2013 thiazolidinones progres throught multifarious applications

Bioorganic & Medicinal Chemistry xxx (2013) xxx–xxx

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Bioorganic & Medicinal Chemistry

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Review

Thiazolidine-2,4-diones: Progress towards multifarious applications

0968-0896/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.bmc.2013.01.029

⇑ Corresponding author. Tel.: +91 022 27572131/1122; fax: +91 022 27574515.E-mail address: [email protected] (C.S. Ramaa).

Please cite this article in press as: Jain, V. S.; et al. Bioorg. Med. Chem. (2013), http://dx.doi.org/10.1016/j.bmc.2013.01.029

Viral S. Jain, Dhagash K. Vora, C. S. Ramaa ⇑Department of Pharmaceutical Chemistry, Bharati Vidyapeeth’s College of Pharmacy, Sector-8, C.B.D. Belapur, Navi Mumbai 400614, Maharashtra, India

a r t i c l e i n f o

Article history:Received 4 December 2012Revised 8 January 2013Accepted 10 January 2013Available online xxxx

Keywords:Thiazolidine-2,4-dioneAnti-hyperglycaemicsAldose reductase inhibitorsAnti-cancerAnti-inflammatoryAnti-arthriticsAnti-microbials

a b s t r a c t

The promising activity shown by compounds containing thiazolidine-2,4-dione nucleus in numerous cat-egories such as anti-hyperglycaemics, aldose reductase inhibitors, anti-cancer, anti-inflammatory, anti-arthritics, anti-microbials, etc. has made it an indispensable anchor for development of new therapeuticagents. Varied substituents on the thiazolidine-2,4-dione nucleus have provided a wide spectrum of bio-logical activities. Importance of this nucleus in some activities like, peroxisome proliferator activatedreceptor c (PPARc) agonism and PPARc-dependent and -independent anti-cancer activities are reviewedseparately in literature. Short reviews on biological importance of this nucleus are also known in litera-ture. However, owing to fast development of new drugs possessing thiazolidine-2,4-dione nucleus manyresearch reports are generated in short span of time. So, there is a need to couple the latest informationwith the earlier information to understand the current status of thiazolidine-2,4-dione nucleus in medic-inal chemistry research. In the present review, various derivatives of thiazolidine-2,4-diones with differ-ent pharmacological activities are described on the basis of substitution pattern around the nucleuscombined with the docking studies performed in the active site of the corresponding receptors withan aim to help medicinal chemists for developing an SAR on thiazolidine-2,4-dione derived compoundsfor each activity. This discussion will further help in the development of novel thiazolidine-2,4-dionecompounds.

� 2013 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.2. Tautomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002.3. Characterisation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

3. Mechanisms of action of TZDs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Application in medicinal chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.1. Anti-hyperglycaemic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.1. Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1.2. Structure of PPARc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1.3. Binding pockets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.1.4. Structure–activity relationships (SARs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Aldose reductase inhibitory activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.3. Anti-cancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.3.1. PPARc dependent anti-tumour mechanisms of TZDs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.3.2. PPARc independent anti-tumour mechanisms of TZDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

4.4. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.5. Anti-arthritic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.6. Anti-microbial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004.7. Miscellaneous activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

5. Metabolism and toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
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2 V. S. Jain et al. / Bioorg. Med. Chem. xxx (2013) xxx–xxx

Pleas

5.2. Hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Bioisosteric replacements of TZDs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Supplementary data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Scheme 1. Conventional method for synthesis of thiazolidine-2,4-dione.

1. Introduction

One of the main objectives of organic and medicinal chemistryis to design, synthesize and produce molecules possessing value ashuman therapeutic agents. Compounds containing heterocyclicring systems are of great importance receiving special attentionas they belong to a class of compounds with proven utility inmedicinal chemistry.1 As an example, five-membered ring hetero-cycles containing three carbon atoms, one nitrogen atom, and onesulfur atom, known as thiazoles (A) are of considerable interest indifferent areas of medicinal chemistry.2

Thiazolidine-2,4-dione (TZD) is a heterocyclic ring system withmultiple applications. Thiazolidine-2,4-dione inhibits corrosion ofmild steels in acidic solution. These are also used in analyticalchemistry as highly sensitive reagents for heavy metals3 and as abrighter in electroplating industry.4

In 1982 a number of TZDs were intensively studied for theiranti-hyperglycaemic property. The first representative of this classwas ciglitazone, whereas other derivatives like englitazone, pioglit-azone and troglitazone followed soon. The thiazolidine-2,4-dionenucleus has been reported for being responsible for majority oftheir pharmacological actions. Henceforth, thiazolidine-2,4-dionederivatives have been studied extensively and found to have di-verse chemical reactivities and broad spectrum of biologicalactivities.

We, in our laboratory, have been investing our efforts in devel-oping novel TZD molecules and have explored and achieved suc-cess in establishing their anti-hyperglycaemic and anti-cancerpotential. Even though these molecules have been established fora long time now, their structural and therapeutic diversity makesthem interesting enough to be explored in depth.

Therefore, this review article is an exhaustive attempt toabridge all the various chemical and therapeutic aspects of thiazol-idine-2,4-diones.

Scheme 2. Microwave assisted synthesis of thiazolidine-2,4-dione ring.

2. Chemistry

1,3-Thiazolidine-2,4-diones (C) are derivatives of thiazolidine(B) with two carbonyl groups at the 2 & 4 positions. Substituentsin the 3 & 5 positions may be varied. The pKa of thiazolidinedionehas been reported to be 6.82.5

Figure 1. Different tautomers of thiazolidine-2,4-dione.

2.1. Synthesis

The thiazolidinedione ring can be synthesized using both con-ventional as well as microwave method. Conventional method iscarried out by refluxing chloroacetic acid and thiourea using wateras a solvent for 12 h and cooled to yield white crystals of thiazoli-dine-2,4-dione (Scheme 1).6

The reported microwave assisted synthesis of thiazolidine-2,4-dione ring (Scheme 2) involves a two-step reaction. In the firststep, chloroacetic acid and thiourea are stirred under ice cold con-dition to obtain a white precipitate of 2-imino-thiazolidin-4-one (i)intermediate, which in the second step is further irradiated withmicrowave at 250 W for 5 min to obtain white crystals of thiazol-idine-2,4-dione (ii).7

e cite this article in press as: Jain, V. S.; et al. Bioorg. Med. Chem. (

2.2. Tautomerism

Since thiazolidine-2,4-dione (C) contains two carbonyl groupsand an a-hydrogen it has an ability to undergo tautomerism8

and different tautomers obtained are shown in Figure 1. It under-goes either amide-imidol (b,c) type of tautomerism or keto-enol(d) type of tautomerism or both (e).9 Of all different tautomericforms mentioned tautomer (a) is found to be stable.

There are various pharmaceutical drugs containing the TZD ringcapable of undergoing tautomerism that usually involve migrationof proton (prototrophy) from one site to another within themolecule.8

2013), http://dx.doi.org/10.1016/j.bmc.2013.01.029


Figure 2. Thiazolidine-2,4-dione, a multifunctional nucleus.

V. S. Jain et al. / Bioorg. Med. Chem. xxx (2013) xxx–xxx 3

It was observed that a compound containing thiazolidinedionering predominantly undergoes amide-imidol type of tautomerismand this fast prototrophy could render either amide (a) or imidol(b) form available for biological activity.

