Compounds 4c, 4d, 4e, 4g, 4h, and 4k, with MIC values of in Table 3.
25 mg mLÀ1, exhibited equivalent activity compared to the standard
According to the DPPH assay, compounds 4c (IC50
=
=
=
=
drug miconazole against the fungicidal strain C. albicans. Among 19.42 mg mLÀ1), 4d (IC50 = 16.25 mg mLÀ1), 4e (IC50
the whole series, the compounds 4d and 4h, with MIC values of 22.30 mg mLÀ1), 4h (IC50 = 18.45 mg mLÀ1), 4k (IC50
25 mg mLÀ1, were found to exhibit equivalent activity, compared 20.39 mg mLÀ1), 4j (IC50 = 26.76 mg mLÀ1), and 4l (IC50
to the standard drug miconazole against the fungal strain 25.30 mg mLÀ1) showed excellent to moderate antioxidant
F. oxysporum. For the fungal strain A. flavus, compounds 4e, activity compared to the standard antioxidant drug BHT
4h, and 4l, with MIC values of 25 mg mLÀ1, were found to exhibit (IC50 = 16.45 mg mLÀ1). From the synthesized compounds, 4a,
equipotent activity compared to the standard drug miconazole. 4b, 4f, 4g, and 4i showed the lowest DPPH radical scavenging
For the fungal strain A. niger, compounds 4c and 4e, with MIC activity when compared with the standard, with IC50 values
values of 25 mg mLÀ1, were found to exhibit equivalent anti- ranging from 33.64 to 48.65 mg mLÀ1
fungal activity compared to the standard drug miconazole. All
.
the synthesized compounds exhibited less antifungal activity
against the fungal strain C. Neoformans.
3. Molecular docking
2.2.2. Antioxidant activity. Thirteen different thiazolidin-4-
one derivatives were synthesized and evaluated for their in vitro Molecular docking has become an integral part of drug dis-
free radical scavenging activity against free radicals. Our findings covery research in recent times and it imparts knowledge on the
provide evidence that the synthetic compounds 4a–m showed structural and functional aspects of proteins and ligands. It gives
a concentration-dependent anti-radical activity resulting from indications on binding affinities, binding modes, and types of
the reduction of DPPH radicals to their non-radical forms, interactions guiding the protein–ligand complexation, and
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Fig. 2 Binding mode of compounds 4c, 4d, 4e, 4g, 4h, and 4k in the active site of sterol 14a-demethylase (CYP51). (The p–p stacking interaction has
been represented using green lines.)
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provides immense opportunities for researchers for generating residues shaping the active site. The compound was observed
and analyzing the potential of existing lead molecules and their to be stabilized within the active site through an extensive network
analogs. Therefore, with the aim of rationalizing the promising of van der Waals interactions with Val461 (À2.92 kcal molÀ1),
antifungal activity demonstrated by the titled thiazolidin-4- Met460 (À2.76 kcal molÀ1), Val359 (À1.18 kcal molÀ1),
one derivatives and to understand the molecular basis of Met358 (À1.00 kcal molÀ1), Leu356 (À2.13 kcal molÀ1), Tyr116
their interactions, a molecular docking study was carried out (À4.59 kcal molÀ1), Met106 (À1.79 kcal molÀ1), and Tyr103
against sterol 14a-demethylase (CYP51) as the target receptor. (À3.99 kcal molÀ1) residues through the phenyl ring at the C2
In the absence of available resources to carry out the enzymatic position of the thiazolidinone scaffold.
assays, molecular modeling techniques like molecular docking
The thiazolidin-4-one nucleus was also involved in signifi-
have gained significant attention to identify the targets for cant van der Waals interactions with Cys422 (À1.99 kcal molÀ1
)
different ligands and the associated thermodynamic inter- and Thr295 (À1.08 kcal molÀ1), while the para-toluene sulpho-
actions with the target enzyme that govern the inhibition of the nyl hydrazide showed a similar type of interactions with
pathogen.
