1

NAME: MUHAMMAD ALI

ROLL NO: 22 F- BSCHY- 13

DEPARTMENT: BS-CHEMISTRY

SUBJECT: ORGANIC CHEMISTRY

SUBMITTED TO: SIR PERVAIZ

2
 3
YEAR 2018
ARTICLE NO 1

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL THIAZOLIDINEDIONE

DERIVATIVES AS IRREVERSIBLE ALLOSTERIC IKK-Β MODULATORS

Highlights
• Twenty four thiazolidinedione-scaffold based have been synthesized.
• Compounds 6v, 6w, and 6x elicited ic50 values = 0.4, 0.7 and 0.9 μm
respectively.
• Kinetic study of compounds 6v and 6w confirmed this class of
modulators as irreversible inhibitors
• Lps-treated RAW 264.7 macrophages proved the anti-inflammatory
activity of compounds 6q and 6v
 4
Abstract
The kinase known as IKK- β initiates NF- κB drooping pathway egging articulation of a
many rates adding to vexation, safe response, and cell expansion. Adjustment of IKK- β
kinase action could be helpful for treatment and the directors of similar ails. Beginning
from a set up perceptibly dynamic megahit emulsion, 24 thiazolidinedione- platform
grounded substance rudiments having a place with five series have been planned,
orchestrated and assessed as anticipated IKK- β modulators.
Among them, composites 6q, 6r and 6u showed low micro molar IC50 values while
composites 6v, 6w, and 6x elicited sub micro molar IC50 values original to0.4,0.7 and0.9
μM independently. These sub micro molar IC50 values are 243,139 and 105 crowds the
worth of the blazoned IC50 of the morning hit emulsion. Motor disquisition of fusions 6v
and 6w affirmed this class of modulators as unrecoverable impediments. LPS- treated
Crude264.7 macrophages demonstrated the comforting movement of fusions 6q and 6v.
Test of hERG restraint showed a defended profile ofemulsion 6q recommending it as a
lead for fresh enhancement of IKK- β modulators.
 GRAPHICAL ABSTRACT
5

Keywords
IKK-β modulatorsNF-κB signaling
pathwayThiazolidinedionesAllosteric modulation

Reference:
Ahmed Elkamhawy a b 1, Nam youn Kim a 1, Ahmed H.E. Hassan c, Jung-eun Park a, Jeong-Eun Yang a,
Kwang-Seok Oh d, Byung Ho Lee d, Mi Young Lee d, Kye Jung Shin e, Kyung-Tae Lee f, Wooyoung Hur a
g, Eun Joo Roh a g
 ARTICLE N0 2 6
An investigation on 4-thiazolidinone derivatives as dual inhibitors
of aldosereductase and protein tyrosine phosphatase 1B, in the
search for potential agents for the treatment of type 2 diabetes mellitus
and its complications.

Highlights
• 4-Thiazolidinones were synthesised and tested as dual AR/PTP1B inhibitors.
• SAR, molecular docking and kinetic studies were carried out
• Two compounds endowed with interesting AR/PTP1B inhibition profiles were
identified.
• Features useful to achieve simultaneous inhibition of both AR and PTP1B emerged.
 Abstract 7
Planned different ligands (DMLs), created to regulate all the while various chose
targets engagedwith etiopathogenetic instruments of a multifactorial infection,
for example, diabetes mellitus (DM), are viewed as a promising option in
contrast to blends ofmedications, when monotherapy results to be unsuitable. In
this work, intensifies 1-17 were blended and in vitro assessed as DMLs
coordinatedto aldose reductase (AR) and protein tyrosine phosphatase 1B
(PTP1B), two key compounds engaged with various occasions which are basic
for the beginning and movement of type 2 DM and related pathologies. Out of
the tried 4-thiazolidinone subordinates, intensifies 12 and 16, which showed
powerful AR inhibitory impacts alongside fascinatingrestraint of PTP1B, can be
accepted as lead mixtures to additionally enhance and equilibrium thedouble
inhibitory profile. Also, a few primary bits were recognized as highlights that
could be helpful to accomplish synchronous hindrance of both human AR and
PTP1B through restricting to
non-synergist districts of both objective chemicals.
 Graphical abstract 8

Keywords
Diabetes mellitusDesigned multiple ligands4-ThiazolidinonederivativesAldose
reductaseProtein tyrosine phosphatase 1B

Reference
Rosanna Maccari a, Antonella Del Corso b, Paolo Paoli c, Ilenia Adornato a,Giulia Lori c,
Francesco Balestri b, Mario Cappiello b, Alexandra Naß d, Gerhard Wolber d, Rosaria Ottanà
 Article No 3 9

Conventional and microwave-assistedsynthesis of new

1H-benzimidazole-thiazolidinedionederivatives: A potential
anticancer scaffold

Highlights

• Conventional and microwave-assisted synthesis of 1H-benzimidazole-

thiazolidinediones.
• Cytotoxicity on selected human cancer cell lines and a normal cell line
• Induction of apoptosis by test compounds 17p and 17q.
• 17p and 17q inhibited cell migration and caused disruption of F-actin
protein.
• 17p and 17q caused the collapse of DΨm and increased the level of ROS.
 Abstract 10
A series of new benzimidazole bearing thiazolidinedione derivatives has
been designed, synthesized by using conventional as well as
microwave-assisted methods. Microwave-assisted synthesis caused a
significant reduction in the reaction times and improvement in the yields of
all the derivatives. All the new synthesized compounds were evaluatedfor
their in vitro cytotoxic potential against selected human cancer cell lines of
breast (MDAMB-231), prostate (PC-3), cervical (HeLa), lung (A549) and
bone (HT1080) along with a normal kidney cells (HeK-293T). The
compounds 17n, 17p and 17q were found to be potent cytotoxic with IC50
values in the range of 0.096–0.63 μM on PC-3, HeLa, A549 and HT1080
cancer cells. Most of the compounds have found to be safe on normal HeK-
293T kidney cells in comparison to cancer cells. The treatment of cells with
17p and 17q showed the typical apoptotic morphological features like
fragmentation and shrinkage of nuclei.
Further, test compounds resulted in inhibition of cell migration through
disruption of F-actin protein assembly. Hoechst, DCFH-DA staining,
mitochondrial membrane and annexin binding assays revealed that the
cancer cell proliferation was inhibited through induction of apoptosis in
A549 cells.
 Graphical abstract 11

Keywords

Benzimidazole Thiazolidinedione Cytotoxicity Apoptosis Microwave

Reference
Pankaj Sharma a, T. Srinivasa Reddy b, Niggula Praveen Kumar a, KishnaRam Senwar
a, Suresh K. Bhargava b, Nagula Shankaraiah
 12
Article no 4
Thiazolidinediones and PPAR orchestra as antidiabetic agents: From past to present

Highlights

• A brief historical search for thiazolidinedione with hypoglycemic activity.

• Classification was based on the nature of linker connecting benzyl/benzylidene TZD
with lipophilic head.
• Oxymethy, oxyethyl, oxyethylamino linkers and their rigid analogues were
summarized.
• PPAR modulatory activity are reported as it appeared in the literature.
 Abstract 13
Thiazolidinediones a class of medication, that gave a significant
forward leap in the administration of type 2 diabetes beginning
around 1990. Following the disclosure of PPARs, TZDs were the top
notch to be accounted for as PPARγ modulators. This survey is an
endeavor to sum up the substance changes around TZDs in beyond
twenty years to get a powerful antidiabetic particle. TZDs writing
were at first overwhelmed by their hypoglycemic and hypolipidemic
exercises, later PPARγ action was likewise been consolidated. In
addition, at times, both benzyl and benzylidene subsidiaries were
accounted for in a similar composition for correlation. We
considered introducing the survey based on the variety in the linker
district. Ideal linker at the hour of revelation of the Ciglitazone was
oxymethyl and it proceeded to advance as oxyethyl (Pioglitazone)
and oxyethylamino (Rosiglitazone). Hardly any endeavors were
made to limit the adaptability of the linker by presenting the cyclic
designs and were summed up following the separate linker class.
 Graphical Abstract 14

Keywords
Thiazolidinedione Glitazones Hypoglycemic PPAROxy methyl linker Oxyethyl
linker Oxy ethyl amino linker Rigid linker analogues

Reference

Sabina Yasmin, Venkatesan Jayaprakash

 15
Article no 5

Synthesis and biological evaluation ofnew benzimidazole-thiazolidinedione hybrids as

potential cytotoxic and apoptosis inducing agents.

