4-Thiazolidinone derivatives: Synthesis, antimicrobial, anticancer evaluation and QSAR studies

Article abstract of DOI:10.1039/c6ra23006g

A series of 4-thiazolidinone derivatives (1-18) was synthesized and tested in vitro for its antimicrobial and anticancer potential. Synthesized compounds were found to be 5 more potent antimicrobial agents than anticancer agents. Anticancer screening resu

Full text of DOI:10.1039/c6ra23006g

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4-Thiazolidinone derivatives: Synthesis, antimicrobial, anticancer
evaluation and QSAR studies.
Aakash Deep$a , Balasubrmanian Narasimhan$b, Siong Meng Limc,e, Kalavathy Ramasamyc,e
Rakesh Kumar Mishrac,d, Vasudevan Manic,d
Received 00th January 20xx,
Accepted 00th January 20xx
,
DOI: 10.1039/x0xx00000x
Abstract: A series of 4-thiazolidinone derivatives (1–18) was synthesized and tested in vitro for its
antimicrobial and anticancer potentials. In general, the synthesized compounds were found to be
potent antimicrobial agents than anticancer agents. Anticancer screening results indicated that
compound 13 (IC50 = 15.18 μM) was the most active anticancer agent and was more potent than
standard drug, carboplatin (IC50 > 100 μM). Antimicrobial activity results indicated that 14 was the
most active antimicrobial agent (pMICec = 2.14 µM) and may serve as important lead for the
discovery of novel antimicrobial agents. The QSAR studies indicated that the antibacterial and
antifungal activities of the synthesized derivatives against different microbial strains were
governed by lipophillic parameter, log P, topological parameter, κα3 and electronic parameters
cos E and Nu. E.
www.rsc.org/
Keywords: 4-Thiazolidinones; Antimicrobial; Anticancer
solid tumors to available anticancer chemotherapy
has been reduced, new drugs with improved
efficacy are desired.1
1.INTRODUCTION
Cancer encompasses many disease states
generally characterized by abnormally proliferating
cell and is a major and often fatal disease.
However, the effect of anticancer drugs on solid
tumors has been poor. Because the response of
Infectious diseases are responsible for great
number of deaths in the world population. The
reduction of sensibility to antimicrobial agents in
current use has been increasing for a great variety
of pathogens and the resistance to multiple drugs
is common for several microorganisms, especially
for Gram positive bacteria. Infection by methicillin-
resistant Staphylococcus aureus (MRSA) and
vancomycin-resistant Enterococci (VRE) presents a
difficult problem for medicine. Given the evidence
for the rapid global spread of resistant, there is
need for discovery or optimization of antimicrobial
agents active against these resistant strains is of
paramount importance.2
aDepartment of Pharmaceutical Sciences, Ch. Bansi Lal
University, Bhiwani-127021, India
bFaculty of Pharmaceutical Sciences, Maharshi Dayanand
University, Rohtak-124001, India
c
Faculty of Pharmacy, Universiti Teknologi MARA (UiTM),
42300 Bandar Puncak Alam, Selangor, Malaysia
dBrain Degeneration and Therapeutics Group, Brain and
Neuroscience Communities of Research, Universiti Teknologi
MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan,
Malaysia
e Collaborative Drug Discovery Research (CDDR) Group, Brain
and Neuroscience Communities of Research, Universiti
Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul
Ehsan, Malaysia
Quantitative
structure–activity
relationships
(QSARs) are among the most widely used
techniques in rational drug design, which finds the
E.mail:naru2000us@yahoo.com,
aakashdeep82@gmail.com,
mathematical
relationship
between
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physicochemical properties of compounds and A mixture of (0.25 M) hipuric acid and excess of
their experimentally determined biological methanol (250 ml) with 1 ml of sulphuric acid was
activities. Thus, the derived QSAR model can be refluxed for 3–4 h in Round Bottom Flask (RBF).
subsequently used to predict the biological The mixture was cooled; the precipitated solid was
activities of new derivatives. A good QSAR model separated by filtration and recrystallized from
both enhances our understanding of the specifics methanol to yield the methyl 2-benzamidoacetate.
of drug action and provides
a theoretical A mixture of methyl 2-benzamidoacetate (0.2 M)
foundation for lead optimization. Moreover, QSAR and excess of hydrazine hydrate (0.3 M), ethanol
techniques increase the probability of success with (250 ml) was refluxed for about 3 h and allowed to
reduced time and cost in drug discovery.3
cool. The resultant solid was separated by
filtration and recrystallized from ethanol to afford
2-benzamidoacetohydrazide.
A mixture of 2-
Thiazolidin-4-one derivatives are known to exhibit
diverse biological activities such as anticancer4,5,
antimicrobial6,8, antiviral9, antimycobacterial10,
analgesic and anti-inflammatory11,12 activities.
benzamido acetohydrazide (0.025 M) and required
aromatic aldehydes (0.025 M) was refluxed in
methanol (50 ml) in the presence of catalytic
amount of glacial acetic acid for about 2 h. The
reaction mixture was then cooled and the
precipitated solid was separated by filtration and
recrystallized from methanol to give the
corresponding hydrazones of hippuric acid. A
mixture of corresponding hydrazone of hippuric
acid (0.015 M) and required amount of thioglycolic
acid (0.015 M) in DMF (50 ml) containing a pinch
of anhydrous zinc chloride was refluxed for about
6 h to yield 4-thiazolidinones (1-18). The reaction
mixture was then cooled and poured onto the
crushed ice. The solid thus obtained was filtered,
washed with water, and the product was
recrystallized from rectified spirit. 12
In the light of abovementioned facts and in
continuation of our research in the field of
antimicrobial, anticancer agents and previously
synthesized novel derivatives of 4-thiazolidinones
13-15, we hereby report synthesis, antimicrobial,
anticancer
evaluation
of
4-thiazolidinone
derivatives and their QSAR study.
