Received: 5 April 2021 Revised: 7 June 2021 Accepted: 17 June 2021

DOI: 10.1002/jhet.4331

ARTICLE

Synthesis and bioactivity evaluation of eugenol

hybrids obtained by Mannich and 1,3 dipolar
cycloaddition reactions

Komuraiah Buduma1 | Niranjana Kumar A1 | Satya Srinivas KVN1 |

Kotesh Kumar J1 | Srinivas Chinde2 | Anand Kumar Domatti3 |
Yogesh Kumar4 | Paramjit Grover2 | Ashok Tiwari2 | Feroz Khan4

1
Natural Product Chemistry Division,
CSIR-Central Institute of Medicinal and
Abstract
Aromatic Plants, Research Centre, Design, synthesis, and bioactivity evaluation of novel mannich bases (2a-2j)
Hyderabad, India and triazole-chalcone derivatives (7a-7k) of Eugenol 1 were reported. Among
2
Toxicology Unit, Biology Division,
all the derivatives tested for antiproliferative activity, di-amine manich deriva-
CSIR-Indian Institute of Chemical
Technology, Hyderabad, India tive 2b (32.92 μM), and 4-methoxy chalcone triazole derivative 7d (33.05 μM)
3
Medicinal Chemistry and Pharmacology significantly inhibited HepG2 cell lines when compared to the standard doxo-
Division, CSIR-Indian Institute of rubicin (37.29 μM). Whereas most of the compounds such as diethylamine 2a
Chemical Technology, Hyderabad, India
4
(17.75 μM), (aminomethyl) methane diamine 2b (17.02 μM), and bis
Metabolic and Structural Biology
Department, CSIR-Central Institute of (chloromethyl) amine 2c (20.12 μM) showed moderate to better inhibition
Medicinal and Aromatic Plants, Lucknow, towards MCF-7 cell lines. The synthesized analogues were also tested for anti-
India
diabetic and antiobesity potentials. Compounds 2f (55.50%), 2c (54.34%), 7g
Correspondence (55.5%), and 2a (55.5%) have shown moderate inhibitory potentials toward
K. V. N. Satya Srinivas, Natural Product intestinal α-glucosidase enzyme when compared to the standard Acarbose
Chemistry Division, CSIR-Central
Institute of Medicinal and Aromatic
(72.86%). Likewise, compounds 7d (82.95%), 7f (76.19%), 7g (74.81%), 7e
Plants, Research Centre, Boduppal, (74.81%), and 2g (72.50%) have shown significant to moderate inhibitory
Hyderabad-500 092, India. potentials toward Pancreatic lipase enzyme when compared to the standard
Email: kvn.satyasrinivas@cimap.res.in
orlistat (91.10%). ROS induces life-threatening diseases like diabetes, cancer,
J. Kotesh Kumar, Natural Product
Chemistry Division, CSIR-Central
etc., and antioxidants play a major role in controlling their production. Com-
Institute of Medicinal and Aromatic pounds 2c (99.81%), 2i (99.80%), 2d (99.26%), 2g (98.79%), and 2f (98.42%) have
Plants, Research Centre, Boduppal, shown significant antioxidant profiles in ABTS assay when compared to the
Hyderabad-500 092, India.
Email: koteshkumarj@yahoo.com standard Trolox (99.07%). Further, In silico Molecular docking and pharmaco-
kinetic screening of the eugenol derivatives complemented the in vitro results
indicating the drug likeness of the obtained active compounds.

KEYWORDS
bioactivity screening, eugenol, Mannich bases, molecular docking, triazolechalcones

1 | INTRODUCTION

Komuraiah Buduma and A. Niranjana Kumar have equal contribution The discovery, development, and application of natural
and considered as first authors. drugs have been done for thousands of years. A recent

J Heterocyclic Chem. 2021;1–12. wileyonlinelibrary.com/journal/jhet © 2021 Wiley Periodicals LLC. 1

