Discovery of Natural Product Derived Labdane Appended Triazoles as Potent Pancreatic Lipase Inhibitors

Article abstract of DOI:10.1021/acsmedchemlett.8b00109

Obesity contributes to the genesis of many metabolic disorders including dyslipidemia, coronary heart disease (CHD), nonalcoholic fatty liver, type 2 diabetes, etc. Pancreatic lipase plays a vital role in food fat digestion and absorption. Therefore, to c

Full text of DOI:10.1021/acsmedchemlett.8b00109

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Letter
Discovery of Natural Product Derived Labdane Appended
Triazoles as Potent Pancreatic Lipase Inhibitors
Renjitha Jalaja, Shyni Gangadharan Leela, Praveen Kumar Valmiki, Chettiyan
Thodi F Salfeena, Kizhakkan T Ashitha, Venkata Rao D Krishna Rao, Mangalam
S Nair, Raghu Kozhiparambil Gopalan, and Sasidhar Balappa Somappa
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.8b00109 • Publication Date (Web): 18 Jun 2018
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ACS Medicinal Chemistry Letters
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Discovery of Natural Product Derived Labdane Appended Triazoles
as Potent Pancreatic Lipase Inhibitors
Renjitha Jalaja,‡,† Shyni G. Leela,§ Praveen K. Valmiki,‡,† Chettiyan Thodi F. Salfeena,‡,† Kizhakkan T.
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Ashitha,‡,† Venkata Rao D. Krishna Rao,¥ Mangalam S. Nair,‡ Raghu K. Gopalan,*,§,† Sasidhar B.
Somappa*,‡,†
.
‡Chemical Sciences and Technology Division, CSIR ꢀ National Institute for Interdisciplinary Science and Technology
(CSIRꢀNIIST), Thiruvananthapuram ꢀ 695 019, Kerala, India.
§AgroꢀProcessing and Technology Division, CSIR –NIIST, Thiruvananthapuram ꢀ 695 019, Kerala, India.
¥CSIR ꢀ Central Institute of Medicinal and Aromatic Plants, Research Centre, Bangaloreꢀ560065, Karnataka, India.
†Academy of Scientific and Innovative Research (AcSIR), CSIRꢀNIIST, Thiruvananthapuram, India.
KEYWORDS. Zingiberaceae, Curcuma amada, Triazoles, Pancreatic lipase inhibition, Obesity related disorders.
ABSTRACT: Obesity contributes to the genesis of many metabolic disorders including dyslipidemia, coronary heart disease
(CHD), nonalcoholic fatty liver, type 2 diabetes etc. Pancreatic lipase plays a vital role in food fat digestion and absorption. Thereꢀ
fore to control obesity, inhibition of pancreatic lipase is the active therapy. Thus, a novel natural product derived labdane appended
triazoles with pancreatic lipase inhibition potential was designed and synthesized. Among these hybrids, 6b and 6f exhibited excelꢀ
lent inhibitory activity (IC50 0.75 ± 0.02 ꢀM and 0.77 ± 0.01 ꢀM), slightly better than that of the positive control Orlistat (IC50 0.8 ±
0.03 ꢀM). Compounds 6c, 6e, and 6g-jinhibited the PL comparable to that of positive control. Interestingly none of the compounds
showed cytotoxicity (Hep G2) in the concentration ranging from 0.5ꢀ100 ꢀM. Overall results reveal potential of labdane appended
triazoles as antiꢀobesity agents.
