INTRODUCTION:
The thiazolidinediones also known as glitazones, are a class of medications used in the treatment of diabetes mellitus type 2. They were
introduced in the late 1990s. They contain a functional
group in which thiazolidine serves as a dione. These (TZDs) are a new class of antidiabetic agents and
include three compounds that have come to clinical use — troglitazone
(Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos) — as well as
several others that have been limited to pre-clinical study[1].
2,4-thiazolidenedione (TZD) is an attractive scaffold because of its
prestigious position in medicinal chemistry as this unit is responsible for
numerous pharmacological and biological activities, e.g., antidiabetic[2,3],antidiarrheal[4],
anticonvulsant[5], antimicrobial[6], antihistaminic[7],
anticancer[8], anti-HIV[9], 15-hydroxyprostaglandin
dehydrogenase inhibitors[10], and anti-ischemic[11].
The position of these molecules seems to be most
significant as they are a subset of commercially employed non-insulin-dependent
diabetes mellitus and insulin-sensitizing agents (Figure 1) such as
rosiglitazone, epalrestat, ciglitazone, AD-5061, pioglitazone, and so on.
The properties of thiazolidinediones includes:
Chemical formula- C3H7NS, Molar mass- 89.16 g·mol−1,
Density-1.131 g/cm3, Boiling point- 72 to 75 °C (162 to 167 °F; 345
to 348 K) at 25 torr where as the Chemical formula of
2,4-Thiazolidinedione is C3H3NO2S and the boiling
point of 2,4-Thiazolidinedione was found to
be 178-179 °C (19 mmHg) and its melting point is 125-127oC(lit.)
Structure of thiazolidinedione
Molecular mechanism of action of thiazolidinedione as
oral hypoglycemic drug:
PPARϒ is a member of a family of nuclear
receptors. Another member of this class, peroxisome proliferator-activated
receptor alpha (PPARϒ), is predominantly expressed in the liver and is
thought to mediate the triglyceride lowering actions of fibrates. PPARϒ is
expressed in many tissues, including colon, skeletal muscle, liver, heart and
activated macrophages, but is most abundant in adipocytes.
Thiazolidinediones are selective agonists of PPARϒ. When activated by a
ligand, such as a thiazolidinedione, PPARϒ binds to the 9-cis retinoic
acid receptor (RXR [retinoid X receptor]) to form a heterodimer. This binds to
DNA to regulate the genetic transcription and translation of a variety of
proteins involved in cellular differentiation and glucose and lipid metabolism[12].
Thiazolidinediones bind to the gamma form of the
peroxisome proliferator- activated receptor (PPAR). This stimulates peripheral
adipocytes to increase their uptake of free fatty acids, which leads to
reductions in the fat stored in muscle, liver and visceral fat deposits. The
thiazolidinediones also lead to an increase in the secretion of adiponectin and
a decrease in the production of resist in and tumour necrosis factor
α(TNF- α ). It is unknown if thiazolidinediones have direct effects
on muscle or liver.
Fig.No. 1: Mechanism
of action of thiazolidinediones
Additional biological effects of the
thiazolidinediones:
Increased HDL and LDL cholesterol concentrations,
Increased LDL cholesterol particle size, Reduced triglyceride
concentrations(particularly pioglitazone), Small reduction in blood pressure,
Reduced incidene of micro albuminuria, Decrease in plasminogen activator
inhibitor-1 and fibrinogen, Vasorelaxation, Increase in vascular reactivity,
Anti-inflammatory effects.
All of these effects, except for increased LDL
cholesterol concentrations, would be regarded as potentially beneficial in
regard to the metabolic syndrome and cardiovascular disease[13].
Structural Activity Relationship:
SAR
of Thiazolidinedione Derivatives as 15-Prostaglandin Inhibitors:
Prostaglandins have a
short life in vivo because they are metabolized rapidly by oxidation to
15-ketoprostaglandins catalyzed by a cytosolic enzyme known as NAD(+)-dependent
15-hydroxyprostaglandin dehydrogenase (15-PGDH). Previously, CT-8, a
thiazolidinedione analogue, was found to be a potent inhibitor of 15-PGDH.