2 BUDUMA ET AL.
review by Newman and Cragg shown that 74.8% of small
molecules used for cancer are from nonsynthetic origin [1].
While semi-synthetic modification of naturally occurring bio-
active phytochemicals leads to the generation of most suc-
cessful anticancer drugs such as paclitaxel I from 10-
deacetylbaccatin, etoposide II from podophyllotoxin,
irinotecan/topotecan from camptothecin and many more [2].
Natural products proved to be an inexhaustible resource of
novel and effective anticancer agents and remain
unchallenged by other alternative drug discovery approaches
[3]. Due to the unique and vast chemical diversity, natural
products are recognized as privileged scaffolds because they
interact with biological macromolecules, especially proteins
[4,5]. Eugenol or 4-allyl-2-methoxyphenol, majorly found in
the essential oil of Ocimum Species, used as raw material in
the manufacture of several drugs has attracted attention due
to its wide range of biological activities [6] such as hypoten-
sive [7], antioxidant [8,9], antitumoral [10], etc. As an essen-
tial oil and antimicrobial agent, Eugenol has wider
applications in fragrance and flavoring industry cosmetic and
food industry [11,12]. Furthermore, many recent studies have
explored the anticancer potential of eugenol and its ability to
induce apoptosis in diverse cancer cell lines as well as in
in vivo tumor models [13,14].
1,2,3-Triazole and its derivatives enhanced consider-
able attention for the past few decades due to their
chemotherapeutical value. Many 1,2,3-triazoles are found
to be more potent antimicrobial [15], antiinflammatory
[16], antimalarial [17], anti-HIV [18], and anticancer
activities [19]. Some of the 1,2,3-triazoles were used as
DNA cleaving agents [20] and potassium channel activa-
tors [21,22]. These moieties have been widely used in the
synthetic intermediates and industrial applications, such
as dyes, anticorrosive agents, photo stabilizers, photo-
graphic materials, and agrochemicals [23]. For example,
carboxyamidotriazole III is shown as an angiogenesis
inhibitor in cancer therapy [24], rufinamide IV exhibits
anticonvulsant activity and has been used to treat child-
hood mental impairment of the Lennox-syndrome [25].
Mannich reaction is the most fundamental way to
introduce the C─C bond formation in organic synthesis
[26]. Mannich base is a three-component condensation
product of active hydrogen-containing compound, alde-
hyde, and a secondary amine. The formation of mannich
base depends on the nucleophilicity of substrate and pH
of the reaction medium [27]. The Mannich bases are
interested pharmacologically because of their antimicro-
bial [28], antimalarial [29], anti-HIV [30], antitubercular
[31], anticancer V and VI [32], antiinflammatory [33],
and antioxidant properties [34]. Few important com-
pounds, belonging to the above said pharmacophore cate-
gories, which gained attention in drug discovery are
shown in Figure 1.
The aim of this research was to develop novel library
of compounds such as manich and triazole chalcone
derivatives from Eugenol to get biologically active Euge-
nol hybrids.
2 | RESULTS A ND DISCUSSION
2.1 | Chemistry
2.1.1 | Synthesis of Manich bases
Aminoalkyl derivative of Eugenol 1 was synthesized by
Mannich reaction via condensation of substituted second-
ary amine in the presence of formaldehyde to obtain com-
pounds (2a–2j) (Scheme 1). The bases were characterized
by spectroscopy. The sharp bands in IR at 3280 and
3350 cm
1 indicated the presence of N─H group, 3050
and 3034 cm
1 for C─H, 2925, and 2923 cm
1for O─H
functional groups.1H NMR spectral data of all the deriva-
tives (2a–2j) showed characteristic signal between δ 3.57
and 3.68 ppm and in 13C NMR, a new signal appeared
between δ55.39 and 58.71 ppm due to the presence of
methelene (CH2), which confirm insertion of aminoalkyl
moiety in 1.
2.1.2 | Synthesis of triazole chalcones
In the second series, the triazole chalcones were synthe-
sized by selective O-propargylation at the hydroxyl group
of 1 to get the intermediate 3 which were further coupled
with different substituted azides by employing facile 1,3
dipolar cycloaddition [35,36] to get distinct derivatives of
1,2,3-triazol-4-yl-eugenol (7a–7k) (Scheme 2).
The 1H NMR signals appeared at δ 5.35–5.39 ppm
confirmed the condensation of propargyl bromide. The
signal at δ 63.34–63.38 ppm attributed to carbon of
the active methylene inserted after O-propargylation of 1.
1
H NMR of all the triazole chalcone derivatives (7a–7k)
has shown a characteristic singlet for triazole proton in
the range δ8.16–8.19 ppm. In addition to that, 13C NMR
spectra exhibited characteristic signals for triazole ring
carbon at δ119.8–121.6 ppm and 144.2–145.8 ppm,
respectively.1H NMR of all the triazole chalcone deriva-
tives (7a–7k) has shown a characteristic signal for
chalcone protons in the range δ7.60–7.91 ppm and 8.10–
8.26 ppm. In addition to that, 13C NMR spectra exhibited
characteristic signals for chalcone carbons at δ119.8–
121.6 ppm and 143.8–146.2 ppm, respectively. In addition
to these, 13C NMR spectra exhibit characteristic signals
for carbonyl group of chalcone at δ189.20–196.2 ppm
clearly indicates the formation of triazole chalcone
BUDUMA ET AL. 3

OAC O O
O O H
HO
NH OH
H
O O
HO O
H H O
HO O HO O
H O Cl O
O NH2
OAC O H2N
O
N N
O O OH Cl Cl N
O O
I II III

OH
F
O
N N
N
N N NH2 N OH
F OH
OH
OH
IV V VI

FIGURE 1 Structures of some biologically active derivatives

S C H E M E 1 Synthesis of Mannich OH
OH
derivatives (2a–2j) [Reagents and O
i O
conditions: Formaldehyde, derivatives of R
secondary amine, dry methanol, RT, 2–4 h]