2.EXPERIMENTAL
Melting points were determined in open capillary
tubes on a sonar melting point apparatus and
were uncorrected. Reaction progress was
monitored by thin layer chromatography on silica
gel sheets (Merck silica gel–G). 1H nuclear
magnetic resonance (1H NMR) and C13 NMR
spectra were recorded on Bruker Avance II 400
NMR spectrometer using appropriate deuterated
solvents and are expressed in parts per million (d,
ppm) downfield from tetramethylsilane (internal
standard). Infrared (IR) spectra were recorded on
Perkin Elmer FTIR spectrometer using KBr pellets.
Mass spectra were taken on Bruker Compass Data
Analysis 4.0 Mass spectrometer.
2.1.1
N-(2-(2-(3-ethoxy-4-hydroxyphenyl)-4-
oxothiazolidin-3-ylamino)-2-oxoethyl)benzamide
(1); IR (KBr pellets, cm-1): 3610(OH),3317(NH),
3034 (C-H aromatic), 1638 (C=C aromatic), 1679
(C=O), 1279 (C-N), 748(C-S), 1178 (C-O-C str.,-
1
OC2H5); H NMR (DMSO-d6, 400 MHz): 7.25-7.91
(m, 8H, ArH), 8.10 (s, 1H, NH), 4.03(s, 1H, OH),
4.09(d, 2H, CH2), 3.34(s, 2H, CH2 of thiazolidinone),
1.36(t, 3H, CH3 of -OC2H5), 3.94(m, 2H, CH2 of -
OC2H5).
2.1.2. N-(2-(2-(4-chlorophenyl)-4-oxothiazolidin-3-
ylamino)-2-oxoethyl)benzamide(2); IR (KBr pellets,
cm-1): 3322(NH), 2971 (C-H aromatic), 1633 (C=C
aromatic), 1689 (C=O), 1289 (C-N), 729(C-S),
2.1 General procedure for synthesis of 2-
disubstituted-4-thiazolidinone derivatives
1
709(C-Cl); H NMR (DMSO-d6, 400 MHz): 7.56-8.69
2 | J. Name., 2012, 00, 1-3
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(m, 9H, ArH), 8.01(s, 1H, NH), 4.43 (d, 2H, CH2), 7.50-8.87 (m, 7H, ArH), 7.93(s, 1H, NH), 4.42(d, 2H,
3.50(s, 2H, CH2 of thiazolidinone).
CH2), 3.43(s, 2H, CH2 of thiazolidinone), 3.74(s, 9H,
(OCH3)3)
2.1.3.N-(2-(2-(4-(dimethylamino)phenyl)-4-
oxothiazolidin-3-ylamino)-2-oxoethyl)benzamide
2.1.8. N-(2-(2-(4-methoxyphenyl)-4-oxothiazolidin-
(3); IR (KBr pellets, cm-1): 3214(NH), 3048 (C-H 3-ylamino)-2-oxoethyl)benzamide (8); IR (KBr
aromatic), 1601 (C=C aromatic), 1673 (C=O), 1227 pellets, cm-1): 3383(NH), 2838 (C-H aromatic),
(C-N), 738(C-S), 1367 (C-N str., aryl tertiary amine), 1645 (C=C aromatic), 1691 (C=O), 1299 (C-N),
2928 (C-H str., CH3).; 1H NMR (DMSO-d6, 400 MHz): 756(C-S), 1162 (C-O-C str., -OCH3); 1H NMR (DMSO-
7.54-8.64 (m, 9H, ArH), 8.08(s, 1H, NH), 4.38(d, 2H, d6, 400 MHz): 7.51-7.98 (m, 9H, ArH), 7.99(s, 1H,
CH2), 3.41(s, 2H, CH2 of thiazolidinone), 2.87(s, 6H, NH), 4.41(d, 2H, CH2), 3.51(s, 2H, CH2 of
N(CH3)2).
thiazolidinone), 3.85(s, 3H, (OCH3).
2.1.4. N-(2-(2-(2-chlorophenyl)-4-oxothiazolidin-3- 2.1.9. N-(2-(2-(4-bromophenyl)-4-oxothiazolidin-3-
ylamino)-2-oxoethyl)benzamide (4); IR (KBr pellets, ylamino)-2-oxoethyl)benzamide (9); IR (KBr pellets,
cm-1): 3361(NH), 2891 (C-H aromatic), 1619 (C=C cm-1): 3316(NH), 3094 (C-H aromatic), 1631 (C=C
aromatic), 1688 (C=O), 1270 (C-N), 750(C-S), 700 aromatic), 1690 (C=O), 1286 (C-N), 709(C-S), 613
1
(C-Cl); H NMR (DMSO-d6, 400 MHz): 7.54-8.01 (m, (C-Br); 1H NMR (DMSO-d6, 400 MHz): 7.51-7.99 (m,
9H, ArH), 8.03(s, 1H, NH), 4.01(d, 2H, CH2), 3.42 (s, 9H, ArH), 8.05(s, 1H, NH), 4.42(d, 2H, CH2), 3.37(s,
2H, CH2 of thiazolidinone)
2H, CH2 of thiazolidinone)
2.1.5.N-(2-(2-(4-formylphenyl)-4-oxothiazolidin-3-
2.1.10. N-(2-(2-(3-nitrophenyl)-4-oxothiazolidin-3-
ylamino)-2-oxoethyl)benzamide (5); IR (KBr pellets, ylamino)-2-oxoethyl)benzamide (10) Mp; IR (KBr
cm-1): 2892(C-H str., CHO),3312(NH), 3060 (C-H pellets, cm-1): 3341(NH), 3044 (C-H aromatic),
aromatic), 1633 (C=C aromatic), 1672 (C=O), 1288 1629 (C=C aromatic), 1686 (C=O), 1246 (C-N),
1
(C-N), 758(C-S);1H NMR (DMSO-d6, 400 MHz): 7.77- 712(C-S), 1347 (C-NO2); H NMR (DMSO-d6, 400
8.77 (m, 9H, ArH), 8.03(s, 1H, NH), 4.00(d, 2H, MHz): 7.72-8.26 (m, 9H, ArH), 8.14(s, 1H, NH),
CH2), 3.50(s, 2H, CH2 of thiazolidinone), 8.88(s, 1H, 4.01(d, 2H, CH2), 3.38(s, 2H, CH2 of thiazolidinone)
CHO).