2.3. Characterisation

The 1H NMR spectrum7 for unsubstituted thiazolidine-2,4-dione shows a characteristic singlet at 3.98 (d ppm) for –CH2– pro-tons and a broad singlet at 12.51 (d ppm) for NH proton. The reasonfor this deshielding is the presence of two electron-withdrawingcarbonyl groups (C@O), on either side of NH group in the thiazoli-dine ring system. Mass spectrum7 of TZD shows a base peak at m/z = 116 (100%). The infrared spectrum9 shows a peak at 3145 cm�1

(N–H(S)), 2923 cm�1 (CH2(S)), 1738 cm�1 (C@O(S) at C4), 1659 cm�1

(C@O(S) at C2), 1318 cm�1 (N–C4(s)), 1165 cm�1 (C2–N(S)), 808 cm�1

(C5–S(S)), 727 cm�1 (C2–S(S)). Melting point of TZD is found to be120–122 �C.9

3. Mechanisms of action of TZDs

Thiazolidine-2,4-diones act mainly by binding to peroxisomeproliferator activated receptors (PPARs), a group of nuclear recep-tor superfamily. They are also known to bind to aldose reductaseenzyme, phosphoinositide 3-kinase c (PI3Kc), pim kinase family;highlighting their versatile roles in multiple indications apart fromdiabetes, spanning from inflammatory diseases to cancers.10 Thedrug discovery community debated until now whether the TZDsare one of the promiscuous ligands that nonselectively bind to var-ious receptors and enzymes. However, these speculations wereended by Mendgen et al. when they showed that TZDs and otherrelated five-membered heterocycles like rhodanine, hydantoinand thiohydantoin possess a distinct intermolecular interactionprofile which is even more pronounced if the heterocycle becomesaromatic as in benzylidene thiazolidinediones. They proved that

Please cite this article in press as: Jain, V. S.; et al. Bioorg. Med. Chem. (

the distinct binding profile is not related to unspecific propertieslike aggregation or reactivity but rather to electronic and hydro-gen-bonding properties that could be explained and understoodand it is this molecular interaction profile of these scaffolds thatmakes them prone to bind to a large number of targets with weakor moderate affinity. Thus, TZDs should not be regarded as prob-lematic or promiscuous ligands.11 Detailed mechanism of actionis explained under each class.

4. Application in medicinal chemistry

There is a plethora of information highlighting various biologi-cal applications of TZDs as a result of certain alterations carried outon TZD ring (Fig. 2). Some of the multitudes of activities encom-passed in detail are:

4.1. Anti-hyperglycaemic activity4.2. Aldose reductase inhibitory activity4.3. Anti-cancer activity4.4. Anti-inflammatory activity4.5. Anti-arthritic activity4.6. Anti-microbial activity4.7. Miscellaneous activities

4.1. Anti-hyperglycaemic activity

In 1997, the World Health Organization (WHO) recognised dia-betes mellitus as a global health problem.12 Diabetes mellitus is agroup of syndromes characterised by hyperglycaemia. Clinically,patients can be classified as having either insulin-dependent dia-betes mellitus [IDDM or type 1 diabetes] or non-insulin-dependentdiabetes mellitus [NIDDM or type 2 diabetes (T2D)]. IDDM is anautoimmune disease that is treated with exogenous insulin admin-istration and patients have an absolute deficiency of insulin,



Figure 4. Structure of PPARc receptor.

Figure 5. Binding of TZDs (ligand) to PPARc and the observed cascade. Abbrevi-ations: N-CoR, nuclear co-repressor; PGC-1, PPARc co-activator-1; HAT, histoneacetyl transferase; SR-1, steroid receptor co-activator-1; cis-RA, cis-retinoic acid.


caused by defective pancreatic cell function. NIDDM has a morecomplex aetiology, including reduced sensitivity of tissues to insu-lin, and is characterised in the later stages by hyperglycaemia,hyperinsulinaemia, and perhaps defects in insulin secretion bythe pancreatic cells. It is a multifactorial disease and of all the pop-ulation affected with diabetes, approximately 90% are affectedwith NIDDM. Untreated T2D leads to several complications, suchas retinopathy, nephropathy and cardiovascular diseases includingatherosclerosis, leading to increased mortality.13 Early stage T2Dmay be managed well with diet and exercise. However, in additionto lifestyle and dietary changes, insulin or oral hypoglycaemicagents (OHA) like insulin sensitizers either alone or in combinationare needed for good control over blood glucose levels.

The concept of insulin sensitizers emerged with the discovery ofthe TZD class of compounds. The first compound was discovered in1982 in Japan by Sohda et al. at Takeda.14 While searching for a po-tent agent for reducing cholesterol and triglyceride, Takeda scien-tists discovered compound AL-294 (1), which was able to reducethe glucose level by 18–41%.15 Search for a suitable acid function-able equivalent of AL-294 led to the discovery of TZD head group inAL-321 (2), which was slightly more potent than AL-294.

Further modification in the lipophilic tail of the molecule led tociglitazone (3),14 which was found to be more potent and wasfound to decrease the glucose level without increasing insulinsecretion. Also, it decreased the insulin level in the hyperinsulinae-mic model, indicating its potency to improve insulin sensitivity.

On the other hand, it neither had any effect in insulin-deficientdiabetic animals, nor did it reduce the glucose level below the nor-mal plasma glucose level (euglycaemic agent).16 This was a break-through discovery for the treatment of T2D, and that followed thediscovery of several glitazones and other heterocycles, which werefound to be insulin sensitizers14 and distinguished themselvesfrom insulin secretagogues such as sulfonylureas and frombiguanides.

Further variations produced different glitazones, which weredeveloped for clinical evaluation, such as pioglitazone (PGZ) (4),rosiglitazone (RGZ) (5), troglitazone (TGZ) (6) (approved in 1997)and englitazone (7).17

However, due to the unacceptable hepatotoxicity of TGZ, it waswithdrawn from the market in 2000, while englitazone, ciglitazoneand darglitazone were not developed for clinical use whereas RGZ(approved in 1999) and PGZ (approved in 2000) have been

Figure 3. Mechanism of action of TZDs.


developed and marketed successfully.17 Unfortunately, RGZ wasalso withdrawn from market in 2010 due to cardiotoxicity.

4.1.1. Mechanism of actionThiazolidinedione derivatives (TZDs) are the most extensively

employed insulin-sensitising drugs which possess a high affinityfor PPARc receptor (a class of PPAR receptors) and act as agonists.PPARc is most abundant in the adipose tissue.18,19 TZDs exert theirinsulin-sensitising action via increased PPARc expression in theadipose tissue, thus increasing adipocytes and subcutaneous adi-pose tissue mass. Increased PPARc expression in the adipose tissueresults in increased fatty acid uptake and storage by increasing thetranscription of fatty acid transport protein-1 and acyl-coenzyme Asynthetase. Decreased circulating free fatty acid levels protect bcells, the liver, and the skeletal muscle from their toxic effects, thusimproving insulin sensitivity.19 Such a phenomenon has beentermed the ‘fatty acid steal hypothesis’. The mechanism of actionof TZDs is summarized in Figure 3.

4.1.2. Structure of PPARcThe structure of PPARc is depicted in Figure 4. The N-terminal

A–B domain confers ligand-independent activation [TAF-1 (trans-activation function 1)] whereas the C domain is required for DNAbinding and contains a P-box (or recognition helix) that interactsdirectly with specific, hexameric DNA sequences and a D-box thatis responsible for selecting the distance between two halves of thehexameric DNA-binding site. The D-domain is termed the hinge re-gion of the receptor; whereas the E-domain is the ligand-bindingdomain of the receptor and is required for receptor dimerizationand ligand-dependent activation [TAF-2 (transactivation function2)]. The function of F-domain is unknown.