Highlights
• A novel series of benzimidazole-thiazolidinedione derivatives was
synthesized.
• Cytotoxicity on selected human cancer cell lines and a normal cell line.
• Test compound 11p induced apoptosis, G2/M cell cycle arrest and disruption
of F-actin assembly.
• 11p Inhibited cell migration, caused the collapse of DΨm and increased the
level of superoxide ROS.
 Abstract 16
A series of new benzimidazole-thiazolidinedione hybrids has been synthesized and
evaluated for their cytotoxic potential against a selected human cancer cell lines of
prostate (PC-3 and DU-145), breast (MDA-MB-231), lung (A549) and a normal
breastepithelial cells (MCF10A). Among the tested compounds, 11p exhibited
promising cytotoxicity with IC50 value of 11.46 ± 1.46 μM on A549 lung cancer cell
line and did not show significant toxicity on normal MCF10A cells. Lung cancer cells
(A549) have been used to know the mechanism of cell growth inhibition and
apoptosis inducing effect with compound 11p. The treatment of A549 cells with 11p
showed typical apoptotic morphology like cell shrinkage, chromatin condensation
and horseshoe shaped nuclei formation. Flow-cytometry analysis revealed the G2/M
phase of cell cycle arrest in a dose dependent manner. Preliminary mechanistic
studies suggested that the cell migration was inhibited through the disruption of F-
actin protein.
Acridine orange-ethidium bromide (AO-EB), DAPI, annexin V-FITC/propidium
iodide, rhodamine-123 and MitoSOX assays suggested the induction of apoptosis in
A549 cellsby compound 11p
 Graphical abstract 17

Keywords
Benzimidazole Thiazolidinedione Apoptosis Mito SOX Annexin Cell migration

Reference

Pankaj Sharma a, T. Srinivasa Reddy b, Dinesh Thummuri c, Kishna Ram

Senwar a, Niggula Praveen Kumar a, V.G.M. Naidu c, Suresh K. Bhargava b,
Nagula Shankaraiaha
 ARTICLE NO 6 18

Energy restriction mimetic agents totarget cancer cells: Comparison

between 2-deoxyglucose and thiazolidinediones

Abstract
The use of energy restriction mimetic agents (ERMAs) to selectively target cancer
cellsaddicted to glycolysis could be a promising therapeutic approach.
Thiazolidinediones (TZDs) are synthetic agonists of the nuclear receptor
peroxisome
proliferator-activated receptor (PPAR)γ that were developed to treat type II diabetes.
These compounds also display anticancer effects which appear mainly to be
independent of their PPARγ agonist activity but the molecular mechanisms involved
in the anticancer action are not yet well understood. Results obtained on ciglitazone
derivatives, mainly in prostate cancer cell models, suggest that these compounds
could act as ERMAs. In the present paper, we introduce how compounds like 2-
deoxyglucose target the Warburg effect and then we discuss the possibility that the
PPARγ-independent effects of various TZD could result from their action as ERMAs.
 Graphical Abstract 19

Warburg effect

As observed by Otto Warburg in the 1920s, the metabolic properties of cancer cells differ
markedly from those of normal cells. Indeed, cancer cells have elevated rates of glucose
consumption and high lactate production but unlike normal cells, lactate production
occurs even in the presence of oxygen. This is known as aerobic glycolysis orWarburg
Effect [1]. High glucose uptake of cancer tissues is clinicallyused to diagnose cancer and
to monitor tumor response to treatmentby imaging uptake
Targeting cancer cell metabolism with2-deoxyglucose 20
The existence of a cancer-specific metabolism and the fact that manycancer cells display a greater
sensitivity to
glucose-deprivation-induced cytotoxicity than normal cells explain why dietary energy restriction is a
potent inhibitor of carcinogenesis.Nevertheless, in Human, it is difficult to sustain chronic caloric restriction
through reduced energy intake. It is better to use ERMAs in order to cause a state of glucose starvation in
cancer cells without limiting caloric intake. This

Thiazolidinediones

Thiazolidinediones (TZD), including Troglitazone (TGZ, Sankyo), Rosiglitazone (RGZ, GlaxoSmithKline) and
Pioglitazone (PGZ, Takeda Pharmaceuticals), constitute a family of synthetic compoundscharacterized by a
thiazolidine-2,4-dione ring(Fig. 2). TZD are agonists of the Peroxisome Proliferator Activated Receptor
gamma (PPARγ), a ligand-activated transcription factor belonging to the steroid hormone receptor
superfamily, that were clinically used for the treatment of noninsulin-dependent type 2

Acknowledgements
The studies on TZD performed in SF team were supported by grants of the 21
“Université de Lorraine”, of the “Conseil Régional de Lorraine”and of the “Ligue
Contre le Cancer”. CC is supported by a “Waxweilergrant for cancer prevention
research” from the Action LIONS “Vaincre le Cancer”. AG is recipient of a post-
doctoral Télévie grant. Research at the Laboratoire de Biologie Moléculaire et
Cellulaire du Cancer (LBMCC) is financially supported by “Recherche Cancer et
Sang” foundation, by

REFERENCE

Sandra Kuntz a b, Sabine Mazerbourg a b, Michel Boisbrun c d, Claudia

Cerella e, MarcDiederich e f, Isabelle Grillier-Vuissoz a b, Stephane Flament a b
 Abbreviations
ADAMTS 22
a disintegrin and metalloproteinase withthrombospondin motifs

BAX
Bcl-2-associated X protein

CC50
half maximal cytotoxic concentration

CDC25V
dual-specificity phosphatase, the “cdc” inname refers to “cell division cycle”

DCC
dicyclohexylcarbodiimide

DTP
Development Therapeutics Program

EC50
half maximal effective concentration

ED50
half maximal effective dose
 IC50
half maximal inhibitory concentration 23
GI50
drug concentration resulting in a 50% reduction
in the net protein increase in control cells during
the drug incubation
HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-t
riazolo[4,5-b]pyridinium 3-oxid
hexafluorophosphate
MIC
minimal inhibitory concentration
MRSA
methicillin-resistant Staphylococcus aureus
MTT
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet
razolium bromide
NCI
National Cancer Institute
PIN1
peptidyl-prolyl cis-trans isomerase NIMA-
interacting 1
 YEAR 2019 24
ARTICLE NO 1
Design, synthesis of (Z)‐3‐benzyl‐5‐((1‐phenyl‐3‐(3‐((1‐ substituted
phenyl‐1H‐1,2,3‐triazol‐4‐yl)methoxy) phenyl) ‐1H‐pyrazol‐4‐yl)
methylene) thiazolidine‐2,4‐dione analogues aspotential cytotoxic
agents.