Ala291 (À1.93 kcal molÀ1), Phe290 (À2.09 kcal molÀ1), Ala288
A perusal of the binding modes of all these thiazolidin-4- (À1.75 kcal molÀ1), Ala287 (À1.02 kcal molÀ1), Met284
one derivatives revealed that they could snugly fit into (À1.63 kcal molÀ1), Leu208 (À1.00 kcal molÀ1), Leu130
the active site of CYP51 by adopting a very similar orientation (À1.08 kcal molÀ1), Leu127 (À1.44 kcal molÀ1), and Phe110
and at coordinates very close to that of the native ligand (À1.68 kcal molÀ1) lining the active site of CYP51. Also a
fluconazole in the crystal structure (Fig. 3). Their complexa- significant van der Waals (À4.03 kcal molÀ1) and electrostatic
tion with the target enzyme is stabilized by the formation of (À8.75 kcal molÀ1) interaction was observed with the heme
several steric and electrostatic interactions. Their binding group present in the active site. Furthermore, two prominent
energies were also found to be negative, ranging from pi–pi (p–p) stacking interactions were observed through the
À50.44 kcal molÀ1 to À21.23 kcal molÀ1, while the docking phenyl ring at the C2 position of the thiazolidin-4-one scaffold,
score ranged from À7.31 to À6.00, which signifies a good first with the phenyl ring of Tyr103 and second with the phenyl
correlation between the docking study and the obtained ring of Tyr116, with a bonding distance of 2.07 Å and 2.47 Å,
biological activity, with the active compounds having higher respectively, which contributed significantly to the stability of
scores, while those with relatively low activity are also pre- the ligand in the active site of the enzyme.
dicted to have a lower score (ESI,† Table S4). The docking
A similar network of interaction was observed for the other
score for the reference ligand fluconazole was found to be active 4-thiazolidinone derivatives as well but decreasing gra-
À7.34, with a binding energy of À52.92 kcal molÀ1. A detailed dually with their observed antifungal activity. The per-residue
per-residue interaction analysis between the enzyme and the interaction analysis revealed that the primary driving forces
most active derivatives (4c, 4d, 4e, 4g, 4h, and 4k) was carried for mechanical interlocking was the steric complementarity
out to identify the most significant interaction among the between the ligand and the active site residues of CYP51, as
residues and the type of thermodynamic interactions govern- was reflected in the relatively higher number of favorable van
ing the binding of these molecules. However, for the sake der Waals interaction over the other components contributing
of brevity, we elucidated this analysis only for one of the to the overall binding scores. Interestingly, all the thiazol-
most active analogs 4c, with the results summarized in the ESI,† idinones investigated herein were found to be coordinated to
Table S4, for 4d, 4e, 4g, 4h and 4k, while their binding modes the iron of the heme group present in the active site. This
are presented in Fig. 2.
is a very important observation considering the fact that even
The lowest energy docking pose of the most active analog 4c fluconazole is also coordinated with the metal ion in the
into the active site of sterol 14a-demethylase (CYP51) revealed enzyme active site. Thus, the 4-thiazolidinone compounds may
that it binds to the enzyme with a significantly higher binding share the same inhibition mechanism as fluconazole, making
affinity, which could be explained in terms of the specific them pertinent starting points for second generation drug
bonding and non-bonding per-residue interactions with the development.
Fig. 3 Overlay of the best scoring pose for fluconazole obtained by docking (green carbon) against the X-ray bound conformation (pink carbon).
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4. Conclusions
5.1.1. 4-Methyl-N-(4-oxo-2-phenylthiazolidin-3-yl)benzene-
sulfonamide (4a). Compound 4a was obtained by a cyclo-
condensation reaction between benzaldehyde 1a, 4-methylbenzene-
sulfonohydrazide 2, and thioglycolic acid 3 as a white solid; Mp
130–132 1C; yield: 90%; FT-IR (KBr, nmax, cmÀ1): 3230 (N–H str.),
3071, 2933 (C–H str.), 1719 (CQO str.), 1597, 1474 (CQC str.),
1330, 1171 (N–SO2– str.); 1H NMR (400 MHz, DMSO-d6, d ppm):
8.03–8.14 (m, 4H, H–Ar–SO2–NH), 7.49–7.58 (m, 5H, Ar–H), 6.88
(s, 1H, S–CH–N), 4.26 (d, 1H, CH2), 4.23 (d, 1H, CH2) and 2.46
(s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d ppm): 165.8,
145.4, 142.3, 134.9, 133.1, 133.0, 131.5, 127.4, 126.3, 52.0, 35.8
and 24.1; HRMS (ESI-qTOF): Calcd for C16H17N2O3S2 [M + H]+,
349.1864: found: 349.1844.