Structure-activity analysis indicated that the N-methylation of
thiazolidine-2,4-dione, CT-8, abolished the inhibitory activity, whereas the
introduction of an ethyl hydroxyl group at amine in CT-8 still had a good
inhibitory effect. Based on the structures of the thiazolidinediones analogues
and inhibitory activity, a range of benzylidene thiazolidinedione derivatives
were synthesized with different substituents on the phenyl ring and their inhibitory
activity was evaluated. Replacement of the cyclohexylethyl group of CT-8 with
the hetero five-member ring increased the inhibitory potency. However,
replacement of the cyclohexylethyl group with a hetero six-member ring
decreased the inhibitory potency significantly. It was found that compound 2
(5-(4-(2-(thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione) was the most
potent inhibitor that was effective in the nanomolar range[14].
Synthesis of thiazolidinedione:
General procedure for the synthesis of
arylidene-thiazolidenes:
A mixture of aldehyde (1 mmol), 2,
4-thiazolidinedione/rhodanine (1 mmol), and [TMG] [Lac] (20 mol%) was
irradiated under ultrasonic irradiation at 80°C for a few minutes (see Table
3). The progress of the reaction was monitored via thin layer chromatography.
After the reaction completion, the reaction mass was cooled (15°C to 20°C) and
stirred with water (10 mL) for 30 min. The solid product was filtered and
dried. The obtained products were recrystallized in EtOH/DMF (3:2). The
products 4–5 were confirmed by their spectral data after
comparison with authentic samples, infrared (IR), proton nuclear magnetic
resonance (1H NMR), mass spectra, and melting points[15].
Microwave synthesis of thiazolidinedione:
Several protocols for the synthesis of
thiazolidinediones are available in the literature; essentially they are two
component reactions involving chloroacetic acid and thiourea. The process can
be either a one-pot two-component condensation or a two-step process4.
Synthesis of thiazolidin edione by refluxing rhodanine, chloroacetic acid and
water for 18 hr followed by washing the solid obtained with water and then air-
drying. Monochloro acetic acid and water can also be used as starting material
followed by addition of sodium bicarbonate with stirring5.
Recrystallization of the residue from ethanol gave sodium thiocyanatoacetate.
By dissolving a portion of this salt in water and treating with sulfuric acid
followed by cooling the mixture on ice bath. The aqueous solution is then
extracted with ether. Evaporation of ether on a steam-bath gives a (1) solid,
as thiazolidinedione which is soluble in chloroform. Thiazolidinedione
synthesized by refluxing a mixture of chloroacetic acid and thiourea in water
for about 40 hrs; the obtained product is crystallized from water(Scheme 1,2).
|
Chloro
acetic acid
|
Thiourea
|
Thiourea
|
Scheme 1
Scheme 2
Microwave
induced synthesis of thiazolidinedione have also been reported. Chloroacetic
acid, thiourea, water are transferred into long necked vial and stirred under
ice cold conditions for about 15min to form a white precipitate of
2-imino-thiazolidine-4-one as intermediate. Irradiation with microwave is
carried out at 250W power for 5 min. Cool the reaction mixture, followed by
collection of the solid that separated by filtration and washing with water to
give white crystals of thiazolidine-2,4-dione.[16]
Synthesis of thiazolidine-2, 4-dione (A):
In a 250 ml round bottomed flask transfer a
56.5 g of chloroacetic acid (0.6mol) in a 60 ml of water and 45.6 g of thiourea
(0.6 mol) dissolved in 60 ml of water. The mixture was stirred for 15 minutes
to form a white precipitate, accompanied by considerable cooling. To this
flask, now add 60 ml of concentrated hydrochloric acid slowly from dropping
funnel. The flask was connected with reflux condenser and gentle heat is
applied to effect complete dissolution, after which the reaction mixture was
stirred and refluxed for 8-10 hrs at 100-110°C. On cooling the content of the
flask solidified to mass of cluster of white needles. The product was filtered
and washed with water to remove traces of hydrochloric acid and dried. It was
recrystallized from ethanol Yield: 73%: M.P: 124-126°C.
Synthesis of 5-benzylidene-2,
4-thiazolidinedione (B):
In a 250 ml round bottomed flask
benzaldehyde (20 g, 0.188 mole) and 2, 4-thiazolidinedione (22 g, 0.188 mole)
were together suspended in dry toluene. To this catalytic amount of piperidine
(1ml) was added. The mixture was refluxed with stirring. After the complete
removal of water and temperature crossed 1100C, the reaction mixture
was stirred for a 1hr. On cooling, the product precipitated from toluene. The
compound was filtered and washed with cold, dry toluene and dry ethanol. Yield:
68%: M.P: 236-2380C.