Abstract
Why of 0.625, 1.25, 2.5, 5, and 10 μM, respectively. The cytotoxic evaluation
assay is presented in terms of IC50 values and percentage cell viability
reduction compared against standard drug cisplatin. Among all novel
synthesized compounds 10a‐n, some of the representative analogues
particularly 10g and 10e exhibit remarkable cytotoxic activity with IC50 values
0.454 and 0.586 μM, comparable to that of the standard drug cisplatin, and
some analogues 10d, 10f, 10k, and 10m also have shown significant activity.
GRAPHICAL ABSTRACT 25
 26
ARTICLE NO 2

Discovery of 5 naphthylidene-2,4-thiazolidinedionederivatives
as selective HDAC8 inhibitors and evaluation of their cytotoxic
effects in leukemic cell lines

Highlights
• Selective and Non-hydroxamate HDAC8 inhibitors instead pan
inhibitors.
•5-Naphthylidene-2,4-thiazolidinedione derivatives were
designed and synthesized.
•Most potent compound 3 k showed HDAC8 inhibition with IC50
of 2.7 µM.
•Antiproliferative effects-HDAC8 inhibition, Apoptosis and Cell
cycle arrest.
•Docking found to be consistent with experimental activity in
terms of IC50-values.
Abstract
27
Histone deacetylases (HDACs) are being explored as a therapeutic targetfor
interventions in different types of cancer. HDAC8 is a class I HDAC that is
implicated as a therapeutic target in various indication areas, including different
types of cancer and particularly childhood neuroblastoma. Most previously
described HDAC8-selective inhibitors contain a hydroxamate function as zinc
binding group (ZBG) to confer potency. However, hydroxamate class HDAC
inhibitors have raised increasing concerns about their mutagenic character.
Therefore,
non-hydroxamate based inhibitors could prove to be safer than
hydroxamates. In the present work, a series of novel
5-naphthylidene-2,4-thiazolidinedione was designed and evaluated as potential
antiproliferative agents targeting selectively HDAC8 enzyme. Eleven novel derivatives
were synthesized, purified and characterized by spectroscopic techniques.
Compounds 3k and 3h was found to be most potent selective inhibitors of HDAC8
with IC50 values of 2.7 μM and 6.3 μM
respectively. 3a to 3i was found to be most cytotoxic in leukemic cell lines. 3a and 3 h
both were found to induce apoptosis and cause cell cycle arrest in G2/M phase.
 GRAPHICAL ABSTRACT
28

Keywords
HDAC8AntiproliferativeThiazolidinedione
(TZD)NaphthaleneLeukemiaCytotoxicity

Abbreviations
TZD thiazolidinedione HDAC histone de acetylase DMF dimethyl Formamide
DCM dichloromethane NMR nuclear magnetic resonance
DMEMD Dulbecco's Modified EagleMediumMTT3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide FBSfetal calf serum RT room temperature
 29
ARTICLE NO 3

Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal

and anticancer activity

Highlights

• New 5-enamine-4-thiazolidinones with trypanocidal and anticancer activity.

• Compound 12 displayed excellent trypanocidal activity and low cytotoxicity.
• Compound 14 demonstrated good anticancer activity in NCI DTP assay.
• Biological activity depends on the 5-enamine fragment nature.
 Abstract 30
A series of novel
2-(5-aminomethylene-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl
esters has been synthesized. Target compounds were evaluated for their
trypanocidal activity towards Trypanosoma brucei brucei and Trypanosoma brucei
gambiense.
Several hit-compounds (8, 10, 12) inhibited growth of the parasites at sub-micromolar
concentrations (IC50 0.027–1.936 µM) and showed significant selectivity indices
(SI = 108–1396.2) being non-toxic towards the human primary fibroblasts. The
screening of anticancer activity in vitro within NCI DTP protocol allowed to identify
active
2-(5-{[5-(2,4-dichlorobenzyl)-thiazol-2-ylamino]-methylene}-4-oxo-2-thioxothiazolidi n-3-
yl)-3-phenylpropionic acid ethyl ester 14 that demonstrated inhibition against all 59
human tumor cell lines with the average GI50 value of 2.57 μM. It was established
that the activity type (antitrypanosomal or anticancer) as well as its level depends on
the character of enamine fragment in the C5 position of thiazolidinone core.
 Graphical abstract 31

Keywords
5-ene-4-thiazolidinonesAntitrypanosomal activity Anticancer activity X-ray
 32
ARTICLE NO 4
Design and evaluation of non-carboxylate 5 arylidene-2
thioxo-4-imidazolidinones as novel non-competitive
inhibitorsof protein tyrosine phosphatase 1B

Highlights
• 5-arylidene-2-thioxo-4-imidazolidinones 7 are novel PTP1B allosteric
inhibitors.
• Most of compounds 7 proved to be interesting PTP1B inhibitors.
• Compound 7e was shown to be a potent insulin-sensitizing agent in HepG2
cells.
• SAR, molecular docking and kinetic studies were carried out.
Abstract 33
Protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of
insulin and leptin signalling and is crucially involved in the development
of type 2 diabetes mellitus, obesity, cancer and neurodegenerative
diseases. Pursuing our efforts to identify PTP1B inhibitors endowed with
drug-like properties, we designed and evaluated
3-aryl-5-arylidene-2-thioxo-4-imidazolidinones (7) as a novel class of
non-carboxylate PTP1B inhibitors. In agreement with our design, kinetic
studies demonstrated that selected compounds 7 act as reversible,
non-competitive inhibitors of the target enzyme at low micromolar
concentrations. Accordingly, molecular docking experiments suggested
that these inhibitors can fit an allosteric site of PTP1B that we previously
individuated. Moreover, cellular assays demonstrated that compound 7e
acts as a potent insulin-sensitizing agent in human liver HepG2 cells.
Taken together, our results showed that these non-competitive PTP1B
inhibitors can be considered promising lead compounds aimed to enhance
druggability of the target enzyme and identify novel antidiabetic drugs.
 Graphical Abstract
34

Keywords
3-aryl-5-arylidene-2-thioxo-4-imidazolidinones Protein tyrosine
phosphatase 1BNon-competitive inhibitors Insulin-sensitizing agents
Cellular assays
 35
ARTICLE NO 5

Experimental and theoretical study of substituent effect on 13C NMR

chemicalshifts of 5-arylidene-2,4-thiazolidinediones

Highlights
• LFER enables a comprehensive analysis of substituent effects on SCS ofCβ and Cα
atoms.
• Theoretical calculations are performed by GIAO/WP04/cc-pVDZ andMP2/6-
311G** method.
• Correlations between calculated and experimental chemical shifts are
demonstrated.
• The Yukawa-Tsuno model has better modelling capability thanReynolds model.
Abstract
The electronic structure of 5-arylidene-2,4-thiazolidinediones has beenstudied by using 36
experimental and theoretical methodology. The theoretical calculations of the investigated
5 arylidene-2,4-thiazolidinediones have been performed by the use of quantum chemical
methods. The calculated 13C NMR chemical shifts and NBO atomic charges provide an insight
into the influence of such a structure on the transmission of electronic substituent effects.
Linear freeenergy relationships (LFERs) have been further applied to their 13C NMR chemical
shifts. The correlation analyses for the substituent-induced chemical shifts (SCS) have been
performed with σ using SSP (single substituent parameter), field (σF) and resonance (σR)
parameters using DSP (dual substituent parameter), as well as the Yukawa–Tsuno model. The
presented correlations account satisfactorily for the polar and resonance substituent effects
operative at Cβ, and C7 carbons, while reverse substituent effect was found for Cα. The
comparison of correlationresults for the investigated molecules with those obtained for seven
structurally related styrene series has indicated that specific
cross-interaction of phenyl substituent and groups attached at Cβ carbon causes increased
sensitivity of SCS Cβ to the resonance effect with increasing of electron-accepting capabilities
of the group present at Cβ.