Obesity is a medical condition with excess body fat accuꢀ
mulation to the extent which leads to serious health conseꢀ
quences. Obesity contributes to the genesis of many metabolic
disorders including dyslipidemia,1 coronary heart disease
(CHD),2 nonalcoholic fatty liver,3 type 2 diabetes4 etc. In 2017
WHO reported that the global obesity has almost tripled since
1975.5 As per literature more than 340 million children and
adolescents between 5 and 19 aged are overweight or obese.5
As a result, physicians are prompted to take aggressive treatꢀ
ments in lifestyle changes, pharmacological interventions, and
surgical therapies before a severe consequence become cliniꢀ
cally apparent. Among these various treatments, pharmaꢀ
cotherapy is the most commonly used one.6ꢀ7
Based on the traditional applications and its large medicinal
properties in a long history of Ayurvedic medicine, we have
selected Curcuma amada Roxb. for the exploration of its inhiꢀ
bition properties against the pancreatic lipase. C. amada, an
edible ginger is one of the rhizomatous species in the Zingiꢀ
beraceae family. The rhizomes of C. amada are a rich source
of essential oils, and more than 130 phytochemicals are isolatꢀ
ed,16 which possesses various biological properties viz. antiꢀ
microbial, antioxidant, antiꢀinflammatory, anticancer, cardioꢀ
vascular and gastrointestinal disorders etc.16ꢀ19
Therefore, in continuation of our focused on going research
interest on natural products and natural product based lead
molecule20ꢀ22 identification for therapeutic applications, in the
present work, we have isolated the major compound (E)ꢀ
Labdaꢀ8(17),12ꢀdieneꢀ15,16ꢀdial. This was synthetically transꢀ
formed to rationally designed triazole appended analogues and
Pancreatic lipase plays a vital role in food fat digestion and
absorption.8 Therefore to control obesity, inhibition of pancreꢀ
atic lipase enzyme is the active therapy. Among the existing
medicines, Orlistat is one such precise drug used for the inhiꢀ
bition of pancreatic lipase. In recent times, natural/herbal
products also considered as an alternative medicine for the
treatment of obesity and related disorders.9ꢀ10 Many plantꢀ
based extracts reported for the treatment of obesity and associꢀ
ated diseases. For instance, ethanolic extracts of Terminalia
paniculata showed very good antiꢀlipase and antiꢀobesity acꢀ
tivities.11 Likewise, some terpenoid saponins from the leaves
of Acantho panaxsenticosus,12 the phenolic acids from ferꢀ
mented oats,13 apple polyphenols,14 and flavanꢀ3ꢀol digalate
esters of oolong tea are found to have substantial pancreatic
lipase inhibitory property.15
Figure 1. Rationale for the synthesis of labdane appended triaꢀ
zoles
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ꢀ evaluated for their pancreatic lipase inhibitory potential. The
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ꢀ and phenacyl azides (5) at room temperature to provide
1,2,3ꢀ triazole appended labdane derivatives (6a-q) in good to
excellent yields (Scheme 2). All the synthesized derivatives
are fully characterized by IR, NMR and HRMS spectral data
(supporting information).
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rationale for the targeted synthesis of triazole appended anaꢀ
logues is based upon its broad spectrum of biological properꢀ
ties.23ꢀ24 Triazole and pyrazole based synthetic drugs are also
wellꢀknown for the treatment of obesity and related disorders
(Figure 1).25ꢀ27 To begin with, the fresh rhizomes of C.amada
were collected from CTCRI, Thiruvananthapuram India in
February 2017. By following standard protocol (supporting
information) compound 1 (E)ꢀlabda 8(17), 12ꢀdiene ꢀ15, 16ꢀ
dial was isolated from the chloroform extract as a colorless
solid and confirmed by using various spectroscopic data IR,
1H NMR, 13C NMR, HRMS, etc.19,28 A series of variously
substituted triazole appended labdane derivatives were preꢀ
pared by a threeꢀstep protocol starting from compound 1.
Compound 1, when subjected to Jone’s oxidation, one of the
aldehydes of compound 1 is selectively oxidized into acid
derivative, Zerumin A (2). The alkyne intermediate (3) of
Zerumin A, prepared in excellent yields by treating 2 with
propargyl bromide (Scheme 1). The propargylated labdane
undergoes the click reaction with various substituted benzyl ꢀ
The isolated Eꢀlabda 8(17), 12ꢀdiene ꢀ15, 16ꢀdial (1), semiꢀ
synthetic intermediates and targeted triazole appendages were
evaluated for the inhibitory activity against pancreatic lipase
(PL) (Method A)29 (supporting information). The parent
molecule labdane dial exhibited moderate activity. Among the
tested, majority of the triazole hybrids showed strong PL inꢀ
hibitory activity in the concentration ranging from 0.75ꢀ14.63
ꢀM. Initially, the percentage of enzyme inhibition of comꢀ
pounds at various concentrations (1, 5, 10, and 20 ꢀM) was
performed. At lower concentration of 1 ꢀM, compounds 6b,
and 6f showed inhibition of 75 to 80 %. At 20 ꢀM concentraꢀ
tion the derivatives 6b, 6c, 6e, 6f, 6g, 6h and 6j exhibited
maximum inhibition percentage of 80 to 85 (Figure 2). The
other compounds (6a, 6k, 6l, 6m and 6q) also showed better
tendency to inhibit the PL. In contrast, few derivatives (6d, 6i,
6n, 6o, and 6p) failed to show any significant effect on panꢀ
creatic lipase. Overall, the labdaneꢀtriazole hybrids inhibited
the PL through the concentration dependent manner.