2.1.11.
N-(2-oxo-2-(4-oxo-2-phenylthiazolidin-3-
2.1.6. N-(2-(2-(2-methoxyphenyl)-4-oxothiazolidin- ylamino)ethyl)benzamide (11); IR (KBr pellets, cm-
3-ylamino)-2-oxoethyl)benzamide (6); Mp (°C); 1): 3316(NH), 3071 (C-H aromatic), 1634 (C=C
Yield –%; IR (KBr pellets, cm-1): 3339(NH), 3037 (C- aromatic), 1688 (C=O), 1280 (C-N), 756(C-S);1H
H aromatic), 1636 (C=C aromatic), 1665 (C=O), NMR (DMSO-d6, 400 MHz): 7.49-8.68 (m, 10H,
1
1246 (C-N), 780(C-S), 1167 (C-O-C str.,-OCH3); H ArH), 8.02(s, 1H, NH), 4.14(d, 2H, CH2), 3.47(s, 2H,
NMR (DMSO-d6, 400 MHz): 7.54- 7.96 (m, 9H, ArH), CH2 of thiazolidinone)
8.18 (s, 1H, NH), 4.41(d, 2H, CH2), 3.36(s, 2H, CH2
of thiazolidinone), 3.83(s, 3H, OCH3)
2.1.12.N-(2-(2-(4-hydroxy-3-methoxyphenyl)-4-
oxothiazolidin-3-ylamino)-2-oxoethyl)benzamide
2.1.7.
trimethoxyphenyl)thiazolidin-3-
N-(2-oxo-2-(4-oxo-2-(3,4,5- (12); IR (KBr pellets, cm-1): ): 3603(OH), 3435(NH),
3027 (C-H aromatic), 1636 (C=C aromatic), 1676
ylamino)ethyl)benzamide (7); IR (KBr pellets, cm-1): (C=O), 1270 (C-N), 710(C-S), 1168 (C-O-C str.,-
3382(NH), 3006 (C-H aromatic), 1647 (C=C OCH3); 1H NMR (DMSO-d6, 400 MHz): 7.25-8.12 (m,
aromatic), 1697 (C=O), 1295 (C-N), 718(C-S), 1184 8H, ArH), 7.91(s, 1H, NH), 4.14(d, 2H, CH2), 3.51(s,
1
(C-O-C str.,- OCH3); H NMR (DMSO-d6, 400 MHz):
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2H, CH2 of thiazolidinone), 3.83 (s, 3H, (OCH3), (m,10H, ArH), 7.96(s, 1H, NH), 3.95(d, 2H, CH2),
4.41(s, 1H, OH).
3.34(s, 2H, CH2 of thiazolidinone), 7.88(d, 1H, CH).
2.1.13.
N-(2-(2-(2-hydroxynaphthalen-1-yl)-4- 2.1.18.
N-(2-(2-(3-methoxyphenyl)-4-
oxothiazolidin-3-ylamino)-2-oxoethyl)benzamide
oxothiazolidin-3-ylamino)-2-oxoethyl)benzamide
(13); IR (KBr pellets, cm-1): 3624(OH), 3416(NH), (18); Mp (°C); Yield –%; IR (KBr pellets, cm-1):
3060 (C-H aromatic), 1634 (C=C aromatic), 1697 3316(NH), 3050 (C-H aromatic), 1635 (C=C
1
(C=O), 1283 (C-N), 747(C-S); H NMR (DMSO-d6, aromatic), 1680 (C=O), 1260 (C-N), 711(C-S), 1193
1
400 MHz): 7.50-8.05 (m,11H, ArH), 8.03(s, 1H, NH), (C-O-C str.,-OCH3); H NMR (DMSO-d6, 400 MHz):
4.07(d, 2H, CH2), 3.53(s, 2H, CH2 of thiazolidinone), 7.38-8.70 (m,9H, ArH), 7.98(s, 1H, NH), 3.97(d, 2H,
4.46(s, 1H, OH)
CH2), 3.38(s, 2H, CH2 of thiazolidinone), 3.80 (s, 3H,
OCH3).
2.1.14.
N-(2-(2-(4-(diethylamino)phenyl)-4-
oxothiazolidin-3-ylamino)-2-oxoethyl)benzamide
(14); IR (KBr pellets, cm-1): 3399(NH), 3050 (C-H
aromatic), 1639 (C=C aromatic), 1702 (C=O), 1266
(C-N), 712(C-S), 1353 (C-N str., aryl tertiary amine),
2895 (C-H str., CH3); 1H NMR (DMSO-d6, 400 MHz):
7.43-7.91 (m, 9H, ArH), 8.06(s, 1H, NH), 3.96(d, 2H,
CH2), 3.36(s, 2H, CH2 of thiazolidinone), 2.89(m,
4H, (CH2)2), 1.14(t, 6H, (CH3)2).