In conclusion, we synthesized a series of new thiazolidin-4-one
pharmacophores combined with sulphonyl hydrazide moieties as
a promising strategy for the development of new 4-thiazoldinone
derivatives 4a–m with potent biological activities. The synthe-
sized compounds 4a–m were examined for their antifungal and
antioxidant activities. Among them, 4c, 4d, 4e, 4g, 4h, 4k, and 4l
showed good vitro antifungal activity, and 4c, 4d, 4e, 4h, and 4k
also possessed strong in vitro antioxidant activity. The trend
in the observed antifungal activity was further rationalized by
molecular docking studies with respect to the binding energy
of these thiazolidin-4-one derivatives toward a target enzyme
lanosterol 14a-demethylase (CYP51). The theoretical predictions
derived from the molecular docking studies were found to be in
harmony with the experimental antifungal data, thereby suggest-
ing that this class of molecule may act as inhibitors of CYP51.
This suggests that the compounds from the present series of 4c,
4d, 4e, 4g, 4h, 4k, and 4l can be further optimized and developed
as lead molecules. Using a [HDBU][HSO4] green protocol offers
advantages, such as excellent yields of products, a shorter reaction
time period, and a more simple procedure and preparation of
catalyst as well as reusability of the catalyst.
5.1.2. 4-Methyl-N-(4-oxo-2-(p-tolyl)thiazolidin-3-yl)benzene-
sulfonamide (4b). Compound 4b was obtained by a cyclo-
condensation reaction between 4-methylbenzaldehyde 1b, 4-methyl-
benzenesulfonohydrazide 2, and thioglycolic acid 3 as a white
solid; Mp 145–147 1C; yield: 88%; FT-IR (KBr, nmax, cmÀ1): 3495
(N–H str.), 2980 (C–H str.), 1677 (CQO str.), 1454, 1399 (CQC
str.), 1339, 1269 (N–SO2– str.); 1H NMR (400 MHz, DMSO-d6,
d ppm): 7.96–8.13 (m, 4H, H–Ar–SO2–NH), 7.66–7.80 (m, 4H,
Ar–H), 7.08 (s, 1H, S–CH–N), 4.29 (d, 1H, CH2, J = 12 Hz), 4.19
(d, 1H, CH2, J = 12 Hz), 2.48 (s, 3H) and 2.34 (s, 3H, CH3); 13C
NMR (100 MHz, DMSO-d6, d ppm): 165.2, 143.1, 139.4, 130.8,
129.3, 129.2, 129.1, 124.1, 123.8, 52.1, 34.6, 24.5 and 19.5.
5.1.3. N-(2-(2-Methoxyphenyl)-4-oxothiazolidin-3-yl)-4-methyl-
benzenesulfonamide (4c). Compound 4c was obtained by a
cyclocondensation reaction between 2-methoxybenzaldehyde
1c, 4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3 as
a white solid; Mp 136–137 1C; yield: 84%; FT-IR (KBr, nmax, cmÀ1):
3442 (N–H str.), 2971 (C–H str.), 1698 (CQO str.), 1658, 1618,
5. Experimental
All the reagents were purchased from Merck and Spectrochem
and used without further purification. Melting points of all the
synthesized compounds were determined in an open capillary
tube and are uncorrected. Infrared (IR) spectra were recorded
1
on a Shimadzu FT-IR spectrometer using KBr pellets. H NMR
1
spectra were recorded on a Bruker DRX-400 MHz NMR spectro-
meter, and the 13C NMR spectra were recorded on a Bruker
DRX-100 MHz NMR in DMSO-d6 using tetramethylsilane
(TMS) as an internal standard, and the chemical shifts recorded
in d ppm. High-resolution mass spectra (HRMS) were recorded
on an Agilent 6520 (QTOF) ESI-HRMS instrument and LC-MS
spectrometer. The purity of each of the compounds was
checked by thin-layer chromatography (TLC) using silica gel,
(60F254), and visualization was accomplished by iodine/ultraviolet
light.