1 2a-2j

Where R =

N N N
N N Cl OH
NH2
OH NH
NH2 Cl
2a 2c 2d 2e
2b

N N N N
N
N N O
COOH
O
2f HO 2g 2h 2i 2j

analogs. The synthetic yields, melting points, molecular evaluated in in vitro mode using 3-(4,5-dimethylthiazol-
weights, and NMR spectra of all the compounds are 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay [37]
described in the experimental section. on the selected human cancer cell lines A-549 (lung ade-
nocarcinoma), Hep-G2 (hematoma), MCF-7 (breast ade-
nocarcinoma), and SKOV3 (ovarian carcinoma). The
2.2 | Pharmocology assay was dependent on the reduction of tetrazolium salt
by the mitochondrial dehydrogenase of viable cells to
2.2.1 | Antiproliferative activity form a blue formazan product dissolved in DMSO and
measured at 570 nm. The results of cytotoxic activity
Antiproliferative activity of the synthesized mannich were expressed as the IC50 (μM), and doxorubicin was
bases and chalcone-triazole derivatives of Eugenol was used as positive control (Table 1). Compounds di-amine
4 BUDUMA ET AL.

Step-I Propargylation S C H E M E 2 Synthesis of Triazole

chalcone derivatives (7a–7k). [Reagents
O O and conditions: i. K2CO3, DMF, RT
OH i O 30 min, ii. a. ii) H2O:HCl (1:1), 0 C,
aq. NaNO2, aq. NaN3, 2 h (5a–5k).ii. b.
R-CHO, EtOH, KOH, RT 1 h, iii. CuI,
THF, RT, 12 h]
1 3

Step-II Chalcone formation

NH2 N3 N3
ii ii
a
b

O O O

R
4
5a-5k 6a-6k
Step-III Triazole formation

O N3 O N N
O O N
iii O

O R
7a-7k
3 6a-6k R

Where R=

F O Cl Cl
7a 7b 7c 7d 7e Cl 7f

O S
O
O 2N
O
7g 7i 7j 7k
7h

manich derivative 2b (32.92 μM) and 4-methoxy chalcone
triazole derivative 7d (33.05 μM) have significantly inhibited
HepG2 cell lines when compared to the standard doxorubi-
cin (37.29 μM). Compound 2b (16.43 μM) was moderately
active against A549 cell lines when compared to the stan-
dard doxorubicin (7.22 μM).While 2b (19.06 μM) and 2a
(21.78 μM) were moderately active against KVO3 cell lines
when compared to the doxorubicin (11.34 μM). Among the
four cell lines, the majority of derivatives showed inhibitory
property toward MCF-7 cell line.
2.2.2 | Antilipase activity
Synthesized eugenol derivatives were evaluated for inhibi-
tory potentials of pancreatic lipase enzyme in in vitro mode
as per the previous reports [40,41]. Lipase, from porcine
pancreas Type II (Sigma product L3126), was dissolved in
ultrapure water at 10 mg/ml and then the supernatant was
used after centrifugation at 16,000 rpm for 5 min. The assay
buffer consisting of 100 mM Tris buffer (pH 8.2) and
p-nitrophenyl laurate (pNP laurate) was used as the sub-
strate. The substrate stock 0.08% w/v pNP laurate was dis-
solved in 5 mM sodium acetate (pH 5.0) containing 1%
Triton X-100 and was heated in boiling water for 1 min to
aid dissolution, mixed well, and then cooled to room tem-
perature. The control assay contained 400 μl assay buffer,
450 μl substrate solution, and 150 μl lipase. The synthesized
compounds were dissolved in DMSO (1 mg/ml) and added
in 50 μl total volume. The buffer, enzyme, and compounds
were added and then substrate was added to start the reac-
tion. The samples were incubated at 37 C for 2 h. Then
samples were centrifuged at 16,000 rpm for 2.5 min and
read at 400 nm in a UV spectrophotometer. An inhibitor
BUDUMA ET AL. 5

TABLE 1 Pharmacological activities of triazole chalcone derivatives (7a–7k)