Keywords
13C NMRSubstituent effectLinear free energy relationshipsYukawa–Tsuno modelQuantum
chemical calculation
 YEAR 2020
ARTICLE NO 1
37
Extension of the neuroprotective timewindow for thiazolidinediones in
ischemic stroke is dependent on time of reperfusion

Abstract
Stroke is a leading cause of death and disability but has limited therapeutic options. Thiazolidinediones (TZDs),
agonists for the nuclear receptor, peroxisome proliferator-activated receptor (PPAR)γ, reduce infarct volume and
improve neurologic function following transient middle cerebral artery occlusion (MCAO) in rats. Translation of
these findings into clinical therapy will require careful assessment of dosing paradigms and effective time windows
for treatment. Understanding the mechanisms by which TZDs protect the brain provides insight into how time
windows for neuro protection might be extended. We find that two TZDs, pioglitazone and rosiglitazone,
significantly reduce infarct volume at doses similar to those used clinically (1 mg/kg for pioglitazone and 0.1 mg/kg
for rosiglitazone). We also find that pioglitazone reduces infarctionvolume in a transient, but not a permanent
MCAO model suggesting that reperfusion plays an important role in TZD mediated neuro protection.
Since PPAR γ agonists reduce inflammation and oxidative stress, both of which are exacerbated by reperfusion,
we hypothesized that TZDs wouldbe most effective if administered prior to reperfusion. We administered TZDs 3
h after MCAO and found that infarction volume and neurologic function are significantly improved in animals
perfused at 3 h and 15 min (after TZD treatment), but not in animals reperfused at 2 h (before TZD treatment)
when assessed either 24 h or 3 weeks after MCAO. While TZDs reduce intercellular adhesion molecule (ICAM)
expression to a similar extent regardless of the time of reperfusion, leukocyte entry into brain parenchyma is
more dramatically reduced when reperfusion is delayed until after drug treatment. The finding that delaying
reperfusion until after TZD treatment is beneficial despite a longer period of ischemia,is dramatic given the
widely held view that duration of ischemia is the most important determinate of injury.
Key words
cerebral is chemianeuroprotectionpioglitazonerosiglitazonePPARγ 38
Abbreviations
ANOVA analysis of varianceAP-1activator protein 1CBFcerebral blood
flowCTcomputed tomographyCtcycle
thresholdCu/Zncopper/zincDMSOdimethyl sulfoxideFDAFederal Drug
AdministrationHPFhigh powered fieldICAMintracellular adhesion
molecule-IRimmunoreactivityMCAOmiddle cerebral artery
occlusionmNSSmodified neurological severity scoreMRImagnetic
resonance imagingNFκBnuclear factor κBPBSphosphate buffered
salinePCRpolymerase chain
reactionPGJ215-deoxy-Δ(12,14)-prostaglandin J2PPARperoxisome
proliferator-activated receptorPPREperoxisome proliferator response
elementROSreactive oxygen speciesRXRretinod X, receptorSEMstandard
error of the meanSTAIRstroke academic industry roundtableSTAT-1signal
transducers and activator of transcription 1SUMO1small ubiquitin-like
modifierTTCtriphenyl tetrazolium chlorideTZDthiazolidinedioneUSUnited
States
 ARTICLE NO 2 39
Title
An efficient one-pot synthesis of pyrazolyl-thiazolidinedione hybrid
analogues and evaluation of their antimicrobial activity

ABSTRACT

An efficient one-pot synthetic protocol developed for pyrazolyl-

thiazolidinedione hybrid analogues by the condensation of chloroacetic
acid, thiourea and pyrazole
aldehydes by using sodium acetate. The synthesized compoundswere screened
for their in vitro antimicrobial activity against four bacterial and two fungal
pathogens, the results showed that moderate to good zone of inhibition
exhibited against all the tested organisms. The compounds structure was
characterized based on spectral data such as IR, 1H-NMR, 13C-NMR, mass
spectrometry and elemental analysis.
 Graphical Abstract
40

Keywords

Thiazolidinedione Pyrazole One-pot multi component synthesis

Antimicrobial activity
 41
ARTICLE NO 3

Capsaicin up-regulates pro-apoptoticactivity of thiazolidinediones

in glioblastoma cell line

Highlights
• Capsaicin induces apoptosis in glioblastoma LN-18 cells.
• Capsaicin-induced apoptosis is not dependent on TRPV1.
• Capsaicin increases PPARγ expression in glioblastoma LN-18 cells.
• Capsaicin and rosiglitazone/pioglitazone evoke synergistic pro-apoptotic
effect.
Abstract
Capsaicin (N-vanillyl-8-methyl-alpha-nonenamide), a spicy, neurotoxic
42
component of hot pepper is a ligand of vanilloid type-I (TRPV1) receptor
ofanti-cancer potential. However, molecular mechanism of its action is
not fully understood. We found that capsaicin stimulated intrinsic and
extrinsic pathway of apoptosis in human glioblastoma LN-18 cell line
and this phenomenon was not dependent on TRPV1. Activation of
peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-
dependent transcription factor, also induced apoptosis in glioblastoma
cells.
Although PPARγ ligands (thiazolidinediones – rosiglitazone,
pioglitazone)promoted apoptosis in LN-18 cells, capsaicin augmented
this effect. We found that capsaicin in a dose dependent manner induced
expression of PPARγ in glioblastoma LN-18 cells. These findings suggest
that
capsaicin-dependent up-regulation of PPARγ represent the mechanism
foraugmentation of cell death by thiazolidinediones.
 Graphical abstract 43

Keywords
Capsaicin Apoptos is Glioblastoma Pioglitazone Rosiglit
azone Troglitazone
1. Introduction
44
Gliomas are relatively rare (incidence rate about 1 per 20000 persons) primary intracranial
tumor, representing 81 % of malignant brain tumors[1]. Glioblastoma, the most common glioma,
is one of the most aggressive brain tumors [2]. Despite significant progress in therapy of this type
of cancer, its effectiveness is still low. The main reason is that central nervous system is protected
by blood-brain barrier against of most anticancer agents [3]. This natural barrier protects glioma
cells and limitssystemic chemotherapy to few agents, in particular temozolomide, an alkylating
pro-drug [4]. However, several in vitro studies suggested
anti-neoplastic potential of capsaicin.

Capsaicin is a lipophilic protoalkaloid recognized as the main pungent component in hot

peppers (Capsicum annuum L.) used for treatment of pain in neuralgias and neuropathies [5].
Numerous studies showed beneficial effects of capsaicin on cardiovascular [6] and gastric
function [7], metabolic regulation [8], as well as its anti-inflammatory [9] and anti-cancer
properties [10]. It has been established that capsaicin evokedpharmacological effects by
transient receptor potential vanilloid subtype1 (TRPV1) [11]. TRPV1 is a Ca2+ permeable non-
selective cation channel expressed in many tissues [12]. The expression of TRPV1 gene and
proteinis inversely correlated with glioma grading. In the majority of
glioblastomas at grade IV, TRPV1 expression is very low [13,14]. Themechanism of this
process is probably due to down-regulation of apoptosis [15]. In fact capsaicin was found to 45
induce apoptosis in
TRPV1-dependent manner in variety of neoplastic cells [13,[16], [17], [18]]. However, it was also
shown that capsaicin may induce apoptosis throughTRPV1-independent way [19].

Another apoptosis-inducing factors in glioma cells are thiazolidinediones [[20], [21], [22], [23],
[24], [25]]. This group of drugs were bring to marketas antidiabetic agents, that function
primarily by increasing insulin sensitivity [26]. Thiazolidinediones are ligands for the
peroxisome proliferator-activated receptor-γ (PPARγ), known as a ligand-activated
transcription factor. PPARγ is activated by several known endogenous lipophilic ligands
emerging from the metabolism of arachidonic acid and linoleic acid as well as synthetic
thiazolidinediones [27]. PPARγ has two isoforms: PPARγ1 which is expressed in nearly most
tissues and PPARγ2 detected only in adipocytes [28,29]. PPARγ is expressed in various cancer
cells, including glioblastomas [[20], [21], [22], [23], [24], [25]]. It has beenfound that activation
of PPARγ was accompanied by several antineoplastic effects in human glioblastoma cell lines
[29].