1452 (CQC str.), 1321, 1250 (N–SO2– str.); H NMR (400 MHz,
DMSO-d6, d ppm): 8.03–8.05 (m, 2H, H–Ar–SO2–NH), 7.53–7.59
(m, 2H, H–Ar–SO2–NH), 7.11–7.25 (m, 4H, Ar–H), 6.88 (s, 1H,
S–CH–N), 4.28 (d, 1H, CH2, J = 8 Hz), 4.17 (d, 1H, CH2, J = 8 Hz),
3.63 (s, 3H, OCH3) and 2.31 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6, d ppm): 164.8, 140.6, 137.0, 131.0, 130.8, 128.8, 128.4,
124.6, 124.0, 61.2, 54.2, 34.1 and 23.0; LC-MS for C17H18N2O4S2
[M]+, 378.
5.1.4. N-(2-(2,4-Dimethoxyphenyl)-4-oxothiazolidin-3-yl)-4-
methylbenzenesulfonamide (4d). Compound 4d was obtained
by a cyclocondensation reaction between 2,4-dimethoxybenz-
aldehyde 1d, 4-methylbenzenesulfonohydrazide 2, and thioglycolic
5.1. Typical procedure for the synthesis of 4-methyl-N-(4-oxo-
2-phenylthiazolidin-3-yl)benzenesulfonamide (4a)
A mixture of benzaldehyde 1a (1 mmol), 4-methylbenzene- cmÀ1): 3353 (N–H str.), 2947, 2834 (C–H str.), 1673 (CQO str.),
sulfonohydrazide 2 (1 mmol), and thioglycolic acid 3 (1 mmol) 1597, 1579, 1511 (CQC str.), 1346, 1106 (N–SO2– str.); H NMR
acid 3 as a white solid; Mp 120–122 1C; yield: 82%; FT-IR (KBr, nmax
,
1
in DBU hydrogen sulfate as the catalyst (20 mol%) were charged (400 MHz, DMSO-d6, d ppm): 8.01–8.03 (m, 2H, H–Ar–SO2–NH),
in a 100 mL round-bottom flask equipped with a mechanical 7.91–7.93 (m, 2H, H–Ar–SO2–NH), 7.47–7.49 (m, 2H, Ar–H), 7.31 (s,
stirrer and a condenser. The reaction mixture was heated at 1H, Ar–H), 6.91 (s, 1H, S–CH–N), 4.16 (d, 1H, CH2, J = 32 Hz), 4.05
80 1C under solvent-free conditions for 1 h. The progress of (d, 1H, CH2, J = 32 Hz), 3.78 (s, 6H, OMe2) and 2.39 (s, 3H, CH3); 13
C
the reaction was monitored by TLC. The completion of the NMR (100 MHz, DMSO-d6, d ppm): 164.4, 148.9, 143.2, 139.0, 135.8,
reaction was confirmed by the TLC using n-hexane : ethyl 132.7, 131.5, 130.1, 129.6, 126.5, 123.9, 62.9, 52.8, 34.6 and 22.6;
acetate (8 : 2) as the solvent. Then, the reaction mixture was LC-MS for C18H21N2O5S2 [M + H]+, 409.
poured in to 50 mL ice water and filtered, washed thoroughly
5.1.5. N-(2-(2-Chlorophenyl)-4-oxothiazolidin-3-yl)-4-methyl-
with NaHCO3, dried, and recrystallized from ethanol to give the benzenesulfonamide (4e). Compound 4e was obtained by a
final product 4a.