3. RESULTS AND DISCUSSION
3.1Antimicrobial assay
3.1.1Determination of MIC
The antimicrobial activity of synthesized
compounds was performed against Gram-positive
bacteria: Staphylococcus aureus MTCC 3160,
Bacillus subtilis MTCC 441, Gram-negative
bacterium: Escherichia coli MTCC 443 and fungal
strains: Candida albicans MTCC 227 and
Aspergillus niger MTCC 281 using tube dilution
method.17 Dilutions of test and standard
compounds were prepared in double strength
nutrient broth – I.P. (bacteria) or Sabouraud
dextrose broth I.P. (fungi) 18. The samples were
incubated at 37 °C for 24 h (bacteria), at 25 °C for 7
d (A. niger) and at 37 °C for 48 h (C. albicans) and
the results were recorded in terms of MIC.
2.1.15.N-(2-oxo-2-(4-oxo-2-p-tolylthiazolidin-3-
ylamino)ethyl)benzamide (15); IR (KBr pellets, cm-
1): 3327(NH), 3069 (C-H aromatic), 1640 (C=C
aromatic), 1688 (C=O), 1295 (C-N), 713(C-S), 2931
1
(C-CH3); H NMR (DMSO-d6, 400 MHz): 7.48-7.91
(m,9H, ArH), 7.98(s, 1H, NH), 3.99(d, 2H, CH2),
3.47(s, 2H, CH2 of thiazolidinone), 2.38(s, 3H, CH3)
2.1.16. N-(2-(2-(4-hydroxyphenyl)-4-oxothiazolidin-
3-ylamino)-2-oxoethyl)benzamide (16); IR (KBr
pellets, cm-1): 3613(OH),3367(NH), 3036 (C-H
aromatic), 1639 (C=C aromatic), 1671 (C=O), 1238
(C-N), 708(C-S); 1H NMR (DMSO-d6, 400 MHz):
7.51-8.12 (m,9H, ArH), 7.95(s, 1H, NH), 3.97(d, 2H,
CH2), 3.48(s, 2H, CH2 of thiazolidinone), 4.38(s, 1H,
OH).
3.2.2 Determination of MBC/MFC
The minimum bactericidal concentration (MBC)
and fungicidal concentration (MFC) were
determined by subculturing 100 µL of culture from
each tube (which remained clear in the MIC
determination) on fresh medium. MBC and MFC
values represent the lowest concentration of
compound that produces a 99.9% end point
reduction.19
2.1.17. (E)-N-(2-oxo-2-(4-oxo-2-styrylthiazolidin-3-
ylamino)ethyl)benzamide (17); IR (KBr pellets,
cm1): 3032 (C-H aromatic), 1567 (C=C aromatic),
1655 (C=O), 1223 (C-N), 2777(C-H str.,-CH=CH-),
1
777(C-S); H NMR (DMSO-d6, 400 MHz): 7.34-7.47
4 | J. Name., 2012, 00, 1-3
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22
3.3 Evaluation of anticancer activity
software for Windows.
Further, the regression
analysis was performed using the SPSS software
package. 23
The anticancer activity of synthesized
compounds (1-18) was determined against an
oestrogen receptor positive human breast 3.5 Results and Discussion
adenocarcinoma, MCF-7 (ATCC HTB-22) cancer cell
line. The cell line was cultured in RPMI 1640
(Sigma) supplemented with 10% heat inactivated
foetal bovine serum (FBS) (PAA Laboratories) and
1% penicillin/streptomycin (PAA Laboratories).
Culture was maintained in a humidified incubator
at 37 °C in an atmosphere of 5% CO2. Anticancer
activity of synthesized compounds at various
concentrations was assessed using 3-(4,5-
3.5.1 Chemistry
Thiazolidin-4-one
derivatives
(1-18)
were
synthesized using the synthetic procedure given in
Scheme 1. The synthesized compounds were
characterized by physicochemical as well as
spectral means. Physicochemical properties and
anticancer activity results of the synthesized
compounds are presented in Table 1.
dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium
bromide (MTT) (Sigma) assay, as described by
Mosmann, but with minor modification, following
72 h of incubation. Assay plates were read using a
spectrophotometer at 520 nm. Data generated
were used to plot a dose-response curve of which
the concentration of test compounds required to
kill 50% of cell population (IC50) was determined.
Anticancer activity was expressed as the mean IC50
of three independent experiments. 20
3.5.2 Antimicrobial activity
The antimicrobial activity results (Table 2)
indicated that the synthesized compounds were
having excellent antimicrobial activity and
compound 9 (pMICsa = 1.84 µM/ml, Table 2) was
the most potent antibacterial agent against S.
aureus. Compound 14 was found to be most active
against E. coli (pMICec = 2.14µM/ml). Compounds 2
and 4 (MICbs = 1.80µM/ml) were found to be active
against B. subtilis. In the case of antifungal activity
against C. albicans, and A. niger, compound 10
(MICca = 2.11µM/ml, MICan = 1.81µM/ml) was
found most effective among the synthesized
series. All the above mentioned compounds having
comparable antimicrobial potential to standard
drugs norfloxacin (pMIC = 2.61 µM/ml) and
fluconazole (pMIC = 2.64 µM/ml), may serve as
important leads for the discovery of novel
antimicrobial agents.