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Scheme 1. Synthesis of propargylated labdane (3) and sub-
stituted benzyl and phenacylazides (5a-q).
H
H
H
OH
O
H
O
O
O
O
O
O
Br
Jone's reagent
Acetone, rt
K2CO3, DMF
0oC
H
H
H
3
1
2
N3
Br
Br
N3
O
R
O
acetone : water
rt
acetone : water
rt
+
NaN3
+ NaN3
R
R
R
4a-l
5a-l
4m-q
5m-q
Scheme 2. Synthesis of labdane appended triazoles by
Click chemistry (6a-q)
Isolates and synthetic derivatives are tested at concentrations 1ꢀ20
µM. Each experiment was independently performed four times in
duplicates and expressed as mean ± SD (n=4).
Figure 2. The percentage inhibition of isolates and synthetic deꢀ
rivatives against pancreatic lipase in various concentrations.
N
N
H
H
N
R
O
O
O
O
O
O
CuSO4.5H2O
RN3
+
Sodium ascorbate
tBuOH : H2O
H
3
H
In an attempt to validate the potential of the compounds, the
PL inhibitory activity was repeated using Human Pancreatic
lipase (Method B)30 (supporting information). As expected,
the compounds followed the similar trend in exhibiting the
inhibitory potential with IC50 values in the range of 1.10ꢀ14.48
ꢀM concentration. The derivatives 6b, 6c, 6g, and 6h presentꢀ
ed maximum PL inhibition percentage of 80 to 85 at 15 ꢀM
concentration (Figure 3). Similarly, triazole analogues 6d, 6i,
6n, 6o, and 6p have failed to inhibit the Human Pancreatic
lipase. The IC50 values of active compounds with maximum
inhibitory potential are calculated and, summarized in Table
1. The IC50 results revealed (Method A) that the labdane
traizole appendages 6b and 6f exhibited an excellent inhibitory
activity with 0.75 ± 0.02 ꢀM and 0.77 ± 0.01 ꢀM respectively,
which is slightly better than that of positive control Orlistat
(IC50 0.8 ± 0.03 ꢀM). Compounds 6c, 6e, and 6g-j inhibited
the pancreatic lipase comparable to that of positive control in
the range IC50 0.8 to 0.9 ꢀM. Whereas, the parent molecule 1, ꢀ
5a-q
6a-q
Cl
F
SCH3
Cl
NO2
6a (61%) 6b (71%)
6c (73%)
6d (80%)
6e (53%)
6f (52%)
Br
Br
Ph
OH
tBu
F
R =
OCH3
H3CO
O2N
6j (75%)
6l (86%)
6g (50%)
6k (66%)
6h (69%)
6i (77%)
O
O
O
O
O
F
Br
6n (72%)
Cl
CN
6m (55%)
6p (53%)
6q (35%)
6o (62%)
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range of 1.65 to 2.31ꢀM. The parent molecule and other derivꢀ
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atives showed moderate activity. The preliminary studies also
revealed that the compounds are bound to the active site of PL
and probably exhibited a covalent interaction with PL. Neverꢀ
theless, extended kinetics and crystallographic studies to be
conducted for further authentication of a mode of interaction.
We believe this is the first report on the pancreatic lipase inꢀ
hibitory activity of labdane dial and its semiꢀsynthetic triazole
appendages.