cyclocondensation reaction between 2-chlorobenzaldehyde 1e,
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4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3 as as a pale yellow solid; Mp 136–137 1C; yield: 85%; FT-IR (KBr,
a pale yellow solid; Mp 146–148 1C; yield: 89%; FT-IR (KBr, nmax
max, cmÀ1): 3427 (N–H str.), 3045, 2914 (C–H str.), 1720 (CQO
,
n
cmÀ1): 3323 (N–H str.), 3055, 2947 (C–H str.), 1685 (CQO str.), str.), 1620, 1583, 1496 (CQC str.), 1336, 1232 (N–SO2– str.);
1620, 1591, 1435 (CQC str.), 1353, 1251 (N–SO2– str.); 1H NMR 1H NMR (400 MHz, DMSO-d6, d ppm): 7.87–8.05 (m, 4H, H–Ar–
(400 MHz, DMSO-d6, d ppm): 7.98–8.14 (m, 4H, H–Ar–SO2–NH), SO2–NH), 7.33–7.46 (m, 4H, Ar–H), 6.78 (s, 1H, S–CH–N), 4.23
7.28–7.46 (m, 4H, Ar–H), 6.90 (s, 1H, S–CH–N), 4.14 (d, 1H, CH2, (d, 1H, CH2, J = 8 Hz), 4.14 (d, 1H, CH2, J = 8 Hz) and 2.46 (s, 3H,
J = 12 Hz), 4.05 (d, 1H, CH2, J = 12 Hz) and 2.49 (s, 3H, CH3); CH3); 13C NMR (100 MHz, DMSO-d6, d ppm): 166.7, 148.8,
13C NMR (100 MHz, DMSO-d6, d ppm): 165.0, 148.1, 143.1, 144.9, 140.1, 138.0, 136.9, 134.1, 132.2, 130.6, 126.8, 125.5,
141.2, 135.1, 133.2, 131.5, 130.1, 129.2, 51.9, 34.6 and 23.5; 53.5, 35.2 and 23.4; HRMS (ESI-qTOF): calcd for C16H16N3O5S2
HRMS (ESI-qTOF): Calcd for C16H16ClN2O3S2 [M + H]+, 383.3150: [M + H]+, 394.0950: found: 394.0981.
found: 383.3137.
5.1.10. 4-Methyl-N-(2-(4-nitrophenyl)-4-oxothiazolidin-3-yl)-
5.1.6. N-(2-(3-Chlorophenyl)-4-oxothiazolidin-3-yl)-4-methyl- benzenesulfonamide (4j). Compound 4j was obtained by a
benzenesulfonamide (4f). Compound 4f was obtained by a cyclocondensation reaction between 4-nitrobenzaldehyde 1j,
cyclocondensation reaction between 3-chlorobenzaldehyde 1f, 4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3
4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3 as as a pale yellow solid; Mp 124–126 1C; yield: 83%; FT-IR (KBr,
a pale yellow solid; Mp 152–154 1C; yield: 88%; FT-IR (KBr, nmax
,
n
max, cmÀ1): 3412 (N–H str.), 3053, 2922 (C–H str.), 1730 (CQO str.),
cmÀ1): 3273 (N–H str.), 3055, 2947 (C–H str.), 1705 (CQO str.), 1622, 1589, 1556 (CQC str.), 1321, 1240 (N–SO2– str.); 1H NMR
1577, 1543, 1481 (CQC str.), 1330, 1257 (N–SO2– str.); 1H NMR (400 MHz, DMSO-d6, d ppm): 7.92–8.07 (m, 4H, H–Ar–SO2–NH),
(400 MHz, DMSO-d6, d ppm): 7.94–8.07 (m, 4H, H–Ar–SO2–NH), 7.75–7.86 (m, 4H, Ar–H), 6.93 (s, 1H, S–CH–N), 4.23 (d, 1H, CH2,
7.37–7.55 (m, 4H, Ar–H), 6.93 (s, 1H, S–CH–N), 4.13 (d, 1H, CH2, J = 12 Hz), 4.14 (d, 1H, CH2, J = 12 Hz) and 2.45 (s, 3H, CH3);
J = 12 Hz), 4.05 (d, 1H, CH2, J = 12 Hz) and 2.42 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d ppm): 166.4, 149.2, 143.1,
13C NMR (100 MHz, DMSO-d6, d ppm): 165.7, 147.6, 143.8, 140.9, 135.7, 132.0, 130.6, 129.2, 127.3, 52.5, 35.0 and 24.1.