Fig.No.3: Synthesis of 5- Benzylidene- 2, 4-
Thiazolidinedione (B)
Synthesis of 4-chloro
sulphonyl-5-benzylidene-2, 4-thiazolidinedione (C):
5-Benzylidene-2, 4-Thiazolidinedione (8 g,
0.0388 mole) was placed in a 100 ml round bottomed flask connected with a
condenser and a dropping funnel. Chlorosulphonic acid (18.08 g, 0.155 mole) was
added at room temperature using the dropping funnel. The reaction was found to
be exothermic. After the addition of chlorosulphonic acid was over the reaction
mixture was refluxed for 1 hr on a water bath. The reaction mixture was cooled
and poured in a thin stream with stirring into crushed ice contained in a 1Lt
beaker. It was filtered and purified by recrystallization from ethanol. Yield:
62%: M.P:180-1820C
Fig.No.4: Synthesis of 4’- Chlorosulphonyl-
5- Benzylidene- 2, 4- Thiazolidinedione (C)
Synthesis of 5-[4’-(substituted)
sulphonylbenzylidene] 2, 4-thiazolidinedione(D):
4-phenoxy benzene amine D1 (0.1
mole) and 4-chloro sulphonyl-5-benzylidene-2, 4-Thiazolidinedione C (0.1 mole)
were added to a mixture of 4 ml of dry pyridine and acetic anhydride. The
mixture was refluxed for 2hrs, reaction mixture was poured into 20 ml of ice
water and solid obtained was filtered and recrystallized from ethanol.
Similarly compounds D2-D8
were prepared by adopting similar procedure using appropriate substituted
4-phenoxy benzene amine[17].
R= -H (D1), 4- OCH3 (D2),
4-Cl (D3), 4-CH3 (D4), 4-OC2H5
(D5), 2-OCH3 (D6), 2-Cl (D7),
2- CH3 (D8)
Fig.No.5: Synthesis of 5-[4’-(substituted)
sulphonyl benzylidene] 2, 4Thiazolidinedione(D)
Therapeutic uses:
Anti-diabetic activity:
Sohda et al. synthesized a series of
4-(2-methyl-2-phenylpropoxy) benzyl derivatives and evaluated their hypoglycemic
and hypolipidemic activities with genetically obese and diabetic mice. Among
these, compound (1) was found to possess good hypoglycemic and hypolipidemic
activities comparable to the standard AL-294(2) [18]
Yoshioka et al. synthesized of a novel series
of chroman thiazolidine-2, 4-diones and evaluated for their hypoglycemic
activity. Among these, compound (3) exhibited hypoglycemic and hypolipidemic
activities and was well established as troglitazone [19]. This was
later followed by pioglitazone (4) and rosiglitazone (5) which were established
as potent hypoglycemic agents [20]. Replacement of the phenyl ring
with a chroman ring in the C-5 position of thiazolidinedione moiety led to the
synthesis of englitazone(6) [21].
7
Nazreen et al. synthesized novel 1, 3,
4-oxadiazole and 2, 4-thiazolidinedione based bis-heterocycles and studied
blood glucose lowering effect comparable with standard drug pioglitazone (4)
and rosiglitazone (5). Compound (7) may be considered as a potential candidate
for the development of new antidiabetic agents [22].
Aldose reductase inhibitory activity:
8
9
Ottana et al. synthesized
5-arylidene-4-thiazolidinediones as aldose reductase inhibitors. Compounds (8)
and (9) showed interesting dual inhibitory activity against aldose reductase
enzyme as well as excellent antioxidant property [23].
10 11
Bruno et al. synthesized (Z)-5-arylidene-2,
4-thiazolidinediones and evaluated as aldose reductase inhibitors. where (11)
N-unsubstituted derivatives exert maximum inhibitory activity same as standard
sorbinil (10) where as introduction of an acidic side chain on N-3 of
thiazolidinedione moeity (12) led to a marked increase in inhibitory activity
which was similar with tolrestat and methyl ester derivative (13) which devoid
of any acidic functionality showed appreciable inhibitory activity similar to
that of the N-unsubstituted compounds [24].
12 13 14
Bozdag-Dundar et al. synthesized novel
flavonyl-2, 4-thiazolidinedione derivatives and evaluated aldose reductase
inhibitory activity and insulinotropic activities in INS-1 cells. Compound (14)
shown the highest aldose reductase inhibitory activity (86.57%)[25].