Anticancer activity (IC50 in μM/ml) Antioxidant activity

DPPH % ABTS %
Inhibition at Inhibition at α-Glucosidase LIPASE %
25 μg/ml (SC50 10 μg/ml Inhibition (%) Inhibition at
Compound A549 HepG2 MCF-7 SKOV3 μg /m l) (SC50 μg/ml) at 20 μg/ml 50 μg/ml
2a > 100 77.72 17.75 21.78 1.24 4.82 51.13 61.29
2b 16.43 32.92 17.02 19.06 54.07 NV 48.49 60.20
2c > 100 > 100 20.12 > 100 30.67 99.81 54.34 NV
2d > 100 > 100 22.15 > 100 46.42 99.26 34.66 45.93
2e > 100 > 100 23.64 > 100 42.10 98.79 42.83 NV
2f > 100 > 100 21.80 > 100 46.52 98.42 55.50 69.12
2g > 100 > 100 33.38 > 100 64.15 98.79 41.35 72.50
2h > 100 77.70 28.60 > 100 54.18 NV 14.41 NV
2i > 100 > 100 36.60 > 100 24.69 99.80 38.59 29.80
2j > 100 > 100 24.98 > 100 60.34 NV 42.77 NV
7a > 100 > 100 33.87 > 100 38.28 NV NV NV
7b > 100 > 100 42.06 > 100 00.86 09.83 26.82 41.01
7c > 100 > 100 32.36 > 100 04.47 05.01 15.37 55.91
7d > 100 33.05 32.77 > 100 05.18 05.38 17.23 82.95
7e > 100 > 100 37.40 > 100 09.54 04.73 32.15 74.81
7f > 100 > 100 31.59 > 100 03.99 04.17 20.77 76.19
7g > 100 > 100 30.34 > 100 15.42 05.75 54.86 74.81
7h > 100 > 100 20.07 > 100 NV 08.07 37.62 NV
7i > 100 > 100 24.00 > 100 08.73 12.80 23.73 43.78
7j > 100 > 100 20.08 > 100 29.87 07.05 07.27 NV
7k > 100 > 100 28.87 > 100 20.75 10.85 NV 14.90
Doxo 07.22 37.29 02.96 11.34 — — — —
Ascorbic Acid — — — — 86.52 — — —
Trolox — — — — — 99.07 — —
Acarbose — — — — — 72.86
Orlistst — — — — — — — 91.1

The bold values are relatively showing significant activities.