Recent approaches to treat cancer are focused on multi-targeted pharmacotherapy. In this

report we provide evidence for the potency of TRPV1 agonist, capsaicin, used in combination
with PPARγ agonists: troglitazone, rosiglitazone and pioglitazone, to evoke strong pro-apoptotic
activity in glioblastoma cell line.
2. Materials and methods 46
2.1. Reagents
Capsaicin (#M2028), rosiglitazone, pioglitazone, capsazepine,
3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide (MTT),
collagenase, glycine, L‐proline, bovine serum albumin (BSA) were provided by
Sigma-Aldrich, as were most other chemicals and buffers used. Troglitazone was
purchased from Selleck Chemicals LLC. Dulbecco'sModified Eagle Medium
(DMEM), penicillin, streptomycin, fetal bovine serum (FBS), trypsin, phosphate
buffered saline and Hoechst 33342 were obtained from Thermo Fisher Scientific.
Nitrocellulose membrane, sodiumdodecylsulphate, acrylamide, molecular
weight standard and nonfat dry milk were received from Bio‐Rad Laboratories.
L‐2,3,4,5[3H]-proline was purchased from Hartmann Analytic.

References
[1] Q.T. Ostrom, L. Bauchet, F.G. Davis, I. Deltour, J.L. Fisher, C.E. Langer, M. Pekmezci, J.A.
Schwartzbaum, M.C. Turner, K.M. Walsh, M.R. Wrensch, J.S. Barnholtz-Sloan

The epidemiology of glioma in adults: a "state of the science" review

47
 48
ARTICLE NO 4
Novel
thiazolidinedione-hydroxamates asinhibitors of Mycobacterium
tuberculosis virulence factor Zmp1

Highlights

• A series of novel thiazolidinediones-hydroxamates were synthesized.

• In silico drug-likeness behavior was evaluated.
• Inhibitory properties towards a recombinant Zmp1 by MALDI-TOF MSwere
assessed.
• Evaluation of in vitro antitubercular activity against MTB H37Ra.
• Molecular docking study against the active site of Zmp1 enzyme was performed.
Abstract 49
Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been
found essential for the intracellular survival and pathogenesis of
Mycobacterium tuberculosis. In this work, we designed and synthesized a
series of novel thiazolidinedione-hydroxamates and evaluated in silico their
drug-likeness behavior. Then, their inhibitory properties towards a
recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by
MALDI-TOF MS. Nine of the tested compounds were found to inhibit the
enzymatic reaction more effectively than the generic metalloprotease inhibitor
phosphoramidon. Furthermore, the synthesized thiazolidinedione-
hydroxamate hybrids were evaluated for their in vitro antimycobacterial
activity and acute cytotoxicity using whole-cell assays.Results showed that
none of the hybrids exhibited acute cytotoxicity against RAW264.7
macrophages. Whereas extracellular antimycobacterial activity was limited,
RAW264.7 macrophage infection results showed that a majority of the hybrids
inhibited the intracellular growth of Mycobacterium tuberculosis at a
concentration of 100 and 10 μM. The thiazolidinedione-hydroxamate
compound 2n was considered to be the best candidate of the evaluated library.
 50
Graphical abstract

Keywords
Zmp1 Mycobacterium Tuber culosis
Thiazolidinediones Hydroxamates MALDI-TOF

REFERNCE
Veronika Šlachtová a, Marek Šebela b, Eveline Torfs c, Lauren Oorts c, DavieCappoen c, Karel Berka d, Václav Bazgier d,
Lucie Brulíková a
 ARTICLE NO 5
51
Design and application of
near-infrared fluorophore based on a novel thiazolidinedione-functionalized
dicyanoisophorone

Highlights
• A novel thiazolidinedione-dicyanoisophorone hybrid-based NIRfluorophore was developed.
• 2, 4-thiazolidinediones as the modification site was designed forfunctional modification.
• A large turn-on fluorescence signal at 720 nm with a remarkable stokesshift (150 nm).
• The probe showed low cytotoxicity, high selectivity and sensitivity.
• Imaging H2O2 in live cells and in mice.

Abstract
A novel dicyanoisophorone (DCI)-based NIR fluorophore employing 2, 4-thiazolidinediones as the modification site
was designed for fluorescence imaging. The fluorophore was assessed as a switchable reporter for H2O2 and the probe
exhibited lysosomes-targeted, a large turn-on fluorescence signal at 720 nm with a large stokes shift (150 nm)
and can be used in biological systems. The ability of the novel fluorophoreto emit NIR fluorescence through a “turn-on”
activation mechanism makes it a promising fluorophore for in vivo imaging applications. The strategy of introducing the
thiazolidinediones with the easy modification site into the fluorophore has a good application prospect to expand the
application of the NIR fluorophore.
Graphical abstract 52

Keywords

Near-infraredFluorophore2, 4 Thiazolidinediones
Dicyanoisophorone H2O2
REFERENCE
Xiao Liang a b, Lu Zhang a b, Bing Shi c, Hao Chang a b, Dan Qiao a b,
Tangliang Shen a b, Wei Zhao a b, Zheng Yin a b, Luqing Shang a b
 ARTICLE NO 6 53

Ethylenic conjugated coumarin thiazolidinediones as new

efficientantimicrobial modulators against clinical
methicillin-resistant Staphylococcus aureus

Highlights

• Novel ethylenic conjugated coumarin thiazolidinediones were

synthesized.
• All the synthesized compounds were evaluated for their
antimicrobialactivity.
• Compound 12b showed excellent inhibitory efficacy against MRSA
and fumigatus.
• Compound 12b with low toxicity did not trigger resistance
developmentin bacteria.
• 12b could effectively permeabilize MRSA cell membrane and
intercalateinto DNA.
Abstract
54
In an effort for the development of novel antimicrobial agents,
ethylenic conjugated coumarin thiazolidinediones as potential
multi-targeting new antimicrobial compounds were synthesized
through convenient procedures from commercially available resorcinol
and were evaluated for their antimicrobial potency. Bioactive
evaluation revealed that some of the prepared compounds showed
strong antimicrobial activities towards the tested microorganisms
including clinically drug-resistant strains. Especially, propargyl
derivative 12b exhibited effective anti-MRSA potency with MIC value of
0.006 μmol/mL, which was highly advantageous over clinical
antibacterial drug norfloxacin. Compound 12b showed rapid killing
effect, low toxicity against hepatocyte LO2 cell line, and no obvious drug
resistance development against MRSA. Preliminary exploration of
action mechanism manifested that molecule 12b acted upon MRSA
through forming stable supramolecular complex with bacterial DNA
which might impede DNA replication. Molecular docking showed that
compound 12b could bind with DNA-gyrase through hydrogen bonds.
Graphical abstract 55
A series of novel ethylenic conjugated coumarin thiazolidinediones
weresynthesized and screened for their antimicrobial activities.

Keywords

CoumarinThiazolidinedioneAntimicrobialMRSADNA

REFERENCE
Chun-Fang Hu a, Peng-Li Zhang a, Yan-Fei Sui a, Jing-Song Lv a, Mohammad Fawad Ansari a 1, Narsaiah
Battini a 2, Shuo Li b, Cheng-HeZhou a, Rong-Xia Geng a
 YEAR 2021 56

ARTICLE NO 1
Synthesis and structure-activity relationship studies of 2,4-
thiazolidinediones and analogous heterocycles as inhibitors of
dihydrodipicolinatesynthase

Abstract
Dihydrodipicolinate synthase (DHDPS), responsible for the first committed step of
the diaminopimelate pathway for lysine biosynthesis, has become an attractive
target for the development of new antibacterial and herbicidal agents. Herein, we
report the discovery and exploration ofthe first inhibitors of E. coli DHDPS which
have been identified from screening lead and are not based on substrates from the
lysine biosynthesis pathway. Over 50 thiazolidinediones and related analogues
have been prepared in order to thoroughly evaluate the structure-activity
relationships against this enzyme of significant interest.
Graphical abstract
57

Keywords
Dihydrodipicolinate synthaseDHDPS inhibitorsEnzyme
inhibitorsThiazolidinediones

REFERENCE
Rebecca M. Christoff a, Tatiana P. Soares da Costa b, Saadi Bayat a, Jessica K.Holien c, Matthew A.
Perugini b, Belinda M. Abbott a
 58
ARTICLE NO 2