In a structureꢀactivity relationship point of view, we obꢀ
served that the labdaneꢀtriazole hybrids incorporating benzyl
azides (6a-l) were more active than the phenacyl azides (6m-
q). Most of the analogues synthesized from benzyl azides exꢀ
hibited excellent inhibition property slightly better than or
equal to that of Orlistat. In contrast, the triazole analogues
synthesized from phenacyl azides (6m-q) did not show any
significant inhibition potential except for the compound 6m.
In precise, among the triazoles incorporated from the variously
substituted benzyl azides, all the paraꢀsubstituted analogues
showed the lowest IC50. However, the unsubstituted (6a), orꢀ
thoꢀ and metaꢀsubstituted benzyl azide incorporated triazole
appendages showed moderate activity. Interestingly, there was
no clear trend followed by the nature of the para substitution,
i.e., among the halogen, electron donating and electron withꢀ
drawing groups. Overall, among the various substituted hyꢀ
brids 6b and 6f with pꢁF and pꢁCl substituted benzyl azide
incorporated triazole appendages were found to be the most
potent candidates of the series.
The molecular docking studies have also performed31 in the
present study to understand the basic knowledge on how these
compounds have blocked human pancreatic lipase activity.
There were twenty compounds docked on human pancreatic
lipase to understand their possible binding site with respect to
the binding energies of structure conformations of compounds
(Figure 4; Figure S, supporting information). The top
ranked stable structure conformations on protein have shown
least Gibb’s free binding energies. The docking results have
shown that all the triazole derivatives are able to interact with
lipase at possible predicted site with different binding energies
(Table S; supporting information). However, further experꢀ
imental studies (ie, site directed mutagenesis) are much needꢀ
ed to understand the precise mechanism of action of these
compounds. This data provided us a vital clue about the interꢀ
action sites, which helps in our future inꢀdepth studies towards
lipase inhibition.
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Isolates and synthetic derivatives are tested at concentrations 0.5ꢀ
15 µM. Each experiment was independently performed four times
in duplicates and expressed as means ± SD (n=4).
Figure 3. The percentage of isolates and synthetic derivatives
against Human pancreatic lipase in various concentrations.
Table 1. 50% inhibitory concentration (IC50) evaluation of
labdane appended triazoles.
IC50 (µM)a
Compound
Method A
14.63 ± 0.11
10.30 ± 2.71
8.64 ± 3.13
5.35 ± 1.20
0.75 ± 0.02
0.85 ± 0.03
0.80 ± 0.05
0.77 ± 0.01
0.91 ± 0.02
0.95 ± 0.02
0.84 ± 0.07
4.43 ± 1.02
10.36 ± 2.20
6.22 ± 2.04
0.80 ± 0.03
Method B
14.48 ± 0.51
11.75 ± 0.64
7.38 ± 0.77
9.15 ± 0.27
1.1 ± 0.53
1
2
3
6a
6b
6c
2.01± 0.73
1.65 ± 0.93
1.25 ± 0.78
2.28 ± 0.88
2.31± 0.62
1.87± 0.14
6.90 ± 0.73
13.48 ± 0.53
7.82 ± 0.48
0.19 ± 0.62
6e
6f
6g
6h
6j
6k
6l
6m
Orlistat
aThe IC50 values of PL inhibitory activity for selected compounds
and the positive control Orlistat. Values are mean ± SD of four
independent experiments performed in duplicates.
ꢀ semisynthetic intermediates 2 and 3, and labdane triazole
derivatives 6a, 6k, 6l and 6m showed moderate potency in the
range of IC50 5.35 ꢀ 14.63 ꢀM. However, against the Human
pancreatic lipase (Method B), labdane triazole appendages 6b
and 6f being the more potent analogues exhibited the inhibitoꢀ
ry activities with IC50 values 1.1 ± 0.53 ꢀM and 1.25 ± 0.78
ꢀM respectively. Compounds 6c, 6e, and 6g-j also showed
promising ability in inhibiting the PL with IC50 values in the
Figure 4. The representative Molecular docking studies of comꢀ
pound 6e.