blank was prepared for each sample and all were assayed in
triplicate. According to the results given in Table 1, com-
pound 7d (82.95%) inhibited the enzyme more potentially,
whereas compounds 7f (76.19%), 7e (74.81%), 7g (74.81%),
and 2g (72.50%) inhibited moderately when compared to
the standard orlistat (91.10%).
2.2.3 | Anti α-glucosidase activity
The inhibitory potentials of the synthesized compounds
against intestinal α-glucosidase enzyme were determined
as per the reported methods [42,43]. Rat intestinal ace-
tone powder in normal saline (100:1; w/v) was sonicated
properly, and the supernatant was used as a source of
crude intestinal α-glucosidase after centrifugation. In
brief, 10 ml of test samples (5 mg/ml DMSO solution)
were reconstituted in 100 ml of 100 mM phosphate buffer
(pH 6.8) in 96-well microplate and incubated with 50 ml
yeast α-glucosidase (0.76 U/ml in same buffer) or crude
intestinal α-glucosidase for 5 min before 50 ml substrate
(5 μM, p-nitrophenyl-α-D-glucopyranoside prepared in
same buffer) was added. Release of p-nitrophenol was
measured at 405 nm spectrophotometrically 5 min after
incubation with substrate. Individual blanks for test sam-
ples were prepared to correct background absorbance
where substrate was replaced with 50 ml of buffer. Con-
trol sample contained 10 ml DMSO in place of test
6 BUDUMA ET AL.
samples. Acarbose was taken as standard reference for
α-glucosidase inhibition. All the samples were assayed in
triplicate. As shown in Table 1, among all the synthesized
derivatives, compound 2f (55.50%) exhibited better inhib-
itory activity, whereas compounds 2c (54.34%), 7g
(54.86%), 2a (51.13%) showed moderate inhibition when
compared to the standard drug Acarbose (72.86%).
2.2.4 | Antioxidant activity
The antioxidant and free radical scavenging activity of the
Mannich bases and chalcone triazoles were measured by
using DPPH and ABTS assays. The 2,2-diphenyl-
1-picrylhydrazyl (DPPH) is a stable free radical, which is
widely used for estimating free radical scavenging activities
of antioxidants. DPPH-based free radical scavenging activ-
ity usually involves hydrogen atom transfer reaction [38].
The reducing power of Mannich bases was determined by
using the standard method [39]. For the above studies,
ascorbic acid was used as reference material. Antioxidant
activity of all the compounds was measured by using ABTS
assay. As per the Table 1, compounds 2c (99.81%), 2i
(99.80%), 2d (99.26%), 2g (98.79%), and 2f (98.42%) have
shown potential antioxidant activity when compared to the
standard Trolox (99.07). Whereas DPPH assay showed that
2g (64.15%), 2j (60.34%) were moderately active when com-
pared to the standard ascorbic acid (86.52%).
2.3 | In silico molecular docking
The molecular docking and visualization studies of eugenol
derivatives were performed through FlexX [44] docking pro-
gram available in Lead IT 2.1.8 version of (Bio Solve IT Ger-
many). FlexX is a fast algorithm for flexible docking of small
ligands into the active protein-binding site using an incremen-
tal construction process. During docking standard parameters
were kept in the FlexX program as implemented in Lead IT
v2.1.8. Chemical structure designing, energy minimization,
and geometry cleaning were done through Chem Draw [45]
and Chem 3D 15.0.0.16 version (Perkin Elmer Informatics).
The protein 3D crystallographic structures for docking were
retrieved through RCSB Protein Data Bank (PDB) (www.
rcsb.org/). To find the possible bioactive conformations of
eugenol derivative compounds, these softwares were used.
2.3.1 | In silico molecular docking study for
cancer targets
Eugenol derivatives synthesized in the above study were
evaluated for their docking/binding efficiency in in silico
mode on different anticancer targets of selected human
cancer cell lines, that is, lung cancer cell line (A549) tar-
get histone deacetylase (PDB: 1C3S) [46], liver cancer cell
line (HepG2) target DNA topoisomerase II (PDB: 1ZXM)
[47], ovarian cancer cell line (SKOV3) target STAT3
(Signal Transducer and Activator of Transcription) (PDB:
3CWG) [48], and breast cancer cell line (MCF7) target
Beta Tubulin (PDB: 1SAO) [49]. Out of all the tested
derivatives, compounds 2b, 2a, 7d, 7h, 7i, 7j, 2h, 2j, 2c,
2d, 2e, 2g, 2i, 7g, 7e, and 7f have shown higher docking/
binding energy for the mentioned targets of given cell
lines when compared to the reported binding affinity of
standard anticancer drug Doxorubicin [50]. According to
the results given in Table S1, the compound 2b showed
the higher docking/binding energy (
15.8365 kJ/mol)
against target 1C3S of A549 cell line. Compounds 2b and