Design, synthesis and bioactivityevaluation of

thiazolidinedione derivatives as partial agonists
targeting PPARγ

Highlights
• The synthesis and antibacterial activities of these
compounds have notbeen reported so far.
• Our current finding are completely new.
• Compound 4 g maybe a new compound as partial
agonist targeting PPARγ.
Abstract 59
Thiazolidinedione (TZD) is a novel peroxides proliferator activated receptor
γ (PPARγ) agonist with many side effects. Herein, we developed aseries of
novel TZD analogues as partial agonists targeting PPARγ. The study of anti-
hyperglycemic activity and anti-inflammatory activity enabled us to
identify a novel compound, 4 g, which quickly recover the blood glucose of
mice at the concentration of 100 mg/kg, and show similar anti-
inflammatory activity to ibuprofen at the concentration of 20 mg/kg.The
competitive binding assay confirmed direct binding of 4 g to the LBD of
PPARγ with IC50 being 1790 nM, and dose-dependently increased the
transcriptional activity of PPARγ. Besides, through computer-aided drug
design software simulation docking, it was found that compound 4 g
showed the best binding ability to target protein PPARγ. Furthermore,
because of the introduction of benzene containing group at N3 position, the
stability of H12 in the active pocket is reduced and the stability of H3 and β-
fold is increased, showing the characteristics of some PPARγ agonists,
based on the docking model analysis. Together, these results suggest that 4
g is a promising PPARγ agonist that deserves further investigation.
Graphical abstract 60
We developed a series of novel Thiazolidinedione analogues with
improved security as partial agonists targeting PPARγ.

Keyword

Thiazolidinedione derivativesPPARγ partial Agonist anti-hyperglycemic activity

Anti-inflammatory activity
 ARTICLE NO 3
61
Thiazolidinediones, alpha-glucosidaseinhibitors, meglitinides,
sulfonylureas, and hepatocellularcarcinoma risk: A meta-analysis

Abstract
Background & Aims
Hepatocellular carcinoma (HCC) remains a leading cause of
cancer-related death worldwide. Effects of second-line oral antidiabeticmedications on incident HCC
risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations
between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and
incident HCC risk.

Methods
We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were
included if they documented: (1) exposureto oral antidiabetic medication classes; (2) HCC incidence; (3)
relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified.
We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95%
confidence intervals (CI).
Results 62
Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with
reduced HCC risk (aOR = 0.92, 95% CI = 0.86–0.97, I2 = 43%), including among Asian subjects
(aOR = 0.90, 95% CI = 0.83–0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87–1.04).
Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was
associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02–1.14, I2 = 21%).
Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with
increased HCC risk in studies including patients with established liver disease (aOR = 1.06,
95% CI = 1.02–1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases)
was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89–1.60, I2 = 72%).

Conclusions

Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes.
Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk;
future research should determine whether those agents should be avoided in patients with chronic
liver disease.
Introduction
As the global incidence of hepatocellular carcinoma (HCC) continues to rise, clinical outcomes remain exceptionally 63
poor, due to a combination ofinadequate cancer surveillance and a paucity of effective treatment options [1]. Type 2
diabetes mellitus independently increases the risk of multiple cancers, including HCC [[2], [3], [4]], and occurs
frequently with concurrent liver disease. Informed selection of antidiabetic regimens may enable providers to mitigate
risk of HCC development in high-risk patientswith diabetes. Given the rapidly increasing prevalence of diabetes, such a
strategy could translate to a considerable decline in overall HCC incidence.

Robust evidence from clinical and epidemiological studies indicates that the risk of HCC in diabetic subjects increases
with insulin use, and decreases with metformin use [[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]]. However,
the effects of second-line oral antidiabetic agents are less well-characterized, and published data are limited and
conflicting. Two prior meta-analyses have reported thiazolidinedione use to be associated with significantly decreased
HCC incidence [17,18], however, Singh et al. did not identify a significant protective association [15], and several recent
studies examining thiazolidinediones in relation toHCC incidence were not included in those prior meta-analyses
[19,20].
Similarly, while prior meta-analyses have indicated use of sulfonylureasto be associated with significantly increased
risk of incident HCC [8,15], they did not include several important, more recent additions to the literature [19,21,22].
Finally, prior meta-analyses of second-line antidiabetic therapies did not evaluate meglitinides, and while a single

meta-analysis reported a trend towards decreased risk of liver cancer in users of alpha-glucosidase inhibitors,
compared to non-users [23], a subsequent analysis by Bosetti et al. [20] found an increased risk of HCC among users
of alpha-glucosidase inhibitors. In light of the growing bodyof primary literature, an updated review of associations
between the use of anti-diabetic medications and risk of incident HCC is warranted.

Therefore, we undertook a systematic review of published literature, and performed a series of meta-analyses to
characterize the relationships between use of second-line oral antidiabetic medication classes and risk ofincident HCC.
Search strategy
A medical librarian (LP) systematically searched PubMed, Embase and Web of Science databases (inception
through March 2020), using keywords and controlled vocabulary (Supplementary Table 1). Titles and
64
abstracts of identified studies were screened by two independent reviewers (AA and ZM), and studies that did
not investigate the association of interest were excluded. Full texts of the remaining studies were reviewed, and
their references examined to identify additional articles of relevance.

Search results
Our search strategy yielded 10,105 individual articles, of which 56 were assessed in full for eligibility. Of
these, 7 studies were published solely in abstract form, and were excluded. 8 studies utilized the Taiwan
National Health Insurance claims database to establish their patient cohort [[30], [31], [32], [33], [34], [35],
[36], [37]], and 2 studies utilized the South Korean National Health Insurance Service-National Sample
Cohort [19,38]: the 2 studies with the largest respective cohort

Discussion
Type 2 diabetes is projected to continue increasing in prevalence during the coming decade [42] and is
frequently comorbid with liver disease (in particular non-alcoholic fatty liver disease). Therefore, informed
and judicious selection of antidiabetic therapy in patients with concurrent diabetes and liver disease
could translate to a meaningful decline in overall rates of incident HCC. We conducted a
comprehensive systematic

References
S. Singh et al.
Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis
eview and a series of meta-analyses, involving more than 19,466
 ARTICLE NO 4
65

Design, synthesis and biologicalevaluation of novel

5-(imidazolyl-methyl)

thiazolidinediones as antidiabeticagents

Highlights
• Some novel TZD derivatives were synthesized and in silico studies
weredone for them.
• Most synthesized TZDs had better anti-hyperglycemic activity
versusthe standard drug.
• No weight gains or severe side effects on the liver and pancreas
wereobserved for 9e.
• Glucose consumption assay showed a significant glucose-
loweringeffect in HepG2 cells.
• The qPCR analysis showed similar behavior of pioglitazone and
9e.
 ABSTRACT
66

A newly designed series of imidazolyl-methyl- l-2,4-thiazolidinediones 9(a-m) were

synthesized and In Silico studies were carried out to

rationalize their anti-diabetic activity. Generally, all newly synthesized

thiazolidinediones had anti-hyperglycemic activity compared with a diabetic-
control group, without toxicity in 3T3 cells (viability ≥ 90%).
These studies revealed that the compounds 9e and 9b (
11∗10-6888/88
) lowered blood glucose more effectively when compared to pioglitazone atthe same
dose. Following the administration of compound 9e, no weight gains or any serious
side effects on liver and pancreas were observed.
Moreover, the glucose consumption assay results showed a significant glucose-
lowering effect (p < 0.001) in HepG2 cells, which were exposed to11 mM of glucose at
concentrations of 1.25–10 mM of compound 9e. Also, the PPAR-γ gene expression study
revealed that pioglitazone and 9e showed similar behavior relative to the control
group.
 Graphical abstract
67