140.1, 137.5, 136.4, 135.4, 132.8, 131.3, 130.6, 126.2, 53.1, 35.3
and 23.7; HRMS (ESI-qTOF): calcd for C16H16ClN2O3S2 [M + H]+, benzenesulfonamide (4k). Compound 4k was obtained by a
383.3170: found: 383.3152. cyclocondensation reaction between 2-hydroxybenzaldehyde
5.1.7. N-(2-(4-Chlorophenyl)-4-oxothiazolidin-3-yl)-4-methyl- 1k, 4-methylbenzenesulfonohydrazide 2, and thioglycolic acid
5.1.11. N-(2-(2-Hydroxyphenyl)-4-oxothiazolidin-3-yl)-4-methyl-
benzenesulfonamide (4g). Compound 4g was obtained by a 3 as a white solid; Mp 139–141 1C; yield: 83%; FT-IR (KBr, nmax
,
cyclocondensation reaction between 4-chlorobenzaldehyde 1g, cmÀ1): 3254 (N–H str.), 3055, 2941 (C–H str.), 1705 (CQO str.),
4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3 as 1575, 1543, 1516 (CQC str.), 1311, 1240 (N–SO2– str.); 1H NMR
a pale yellow solid; Mp 134–135 1C; yield: 90%; FT-IR (KBr, nmax
,
(400 MHz, DMSO-d6, d ppm): 8.28–8.38 (m, 4H, H–Ar–SO2–NH),
cmÀ1): 3306 (N–H str.), 3032, 2956 (C–H str.), 1685 (CQO str.), 7.66–7.68 (m, 2H, Ar–H), 7.37–7.39 (m, 2H, Ar–H), 6.72 (s, 1H,
1583, 1506, 1437 (CQC str.), 1325, 1251 (N–SO2– str.); 1H NMR S–CH–N), 5.58 (s, 1H, OH), 4.19 (d, 1H, CH2, J = 28 Hz), 4.13 (d,
(400 MHz, DMSO-d6, d ppm): 7.98–8.01 (m, 2H, H–Ar–SO2–NH), 1H, CH2, J = 12 Hz) and 2.47 (s, 3H, CH3); 13C NMR (100 MHz,
7.69–7.71 (m, 2H, H–Ar–SO2–NH), 7.40–7.42 (m, 2H, Ar–H), DMSO-d6, d ppm): 165.6, 147.7, 135.4, 133.8. 133.4, 131.0,
7.14–7.16 (m, 2H, Ar–H), 6.94 (s, 1H, S–CH–N), 4.16 (d, 1H, 130.6, 129.8, 129.2, 126.9, 124.3, 52.5, 35.2 and 22.8; LC-MS
CH2), 4.04 (d, 1H, CH2) and 2.44 (s, 3H, CH3); 13C NMR for C16H16N2O4S2 [M + H]+, 364.
(100 MHz, DMSO-d6, d ppm): 165.2, 147.4, 143.5, 137.4, 136.5,
134.4, 129.2, 129.0, 124.1, 52.1, 35.8 and 23.7; LC-MS for benzenesulfonamide (4l). Compound 4l was obtained by a
16H16ClN2O3S2 [M + H]+, 383.