7d showed significant docking/binding energy (
22.8615
and
22.6069 kJ/mol) against target 1ZXM of HEPG2
cell line. Compounds 2a (
11.5349 kJ/mol), 2b
(
27.2327 kJ/mol), 7h (
27.4181 kJ/mol), 7i (
18.5166
kJ/mol), and 7j (
18.4119 kJ/mol) showed higher dock-
ing/binding energy, respectively, on docking with targe
1SAO of MCF7 cell line. Similarly, compounds 2b-
(23.9803 kJ/mol) and 2a (
14.4954 kJ/mol) showed
higher docking/binding energy on docking with targe
3CWG of SKVO3 cell line, respectively, and formed
hydrogen bonds with the interacting residues within the
radius of 4 Å. All the above results complement the
reported in vitro results and are also comparable with the
docking/binding energy of Doxorubicin with respective
targets of A549 (
26.0596 kJ/mol), HepG2 (
27.7295
kJ/mol), MCF7 (
32.5618 kJ/mol), and SKOV3
(
30.0418 kJ/mol) cell lines, respectively. The docking
pose of all the compounds showed significant interaction
within the active site of respective targets. Moreover,
potential hydrophobic contacts were found at the active
site of receptor (Tables S1 and S3).
2.3.2 | In silico molecular docking studies for
antidiabetic and antilipase targets
The synthesized Eugenol derivatives were tested for anti-
diabetic activity by docking with target human intestinal
maltase-glucoamylase (PDB: 2QMJ), for pancreatic anti-
lipase activity by docking with target colipase (PDB:
1LPB) and for antioxidant activity by docking with target
hematopoietic cell kinase Hck (PDB: 2HCK), respectively.
The compounds 2a, 2c, 2g, and 7g which were experimen-
tally validated as α-glucosidase inhibitors have docked in
the active pocket of 2QMJ and showed the higher binding
energy of
12.4824,
13.5502,
24.997, and
27.8332
kJ/mol, respectively, and formation of hydrogen bonds.
BUDUMA ET AL.
The standard Acarbose showed comparable docking/bind-
ing energy of
28.3427 kJ/mol (Tables S2 and S3).
Similarly docking studies for human pancreatic lipase
colipase (PDB: 1LPB) with compounds 2h (
18.2392
kJ/mol), 7d (
23.4847 kJ/mol), 7e (
23.214 kJ/mol), 7f
(
25.5355 kJ/mol), and 7g (
25.4344 kJ/mol) have
shown higher docking/binding energy and, respectively,
as compared to the control drug Orlistat (
6.3146
kJ/mol). This study showed that all the studied com-
pounds were showing almost similar binding affinity
with the targeted proteins.
2.3.3 | In silico pharmacokinetic parameters
screening
The pharmacokinetics (PK) is important to determine
the fate of substances administered externally to living
organism. PK is composed of important parameters as
ADMET (Absorption, Distribution, Metabolism, Excre-
tion, and Toxicity). All these parameters will determine
the levels and kinetics of the drug exposed to the tissue
to influence the performance and pharmacological
action.Pharmacokinetic screening of eugenol deriva-
tives 2b, 2a, 7d, 7h, 7i, 7j, 2h, 2j, 2c, 2d, 2e, 2g, 2i, 7g,
7e, and 7f with controls Orlistat, Acarbose, Trolox,
Ascorbic Acid, and Doxorubicin was performed by Dis-
covery Studio v3.5 software (Accelrys), ADMET mod-
ule. Mathematical predictive ADMET QSAR models
were used for PK parameters such as aqueous solubil-
ity, blood–brain barrier (BBB) penetration, cytochrome
P4502D6 inhibition, hepatotoxicity, human intestinal
absorption, and plasma protein binding. The studied
compounds were also evaluated against the Lipinski's
rule of five [51]. The toxicity that is often used in drug
development, was calculated for all designed com-
pounds by DS_TOPKAT module of Discovery Studio
3.5 software (Accelrys). Results showed that all the
compounds including standard drugs except Trolox, 2e,
2g, 2h, 2i, 2d, 2a, 2b, 2c, and ascorbic acid violated the
Lipinski rule of five, therefore seems to be low oral bio-
available (Table S4). Evaluation through standard
ADMET parameters showed that most of the studied
compounds have very low aqueous solubility level and
BBB penetration level similar to standard drugs. Most
of the compounds showed noninhibitor activity toward
Cytochrome (CYP-2D6), which is an important enzyme
of drug metabolism. Most of the compounds showed
non hepatotoxicity (liver toxicity) except 7h, 7i, 7e, 2d,
2a, 2c, Doxorubicin, and Trolox, respectively. Plasma
protein binding (PPB) was high for most of the com-
pounds thus seems to be easily distributed in the body.
All the studied compounds were predicted as
7
nonmutagenic except standard orlistat which is
predicted as mutagenic. Drug likeness evaluation was
done with the help of bi-plot between AlogP98 and
PSA_2D (polar surface area) (Table S6). The bi-plot
showed confidence ellipses of 95% and 99% for the BBB