Keywords
Thiazolidinedione Pioglitazone Synthetic analogue Diabetes Glucose

Abbreviations
T2D Type 2 diabetes NIDDM Non-insulin-dependent diabetes mellitus PPAR-γ Peroxisome proliferator-
activated receptor- γ TZDs Thiazolidinediones MD Molecular dynamic RMSF Root-mean-square
fluctuation RMSD Root-mean-square derivations RgRadius of gyration SS Secondary structures TRβ
Thyroid receptor β AR Androgen Receptor GR Glucocorticoid receptor TP Toxic potential FBG Fasting
bloodglucose AUC Area under curve SAR Structure-activity relationship IQR Interquartile range
RT-PCR Reverse transcription polymerase chain reaction TLC Thin-layer chromatography ESIEl
ectrospray ionization DMG Dimethylglyoxime PDB Protein Data Bank VMD Visual Molecular Dynamics
PPARc Peroxisome proliferator-activated receptor chERGTeh human Ether-à-go-go-Related GeneFBSFetal
bovine serum STZ Streptozocin
 ARTICLE NO 5
68
Bioactive isatin (oxime)-triazole-thiazolidinedione ferrocene molecular conjugates:
Design, synthesis and antimicrobialactivities

Highlights
• In this article, a series of novel bioactive agents of Triazole tetheredisatin and 2,4
Thiazolidinedione.
• These compounds were characterized by spectroscopic means and theywere screened for the
antimicrobial activity.
• The UV–Vis and electrochemical studies of these compounds wereperformed in CH3CN
solution.

Abstract

Molecular conjugates often combine the inherent properties of the individual

components and exhibit a different characteristic feature. Introduction of an
organometallic moiety can indeed augment the overall effect. This article narrates
the synthesis of ferrocene appended isatin−2,4-thiazolidinedione molecular hybrid
linked via a triazole moiety. Isatin and 2,4-thiazolidinedione were linked via a
triazole unit formed by a simple copper catalysed alkyne-azide 1,3-dipolar
cycloaddition reaction. The UV–vis and electrochemical studies on all the new
compounds are reported. Antimicrobial activity against some selected gram-
positive and gram-negative strains was also examined for all the new derivatives
and compounds 6(b), 6(c), 6(h) and 6(i) revealed similar antimicrobial activity for
all tested microbes and similar pattern to that of standard antibiotics.
 Graphical abstract 69

Keywords

Ferrocene-molecular conjugates Isatin (Oxime) 1,2,3-Triazole2,4-

ThiazolidinedioneElectrochemistryAntimicrobial activity
 ARTICLE NO 6 70
SP1-independent inhibition of FOXM1by modified thiazolidinediones

Highlights
• The thiazolidinedione scaffold was modified to target the FOXM1protein, selectively.
• “Direct” FOXM1 inhibition requires a π-sulfur binding interaction.
• FOXM1 inhibitors exert weak binding interactions, suggesting the needfor a different strategy.

Abstract

This research article describes an approach to modify the thiazolidinedione scaffold to produce test drugs capable of binding
to, and inhibit, the in vitro transcriptional activity of the oncogenic protein FOXM1. This approach allowed us to obtain
FOXM1 inhibitors that bind directly to the FOXM1-DNA binding domain without targetingthe expression levels of Sp1, an
upstream transcription factor protein known to activate the expression of FOXM1. Briefly, we modified the chemical structure
of the thiazolidinedione scaffold present in anti-diabetic medications such as pioglitazone, rosiglitazone and the former anti-
diabetic drug troglitazone, because these drugs have been reported to exert inhibition of FOXM1 but hit other targets as well.
Afterthe chemical synthesis of 11 derivatives possessing a modified thiazolidinedione moiety, we screened all test compounds
using in vitroprotocols to measure their ability to (a) dissociate a FOXM1-DNA complex (EMSA assay); (b) decrease the
expression of FOXM1 in triple negative-breast cancer cells (WB assay); (c) downregulate the expression of FOXM1
downstream targets (luciferase reporter assays and qPCR); and inhibit the formation of colonies of MDA-MB-231 cancercells
(colony formation assay). We also identified a potential binding mode associated with these compounds in which compound
TFI-10, one of the most active molecules, exerts binding interactions with Arg289, Trp308, and His287. Unlike the parent drug,
troglitazone, compound TFI-10 does not target the in vitro expression of Sp1, suggesting that it is possible to design FOXM1
inhibitors with a better selectivity profile.
 Graphical abstract 71

Keywords
FOXM1Transcription factorsTroglitazoneThiazolidinediones.AnticancerMDA-MB-231Breast cancer

REFERENCE
Seyed Amirhossein Tabatabaei Dakhili a, David J. Pérez a b, Keshav Gopal a, Moinul Haque c d, John R.
Ussher a, Khosrow Kashfi e f, CarlosA. Velázquez-Martínez a
 YEAR 2022
72
ARTICLE NO 1

Design, synthesis and biological evaluation of selective hybrid

coumarin-thiazolidinedione aldosereductase-II inhibitors as
potentialantidiabetics

Highlights
• Synthesis of coumarin-TZD inhibitors of aldose reductase II based on benzopyran
and 1,3-thiazolidine-2,4-dione fragments.
• Design embellished with strategies- simplification of the structure, change of
position and grafting TZD moiety.
• Inhibition potencies of compounds 10a-n obtained invitro were verified with
invivostudies.
• Compound 10c emerged as the potent candidate in arresting the cataract
progressionin diabetes-induced STZ rats.
• Further binding interactions of 10a-n were studied using docking studies.
Abstract 73
Thiazolidinediones (TZD), benzopyrans are the proven scaffolds for inhibiting Aldose
reductase (ALR2) activity and their structural confluence with the retention of necessary
fragments helped in designinga series of hybrid compounds
2-(5-cycloalkylidene-2,4-dioxothiazolidin-3-yl)-N-(2-oxo-2H-chromen-3-yl
)acetamide (10a-n) for better ALR2 inhibition. The compounds were synthesized by treating
substituted 3-(N-bromoacetyl amino)coumarins(9a-d) with potassium salt of 5-cyclo
alkylidene-1,3-thiazolidine-2,4-diones (4a-d). The inhibition activity against ALR2 with
IC50 values range from 0.012 ± 0.001 to 0.056 ± 0.007μM.
N-[(6-Bromo-3-coumarinyl)-2-(5-cyclopentylidene-2,4-dioxothiazolidin-3- yl)] acetamide
(10c) with cyclopentylidene group on one end and the
5 bromo group on the other end showed better inhibitory property (IC50 =
0.012 μM) and selectivity index (324.166) against the ALR2, a forty fold superiority over
sorbinil, a better molecule over epalrestat and rest of the analogues exhibited a far superior
response over sorbinil and slightly better as compared with epalrestat. It was further
confirmed by the insilico studies that compound 10c showed best inhibition activity among
the synthesized compounds with a high selectivity index against the ALR2. In invivo
experiments, supplementation of compound 10c to STZ induced rats delayed the progression
of cataract in a dose-dependent manner warranting its further development as a potential
agent to treat the diabetic secondary complications especially cataract.
Graphical abstract 74
Confluence of two promising skeletons helped in planning the design of thetest compounds
10a-n as selective aldose reductase II inhibitors, in which 10c emerged as the potent inhibitor
in arresting the progression of cataract, creating interest further in the treatment in a
chemically more advanced manner. This revelation was further verified with invivo and Insilco
studies.