Binding of TZDs to PPARc leads to the formation of heterodi-mers with retinoid-X receptors (RXRs). This is followed by bindingto specific DNA sequences termed peroxisome proliferator re-sponse elements (PPREs), found on the promoters of PPARc target



Figure 6. Binding sites of TZDs with PPARc receptor.


genes, thereby stimulating their transcription (a mechanismtermed ‘transactivation’) (Fig. 5). Several of these target genes areinvolved in metabolic homeostasis.20 Simultaneously, PPARc stim-ulation downregulates genes of adipocyte-derived insulin-resis-tant factors, especially TNF-a, thereby intensifying the signaltransduction associated with insulin response.

Therefore, PPARc seems to be a potential and useful drug targetin treating insulin resistance. The glitazones lower circulating insu-lin relative to plasma glucose, but do not return glucose levels tonormal.19

4.1.3. Binding pocketsThe X-ray crystal structure of PPARc-ligand binding domain

(PPARc-LBD) complexed with RGZ21 suggests that the TZDs bindwith the PPARc receptor using mainly a three-point recognitionelement, ‘cationic site or hydrophilic site’, ‘flat aromatic region’and ‘‘O’ atom anchor’. There is also a large variable hydrophobic re-gion, ‘hydrophobic binding site’ essential for activity (Fig. 6).

Figure 7. Initial lead molecule and its different regions.


1. In the cationic/hydrophilic site, TZDs form hydrogen bonds withthe active site of the receptor with Ser289 of helix 3.22 It alsoforms several primary and secondary hydrogen bonds with crit-ical residues of the activation function helix 2 (AF-2 helix) ofPPARc including His323, His449 and Tyr473. The presence ofthese hydrogen bonds is crucial for agonistic activity of PPARcligands. It is believed that in response to these hydrogen bond-ing interactions, the AF-2 helix closes onto the ligand bindingsite and establishes a transcriptionally active form of the recep-tor which further recruits a co-activator protein to effectivelystimulate gene transcription. A large number of variations tothis ring were reported but no correlation was observed withthe acid strength and activity.

2. In the flat linker region an aromatic ring is favourable as itforms p–p stacking interactions with the receptor. Absoluteplanarity in this region is essential for activity. Also this regionhas limited space and hence large substructure fragments in thecentral aromatic region lead to reduced activity. The linkerregion occupies a narrow groove formed by Cys285, Ile326,Leu330, Leu333, Val339, and Met364 and makes hydrophobicinteractions with the surrounding residues, particularly withCys285.

3. Another important recognition element is ‘O’ atom of etherlinkage. This forms a hydrogen bond with the receptor. Exactsuperimpositions of this atom help to place the terminal lipo-philic fragment of the molecule in a proper spatial orientationwhich is important for activity.

4. In the hydrophobic region a large steric interaction with thereceptor is observed. This region can accommodate various sub-structure fragments. Though this region is very large there is alimiting size and shape for the substituent that would be effec-tive for binding. The substituents in this region should be suchthat they not only modulate the binding with the receptor butalso influence the factors involved in non-receptor events suchas pharmacokinetic and toxicity profiles. This is an importantregion of the molecule where wide choice of substituents can




be made to design better anti-hyperglycaemic agents. In thisregion steric interactions are more important than the hydro-phobic interactions.23

4.1.4. Structure–activity relationships (SARs)The majority of TZD containing anti-hyperglycaemic agents re-

ported in literature have a polar TZD ring system as a head fol-lowed by hydrophobic benzyloxy moiety as their trunk which isin turn connected to the hydrophobic tail via a two carbon linker.

Based on the initial lead molecule, ciglitazone, that bears 5 dif-ferent regions (A to E) (Fig. 7), the generalised structure for TZDclass of molecule was deduced as follows:17

(a) Pharmacophore (E): The arm I of PPARc pocket consists ofmainly polar residues and includes the AF-2 helix, whichactivates transcription if the hydrophilic head group of thePPARc agonist forms a hydrogen bond network with the cor-responding residues of the helix. This network stabilizes aconformation of the AF-2 helix that allows the binding ofco-activator proteins, which in turn leads to gene transcrip-tion.22,24 This indicates the necessity of a relatively morepolar head group and compounds with TZD moiety as a headgroup show better activity.25 Substitution on nitrogen atomof TZD ring with methyl group decreases the activity.14 Also,reduction of double bond of TZD ring or change in the size ofring decreases the activity.14 When the C-5 of thiazolidine-2,4-dione ring is substituted with a benzyl moiety (as inPGZ, RGZ and TGZ), a chiral centre is generated at C-5. Ithas been shown that only the S enantiomer binds to thereceptor with high affinity. However, these can be developedas racemates since they undergo racemization under physi-ological conditions due to the acidic nature of the TZD ring.22

(b) Linker between C and E (D): The acidic fragment should beattached to the central aromatic (aryl) fragment by a carbonatom spacer. This carbon atom could be sp2 or sp3 hybri-dised.23 In case of sp2 hybridised carbon atom, chirality atthe attachment position shows that both the isomers areactive23 and removal of this carbon atom spacer causescomplete loss of activity.26 Saturated derivatives are muchmore active than their corresponding unsaturatedderivatives.25–29 Other linkers such as thio, oxy, and sulfinyllead to decreased anti-hyperglycaemic activity.30

(c) Central aryl part (C): Most favourable substituent at this posi-tion is a phenyl ring substituted at para position with anether linkage that is, phenoxy group.31 Replacement of thisoxygen atom with carbon atom causes decrease in activity.22

Also, substitution of ether group that is, ethoxy or methoxylinkage at ortho or meta position of phenyl ring causesdecrease in activty and para position is the only favouredposition for substitution.22 Substitution at ortho position ofether linkage with a methoxy group produces good resultin comparison to an unsubstituted one.31 Replacement ofphenoxy group with nitrogen bearing moiety like quinolonering decreases the activity, as the basic nitrogen interfereswith receptor interaction thereby reducing the affinity.32

(d) Linker (B): Linker consisting of two carbon atoms spacedbetween the oxygen atom and the alicyclic ring has beenreported to be ideal for activity.33 Decrease in number of car-bon atoms at linker B with a simultaneous increase in num-ber of carbon atoms at a linker between C and E causesincrease in activity and vice versa causes decrease in activ-ity.22 Introduction of an N–CH3 group between the lipophilicregion and the phenoxyethyl moiety would lead to a several-fold increase in potency.17 Replacement of N–CH3 by N–H orN–CH2CH3 leads to a reduction of plasma glucose-lowering


activity.17 Presence of sulfur causes a distinct reduction inactivity.33 It has also been reported that the putative ketonemetabolite (8) of PGZ is described as a potential anti-hyper-glycaemic PGZ congener with somewhat greater potencyand a better metabolic profile.34

(e) Lipophilic tail (A): The tail portion is represented by either anaromatic or an alicyclic ring system which generally con-tains an H-bond acceptor.22 Several heterocyclic rings, likea fused heterocyclic,35–37 five-membered ring,33,37 or six-membered ring23 have been reported with glucose loweringactivity. In the case of phenyl ring, substitution with an H-bond acceptor was found to be more active as compared tothe unsubstituted phenyl ring.25

(f) Linker and lipophilic tail: Introduction of a cyclic linker moi-ety obtained by combining lipophilic tail and ethoxy linkerimproved the anti-hyperglycaemic activity of the com-pounds compared to the N–CH3 ethoxy linker.17 Various cyc-lic linkers like azaindole, pthalazinone, benzoxazinone,pyrimidinone,17 oxime attached to an aromatic ring,38 andindole39,40 were known to have glucose lowering activity.

Following the findings of Tanis et al,34 we hypothesised that theintroduction of a carbonyl group in the form of ketone or amide inlinker chain (B), may serve as a useful strategy in drug design in thearea of anti-hyperglycaemic TZDs. Based on this hypothesis, our re-search group synthesized various derivatives of thiazolidine-2,4-dione of which the reported compound 9 [(Z)-2-(4-((2,4-dioxo-thizolidin-5-ylidene)methyl)phenoxy)-N-(5-nitrothiazol-2yl)acet-amide] and compound 10 [(Z)-5-(2-(4-((2,4-dioxothizolidin-5-ylidene)methyl)phenoxy)acetyl)-2-hydroxy benzamide] werefound to be active.37 An extensive research work is still beingworked upon in our laboratory so as to develop more potent novelTZD entities.