penetration and human intestinal absorption models
(Figure S1). Most of the compounds were found inside
the plot, which represent good bioavailability and
permeability, whereas the compounds shown outside
having poor bioavailability and permeability. The toxic
effect of the studied compounds was calculated in com-
parison to the standard control drugs (Doxorubicin,
Orlistat, Ascorbic acid, Acarbose, and Trolox) (Table S5).
The computed toxicity results showed that all the com-
pounds were nonmutagenic, except Doxorubicin, most of
the compounds showed mild type of skin irritancy and
severe type of ocular irritancy.
3 | CONCLUSION
The synthesis of novel derivatives of Eugenol 1 was car-
ried out by two distinct reactions, that is, by Mannich
reaction via condensation of substituted secondary amine
in the presence of formaldehyde to yield 2a–2j and tri-
azole chalcones by selective O-propargylation at the
hydroxyl group of 1 afforded the intermediate 3 which
was further, coupled with different substituted chalcone
azides by employing facile click chemistry to get distinct
derivatives of 1,2,3-triazol-4-yl-eugenol (7a–7k).All the
synthesized compounds were screened for antip-
roliferative, antidiabetic, antilipase, and antioxidant
activity in in-vitro mode. Under antiproliferative activity,
compounds 2b and 7d were potent against HepG2 cancer
cell lines. α-Glucosidase inhibition results showed that
compounds 2f, 2c, 7g, and 2a were significant. Under
lipase inhibition activity compound 7d is potent. Three
compounds 2c, 2d, and 2i shown more potent in vitro
antioxidant activity than the standard Trolox. Further, in
silico molecular docking and pharmacokinetic screening
of the eugenol derivatives complemented the invitro
results indicating the drug likeliness of active
compounds.
4 | EXPERIMENTAL SECTION
4.1 | Chemistry
Melting points of all the compounds were recorded on
Casia-Siamia (VMP-AM) melting point apparatus and
uncorrected. IR spectra were recorded on a Perkin–
Elmer FT-IR 240-C spectrometer using KBr optics.
8 BUDUMA ET AL.
NMR spectra were recorded on Burker Avance
500 MHz in CDCl3 and DMSO-d6 using TMS as internal
standard. Electron impact (EI) and chemical ionization
mass spectra were recorded on a VG Micro mass model
7070H instrument. All the reactions were monitored on
silica gel percolated TLC plates of Merck and spots
were visualized with UV light. Silica gel (100–200
mesh) used for column chromatography was procured
from Merck.
4.2 | General procedure and spectral
data of synthesized compounds
4.2.1 | Synthetic procedures for amino alkyl
derivatives (2a–2j)
Compound 1 (1.0 equiv) was dissolved in anhydrous
methanol (5 ml) and added 37% formaldehyde solution
50 ml after stirring 30 min at room temperature added
1.4 equivalent distinct derivatives of secondary amines.
The reaction mixture was stirred at room temperature for
2–3 h. After reaction completion, the mixture was
quenched with water and extracted with ethyl acetate
three times. The solvent was evaporated in vacuum, and
the crude product was purified by column chromatogra-
phy using silica gel (100–200 mesh) as a stationary phase
to get pure products (2a–2j) with good yields.
3-allyl-2-([diethylamino]methyl)-6-methoxyphenol (2a)
Colorless crystal, yield: 92%, m.p.149–151 C, 1H NMR
(CDCl3, 500 MHz) δ (ppm): 1.16 (t, 6H), 2.47 (q, 4H), 3.29
(d, 2H), 3.51 (t, 4H), 3.57 (s, 2H), 3.70 (s, 3H), 4.94 (m,
2H), 5.85 (m, 1H), 6.53 (s, 1H), 6.66 (s, 1H). ESIMS (m/z)
250 (M+ 1) observed for C15H23NO2.
3-Allyl-2-((bis(aminomethyl)amino)methyl)-
6-methoxyphenol (2b)
Viscous liquid, yield: 84%, 1H NMR (CDCl3, 500 MHz) δ
(ppm): 3.33 (s, 2H), 3.53 (s, 2H), 3.68 (s, 3H), 3.80 (m,
4H), 4.98 (m, 2H), 5.90 (m, 1H), 6.48 (d, 1H), 6.62 (d, 1H).
13
C NMR (125 Hz, DMSO-d6) δ (ppm): 39.59, 55.90,
75.73, 110.64, 111.76, 112.00, 115.83, 119.24, 120.94,
122.05, 123.62, 138.22, 144.34, 147.80. ESIMS (m/z)
252 (M+ 1) observed for C13H21N3O2.
3-Allyl-2-((bis(chloromethyl)amino)methyl)-
6-methoxyphenol (2c)
Viscous liquid, yield: 90%, 1H NMR (CDCl3, 500 MHz) δ
(ppm): 3.29 (s, 2H), 3.63 (s, 2H), 3.69 (s, 3H), 4.24 (s, 4H),
4.97 (m, 2H), 5.83 (m, 1H), 6.46 (d, 1H), 6.62 (d, 1H), 9.67
(s, 1H). ESIMS (m/z) 290 (M+ 1) observed for
C13H17Cl2NO2.
([6-Allyl-2-hydroxy-3-methoxybenzyl]azanediyl)
dimethanol (2d)
Viscous liquid, yield: 87%, 1H NMR (CDCl3, 500 MHz) δ
(ppm): 3.34 (s, 2H), 3.64 (s, 2H), 3.65 (s, 3H), 4.77 (s, 4H),
4.91 (s, 2H),5.80 (m, 2H), 6.69 (m, 1H), 7.23 (d, 1H), 7.41
(d, 1H), 8.71 (s, 1H). 13C NMR (125 Hz, DMSO-d6) δ
(ppm): 39.82, 58.71, 63.07, 86.72, 112.02, 115.88, 121.14,
123.48, 130.22, 138.49, 145.17, 147.90. ESIMS (m/z)