3.4 QSAR Studies
The structures of synthesized compounds (1-18)
were first pre-optimized with the Molecular
Mechanics Force Field (MM+) procedure included
in Hyperchem 6.0321 and the resulting geometries
were further refined by means of the
semiempirical method PM3 (Parametric Method-
3). We chose a gradient norm limit of 0.04 kJ/A˚
for the geometry optimization. The lowest energy
structure was used for each molecule to calculate
physicochemical properties using TSAR 3.3
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O
O
O
H
N
H
N
N
H
NH
N
CH
N
S
O
O
SHCH2COOH
OH
OH
CHO
(13)
OH
O
CH3OH
H2SO4
O
H
N
H
N
O
NH2NH2.H2O
H
N
OH
OCH3
NHNH2
O
2-benzamidoacetohydrazide
O
Hippuric acid
O
methyl 2-benzamidoacetate
O
ArCHO
O
O
H
N
N
H
SHCH2COOH
N
S
O
O
H
N
O
H
N
Ar
NH
N
NH
N
CH
O
CH
Ar
2-substituted 4-thiazoldinone
(1-12, 14-16,18)
O
SHCH2COOH
O
O
H
N
N
H
N
S
O
(17)
Scheme 1. Scheme for the synthesis of 4ꢀthiazolidinone derivatives (1ꢀ18)
Comp.
Ar
Comp.
Ar
Comp.
Ar
OCH3
OC2H5
1
7
13
ꢀꢀ
OCH3
OCH3
OH
C2H5
Cl
OCH3
2
3
4
8
9
14
15
16
N
C2H5
CH3
Br
CH3
N
CH3
Cl
NO2
OH
10
CHO
5
6
11
12
17
18
ꢀꢀ
H3CO
OCH3
OCH3
OH
In general, the results of MBC/MFC studies and MBC values were (ranging from >0.11 to
revealed that the synthesized compounds were >0.14 µM/ml) 3ꢀfold higher than their MIC values
bacteriostatic and fungistatic in action as their MFC (a drug is considered to be bacteriosatic/fungistatic
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when its MFC and MBC values are 3ꢀ fold higher than its MIC value). 24
Table 1. Physicochemical properties and anticancer activity of the synthesized 4-thiazolidinone derivatives (1-18)
Comp.
M. Formula
M. Pt. (oC)
M. Wt.
Rf value*
% yield
IC50 (µM)
(MCFꢀ7)
180.67
48.75
>250.95
C20H21N3O5S
C18H16ClN3O3S
C20H22N4O3S
195ꢀ197
201ꢀ203
178ꢀ180
415.12
389.86
398.48
0.61
0.59
0.68
68
75
82
1
2
3
C18H16ClN3O3S
C19H17N3O4S
C19H19N3O4S
C21H23N3O6S
C19H19N3O4S
C18H16BrN3O3S
C18H16N4O5S
C18H17N3O3S
C19H19N3O5S
166ꢀ168
186ꢀ188
182ꢀ184
155ꢀ157
161ꢀ163
150ꢀ152
191ꢀ193
222ꢀ224
174ꢀ176
389.86
383.42
385.44
445.49
385.44
434.31
400.41
355.41
401.44
0.72
0.60
0.75
0.67
0.68
0.59
0.71
0.58
0.59
74
77
83
78
72
69
80
71
76
225.72
>260.81
207.56
>224.47
67.456
66.77
62.44
>281.37
234.16
4
5
6
7
8
9
10
11
12
C22H19N3O4S
C22H26N4O3S
C19H19N3O3S
C18H17N3O4S
C20H19N3O3S
C19H19N3O4S
209ꢀ211
181ꢀ183
157ꢀ159
170ꢀ172
144ꢀ146
234ꢀ236
421.47
426.53
369.44
371.41
381.45
385.44
0.72
0.66
0.55
0.50
0.54
0.62
83
65
63
76
79
81
15.18
112.54
35.19
>269.24
83.89
179.02
0.0052
> 100
13
14
15
16
17
18
5ꢀFU
Carboplatin
*TLC mobile phase : Benzene
3.5.3 Anticancer activity
Anticancer activity results (Table 1) indicated
that besides having excellent antimicrobial
activity, the synthesized compounds were also
having good anticancer activity against MCF 7
anticancer activity of the synthesized
compound against E. coli and MCF-7
(ATCC HTB-22) cancer cell line.
3. The presence of fused aromatic ring
substitution (2-OH naphthaldehyde,
Compound 13) in moiety improves
anticancer activity of synthesized
compounds against an oestrogen
receptor positive human breast
adenocarcinoma, MCF-7 (ATCC HTB-22)
cancer cell line.
cancer cell line and compounds 2, 8, 9, 10, 13,
15 and 17 showed more potent anticancer
activity than carboplatin (IC50 > 100 µM).
Compounds 13 (IC50 = 15.18 µM) was found to
be most potent anticancer agent.
3.6SAR (Structure Activity Relationship)
studies
The antimicrobial and anticancer results
revealed that the nature of the substituents
4. From these result we may conclude that
different structural requirements are
required for a compound to be effective
against different targets.25
has a considerable impact on the biological The above mentioned findings are summarized
activities of thiazolidin-4-one derivatives and in Fig. 1.
the following structure activity relationship
(SAR) can be deduced:
1. Presence of electron withdrawing groups
(-Cl, -NO2, -Br, Compounds 4, 9 and 10
)
on moiety improved the antimicrobial
activity of the synthesized compounds
against C. albicans, A. niger, S. aureus
and B. subtilis.
2. Presence of electron releasing groups
(Compounds 14 and 15) on moiety
improved
the
antibacterial
and
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Increase antimicrobial activity against
C. albicans.,B. subtilis, S.aureus and A. niger
Electron
withdrawing groups
R
O
O
Increase antibacterial and anticancer activity against
E. coli and MCFꢀ7 (ATCC HTBꢀ22) cancer cell
line.