4.2. Aldose reductase inhibitory activity

Diabetes mellitus is recognised as a leading cause of new casesof blindness and is associated with increased risk for painful neu-ropathy, heart disease and nephropathy. Many theories have beenadvanced to explain mechanisms leading to diabetic complica-tions, including stimulation of glucose metabolism by the polyolpathway involving the aldose reductase enzyme. Aldose reductase(ALR2), a member of the aldo-ketoreductase superfamily, is thefirst enzyme of the polyol pathway; it catalyses the NADPH-depen-dent reduction of glucose to sorbitol, which in turn is oxidised bysorbitol dehydrogenase to fructose. Under normal glycaemic con-ditions, only a small fraction of glucose is metabolised throughthe polyol pathway, as the majority is phosphorylated by hexoki-nase, and the resulting product, glucose-6-phosphate, is utilisedas a substrate for glycolysis or pentose phosphate metabolism.However, in response to the chronic hyperglycaemia found in dia-betics, glucose flux through the polyol pathway is significantly in-creased. Additionally, the enzyme is located in the eye (cornea,retina, lens), kidney, and the myelin sheath-tissues that are ofteninvolved in diabetic complications. Therefore, ALR2 inhibition hasreceived attention as an attractive strategy to prevent or delaythe onset and to minimize the seriousness of chronic diabeticcomplications.

Two main classes of orally active aldose reductase inhibitors(ARIs) have been clinically tested: cyclic imides (mostly hydanto-ins, e.g., sorbinil) and carboxylic acids (e.g., tolrestat). The carbox-ylic acid derivatives in vitro are very active; however, in vivo theyare generally less active than imides, probably owing to their lowerpKa values that can result in less favourable pharmacokinetics.Currently, epalrestat (ONO-2235) is the only ARI available in the



Figure 9. A schematic diagram illustrating the hydrogen bond interactions ofinhibitor 16 with the ALR2.


market. Additional reductase inhibitors such as ranirestat, ponalre-stat, rinalrestat, risarestat and berberine are currently in clinicaltrials.

There is a great interest in 2,4-thiazolidinedione derivatives asARIs, since they can be viewed as hydantoin bioisosteres poten-tially free of the hypersensitivity reactions which are linked tothe presence of the hydantoin system.41–43

In fact, to date, several thiazolidine-2,4-diones have been pat-ented with dual activity as anti-hyperglycaemic and ALR2 inhibi-tory agents.44,45

Based on these considerations, in a search for new ARIs, Maccariand co-workers, in 2002, synthesized and tested 3 different seriesof 5-arylidene-2,4-thiazolidinediones.41 The first series of com-pounds (11) possessed the acidic hydrogen of the thiazolidinedi-one imidic moiety, with pKa higher than those of carboxylicacids. The second series (12) consisted of the corresponding car-boxylic acids by replacing the imidic hydrogen with the acetic acidmoiety, while the third series (13) consisted of the acetate esterswhich do not possess the acidic proton. The first and second seriesappeared to possess the essential structural requisites (an acidicproton, hydrogen-bond acceptor groups and a lipophilic aromaticmoiety) for ALR2 inhibitory effect, in accordance with known phar-macophoric requirements. In particular it is known that the pres-ence of an acidic functionality is an important requirement for allARIs, since they interact, in their ionised form, with the active siteof the enzyme.

Later, in continuation of their work, Maccari et al. in 2005, car-ried out the molecular modelling at the active site of the ALR2 en-zyme and also formulated an SAR identifying the key molecularfeatures required for the best activity.42

In general, the presence of an additional aromatic ring or an H-bond donor group on the 5-benzylidene group increased the ALR2inhibitory activity of 5-arylidene-2,4-thiazolidinediones. meta-Substitution patterns on the 5-benzylidene moiety improved activ-ity, independently of the nature of the substituent group.

The introduction of an acetic chain on N-3 of the thiazolidine-2,4-dione ring led to a marked increase in inhibitory potency. Thisfinding suggested that the polar N-3 acetate chain was able bindthe polar, positively charged recognition region of the ALR2 activesite formed by Tyr48, His110, Trp111 residues and the nicotin-amide ring of cofactor NADP+. Also, the length of the carboxylicchain on N-3 was shown to be critical for activity; the replacementof the N-3 acetic chain with the residue of 2-butenoic acid wasfound to be detrimental for activity.

On the other hand, esters (13), devoid of any acidic proton, ingeneral proved to have ALR2 inhibitory properties similar to thoseof thiazolidine-2,4-diones with acidic imidic hydrogen (11).

Figure 8. A schematic diagram illustrating the hydrogen bond interactions ofinhibitor 15 with the ALR2.


ALR2 inhibition strongly depends on charge–charge interac-tions and hydrogen bonds of inhibitors and on aromatic–aromaticinteractions with the hydrophobic region of the ALR2 active site.Most of these bonds as well as new possibilities for interactionwere evidenced when the 5-arylidene-2,4-thiazolidinediones un-der study were docked into the active site of the enzyme (Figs. 8and 9). The compounds (14), (15), (16) and the known inhibitorIdd384 (17) were considered for docking studies.

Based on Maccari’s work, Bozdag-D}undar et al., in 2008, synthe-sized derivatives containing acetic acid (18)/acetic acid ethyl ester(19) groups on N-3 position of the 2,4-TZD ring system and a fla-vone moiety instead of 5-benzylidene moiety and further screened

Figure 10a. Mechanisms of TZD-induced apoptosis.



Figure 10b. Mechanisms of TZD-induced growth arrest.

Figure 11. A schematic diagram depicting the major PPA



them for their insulin releasing activities in INS-1 cells and ALR2inhibitory effects.43

Among the above newly synthesized acetic acid derivatives,compounds with methylene carbon attached to flavone ring at 6and 30 position of flavones ring showed ARI activity with IC50

<1 lM.In yet another work, Bozdag-D}undar et al. synthesized various

chromonyl-2,4-thiazolidinediones (20) derivatives and evaluatedtheir aldose reductase inhibitory activity of which compound(21) was found to be the most active with IC50 value of 0.261 ±0.021 lM.46

4.3. Anti-cancer activity

Ever since the discovery of cancer as a disease it has always in-trigued man regarding its mysterious genesis and even more mys-terious mechanisms of its propagation. Scientists all over the worldhave been working diligently & industriously from over the yearstrying to solve these mysteries of cancer.

We are living through an incredibly exciting era for anti-cancerdrug discovery and development; one that is full of enormousopportunities and challenges.

The biomedical community has an insatiable appetite for newanticancer drugs and the development of more effective anti-can-cer drugs has been a major human endeavour over the past50 years. The 21st century now promises some dramatic newdirections.

While improvements in surgery and radiotherapy have had amajor impact on cancer treatment, the concept of systemic chemo-therapy, specific for cancer cells and free of major side effects,

Rc-independent anti-tumour mechanisms of TZDs.




remains a critical goal for the future. The issues underlying theachievement of this goal are complex, extending from an under-standing of how cancer growth is controlled, through the technol-ogy of drug synthesis and testing, to the multifactorialrequirements for clinical trial.

While many chemotherapeutic strategies for cancer treatmenthave been proposed, tested and in some cases implemented inthe past few decades, these diseases remain tenacious and deadly.Therefore, there is a desperate need to develop treatments with no-vel mechanisms to combat this disease.