Further, in vitro toxicity of isolated and semiꢀsynthetic deꢀ
rivatives is carried out to analyze the effect of compounds on
human liver cell lines. This method is primarily used to identiꢀ
fy potentially hazardous compounds and their toxic effect in
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Experimental details of synthesis, pancreatic lipase activity assay
the early stage of development of therapeutic drugs. The cytoꢀ
toxicity of compounds on Hep G2 human liver carcinomaꢀ
derived cell lines was measured by MTT assay.32 The cytotoxꢀ
ic effect of each compound was estimated by calculating the
percentage of cell viability in a doseꢀdependent manner rangꢀ
ing from 0.5 ꢀM to 100 ꢀM (Figure 5). Based on the percentꢀ
age of cell viability, compound 6a, 6c, 6f, 6g, 6h, 6j, 6k and
6q were found to be the least toxic on Hep G2 human liver
cell lines, and none of the compounds showed any signs of
toxicity at all the tested concentrations.
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3
4
5
6
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MTT assay, Molecular docking studies, characterization data and
copies of 1H, 13C NMR spectra of all the newly synthesized comꢀ
pounds (PDF).
AUTHOR INFORMATION
Corresponding Author
Sasidhar B. S.
Eꢁmail: drsasidharbs@niist.res.in
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Raghu K. Gopalan
Eꢁmail: raghukgopal@niist.res.in
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the DSTꢀScience & Engineering Research
Board (SERB), Government of India, New Delhi, India, (Grant
no.EEQ/2016/000089) is gratefully acknowledged. R.J and P.K.V
thank CSIR and UGC for research fellowships.
Cytotoxic effect of each compound is expressed as percentage of
cell viability in dose dependent manner. Values are mean ± SD of
four independent experiments performed in duplicates.
Figure 5. Cytotoxic study of isolates and selected semi synthetic
derivatives by MTT assay.
REFERENCES
(1) Barnes, A. Overweight versus Obese: Different Risk and Difꢀ
ferent Management. Tex Heart Inst. J. 2015, 42, 237ꢀ238.
(2) Donahue, R. P.; Abbott, R. D.; Bloom, E.; Reed, D. M.; Yano,
K. Central Obesity and Coronary Heart Disease in Men. The Lancet
1987, 11, 821ꢀ824.
(3) Fabbrini, E.; Sullivan, S.; Klein, S. Obesity and nonalcoholic
fatty liver disease: biochemical, metabolic, and clinical implications.
Hepatology. 2010, 51, 679ꢀ89.
(4) Golay, A.; Ybarra, J. Link between obesity and type 2 diabetes.
Best Pract. Res. Clin. Endocrinol. Metab. 2005, 19, 649ꢀ63.
(5) Obesity facts from:
http://www.who.int/mediacentre/factsheets/fs311/en/index.html.
(6) Fu, C.; Jiang, Y.; Guo, J.; Su, Z. Natural Products with Antiꢀ
obesity Effects and Different Mechanisms of Action. J. Agric. Food
Chem. 2016, 64, 9571−9585.
(7) Cosentino, G.; Conrad, A. O.; Uwaifo, G. I. Phentermine and
topiramate for the management of obesity: a review. Drug Des. Devel.
Ther. 2013, 7, 267–278.
(8) Wang, T. Y.; Liu, M.; Portincasa, P.; Wang, D. Q. New inꢀ
sights into the molecular mechanism of intestinal fatty acid absorpꢀ
tion. Eur. J. Clin. Invest. 2013, 43, 1203ꢀ23.
(9) Sun, N. N.; Wu, T. Y.; Chau, C. F. Natural Dietary and Herbal
Products in AntiꢀObesity Treatment. Molecules 2016, 21, 1351.
(10) Fu, C.; Jiang, Y.; Guo, J.; Su, Z. Natural Products with Antiꢀ
obesity Effects and Different Mechanisms of Action. J. Agric. Food
Chem. 2016, 64, 9571−9585.
(11) Mopuri, R.; Meriga, B. AntiꢀLipase and AntiꢀObesity Acꢀ
tivities of Terminalia paniculata Bark in High Calorie DietꢀInduced
Obese Rats. Global J. Pharmacol. 2014, 8, 114ꢀ119.
In summary, a new series of natural product derived labꢀ
daneꢀtriazole hybrids were designed, synthesized and evaluatꢀ
ed for pancreatic lipase inhibitory potential. Among the semiꢀ
synthetic derivatives, 6b and 6f are most active candidates of
the series with excellent PL inhibitory activity slightly higher
than that of the positive control Orlistat. Hybrids 6c, 6e, and
6g-j inhibited the PL comparable to that of positive control.