S
Electron
releasing groups
N
N
H
O
NH
Y
OH
Increase anticancer activity against MCFꢀ7 (ATCC HTBꢀ22) cancer cell line.
Fig. 1. Structural requirements for the antimicrobial and anticancer activities of 4-thiazolidinone
derivatives (1-18).
10
11
12
13
14
15
16
17
18
SD
Std.
1.51
1.45
1.21
1.53
1.53
1.47
1.17
1.56
1.19
0.25
1.20
1.45
1.51
1.23
2.14
1.47
1.17
1.86
1.49
0.27
1.20
1.15
1.81
1.53
1.53
1.47
1.77
0.96
1.49
0.29
1.81
0.85
1.21
1.53
1.53
1.17
1.77
1.26
1.79
0.29
2.11
1.15
1.51
1.23
1.53
0.87
1.17
1.56
2.09
0.36
3.7 QSAR study
In order to identify the substituent effect on
the antimicrobial activity, quantitative
structure activity relationship (QSAR) studies
were undertaken, using the linear free energy
relationship (LFER) model described by Hansch
and Fujita (1964).26 Biological activity data
determined as MIC values were first
transformed into pMIC values (i.e. –log MIC)
and used as dependent variables in QSAR study
(Table 2). The different molecular descriptors
selected for the present study and the values
of selected descriptors are presented in Table
3.
In the present study, a dataset of 18
thiazolidinone derivatives (1–18) was used for
linear regression model generation. The
standard drugs norfloxacin and fluconazole
were not included in model generation
because of dissimilarity in structure with
synthesized compounds. Different outliers are
identified against different microorganisms,
and the models have been developed after
removal of the outliers (compound numbers in
brackets) B. subtilis (2, 4, 6, 7, 9 and 17), E. coli
2.61* 2.61* 2.61* 2.64* 2.64**
*Norfloxacin **Fluconazole
As there was no difference in the activity
(Table 2) as well as the molecular descriptor
range (Table 3) of these outliers when
compared to other synthesized compounds,
these outliers belong to the category of Y
outliers (substances for which the reference
value of response is invalid.
Preliminary analysis was carried out in terms of
correlation analysis. A correlation matrix
constructed for antibacterial activity against B.
subtilis is presented in Table 4. The correlation
of
molecular
descriptors
with
their
antimicrobial activity against different strains is
given in Table 5. In general, high colinearity (r >
0.5) was observed between different
parameters. The high interrelationship was
observed between Ne and W (r = 0.995) and
low interrelationship was observed between
Cos E and HOMO (r = -0.087, Table 4).
(
10 15 and 18) and A. niger (4, 6, 9, 10, 11, 16
4, 7, 8, 10, 14 and 16), C. albicans (
,
1, 6, 7, 9,
and 18). In multivariate statistics, it is common
to define three types of outliers.27
Table 2. Antimicrobial activity (pMIC in µM/ml)
of synthesized compounds
Com pMIC pMIC pMICs pMICa pMICc
p.
bs
ec
a
n
a
1
2
3
4
5
6
7
8
9
1.22
1.80
1.20
1.80
1.19
1.49
0.95
1.19
0.94
1.82
1.49
1.50
1.80
1.49
1.19
1.25
1.19
1.54
0.92
1.19
1.50
1.49
0.88
1.49
1.55
1.49
1.84
1.52
1.19
1.20
1.80
1.19
1.79
1.55
1.19
1.54
0.92
1.19
1.50
1.19
1.49
1.79
1.55
1.19
1.84
8 | J. Name., 2012, 00, 1-3
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Table 3. Values of selected descriptors calculated for QSAR studies
Ne
0χ
κα3
Comp.
Cos E
log P
MR
W
LUMO
ꢀ0.29
HOMO
ꢀ8.75
µ
1
2
ꢀ2.12
ꢀ1.39
1.94
1.58
108.12
100.02
108.92
100.02
101.81
101.68
114.60
101.68
102.84
102.54
95.21
20.80
18.52
20.10
18.52
19.23
19.23
22.38
19.23
18.52
20.10
17.65
20.10
21.09
21.51
18.52
18.52
23.05
19.23
5.36
4.79
5.13
4.59
4.75
4.68
5.43
4.88
4.88
4.95
4.40
4.92
4.35
5.63
4.66
4.64
6.12
4.88
2514.00
1877.00
2333.00
1839.00
2104.00
2028.00
2936.00
2104.00
1877.00
2276.00
1676.00
2274.00
2609.00
2851.00
1877.00
1877.00
3898.00
2066.00
34431.60
27578.20
32503.40
28029.90
30277.40
31216.10
39949.90
29594.20
28154.20
31868.50
25929.80
32848.10
35959.30
38341.30
28296.20
27759.40
37017.60
30022.10
3.78
2.49
1.70
1.88
2.59
3.38
3.69
1.76
2.76
4.42
2.71
4.09
3.61
5.38
2.94
1.22
2.74
1.21
2.29
1.56
2.29
1.45
1.52
1.01
1.52
2.56
1.72
1.77
1.23
2.49
2.25
2.24
1.49
3.99
1.52
ꢀ0.48
ꢀ0.27
ꢀ0.42
ꢀ0.88
ꢀ0.30
ꢀ0.39
ꢀ0.24
ꢀ0.56
ꢀ1.12
ꢀ0.26
ꢀ0.36
ꢀ0.78
ꢀ0.24
ꢀ0.30
ꢀ0.26
ꢀ0.69
ꢀ0.24
ꢀ9.09
ꢀ8.44
ꢀ9.00
ꢀ9.21
ꢀ8.80
ꢀ8.95
ꢀ8.91
ꢀ9.04
ꢀ9.34
ꢀ8.99
ꢀ8.84
ꢀ8.85
ꢀ8.44
ꢀ8.90
ꢀ8.95
ꢀ8.65
ꢀ8.93
3
4
ꢀ0.50
7.17
5
6
0.69
7
12.95
ꢀ0.18
ꢀ0.51
8.69
8
9
10
11
12
13
14
15
16
17
18
0.94
2.31
103.37
113.36
118.42
100.26
96.91
ꢀ4.28
9.39
ꢀ5.30
ꢀ5.83
5.20
130.67
101.68
ꢀ0.55
From the correlation Table 4, it was observed B. subtilis. This is indicated by low antibacterial
that lipophilic parameter, log P was found to activity value of compound (pMICbs = 0.95
be the dominating descriptor for antibacterial µM/ml) having low log P value (1.01).