Diabetes mellitus has been reported to be associated with an in-creased risk for colorectal cancer.47 In addition to this, severalstudies have shown TZDs to suppress tumour development in sev-eral in vitro and in vivo models. Among the proposed mechanismsfor the anti-tumour effects of TZDs, apoptosis induction, cell cyclearrest, and differentiation have been extensively reported. Theanti-tumour effects of TZDs are exerted by the PPARc-dependent(Figs. 10a and 10b) and PPARc-independent (Fig. 11) mechanisms.

4.3.1. PPARc dependent anti-tumour mechanisms of TZDsThe PPARc-dependent mechanism involves two end effects,

namely, apoptosis (Fig. 10a) & growth arrest (Fig. 10b).48,49

Figure 12. A schematic diagram illustrating the hydrogen bond interactions ofcompounds I and II with the IGF-1R.


TZDs activate PPARc by stimulating hetero-dimerization withthe retinoid X receptor, followed by recruitment of co-activatorsand the dissociation of co-repressors which ultimately causesapoptosis by decreasing anti-apoptotic proteins such as Bcl-2/Bcl-x and survivin, while increasing the levels of the pro-apoptoticproteins, p53, bad and phosphatase and tensin homologue (PTEN).

In addition to apoptosis, PPARc activation may reduce tumourdevelopment through the arrest of cancer cell proliferation and ef-fects on cell cycle checkpoints. Activation of PPARc decreases theprotein levels of activated cyclins that regulate progress throughthe cell cycle. These include: cyclin D1 (Cd1), as well as cyclindependent kinase 4 (CDK4), Cyclin E, Cd2, and CDK2. Conversely,TZDs increase the cyclin-dependent kinase inhibitors p21 andp27 that can inhibit CDK2/CDK4 and CDK2, respectively, ultimatelycausing cell cycle arrest.

4.3.2. PPARc independent anti-tumour mechanisms of TZDsAlthough the functional role of PPARc in regulating cell prolifer-

ation and differentiation varies in different cellular contexts,mounting evidence indicates that the effect of TZDs on inducingapoptotic death in cancer cells is, to a large extent, attributableto ‘off-target’ mechanisms. Three aspects of the PPARc-indepen-dent antitumor activities of TZDs are noteworthy because theyare amenable to pharmacologic exploitation that could foster novelstrategies for cancer treatment/prevention, namely, inhibition ofBcl-2/Bcl-x function, proteasomal degradation of target proteins,and transcriptional repression of AR through Sp1 degradation49

(Fig. 11).Detailed information regarding the various PPARc-dependent

and -independent anti-tumour mechanisms exerted by TZDs hasbeen reviewed by many authors.48–52

In 2010, Liu et al. synthesized novel 5-benzylidene thiazolidine-2,4-dione (22) and 5-(furan-2-ylmethylene) thiazolidine-2,4-dione(23) compounds which were identified as potent and selectiveinsulin-like growth factor-1 receptor (IGF-1R) inhibitors.53

IGF-1R is a growth factor receptor of tyrosine kinase family act-ing as a critical mediator of cell proliferation and survival.Although highly related to insulin receptor (IR), it plays a differentrole in organism development, being responsible for normalgrowth and development as opposed to glucose homeostasis. Epi-demiological studies indicate that the IGF-1R is overexpressed inhuman cancers and is primarily responsible for tumourigenesis.Signalling through IGF-1R includes the activation of PI3K and Rafpathways. Inhibition of both of these pathways makes IGF-1Rkinase a promising target for cancer therapy. The docking interac-tions of the representative compounds into the active site ofIGF-1R receptor is shown in Figure 12. Authors have also reportedstructural optimization and SAR analysis which led to the most po-tent analogue (24) with in vitro IC50 amounting to 57 ± 10 nM.53

Our research group has also been exploring the anti-cancer fa-cet of the novel TZDs synthesized. Ten novel derivatives of 5-ben-zylidene-2,4-thiazolidinediones (25) were synthesized andevaluated for their anti-proliferative activity in a panel of 7 cancercell lines using four concentrations at 10-fold dilutions. Though thecompounds showed varying degrees of cytotoxicity in the testedcell lines, most marked effect was observed by compound (26) inMCF7 (breast cancer), K562 (leukaemia) and GURAV (nasopharyn-geal cancer) cell lines with log10 GI50 values of �6.7, �6.72 and�6.73, respectively.54

We have also reported a detailed work on the design and synthe-sis of two novel compounds targeting histone deacetylase (HDAC)with 2,4-thiazolidinedione as zinc chelating group, as a part ofongoing efforts to find alternate chemotherapeutic agents for hepa-tocellular carcinoma. Further, we have demonstrated that thesecompounds show cytotoxicity that parallels their ability to inhibitHDACs activity in human liver cancer cell line HepG2. We designed



Karolis

Highlight

Karolis

Highlight

Karolis

Highlight

Figure 13. General structure of designed histone deacetylase inhibitors.

Figure 14. A schematic diagram illustrating the zinc chelation interactions SRR1 (A)and SRR2 (B) with HDLP.


and docked several molecules having the general structure asshown in Figure 13 into the active pocket of histone deacetylase-likeprotein (HDLP). Based on the scoring values, it was observed thatcompounds N-(6-(2,4-dioxothiazolidin-3-yl)hexyl) benzamide(SRR1) (27) and N-(6-(2,4-dioxothiazolidin-3-yl)hexyl)benzene sul-fonamide (SRR2) (28) both having 2,4-thiazolidinedione as the en-zyme inhibiting group, showed better affinity for the receptor ascompared to other molecules (Fig. 14). The findings obtained in thisstudy indicated that 2,4-thiazolidinedione group may be utilisedsuccessfully to inhibit HDAC activity with future potential for leadoptimization by chemical derivatization of active compound (28).55

Survival signalling pathways under growth factor loops havebeen implicated in cancer development, progression, and metasta-sis, among which the Raf/MEK/extracellular signal regulated kinase(ERK) and phosphatidyl inositol 3-kinase (PI3K)/Akt signalling cas-cades are the most commonly up-regulated in human cancers.More importantly, these two signalling pathways have been shownto function cooperatively to promote transformed cancer cell sur-vival. Thus, development of novel compounds that can co-targetthe Raf/MEK/ERK and PI3K/Akt signalling pathways may representan innovative strategy to provide clinically beneficial pharmaco-therapy for human cancer.56–62

In 2012, Liu et al. synthesized a series of 3,5-disubstituted-thi-azolidine-2,4-dione analogues based on the newly identified lead(29), as potential anticancer agents via the inhibition of the Raf/MEK/ERK and PI3K/Akt signalling cascades.63 Authors carried outvariations in the structures at 3 different positions of (29) whichare denoted by structures (30), (31), (32) in Figure 15. A new leadstructure (33) was identified to have improved anti-proliferativeactivities in U937 (human leukaemia) cells, to induce apoptosisin U937, M12 (prostate cancer) and DU145 (prostate cancer) cells,and to arrest U937 cells at the S-phase and demonstrated a corre-lation of the anti-proliferative activity and blockade of the Raf/MEK/ERK and PI3K/Akt signalling pathways. The docking studiesperformed by them are shown in Figure 16.