The structureꢀactivity relationship studies suggested that the pꢁ
substitution on benzyl azides seems to be vital for improved
PL inhibition. Cytotoxicity of the compounds on Hep G2 huꢀ
man liver carcinomaꢀderived cell line was measured by MTT
assay. Based on the percentage of cell viability, none of the
compounds showed any signs of toxicity at all the tested conꢀ
centrations. This is the first report on the PL inhibitory activity
of labdane dial and its semi synthetic triazole appendages. Our
findings will provide useful insights for the design and syntheꢀ
sis of novel PL inhibitors. Presently, a detailed study to eluciꢀ
date the molecular mechanistic action of an antiꢀobesity effect
of the compounds 6b and 6f by using in vitro and in vivo exꢀ
perimental models and structural optimization are in progress
in our laboratory.
(12) Jiang, W.; Li, W.; Han, L.; Liu, L.; Zhang, Q.; Zhang, S.;
Nikaido, T.; Koike, K. Biologically Active Triterpenoid Saponins
from Acantho panaxsenticosus. J. Nat. Prod. 2006, 69, 1577ꢀ1581.
(13) Cai, S.; Wang, O.; Wang, M.; He, J.; wang, Y.; Z hang, D.;
Zhou, F.; Ji, B. In Vitro Inhibitory Effect on Pancreatic Lipase Activiꢀ
ty of Sub fractions from Ethanol Extracts of Fermented Oats (Avena
sativa L.) and Synergistic Effect of Three Phenolic Acids. J. Agric.
Food Chem. 2012, 60, 7245−7251.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
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(14) Sugiyama, H.; Akazome, Y.; Shoji, T.; Yamaguchi, A.;
zino[1,2,3] triazolyl[4,5ꢀc]quinolinone derivatives and their antiꢀ
cancer activity. RSC Adv. 2016, 6, 74332.
Yause, M.; Kanda, T.; Ohtake, Y. Oligomeric Procyanidinsin Apple
Polyphenol Are Main Active Components for Inhibition of Pancreatic
Lipase and Triglyceride Absorption. J. Agric. Food Chem. 2007, 55,
4604ꢀ4609.
(15) Nakai, M.; Fukui, Y.; Asami, S.; ToyodaꢀOno, Y.; Iwashita,
T.; Shibata H.; Mitsunaga, T.; Hashimoto, F.; Kiso, Y. Inhibitory
Effects of Oolong Tea Polyphenols on Pancreatic Lipase in Vitro. J.
Agric. Food Chem. 2005, 53, 4593ꢀ4598.
(16) Jatoi, S. A.; Kikuchi, A.; Gilani, S. A.; Watanabe, K. N.
Phytochemical, Pharmacological and Ethnobotanical Studies in Manꢀ
go Ginger. Phytother. Res. 2007, 21, 507–516.
(17) Behera, K. K.Ethnomedicinal Plants used by the Tribals of
Similipal Bioꢀreserve, Orissa, India: A Pilot Study. Ethnobotanical
Leaflets 2006, 10, 149ꢀ173.
1
2
3
4
5
6
7
8
(24) Tantray, M. A.; Khan, I.; Hamid, H.; Alam, M. S.; Umar, S.;
Ali, Y.; Sharma, K.; Hussain, F. Synthesis of Novel Oxazolo[4,5ꢀ
b]pyridineꢀ2ꢀone based 1,2,3ꢀtriazoles as Glycogen Synthase Kinaseꢀ
3b Inhibitors with Antiꢀinflammatory Potential. Chem. Biol. Drug.
Des. 2016, 87, 918–926.
(25) Kharb, R.; Sharma, P. C.; Yar, M. S. Pharmacological sigꢀ
nificance of triazole scaffold. J. Enzyme Inhib. Med. Chem. 2011, 26,
1–21.
(26) Kinfe, H. H.; Belay, Y. H.; Joseph, J. S.; Mukwevhs, E.
Evaluation of the Influence of thiosemicarbazone–triazole hybrids on
genes implicated in lipid oxidation and accumulation as potential antiꢀ
obesity agents. Bioorg. Med. Chem. Lett. 2013, 23, 5275–5278.