activity of the synthesized compounds against Log P is the logarithm of the ratio of the
B. subtilis (Eq. 1). concentrations of the un-ionized solute in two
QSAR model for antibacterial activity against solvents, which is calculated according to
B. subtilis following equation, where o is octanol and w is
pMICbs = 0.348 log P + 0.719 un-ionized water
n = 12
r = 0.849 q2 = 0.632 s = 0.087 F log Po/w = log ([soluteo] / [solutew])
= 25.85 The hydrophobic effect is the major driving
7
Eq. 1
Here and thereafter, n - number of data points, force for the binding of drugs to their receptor
r - correlation coefficient, q2 -cross validated r2 targets in pharmacodynamics, and is based on
obtained by leave one out method, s - the log P contribution of each atom. Each atom
standard error of the estimate and F - Fischer in a molecule contributes to the log P by the
statistics. amount of its atomic parameter multiplied by
The developed QSAR model for antibacterial the degree of exposure to the surrounding
activity (Eq. 1) indicated that there is a positive solvent.28
correlation between log P and antibacterial The developed QSAR model (Eq. 1) was cross
activity of the synthesized compounds against validated by q2 value (q2 = 0.632) obtained by
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leave one out (LOO) method. The value of q2 pMICbs (Fig. 2) also favors the developed model
more than 0.5 indicated that the model expressed by Eq. 2. Further, the plot of
developed is a valid one. As the observed and observed pMICbs vs residual pMICbs (Fig. 3)
predicted values are close to each other (Table indicated that there was no systemic error in
6), the QSAR model for antibacterial activity model development as the propagation of
against B. subtilis (Eq. 1) is a valid one.29 The error was observed on both sides of zero. 30
plot of predicted pMICbs against observed
Table 4. Correlation matrix for the antibacterial activity of the synthesized compounds against B.
subtilis
pMICbs Cos E log P 0χ
pMICbs 1.000
κ
α3
W
Ne
LUMO HOMO
µ
Cos E
log P
0χ
0.199
0.849
0.233
-0.098
0.268
0.296
-0.337
1.000
-0.124 1.000
0.340 0.307 1.000
0.508 -0.115 0.621 1.000
0.372 0.358 0.991 0.647 1.000
0.358 0.380 0.987 0.618 0.995 1.000
-0.422 -0.125 -0.216 0.234 -0.164 -0.160 1.000
-0.087 0.226 0.456 0.542 0.510 0.515 0.667
0.520 0.422 0.643 0.423 0.652 0.683 -0.337 0.103
κ
α3
W
Ne
LUMO
HOMO -0.030
0.657
1.000
µ
1.000
Table 5. Correlation of antibacterial, antifungal and antimicrobial activities of synthesized
compounds with their molecular descriptors
Descriptors
pMICbs
0.199
0.849
0.346
0.233
0.233
0.287
0.359
0.309
0.366
0.138
0.156
0.179
0.116
-0.065
0.135
0.064
-0.098
0.287
-0.413
0.268
-0.097
-0.283
0.296
0.189
0.030
-0.337
-0.030
0.657
pMICec
0.289
0.386
0.495
0.466
0.522
0.442
0.515
0.425
0.430
0.291
0.199
0.528
0.624
0.791
0.563
0.682
0.838
0.442
-0.246
0.550
-0.440
-0.306
0.292
0.592
-0.227
-0.013
0.227
-0.043
pMICan
0.291
-0.056
0.480
0.650
0.633
0.588
0.581
0.539
0.436
0.504
0.070
0.642
0.512
0.197
0.684
0.564
0.257
0.588
-0.001
0.443
-0.730
-0.805
0.807
0.591
-0.281
0.045
0.281
0.701
pMICca
0.789
0.195
0.666
0.718
0.696
0.656
0.633
0.612
0.600
0.524
0.464
0.768
0.763
0.748
0.775
0.767
0.745
0.656
-0.195
0.676
-0.687
-0.722
0.721
0.755
-0.566
-0.241
0.566
0.482
Cos E
log P
MR
0χ
0χv
1χ
1χv
2χ
2χv
3χ
3χv
κ1
κ2
κ3
κα1
κα2
κα3
R
J
W
Te
Ee
Ne
SA
IP
LUMO
HOMO
µ
10 | J. Name., 2012, 00, 1-3
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.1
1.6
1.5
1.4
Residual pMICbs
0.0
Predicted pMICbs
1.3
1.2
-.1
1.2
1.3
1.4
1.5
1.6
1.2
1.3
1.4
1.5
1.6
Observed pMICbs
Observed pMICbs
Fig. 2. Plot of observed pMICbs against predicted pMICbs
Fig. 3. Plot of observed pMICbs against residual pMICbs
by Eq. 1.
by Eq. 1.