In 2012, Boisbrun and co-workers synthesised new derivativesof TGZ based on the finding that the double bond adjacent to theTZD ring yielded compounds with anti-proliferative activity.Among the compounds prepared, the following three compounds(34), (35), (36) displayed the best activity in the micromolar(lM) range against hormone-dependent and hormone-indepen-dent breast cancer cells.64

A series of 5-arylidene-2,4-thiazolidinediones (37) derivativeswere synthesized and studied for their radical scavenging activityusing 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Compound(38) was found to show good activity (IC50: 2.49 lM) and couldthus serve as an anti-cancer agent with radical scavengingactivity.65

Several minor researches have been carried out by numerousscientists for evaluating the role of TZDs in cancer treatment. Inone of the studies, TGZ was shown to inhibit colon cancer cell


growth via inactivation of NF-jB by suppressing GSK-3b activity.66

In another study, TGZ analogues were shown as cyclin D1 ablativeagents thereby proving to be the potential drugs for breast cancertherapy.67 Several studies have also shown that PPARc agonistsplay a role in the regulation of lymphocytes function and apoptosisof Jurkat and Raji cells (human T and B lymphocytes, respectively).The mechanism whereby PPARc agonists induce cytotoxicity is viaapoptosis as shown by DNA fragmentation, nuclear condensationand phosphatidyl serine externalisation.68

Cancer cells gain growth advantages in the microenvironmentby shifting cellular metabolism to aerobic glycolysis, the so-calledWarburg effect. There is a growing interest in targeting aerobic gly-colysis for cancer therapy by exploiting the differential susceptibil-ity of malignant versus normal cells to glycolytic inhibition andsearching for energy restriction-mimetic agents (ERMAs).Researchers have identified TZDs as a novel class of ERMAs. Theyelicit hallmark cellular responses characteristic of energy restric-tion, including activation of the intracellular fuel sensor AMP-acti-vated protein kinase (AMPK), transient induction of silentinformation regulator 1 (SIRT1) expression, and endoplasmic retic-ulum stress. This interplay culminates in autophagic and apoptoticdeath.69 Many authors have debated over inter-connection be-tween AMPK and SIRT1. Few of them have demonstrated AMPKactivation by SIRT1 expression70,71 while few others have reportedthat AMPK activation can function as a SIRT1 expression activa-



Figure 15. Lead compound 29 and various modification sites (30), (31) & (32).


tor.72,73 However, a review by Ruderman et al. highlighted thatAMPK is an early event, whereas SIRT1 activation appears to takeplace much later suggesting that AMPK activation induces SIRT1expression.74

Several studies have shown the role of PPARc agonists in thetreatment of endocrine malignancies like thyroid cancer, etc.75–77

and gastrointestinal cancers.78 Also it has been shown that TZDsimpart anti-proliferative response in pancreatic cancer cells byPPARc-independent upregulation of KLF4.79

Researchers have also identified the potential anti-angiogenicapplication of the TZDs via the inhibition of the expression of theimportant genes involved in the angiogenic process, viz. the Flk/KDR and Flt-1 receptor subtypes of vascular endothelial growthfactor receptor (VEGFR) by the PPARc thereby adding on to yet an-other plausible mechanism of anti-cancer activity of the TZDs.80–83

Based on the aforementioned reports, our research group has beenworking towards developing novel anti-angiogenic TZDs.

Shimazaki et al. investigated the anti-tumour activity of CS-7017 (39) both in vitro, on various cancer cell lines, and in vivoand obtained excellent results with in vitro concentrations aslow as 10 nM.84 Extensive literature survey highlights that, this isthe first TZD compound which is into clinical trials for its anti-can-cer activity. This will encourage other scientists and further boostup the active research directed towards anti-cancer activity ofTZDs and could plausibly be a part of the anti-cancer regimen infuture.


The noteworthy point is that the concentration of TZDs requiredfor cancer treatment is far lower than that required for elicitingdose-dependent toxicity. This could be very beneficial in develop-ing TZDs as the anti-cancer agents of future as they can evade thehepatotoxicity issues.

4.4. Anti-inflammatory activity

When tissues are injured through physical damage or are in-fected by exogenous microbial organisms, local and systemic re-sponses are activated with the primary goals of eliminating theoffending factors as fast as possible, restoring the tissue integrity,and retaining information about the offending agent to facilitaterecognition and elimination on a future encounter. The outcomeof these responses is a rapid physiological response of the bodyto damage and infection, that is, inflammation.

The involvement of PPARc in inflammatory processes was firstsuggested by the antagonism between the activities of pro-inflam-matory cytokines and PPARc.85 Additionally, macrophage activa-tion is inhibited by several PPARc agonists.86

The role of PPARc in anti-inflammatory effects has been exten-sively reviewed.87–89

Further, these receptors have an important role in the modula-tion of asthmatic and other allergic inflammatory respiratory dis-orders. GATA-3 is thought to be a key transcription factor in theexpression of TH2 cytokines in allergic respiratory diseases.



Figure 16. A schematic diagram illustrating the hydrogen bond interactions ofcompound 33 with MEK1 and PI3Ka.


Although there are no current synthetic inhibitors of GATA-3,PPARc agonists have been shown to inhibit GATA-3 expressionand TH2-driven inflammatory responses.90,91

Therefore, this receptor is an attractive target for the develop-ment of anti-inflammatory agents due to its key role at variousstages in the inflammatory process.

Garg et al. synthesized 5-substituted arylidine-2, 4-thiazolidin-ediones derivatives (40) and evaluated for their in vivo anti-inflammatory & analgesic activities and in vitro anti-oxidantactivity. The 3-Cl derivative (41) gave the best anti-inflammatory

Figure 17. A schematic diagram illustrating the hydrogen bond interactions ofcompound 45 with human PI3Kc.


(71.63%) (comparable to that of indomethacin), analgesic activityand anti-oxidant activity (IC50: 7.73 lg/ml).92

Pitta and co-workers synthesized 5-arylidene-3-benzyl-thiazol-idine-2,4-diones (42) with halide groups on their benzyl rings andassayed in vivo to investigate their anti-inflammatory activities.85

The effects of the substitutions on the biological response wereanalysed and docking studies were performed to investigate thebinding patterns with the PPARc structure. The compound (43)was found to be the best with anti-inflammatory activity of73.3%, which was slightly higher than that of RGZ (72.0%). In addi-tion, the Z isomer was found to be the most stable for all of thecompounds. The docking poses of the arylidene-thiazolidinedionecompounds in the PPARc structure were compared to the positionof the RGZ docked in this receptor which revealed that some keyresidues were involved in important hydrophilic interactions(hydrogen bonds) with the arylidene thiazolidinediones. This wasfurther established in the docking model of (43) which was super-posed with co-crystallised RGZ in the presence of important resi-dues of the active site where it showed hydrophilic interactionswith Ser289, His323, His449 and Tyr473; and hydrophobic interac-tions with Cys285, Ser289, Ile241 and His449. These interactionswere the same as those shown by RGZ. In addition, few otherhydrophilic interactions were observed with Arg288 and Tyr327;and hydrophobic interactions with Arg288, Leu330, Leu333,Ser342 and Glu343.

Figure 18. Molecular mediators in signalling pathways implicated in the patho-genesis of arthritis which have been considered as potential targets for PPARcligands.




Class I phosphatidyl inositol 3-kinases (PI3Ks), in particularPI3Kc, play a crucial role in mediating leukocyte chemotaxis aswell as mast cell degranulation, making it a potentially interestingtarget for autoimmune and inflammatory diseases.93,94

Pomel et al. synthesized a series of furan-2-ylmethylene thiazo-lidinediones (44) as selective, ATP-competitive PI3Kc inhibitors.95

They identified the key pharmacophoric features for potency andselectivity, also found that an acidic NH group on the thiazolidin-edione moiety and a hydroxy group on the furan-2-yl-phenyl partof the molecule play crucial roles in binding to PI3K and contributeto PI3Kc selectivity. Compound 45 (AS-252424) was identified as apotent and selective small-molecule PI3Kc inhibitor (IC50:33 ± 10 nM) and its interactions with the key residues at the activesite were studied providing insights into its binding mode (Fig. 17).