Keywords
Benzopyrans1,3-Thiazolidine-2,4-dionesDiabetic complications Aldose reductase
inhibitors Molecular modeling
 ARTICLE NO 2 75
Methylene Thiazolidinediones as Alkylation Reagents in Catalytic C–
HFunctionalization: Rapid Access to Glitazones

ABSTRACT
The straightforward and rapid incorporation of a thiazolidinedione scaffold
into prefunctionalized (hetero)aromatic compounds is in demandfor the
development of antidiabetic glitazones and other pharmaceuticals. Herein, we
report the unprecedented N- and O-directed C–H alkylation of various
(hetero)arenes with methylene thiazolidinediones under rhodium(III)
catalysis. The applicability of the developed protocol in challenging contexts is
exhibited by the late-stage installation of a methylene thiazolidinedione
moiety on the C–H bond of commercially available drug molecules. Combined
mechanistic investigations aided the elucidation of a plausible reaction
mechanism.
 76
Graphical Abstract
 ARTICLE NO 3 77
New 1,2,3‐Triazole‐Tethered Thiazolidinedione Derivatives:
Synthesis, Bioevaluation and Molecular Docking Study

Abstract
In search of new active molecules, a small focused library of 1,2,3-triazoles
based 2,4-thiazolidinedione derivatives has been efficiently prepared via the
click chemistry approach. Several derivatives were exhibited excellent anti-
inflammatory activity compared to the standard drug. Further, the synthesized
compounds were found to have potential antioxidant activity. Furthermore, to
rationalize the observed biological activity data, the molecular docking study
has also been carried out against the active site of inflammation enzyme
PPARγ, which revealed a significant correlation between the binding score and
biological activity for these compounds.
The results of the in vitro and in silico study suggest that the triazole
incorporated 2,4-thiazolidinedione derivatives may possess the ideal
structural requirements for the further development of novel therapeutic
agents.
 Graphical Abstract 78

Keywords
Click chemistry1,2,3-triazolesanti-inflammatory activity
antioxidantactivity2,4-thiazolidinedione
 79
ARTICLE NO 4

Experimental and first-principles DFTinsights into the corrosion

protection mechanism of carbon steel in an HCl medium by two
thiazolidinedione compounds

Highlights
• Thiazolidinedione compounds are high effective corrosion inhibitors of
carbon steel.
• An inhibition efficiency over 92% is obtained by themethoxy-substituted
compound.
• AFM and SEM images reveal the formation of protective barrier on steel
surface.
•First-principles DFT reveals the formation of covalent bonds upon
adsorption of inhibitors on steel.
 Abstract
80
Researchers have investigated various approaches to avoid corrosionproblems in different industries in
recent decades. In line with the research trend in this field, we synthesized and characterized two
thiazolidinedione derivatives, namely (Z)−
5-(4-hydroxy-3-methoxybenzylidene)thiazolidine-2,4-dione (HMTZD) and(Z)− 5-(4-
fluorobenzylidene)thiazolidine-2,4-dione (FTZD), and then used them as potential inhibitors for protecting
the corrosion of carbon steel (CS) in 1.0 mol/L. Corrosion inhibition performances were evaluated using
electrochemical techniques such as electrochemical impedance spectroscopy (EIS), potentiodynamic
polarization (PDP), linear polarization resistance (LPR), and surface characterization using a scanning
electron microscope (SEM). Besides, first principles Density Functional Theory (DFT) calculations were
employed to investigate the potential bonding and charge transfer between inhibitor molecules and Fe(110)
surface. Electrochemical results indicated that the addition of tested inhibitors to corrosive 1.0 mol/L HCl
solution significantly reduced

carbon steel corrosion by increasing the polarization resistance and blocking both anodic and cathodic
corrosion reactions. Further, results indicated that HMTZD and FTZD are adsorption inhibitors following
Langmuir adsorption isotherm. The HMTZD demonstrated an inhibition performance of 96% at 5 × 10-3 M. In
addition, the morphological analysisrevealed the formation of a protective barrier onto the CS surface,
which reduced corrosion attack. The adsorption mechanism was further evaluated using first-principles DFT
calculations, which showed that bothinhibitors can form chemical bonds with Fe-atoms. Partial density of
states (PDOSs) suggested that inhibitor molecules adsorbed through charge transfer between oxygen/sulfur
of molecules and Fe-atoms. The outcomes from the present work are intended to encourage further
exploration of thiazolidinediones in the corrosion protection of metals.
 Graphical Abstract 81

Keywords

Thiazolidinedi one Carbon steel Corrosion inhibitor PDOSDFT

 82
ARTICLE NO 5

Research progress on 2,4-thiazolidinedione and

2-thioxo-4-thiazolidinone analoguesas aldose reductase inhibitors

Highlights
• Aldose reductase is a viable target for the management of diabetic
complications.
• TZDs and 2-thioxo-4-thiazolidinones are explored as ALR2 inhibitors.
• Synthetic strategies, SAR, docking, QSAR, and patent status have been
illustrated.
• The review offers strategies for rational designing of target selective
potent ARIs.
Abstract 83
Diabetes-associated complications are a major global health concern. In diabetics, the increased
accumulation of sorbitol, produced via overactivated polyol pathway, from glucose by the action
of aldose reductase (AR, ALR2, or AKR1B1), has been associated with
life-threatening co-morbidities. Aldose reductase is crucial in detoxifying certain hazardous
aldehydes. However, aldose reductase overexpression in the hyperglycemic state results in
microvascular andmacrovascular diabetic complications through the consequences of the
activated polyol pathway. Accordingly, aldose reductase inhibition hasbeen identified as a viable
strategy for dealing with diabetes-associated complications, and it has been put under
investigation by various researchers around the world. 2,4-Thiazolidinedione (TZD) and its
bio-isosteric analog 2-thioxo-4-thiazolidinone (rhodanine) have been explored as potential
inhibitors of aldose reductase to find new molecules. The current review provides a
comprehensive insight into the development and medicinal chemistry of TZD and rhodanine
derivatives as aldose reductase inhibitors during the last twenty years(2002–2021). Here, the
synthetic strategies, SAR, and binding mode ofvarious compounds, Quantitative structure
activity relationship (QSARs) are discussed with an emphasis on structural changes to the both
moieties for optimizing/designing potent target-specific inhibitors, which is expected to be
beneficial for the further design anddiscovery of newer agents for the treatment of diabetic
complications. In addition, the patents on TZDs and rhodanine derivatives as aldose reductase
inhibitors are summarized to illustrate the current status.
 Graphical Abstract 84

Keywords

Aldose reductaseDiabetic complicationsDiabetesmellitusPolyol pathway2,4-

thiazolidinedione, 2-thioxo-4-thiazolidinone
 ARTICLE NO 6 85
Discovery of Rhodanine and Thiazolidinedionesas Novel Scaffolds for EGFR Inhibition:
Design, Synthesis, Analysis and CoMSIA Studies

Abstract

This study reports, 35 novel rhodanine, its bioisosteres thiazolidinedionesand is tested for EGFR inhibition.
These molecules are designed by using apharmacophore-based superimpose approach taking Gefitinib as a
core structure or reference. All the designed molecules were synthesized from 3-chloro and 4-fluoro
substituted aniline as the precursors and converted to corresponding dithiocarbamate (3a, b) by reacting
with carbon disulfide in presence of ammonia. Further, it was cyclized to rhodanine (4a, b) and subjected to
Knoevenagel condensation to find compounds
5(a-j) and 6(a-i). All the compounds are analyzed and from the NMR results, we found that Knoevenagel
condensed products are of “Z” geometrical isomers. Further, rhodanine was converted to its bioisosteric
form thiazolidinedione by reacting it with a catalytic amount of diacetoxy-iodobenzene in presence of
alcohol. All the synthesized compounds are characterized by IR, 1H NMR, 13C NMR, and Mass analysis,and
screened for their EGFR inhibition, among all the synthesized compounds, compound 5i, 6 h, 7c, and 8f
showed promising results by inhibiting EGFR at <10 nM. Further, structure-activity relationships were
established via CoMSIA studies.
A series of 35 novel rhodanine, its bioisosteres thiazolidinediones were
synthesized by taking 4-fluoro and 3-chloro aniline as a precursors 86
and different aldehydes via Knoevenagel condensation. The
synthesized compounds were subjected to In vitro EGFR assay. All the
compounds showed a comparable biological activity compared to the
standard drug. Additionally, molecular docking and CoMSIA study
were performed to support the hypothesis.

Keywords

CoMSIA studies docking EGFR inhibition hodanine thiazolidinedione

87