cyclocondensation reaction between 4-hydroxybenzaldehyde
5.1.8. N-(2-(2-Fluorophenyl)-4-oxothiazolidin-3-yl)-4-methyl- 1l, 4-methylbenzenesulfonohydrazide 2, and thioglycolic acid
5.1.12. N-(2-(4-Hydroxyphenyl)-4-oxothiazolidin-3-yl)-4-methyl-
C
benzenesulfonamide (4h). Compound 4h was obtained by a 3 as a white solid; Mp 119–120 1C; yield: 86%; FT-IR (KBr, nmax
,
cyclocondensation reaction between 2-fluorobenzaldehyde 1h, cmÀ1): 3482 (N–H str.), 3081, 2975 (C–H str.), 1682 (CQO str.),
4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3 as 1598, 1488, 1470 (CQC str.), 1350, 1226 (N–SO2– str.); 1H NMR
a pale yellow solid; Mp 127–128 1C; yield: 87%; FT-IR (KBr, nmax
,
(400 MHz, DMSO-d6, d ppm): 7.96-8.07 (m, 4H, H–Ar–SO2–NH),
cmÀ1): 3429 (N–H str.), 3053, 2935 (C–H str.), 1728 (CQO str.), 7.73–7.80 (m, 4H, Ar–H), 6.89 (s, 1H, S–CH–N), 5.32 (s, 1H, OH),
1614, 1579, 1500 (CQC str.), 1334, 1253 (N–SO2– str.); 1H NMR 4.16 (d, 1H, CH2, J = 16 Hz), 4.09 (d, 1H, CH2, J = 16 Hz) and 2.41
(400 MHz, DMSO-d6, d ppm): 8.04–8.13 (m, 4H, H–Ar–SO2–NH), (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d ppm): 166.4,
7.28–7.36 (m, 4H, Ar–H), 6.81 (s, 1H, S–CH–N), 4.20 (d, 1H, 147.6, 142.5, 134.5, 131.4, 130.6, 130.0, 129.2, 125.0, 54.0, 35.2
CH2), 4.16 (d, 1H, CH2, J = 4 Hz) and 2.44 (s, 3H, CH3); 13C NMR and 22.3.
(100 MHz, DMSO-d6, d ppm): 165.9, 148.6, 140.4, 139.0, 137.0,
135.0, 131.7, 127.8, 127.1, 122.8, 119.9, 51.9, 35.8 and 22.8; yl)-4-methylbenzenesulfonamide (4m). Compound 4m was
LC-MS for C16H16FN2O3S2 [M + H]+, 367.
obtained by a cyclocondensation reaction between 4-N-dimethyl-
5.1.13. N-(2-(4-(Dimethylamino)phenyl)-4-oxothiazolidin-3-
5.1.9. 4-Methyl-N-(2-(3-nitrophenyl)-4-oxothiazolidin-3-yl)- aminobenzaldehyde 1m, 4-methylbenzenesulfonohydrazide 2,
benzenesulfonamide (4i). Compound 4i was obtained by a and thioglycolic acid 3 as a white solid; Mp 155–157 1C; yield:
cyclocondensation reaction between 3-nitrobenzaldehyde 1i, 82%; FT-IR (KBr, nmax, cmÀ1): 3348 (N–H str.), 3066, 2942
4-methylbenzenesulfonohydrazide 2, and thioglycolic acid 3 (C–H str.), 1696 (CQO str.), 1599, 1509, 1435 (CQC str.),
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1335, 1202 (N–SO2– str.); 1H NMR (400 MHz, DMSO-d6, d ppm): in place, the grid was defined by a box with dimensions of
8.02–8.12 (m, 4H, H–Ar–SO2–NH), 7.40–7.42 (m, 2H, Ar–H), 10 Â 10 Â 10 Å centered on the centroid of fluconazole in the
7.11–7.13 (m, 2H, Ar–H), 6.92 (s, 1H, S–CH–N), 4.18 (d, 1H, crystal complex so as to explore a large portion of the protein.
CH2, J = 8 Hz), 4.17 (d, 1H, CH2, J = 8 Hz), 3.07 (s, 6H, N-Me2) These optimized protein and ligand geometries were then used
and 2.45 (s, 3H, CH3); 13C NMR (100 MHz, DMSO-d6, d ppm): as inputs for the docking study, utilizing the extra precision
165.7, 147.9, 144.8, 138.8, 134.5, 131.6, 130.8, 128.0, 123.2, 51.0, (XP) Glide scoring function to rank the docking poses and to
38.4, 34.22 and 22.40; LC-MS found C18H21N3O3S2 [M]+, 391.
estimate the protein–ligand binding affinities. The output files
generated from the docking simulation in terms of the docking
poses of the ligands were visualized and analyzed for the key
5.2. Antifungal activity
All the Compounds 4a–m were tested for in vitro activity elements of interaction with the receptor using the Maestro’s
(Table 3) against the five human pathogenic fungal strains, Pose Viewer utility.