Anticancer activity:
Shibata et al. synthesized 2-[4-(2,
4-thiazoldinedione -5-ylmethyl) phenoxymethyl]-1H benzimidazoles, among which compounds
(15) and (16) showed significant inhibitory activity against human large bowel
cancer cell growth [26].
|
COMPOUND NUMBER
|
X
|
Y
|
|
15
|
O
|
CH or N
|
|
16
|
S
|
CH or N
|
15-6
Gududuru et al. synthesized a new series of
2-aryl-4-oxo-thiazolidin-3-yl amides (17) were designed and synthesized by all
the synthesized compounds were evaluated against five human prostate cancer
cell lines. Increase in the alkyl chain enhanced antiproliferative activity
while replacement of the alkyl chain with aryl group reduced biological
activity [27].
17 18
Chandrappa et al. synthesized a new series of
2-(5-((5-(4-chlorophenyl) furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-
yl)acetic acid derivatives (18) and evaluated these for their cytotoxic
activity [28].
ANTIMICROBIAL:
·
ANTIBACTERIAL AND
ANTIFUNGAL:
Aneja et al synthesized three series of
compounds, namely, ethyl 2-((Z)-5-((3-aryl-1-
phenyl-1H-pyrazol-4-yl)methylene)-2,
4-dioxothiazolidin-3-yl)acetates (A), methyl 2-((Z)-5-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-2,
4-dioxothiazolidin-3-yl)acetates (B), and
2-((Z)-5-((3-aryl-1-phenyl-1H-pyrazol-4-yl)methylene)-2, 4-
dioxothiazolidin-3-yl)acetic acids (C). All
the new compounds were tested for their in vitro antibacterial and antifungal
activity using all the new compounds were tested for their in vitro
antibacterial and antifungal activity. The antifungal and antibacterial
acitvites were carried out by Sabouraud dextrose agar (SDA) is used as medium
and Fluconazole is used as Standard antibiotic and agar well-diffusion method
respectively. Antifungal evaluation of the compounds has shown signifincant
antifungal activity against Aspergillus flavus and Aspergillus niger
and the mycelia growth of inhibition(%) varies between 54.4 to 77.7 and
60.0 to 81.1.Moreover the compounds have also shown antibacterial activity
against Staphylococcus aureus and Bacillus subtillis.[29]
19
Harnden et al. synthesized a series of
2-methylaminothiazoliinones. Among all the compounds, compound (19) showed
significant antiviral and antibacterial activity [30].
20 21
Mizzoni et al. synthesized a series of
thiazolines (20) and thiazolidinones (21) exhibiting significant
antimycobacterial activity [31].
22
Babaoglu et al. prepared a library of 2, 3,
5-trisubstituted-4-thiazolidinones and evaluated them for antimycobacterial
activity. Compound (22) showed potent activity against Mycobacterium
tuberculosis in vitro [32].
·
Antiviral:
Balzarini et al. studied the QSAR and suggested
that molecules with higher lipophilicity improved activity. [33].
Novel thiazolidinones with 3-hydrazono-5-nitro-2-indolinone linked at the N-3
of the thiazolidinone ring were screened by against yellow fever virus and
bovine viral diarrhea virus (BVDV). Among all the compounds, compound
(23) showed highest activity which was attributed to the methyl group at C-5 of
the thiazolidinone ring [34].
23
24
Balzarini et al. prepared
2-adamantyl-substituted thiazolidin-4-ones. Compound (24) exhibited very high
inhibitory activity with an EC50 of 0.35μM, which was attributed to the
presence of adamantyl moiety at C-2 position. The other derivatives lacking the
adamantyl moiety were devoid of HIV-1RT inhibitory activity [35].
·
Anti-psychotic
activity:
25 26
Hrib et al. studied the structure-activity
relationships of a series of novel (piperazinylbutyl) thiazolidinone related to
3-[4-[4-(6-flurobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2,5,5-trimethyl-4-thiazolidinone
maleate as antipsychotic and evaluated in vitro for dopamine D2 and serotonin
5HT2 and 5HT1A receptor affinity. The compounds were examined in vivo in animal
models of male CD-1mice and male wistar rats for potential antipsychotic
activity. The compounds (25) and (26) showed potential efficacy against the
negative symptoms of schizophrenia [36].
·
Anti
arrythmic :
Jackson et al. synthesized a series of
thiazolidinones and evaluated these for the treatment of arterial arrhythmias.
The 3, 4- dimethyl derivatives (26) and (27) were found to be the most potent
compounds of this series [37].