In case of antibacterial activity against E. coli, topological parameter, Kier’s alpha third order
shape index ( α3, Table 5) was found most dominant in expressing antibacterial activity of the
synthesized compounds against E. coli. So, QSAR model for antibacterial activity against E. coli (E
2) was developed using α3.
κ
κ
As in case of antibacterial activity against B.
QSAR model for antibacterial activity against Subtilis, antibacterial activity of the
E. coli
synthesized compounds against E. coli is also
positively correlated with their kα3 values
which means that antibacterial activity of the
pMICec = 0.342
Eq. 2
n = 12
κ
α3 – 0.177
r = 0.838 q2 = 0.531 s = 0.109 F synthesized compounds against E. coli will
= 23.62
increase with increase in their
(Tables 2 and 3).
Table 6. Observed, predicted and residual antimicrobial activities of the synthesized compounds
obtained by developed QSAR models.
Comp. pMICbs pMICec
Obs. Pre. Res. Obs. Pre. Res. Obs. Pre. Res. Obs. Pre.
κα3 values
pMICan
pMICca
Res.
1
2
3
4
5
6
7
8
1.22 1.27 -0.05 1.82 1.65 0.17 1.52 1.37 0.15 0.92 1.23 -0.31
1.80 1.52 0.28 1.49 1.46 0.03 1.19 1.14 0.05 1.19 1.26 -0.06
1.20 1.26 -0.06 1.50 1.58 -0.08 1.20 1.30 -0.10 1.50 1.36 0.15
1.80 1.52 0.28 1.80 1.39 0.40 1.80 1.16 0.64 1.19 1.28 -0.09
1.19 1.22 -0.04 1.49 1.45 0.04 1.19 1.23 -0.05 1.49 1.51 -0.03
1.49 1.25 0.24 1.19 1.42 -0.24 1.79 1.26 0.53 1.79 1.32 0.47
0.95 1.07 -0.12 1.25 1.68 -0.43 1.55 1.55 0.00 1.55 1.69 -0.13
1.19 1.25 -0.06 1.19 1.49 -0.30 1.19 1.21 -0.02 1.19 1.29 -0.10
0.94 1.61 -0.67 1.54 1.49 0.05 1.54 1.16 0.38 1.84 1.28 0.56
1.51 1.32 0.19 1.20 1.52 -0.31 1.81 1.28 0.52 2.11 1.56 0.55
1.45 1.34 0.12 1.45 1.33 0.13 0.85 1.09 -0.24 1.15 1.33 -0.17
1.21 1.15 0.06 1.51 1.50 0.00 1.21 1.32 -0.11 1.51 1.37 0.14
1.53 1.59 -0.06 1.23 1.31 -0.09 1.53 1.42 0.11 1.23 1.17 0.06
1.53 1.50 0.03 2.14 1.75 0.39 1.53 1.50 0.04 1.53 1.58 -0.05
1.47 1.50 -0.03 1.47 1.42 0.05 1.17 1.17 0.00 0.87 1.14 -0.27
1.17 1.24 -0.06 1.17 1.41 -0.24 1.77 1.15 0.63 1.17 1.12 0.05
1.56 2.11 -0.54 1.86 1.92 -0.05 1.26 1.45 -0.19 1.56 1.45 0.11
1.19 1.25 -0.06 1.49 1.49 0.00 1.79 1.22 0.57 2.09 1.28 0.81
9
10
11
12
13
14
15
16
17
18
Electronic parameter, cosmic total energy (cos QSAR model for antifungal activity against C.
E) was found to be effective in describing the albicans
antifungal activity of the synthesized
compounds against C. albicans (Eq. 3, Table 5).
pMICca = 0.0300 cos E + 1.297
Eq. 3
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n = 11
= 14.82
r = 0.789 q2 = 0.503 s = 0.113 F more potent than standard drug, carboplatin
(IC50 > 100 μM). Antimicrobial activity results
In case of antifungal activity of the synthesized indicated that 14 was the most active
compounds against A. niger, electronic antimicrobial agent (pMICec = 2.14 µM) and
parameter, nuclear energy (Nu. E) was found may serve as important lead for the discovery
to be the most dominating descriptor for of novel antimicrobial agents. The QSAR
describing the antifungal activity of the studies indicated that the antibacterial and
synthesized compounds against A. niger (Eq. 4, antifungal activities of the synthesized
Table 5).
QSAR model for antifungal activity against A. were governed by lipophillic parameter, log P,
niger topological parameter, α3 and electronic
pMICan = 0.000033 Nu. E + 0.232 parameters cos E and Nu. E.
References
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κ
Eq. 4
n = 11
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r = 0.807 q2 = 0.529 s = 0.105 F
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,
1
It was observed from developed QSAR models
[Eq. 1-4] that the antibacterial and antifungal
activities of the synthesized 4-thiazolidinone
derivatives against different microbial strains
were governed by lipophillic parameter, log P,
,
7
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topological parameter,
parameters cos E and Nu. E.
κ
α3 and electronic
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J. Balzarini, K. V. Hecke, L. V. Meervelt
When biological activity data lies in the narrow
range, the presence of minimum standard
deviation of the biological activity justifies its
use in QSAR studies.31 The minimum standard
deviation (Table 2) observed in the
antimicrobial activity data justifies its use in
QSAR studies.
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7.8 Conclusion
A series of 4-thiazolidinone derivatives (1–18
)
was synthesized and tested in vitro for its
antimicrobial and anticancer potentials. In
general, the synthesized compounds were
found to be potent antimicrobial agents than
anticancer agents. Anticancer screening results
indicated that compound 13 (IC50 = 15.18 μM)
was the most active anticancer agent and was
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Mishra, Mani V, k. Ramasamy and L.S.
12 | J. Name., 2012, 00, 1-3
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