namely Candida albicans (NCIM 3471), Fusarium oxysporum
To gauze the precision and accuracy of the docking protocol,
(NCIM 1332), Aspergillus Flavus (NCIM 539), Aspergillus niger the cocrystallized ligand (fluconazole) was extracted from the
(NCIM 1196), and Cryptococcus neoformons (NCIM 576), as crystal structure and re-docked using the above-mentioned
compared with the standard reference drugs miconazole and parameters. A very good agreement was observed between the
fluconazole. The minimum inhibitory concentration (MIC) values localization of the fluconazole upon docking and from the X-ray
were determined using the standard agar method.
bound conformation, as was evident from the low rmsd of less
than 1.0 Å. Hence, the reliability of the docking protocol for
predicting the binding modes of other molecules in the dataset
5.3. Molecular docking33
A molecular docking study was carried out using the Glide was confirmed. The best scoring pose for fluconazole obtained
(Grid-Based Ligand Docking with Energetics) program incorpo- by docking is compared against the X-ray bound conformation
rated in the Schrodinger molecular modeling package. This is in Fig. 3.
an interactive molecular graphics program for docking calcula-
tions, for identification of the probable binding site of the bio-
molecules, and for visualizing ligand-receptor interactions. The
Acknowledgements
X-ray structure of sterol 14a-demethylase (CYP51) in complex with
The authors D. D. S. and M. H. S. are very much grateful to the
an inhibitor-fluconazole (PDB code:3KHM) was retrieved from
Council of Scientific and Industrial Research (CSIR), New Delhi
the RCSB Protein Data Bank (PDB) (http://www.rcsb. org/pdb).
for the award of Senior Research Fellowship. We are thankful to
The protein–inhibitor complex was refined for the Glide calcu-
the Head, Department of Chemistry, Dr Babasaheb Ambedkar
lations by running the protein preparation wizard applying the
Marathwada University, for providing laboratory facility. Authors
OPLS-2005 force field. Any crystallographic water, if present,
are also thankful to Schrodinger Inc. for providing the Demo
was eliminated since no water molecule was observed to be con-
license of Schrodinger Suite and especially Craig Coel for the
served, and hydrogens were added to the structure corres-
valuable support that has tremendously helped in this work.
ponding to pH 7.0, considering the appropriate ionization states
for both the acidic and basic amino acid residues. Following the
assignment of the appropriate charge and protonation state, the
prepared complex was subjected to energy minimization until
Notes and references
the average root mean square deviation (r.m.s.d.) reached 0.3 Å
in order to relieve the steric clashes among the residues caused
due to addition of hydrogen atoms. The 3D structures of the
4-thiazolidinone 4a–m were sketched with the build panel in
Maestro and subsequently optimized using the LigPrep module,
which generates a number of low energy 3D structures with
various ionization states, tautomers, stereochemistries, and
ring conformations, for each input molecule. Partial atomic
charges were ascribed for these structures using the OPLS-2005
force-field, and possible ionization states were generated at a
pH of 7.0. The ligand structures thus obtained were further
optimized by energy minimization using the LBFGS method,
until a gradient of 0.01 kcal molÀ1 ÅÀ1 was reached. After
ensuring that the enzyme and ligands were in the correct form,
the shape and properties of the active site of the enzyme were
characterized using the receptor grid generation panel in Glide.
This generates two cubical boxes with a common centroid for
organizing the calculations: a larger enclosing and a smaller
binding box. With the non-covalently bound native ligand-fluconazol
1 D. L. Hawksworth, Mycol. Res., 2001, 105, 1422.
2 F. C. Odds and N. Gow, Trends Microbiol., 2003, 11, 272.
3 (a) D. P. Kontoyiannis, Lancet, 2002, 359, 1135; (b) K. A. Marr,
Oncology, 2004, 18, 9; (c) R. P. Vonberg and P. Gastmeier,
J. Hosp. Infect., 2006, 63, 246.
4 (a) A. Barik, B. Mishra, A. Kunwar, R. M. Kadam, L. Shen,
S. Dutta, S. Padhye, A. K. Satpati, H. Zhang and K. I. Priyadarsini,
Eur. J. Med. Chem., 2007, 42, 431; (b) D. Hadjipavlou-Litina,
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