26 27
28
Bhandari et al. synthesized 2-(2-
(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-
hydroxypropylamino) benzoyl) hydrazinyl)-2-oxoethyl nitrates and evaluated them
for electrocardiographic, antiarrhythmic, vasorelaxing and antihypertensive
activity as well as for in-vitro nitric oxide (NO) releasing ability. Compound
(28) was found to be the most potent in this series [38].
·
Anti
convulsants and antidepressants :
29
Karall et al. synthesized a series of
3-[(3-substituted-5-methyl-4-thiazolidinon-2-ylidene) hydrazono]-1H-2-indolinone
derivatives and evaluated for CNS antidepressant activity. Compound (29) with
para methyl phenyl group on thiazolidinone ring exhibited reasonable
anticonvulsant activity. Replacement of para methyl phenyl group with an allyl
group was found to increase its antidepressant activity [39].
Agrawal et al. reported a new series of
thiazolidinonyl2-oxo/thiobarbituric acids. Compound (30) exhibited highest
anticonvulsant activity, higher than the standard drug sodium phenytoin (31) [40].
30 31
32
Kaur et al. synthesized a number of substituted
thiazolidinones. Among all the compounds, compound (32) exhibited potent
antipsychotic as well as anticonvulsant activities [41].
Anti-inflammatory and analgesic
agents :
33
Goel et al. synthesized new anthranilic acid
derivatives of 4-thiazolidinone and evaluated for their anti-inflammatory
activity against carageenan- induced oedema in albino rats by Compound (33)
showed maximum antiinflammatory activity [42].
34
Ali et al. reported a series of thiazolidine-2,
4-diones and proved that absence of 5-arylmethylidene moiety in compound (34)
enhanced its anti-inflammatory activity and decreased the analgesic activity.
Bulky groups incorporated at the N position of thiazolidine-2,4-dione ring
either decreased or abolished the anti-inflammatory activity [43].
35
Amin et al. prepared several spiro [(2H,3H)
quinazoline-2,10-cyclohexan]-4(1H)-ones which were evaluated for their
antiinflammatory, ulcerogenic and analgesic activities. Compound (35) showed
highest anti-inflammatory activity and considerable analgesic activity [44].
·
Anti
hyperlipidemic :
Lohray et al. synthesized indole containing
thiazolidinedione derivatives as potent euglycemic and hypolipidemic agents.
Compound (36) consider as a superior euglycemic and hypolipidemic agent than
troglitazone (37) [45].
36 37
38 39
Lee et al. synthesized novel pyrimidine
derivatives having thiazolidinedione and were evaluated for their glucose and
lipid lowering activity in 3T3-L1 cells of KKAy mice. Compound (38) and (39)
exhibit more potent biological activity than that of the reference compounds
pioglitazone (4) and rosiglitazone (5) [46].
40
41 42
Leite et al. synthesized novel arylidene thiazolidinedione
and compound (40), (41), (42) showed potential hypoglycemic and hypolipidemic
activities [47].
·
Antiobesity:
43
Bhattaraj et al. synthesized benzylidene-2, 4-thiazolidinedione
derivatives with substitutions on the phenyl ring at the ortho or para
positions of the thiazolidinedione group were synthesized as PTP1B inhibitors.
(43) compound bore an IC50 of 5.0μm and show potential activity [48].
44
Bhattaraj et al. synthesized novel benzylidene
-2, 4-thiazolidinedione derivatives as PTP1B inhibitors. Compound (44) bore an
IC50 of 1.3 μm to activate the transcription of the receptor comparable
with troglitazone (37), rosiglitazone (5), and pioglitazone (4) [49].
·
Anti
malarial :
45
Sharma et al. synthesized a series of
thiazolidinedione as plasmodium falciparum cysteine protease falcipain-2 inhibitor
as well as antiparasitic. Compound (46) show modest activity due to presence of
methyl substituents bore an IC50 of 45.33 [50].
CONCLUSION:
The article has outlined the synthesis, mechanism of
action, various pharmacological activities and adverse effects of
thiazolidinediones and some of its derivatives. The survey of the literature
revealed that, thiazolidione is a versatile lead molecule for designing
potential bioactive agents and its derivatives were reported to possess
broad-spectrum antidiabetic, aldose reductase inhibitory activity, anticancer,
antimicrobial (antibacterial, antifungal and antiviral), antipsychotic,
antiarrhythmic, anticonvulsant and antidepressant, anti-inflammatory and
analgesic, antihyperlipedimc, anti obesity, anti malarial activities. Further
we can conclude that many other derivatives of thiazolidione can be synthesized
which will be expected to show potent pharmacological activities.
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