4.5. Anti-arthritic activity

Rheumatoid arthritis (RA) is a chronic and autoimmune diseasecharacterised by infiltration of macrophages and lymphocytes intothe synovial tissue and synovial fluid of the joint tissue and thenresulting in the cartilage and bone destruction.96 Activation ofmacrophages and mitogen-activated protein kinases (MAPKs) inRA patients is characterised by the increased expression of pro-inflammatory mediators such as interleukin-1b (IL-1b), tumournecrosis factor-a (TNF-a), cyclooxygenase-2 (COX-2) and IL-6.97,98

Hence, several therapies are mainly directed towards cytokineinhibition. Anti-TNF therapy is a novel therapeutic strategy devel-oped on the basis of molecular mechanisms of this disease.99 Clin-ical studies have showed that anti-IL-1 and anti-IL-6 therapiesameliorate rheumatoid arthritis in patients.100,101

Existing therapeutic agents, however, have limitations owing totheir expensive costs and hypersensitivity. Additionally, as achronic autoimmune disease, RA requires a long term treatment,102

which calls for an alternative therapy to arthritis.Many researchers have found the involvement of PPARc in sev-

eral inflammatory signalling pathways associated with arthritis(Fig. 8).

PPARc were reported to be expressed at both mRNA and proteinlevel by the major cell population in joints. Several natural andsynthetic PPARc ligands have been proved to be capable of inhib-iting major signalling pathways of inflammation, thereby reducingthe synthesis of cartilage catabolic factors responsible for articularcartilage degradation in arthritis. In fact, PPARc ligands wereshown to inhibit the production of several pro-inflammatory medi-ators, such as the cytokines, matrix metalloproteinases (MMPs),the chemokines and the metabolic proteins: COX-2 and induciblenitric oxide synthase (iNOS).103

Two inflammatory signalling pathways have mainly been con-sidered as potential targets for PPARc ligands. First, MAPKs, whichare implicated in the production of pro-inflammatory cytokinesand downstream signalling events leading to joint inflammationand destruction, appear to be potential targets for PPARc ligands.Second, NF-jB activation, which results in the transactivation ofresponsive genes that contribute to the inflammatory phenotypeof arthritis, including TNF-a, MMPs and chemokines, seems to besuppressed by PPARc ligands. As the available evidence so far is re-stricted to in vitro experiments and animal studies, evaluation ofthe clinical outcome of PPARc ligands in the management of pa-tients with different types of arthritis is also recommended. Thishas been discussed in detail in the review by Giaginis et al.103

Chen and co-workers found a novel analogue of thiazolidinedi-ones, (Z)-5-(4-methoxybenzylidene) thiazolidine-2,4-dione (46)(named SKLB010), that inhibited the increase in inflammatorymediators in joint tissues of adjuvant induced arthritis rats. Themechanism is thought to involve the downregulation of cytokinemRNA expression and inhibition of migration of macrophages.102


4.6. Anti-microbial activity

TZDs are known to have anti-fungal,104 anti-bacterial,105,106 andanti-viral,107,108 potential. Anti-bacterial activity is of particularimportance, given the dramatic rise of drug-resistant bacteriaand the paucity of new agents currently in development. Recentlyscientists have synthesized and evaluated various thiazolidinedi-one scaffolds for their activity against Gram positive bacteria,namely Staphylococcus aureus, Staphylococcus epidermidis & Bacillussubtilis and the fungal strain Candida albicans and found moderateto high activities.109–111

However, the detailed mechanism by which the TZDs exhibittheir anti-microbial activities is yet unknown. Therefore, a morefocused work needs to be done in this direction.

4.7. Miscellaneous activities

Several researchers have identified the potential applications ofPPARc agonists and TZDs in the treatment of various cardiovascu-lar diseases including myocardial infarction,112,113 ischemic heartdisease,114,115 arrhythmia (by increasing myocardial lipoxin A4

content),116 aortic aneurysm syndrome (AAS),117 cardiac cachex-ia,118 atherosclerosis.119 In addition, TZDs have also shownactivities as neurotherapeutics in treating mood disorders,120 pre-venting development of autism in the foetus,121 Alzheimer’s dis-ease and psychotic disorders. Last but not least, they have alsoshown to exert effects on inhibition of cholesterol esterase leadingto prevention of hypercholesterolemia,122 mediating lipolysis inwhite adipose tissue (WAT), thermogenesis in brown adipocyte tis-sue (BAT) and relaxation of urinary bladder detrusor tissue via b3-adrenergic receptor agonistic activity,123 and inhibition of tyrosi-nase which leads to melanogenesis thereby aiding in treatmentof hyperpigmentation.124

5. Metabolism and toxicity

Troglitazone was the first-in-class of TZDs which was marketedas anti-hyperglycaemic drug, followed by PGZ and RGZ. However,unfortunately TGZ was withdrawn from the market in 2000 dueto fatalities caused by hepatotoxicity.125 This hepatotoxicity wasa direct result of TGZ metabolism. In addition to hepatotoxicity,TZDs, especially PGZ, have been shown to cause bladder cancerin patients with T2DM.126,127

5.1. Metabolism

TZDs are mainly metabolised by cytochrome 3A4 (CYP3A4) and2C8 (CYP2C8).128–130 To determine the metabolic pathway and thehepatotoxicity associated with TGZ, in depth study of metabolismassociated with TGZ was carried out.131 The various routes ofmetabolism of TGZ in liver include oxidation (phase I), sulfationand glucuronidation (phase II).125 Oxidation of TGZ leads to cleav-age of TZD ring (Fig. 19) which produces reactive intermediates ormetabolites (RMs),131 as well as formation of quinone metabolite(benzoquinone) (V) (Fig. 20). Sulfation of TGZ (6) occurs at 6-hy-droxy position of chromane ring (47) (Fig. 21).132 Glucuronidemetabolite is found in human plasma at very low concentra-tion.125,133,134 To determine the role of various metabolites inoccurrence of hepatotoxicity, metabolism and hepatotoxicity studyof TGZ was studied in detail.128

5.2. Hepatotoxicity

The exact nature of TGZ causing hepatotoxicity has not beenestablished but many mechanisms have been proposed which



O

HOO

NHS

O

O

Troglitazone

NHS+

O

O-O

3A4

S

R

HO

N C O

O

S

R

HO

HN

OO

SGGSH

I

II III

S

R

HO

HN

OO

SG

[O]

O

R

R=

O

HO

O

where

S

RNH2

O

GS

+GSH+H2O-CO2

M1 M2

S+

R

HN

OO

SG

O-

M3

-H2O

Figure 19. Oxidation of troglitazone causing TZD ring cleavage.


include the formation of electrophilic RMs, direct role of PPARcbinding, role of mitochondrial injury and inhibition of bile salt ex-port pump (BSEP) by TGZ and sulfate conjugate of TGZ (TGZS).125

One mechanism suggests that TGZS may cause hepatotoxicityby inhibition of BSEP. TGZS has been demonstrated to inhibit BSEPwhich plays an important role in removing bile salts from livercells using energy in the form of ATP.135 Inhibition of BSEP resultsin accelerated accumulation of bile salts which may lead to chole-stasis and subsequent hepatocyte apoptosis.