(27) Sharma, M. K.; Machhi, J.; Murumkar, P.; Yadav, M. R.
New role of phenothiazine derivatives as peripherally acting CB1
receptor antagonizing antiꢀobesity agents. Sci. Rep. 2018, 8, 1650.
(28) Sheeja, A. D. B.; Nair, M. S. Facile isolation of Eꢀlabda
8(17), 12ꢀdieneꢀ15, 16ꢀdial from curcuma amada and its conversion to
9
10
11
12
13
14
15
16
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25
26
27
28
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35
36
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39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(18) Ramachandran, C.; Quirin, K. W.; Escalon, E. A.; Lollett, I.
V.; Melnick, S. J. Therapeutic Effect of Supercritical CO2 Extracts of
Curcuma Species with Cancer Drugs in Rhabdomyosarcoma Cell
Lines. Phytother. Res. 2015, 29, 1152–1160.
(19) Singh, S.; Kumar, J. K.; Saikia, D.; Shanker, K.; Thakur, J.
P.; Negi, A. S.; Banerjee, S.A bioactive labdane diterpenoid from
Curcuma amada and its semiꢀsynthetic analogues as antitubercular
agents. Eur. J. Med. Chem. 2010, 45, 4379ꢀ4382.
(20) Shilpa, G.; Renjitha, J.; Saranga, R.; Sajin, K. F.; Nair, M.
S.; Joy, B.; Sasidhar, B. S.; Priya, S. Epoxyazadiradione Purified from
the Azadirachta indica Seed Induced Mitochondrial Apoptosis and
Inhibition of NFκB Nuclear Translocation in Human Cervical Cancer
Cells. Phytother. Res. 2017, 31, 1892–1902.
(21) Kumar, V. P.; Renjitha, J.; Salfeena, C. T. F.; Ashitha, K. T.;
Keri, R. S.; Varughese, S.; Sasidhar, B.S. Antibacterial and anꢀ
titubercular evaluation of dihydronaphthalenoneꢀindole hybrid anaꢀ
logs. Chem. Biol. Drug Des. 2017, 90, 703–708.
(22) Ashitha, K. T.; Kumar, V. P.; Salfeena, C. T. F.; Sasidhar, B.
S. BF3·OEt2ꢀMediated Tandem Annulation: A Strategy To Construct
Functionalized Chromenoꢀ and PyranoꢀFused Pyridines. J. Org.
Chem. 2018, 83, 113ꢀ124.
other biologically active compounds.
2014, 53, 319ꢀ324.
Indian. J. Chem. Sect. B.
(29) Bustanji, Y.; Issa, A.; Mohammad, M.; Hudaib, M.; Tawah,
K. Inhibition of hormone sensitive lipase and pancreatic lipase by
Rosmarinus officinalis extract and selected phenolic constituents. J.
Med. Plants Res. 2010, 4, 2235ꢀ2242.
(30) Kido, Y.; Hiramoto, S; Murao, M.; Horio, Y; Miyazaki, T;
Kodama, T.; Nakabou, Y. Epsilonꢀpolylysine inhibits pancreatic liꢀ
pase activity and suppresses postprandial hypertriacylglyceridemia in
rats. J. Nutr. 2003, 133, 1887ꢀ91.
(31) Morris, G. M.; Goodsell, D. S.; Halliday, R.S.; Huey, R.;
Hart, W. E.; Belew, R. K.; Olson, A. J. Automated Docking Using a
Lamarckian Genetic Algorithm and and Empirical Binding Free Enꢀ
ergy Function. J. Computational Chemistry, 1998, 19, 1639ꢀ1662.
(32) Wilson, A. P. Cytotoxicity and viability assay, in Animal
cell culture: A practical approach, 2nd edition, ed. Masters JRW, Oxꢀ
ford University Press, Oxford, 2000, 175ꢀ219.
(23) Narasimha, S.; Battula, K. S.; Nukala, S. K.;Gondru, R.;
Reddy, Y. N.; Nagavelli, V. R. Oneꢀpot synthesis of fused benzoxaꢀ
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Figure 1. Rationale for the synthesis of labdane appended triazoles
272x103mm (300 x 300 DPI)
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