High levels of bile salt have been shown to induce cell death andmitochondrial dysfunction due to their detergent properties. Thesecholestatic potential of TGZ and TGZS have also been studied usingin vitro and in vivo rat models.136

Another mechanism suggests that formation of electrophilic RMdue to oxidation of TGZ may cause hepatotoxicity. Oxidation ofTGZ via CYP3A4 produces benzoquinone and reactive intermediatevia oxidation of sulfur atom. TGZ is an inducer of hepatic P450 3A4enzyme.137 However, the presence of a quinone metabolite may bethe potential cause of TGZ toxicity as the safer analogues such asRGZ and PGZ neither contain a chromane ring nor do they generatethe quinone metabolite.125 Thus, it indicates that toxicity may be


dose-dependent as TGZ has been shown to activate the humanpregnane X receptor (PXR) at the concentrations (200–600 mg/day) needed to activate PPARc where as PGZ and RGZ require45 mg/day and 4–8 mg/day, respectively. PXR is a recently isolatedorphan member of the nuclear receptor gene family that wasshown to be a key transcriptional regulator of hepatic CYP3A4 geneexpression.138,139 Since CYP3A4 is responsible for the oxidativemetabolism of around 60% of all clinically used drugs, activationof PXR induces metabolism of TGZ.140 Thus, the cross reactivityof TGZ on PXR may lead to increased hepatic levels of the quinonemetabolite in some patients.141,142 PXR is remarkably divergentacross species, and TGZ does not activate the mouse or rat receptor.This may explain why hepatotoxicity was not seen in the rodentsafety studies of the drug.141

However, it had been observed that the quinone metabolite ofTGZ was not as cytotoxic as the parent drug in human and porcinehepatocytes.137 On the other hand, all TZD drugs are capable of TZDring opening to generate reactive intermediates. Thus the role ofTZD ring in TGZ hepatotoxicity requires further exploration.125

The role of TZD ring, and the S atom in particular, in inducingliver toxicity via the formation of RMs, was determined by using



O

HOO

NHS

O

O

Troglitazone

P450

IV

GSH

H2O

Hydroxymethylmetabolite

M5

O

O OHR

TZD ring oxidation,GSH

O

HO

SG

R

O

HO

CH2OH

R

O

-O

R

O

O

R

O

O OHO

S

O

NH2

SG

M4

O

NHS

O

O

R=

O

O

CH2

R

O

O

OH

R

V

Figure 20. Oxidation of troglitazone leading to formation of metabolite M4 and M5.

OO

SNH

HO

O

O

OO

SNH

HOO2SO

O

O

sulphation

6

47

Figure 21. Sulfation of troglitazone.


trosuccinimide (48), a chemical analogue of TGZ where TZD ringwas replaced by pyrrolidine-2,5-dione (PRD) (49) ring.128 Whilethe PRD ring shares similar five-membered ring structure, molecu-lar size and lipophilicity with the TZD ring, it lacks the reactive


thiol group and possesses the methylene group instead. This subtleisosteric replacement provides a useful chemical tool to ascertainthe role of the sulfur moiety not only in TGZ hepatotoxicity, butalso in PPARc binding.128

It was observed that sulfur moiety of the TZD ring was partiallyresponsible125 for hepatotoxicity via the formation of reactiveintermediates as these intermediates were detected in human livermicrosomes (HLM) and THLE-2 (normal human hepatocytes) cellsusing GSH trapping and no such intermediates were detected withregards to the PRD analogues. Also PPARc binding assay depictedthat both the TZD and PRD analogues had binding affinities tothe PPARc. As both types of analogues were shown to bind to thePPARc and express the aP2 (adipocyte fatty acid) gene, the substi-tution of the TZD ring with PRD ring may be beneficial from a drugdesign perspective. Thus, the substitution of the TZD ring by PRDring seems to be a viable strategy to develop safer PPARc agonistsin future.128

6. Bioisosteric replacements of TZDs

Although treatment with TZDs improve insulin resistance, theyoffer little protection from the eminent hepatotoxicity caused bythe ‘S’ atom of TZD ring in conjunction with side effects like



O ONH

O

N

O

O O

O

N

CONH2

HOOC

52 53

Figure 22. Metabolism of isoxazolidine-3,5-dione compound.


cardiotoxicity, weight gain, fluid retention and oedema are issuesof major concern for these agents which limit their general clinicaluse.143 Therefore, the development of new surrogate treatmentswith insulin-sensitising and cholesterol/triglyceride-lowering ef-fects is of particular interest.144 Based on these considerations,the tool of bioisosteric replacement of TZD ring could serve to solvethe toxicity problems.

The acidity of the thiazolidine-2,4-dione moiety is consideredessential for its insulin-sensitising activity. Bioisosteric replace-ments of thiazolidine-2,4-dione ring with various acidic groups,either cyclic or non-cyclic, such as oxazolidine-2,4-dione rings,isoxazolidine-3,5-dione rings, 1-oxa-2,4-diazolidine-3,5-dionerings, carbonylated hydroxyureas,145 a-heteroatom-substitutedcarboxylic acids, a-carbon substituted carboxylic acids,5146 PRDring,147 etc. would thus prove to be beneficial.

PRD ring compound, trosuccinimide, (48) shares a similar five-member ring structure, molecular size and lipophilicity with theTZD ring obtained by replacing ‘S’ of TZD with –CH2– group125

and it also causes significant reduction in plasma glucose level.Oxazolidine-2,4-dione ring compounds (50) retain the potent

anti-hyperglycaemic activity. However, in case of oxazolidine-2,4-dione derivatives, R isomer is more active than S.147,22

Work has also been done on replacing the TZD ring with pyra-zole (51) or pyrazol-3-one which led to significant plasma glu-cose-lowering activity.148

Isoxazolidine-3,5-dione ring compound (JTT-501) (52) has beenshown to cause a 50% increase of triglyceride accumulation and a25% decrease of blood glucose. This compound was in phase II clin-ical trial particularly due to lack of significant toxicity.5 However,the further clinical trial was terminated in 2002 as the phase IIclinical trial did not confirm its efficacy.149

The main metabolite of isoxazolidine-3,5-dione (52) in humanswas identified as malonic amide (a-carbon substituted phenylpropanoic acid) (53), created by reductive cleavage of isoxazoli-dine-3,5-dione (Fig. 22), the insulin-sensitising activity of malonicamide was as potent as that of isoxazolidinedione.5

Thus, in case of non-cyclic acidic groups, a-carbon substitutedphenyl propanoic acid can be used as a bioisostere of TZD ring.The unsubstituted hydrocinnamic acid and the corresponding cin-namic acid were found to be inactive or less active150 indicatingthat substitution at a-position is important for activity. Com-pounds with substitution at a-position with an amide (53) or estergroup (54) were active and monocarbonyl compounds (55) and the1,4-dicarbonyl compound (56) showed decreased activity, indicat-ing the importance of the 1,3-dicarbonyl structure. Also substitu-tion at a-position with thio or ether group retains the activity.

In our laboratory, we have synthesized various acidic bioisos-teres of TZD ring viz., isoxazolidine-3,5-dione derivatives of which2-[4-[(3,5-dioxoisoxazolidin-4-ylidene)methyl]phenoxy]-N-[3-(trifluoromethyl)phenyl] acetamide (57),151 and 2-[4-[(3,5-diox-oisoxazolidin-4-ylidene)methyl]phenoxy]-N-(5-methylthiazol-2-yl)acetamide (58)152 were found to be active having anti-hyper-glycaemic as well as anti-cancer properties.

Thus, by replacing TZD ring with various cyclic or non-cyclicbioisosteres, the affinity towards PPARc receptor can be retainedwith a considerable decrease in the toxicity associated with theTZD compounds.


7. Concluding remarks

In this article, we have aimed to highlight the versatile role ofTZD compounds in the treatment of various disorders. Despitethe meticulous and target based research on the development ofTZDs with varied activities, their therapeutic focus still remainson treatment of diabetes; however, only CS-7017 (Daiichi Sankyo)(39), has reached clinical trials for anti-cancer activity. It can beprobably due to lack of a comprehensive compilation of various re-search reports in each activity capable of giving an insight into theSAR of the compounds. The present review would provide drugdesigners and medicinal chemists a comprehensive informationfor development of clinically useful molecules.

Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.bmc.2013.01.029.These data include MOL files and InChiKeys of the most importantcompounds described in this article.

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