254 (M+ 1) observed for C13H19NO4.
3-Allyl-6-methoxy-2-(piperazin-1-ylmethyl)phenol (2e)
White solid, yield: 93%, m.p.145–147 C, IR (KBr): 2930,
2831, 2788, 1740, 1639, 1597, 1493, 1457, 1411, 1352,
1242, 1151, 1088, 1003, 908, 830, 795, 704 cm
1; 1H NMR
(CDCl3, 500 MHz) δ (ppm): 1.24 (s, 1H), 2.85 (t, 4H), 3.24
(t, 4H), 3.34 (d, 2H), 3.58 (s, 2H), 3.72 (s, 3H), 5.02 (m,
2H), 5.92 (m, 1H), 6.48 (s, 1H), 6.65 (s, 1H). 13C NMR
(125 Hz, DMSO-d6) δ (ppm): 39.85, 53.21, 55.53, 60.16,
111.59, 115.32, 120.57, 121.99, 129.45, 138.14, 144.77,
147.21. ESIMS (m/z) 263 (M+ 1) observed for
C15H22N2O2.
6,60 -(Piperazine-1,4-diylbis[methylene])bis(5-allyl-
2-methoxyphenol) (2f )
Colorless crystal, yield: 89%, m.p.141–143 C, IR (KBr):
2948, 2820, 1749, 1597, 1494, 1459, 1408, 1343, 1236,
1150, 1085, 1003, 909, 851, 792, 702 cm
1; 13C NMR
(125 Hz, DMSO-d6) δ (ppm): 39.84, 52.18, 55.76, 58.64,
111.64, 115.61, 121.16, 122.24, 129.92, 138.29, 144.30,
147.43. ESIMS (m/z) 439 (M+ 1) observed for
C26H34N2O4.
3-Allyl-6-methoxy-2-([4-methylpiperazin-1-yl]methyl)
phenol (2g)
White solid, yield: 96%, m.p. 153–155 C, IR (KBr): 3012,
2951, 2835, 2804, 1740, 1599, 1496, 1455, 1358, 1285,
1222, 1150, 1087, 999, 817, 776, 706 cm
1; 1H NMR
(CDCl3, 500 MHz) δ (ppm): 2.09 (s, 3H), 2.51 (t, 4H), 3.73
(t, 4H), 3.29 (d, 2H), 3.60 (s, 2H), 3.77 (s, 3H), 4.79 (m,
2H), 5.04 (m, 1H), 5.92 (s, 1H), 6.66 (s, 1H). 13C NMR
(125 Hz, DMSO-d6) δ (ppm): 39.84, 49.56, 53.58, 55.77,
56.51, 110.31, 111.37, 115.30, 120.91, 123.30, 129.47,
138.13, 144.03, 147.39. ESIMS (m/z) 277 (M+ 1) observed
for C16H24N2O2.
3-Allyl-6-methoxy-2-(morpholinomethyl)phenol (2h)
Brown solid, yield: 90%, m.p.39–41 C, IR (KBr): 2961,
2822, 1740, 1596, 1493, 1457, 1399, 1234,1113, 1079,
990, 864, 796, 701 cm
1; 1H NMR (CDCl3, 500 MHz) δ
(ppm): 2.38 (t, 4H), 3.33 (d, 2H), 3.52 (t, 4H), 3.55 (s, 2H),
3.68 (s, 3H), 4.96 (m, 2H), 5.90 (m, 1H), 6.48 (s, 1H), 6.63
(s, 1H). 13C NMR (125 Hz, DMSO-d6) δ (ppm): 39.81,
52.86, 55.96, 59.28, 66.46, 111.85, 112.89, 115.73, 115.90,
BUDUMA ET AL.
120.99, 122.07, 130.46, 138.54, 144.34, 147.64. ESIMS (m/
z) 264 (M+ 1) observed for C15H21NO3.
1-(6-Allyl-2-hydroxy-3-methoxybenzyl)piperidine-
4-carboxylic acid (2i)
White solid, yield: 94%, m.p.145–147 C, IR (KBr): 3363
(br), 2963, 2933, 1739, 1568, 1501, 1437, 1393, 1342,
1291, 1243, 1090, 921, 864, 778, 699 cm
1; 1H NMR
(CDCl3, 500 MHz) δ (ppm): 2.55 (t, 4H), 2.88 (t, 4H),
3.26 (d, 2H), 3.63 (s, 2H), 3.77 (s, 3H), 5.06 (m, 2H),
5.93 (m, 1H), 6.49 (s, 1H), 6.66 (s, 1H), 8.28 (s, 1H). 13C
NMR (125 Hz, DMSO-d6) δ (ppm): 27.76, 40.01, 51.68,
55.39, 111.40, 115.05, 120.46, 129.43, 137.77, 144.60,
147.05, 175.56. ESIMS (m/z) 306 (M+ 1) observed for
C17H23NO4.
3-Allyl-2-((sec-butyl[pentan-2-yl]amino)methyl)-
6-methoxyphenol (2j)
White solid, yield: 93%, m.p.147–149 C, 1H NMR (CDCl3,
500 MHz) δ (ppm): 1.15–1.58 (m, Cyclohexane ring
hydrogens), 2.88 (t, 4H), 3.22 (d, 2H), 3.59 (s, 2H), 3.82 (s,
3H), 5.08 (m, 2H), 5.91 (m, 1H), 6.50 (s, 1H), 6.64 (s, 1H).
ESIMS (m/z) 358 (M+ 1) observed for C23H35NO2.
4.2.2 | Synthetic procedure for
propargylation (3)
Eugenol 1 (1.0 equiv) along with 1.5 mol of potassium
carbonate was taken in dimethyl formamide (DMF) in
clean rb flask and added propargyl bromide (1.5 equiv) to
this solution. Reaction mixture was stirred at RT for
30 min to afford crude propargyl derivative. This crude
compound was column chromatographed over silica gel
(100–200 mesh) and eluted with 10% ethyl acetate in n-
hexane to obtain pure compound 4-allyl-1-methoxy-
2-(prop-2-yn-1-yloxy)benzene 3.
4.2.3 | Synthetic procedures for 1-azido
derivatives (5a–5k)
Eleven aromatic ring substituted 1-azido derivatives
were synthesized by dissolving 4-amino aetophenone
in H2O:HCl (1:1) and stirred at 0–5 C for 30 min. The
aqueous NaNO2 was added drop wise to diazotize
amine hydrochloride. After stirring at 0–5 C, the solu-
tion was treated with aqueous NaN3 and further stirred
for 1 h. Finally, the reaction mixture was extracted
with EtOAc, dried over Na2SO4 and concentrated in
vacuo afforded eleven different substituted derivatives
of 1-azido compound (5a–5k in Scheme 2) in quantita-
tive yields.
9
4.2.4 | Procedure for the synthesis of azido-
chalcones (6a–6k)
To a solution of azido derivatives (5a–5k) in THF KOH
(1.4 equiv) was added and a solution of 3 (1 equiv) in
methanol (5 ml), and the mixture was stirred at RT for
1 h. After dilution with water (100 ml), the resulting solid
filtered off, washed with water, and recrystallized from
petroleum ether to get yellow needles 6a–6k.
4.2.5 | Synthesis of chalcones triazole
derivatives (7a–7k)
Intermediate 4-allyl-1-methoxy-2-(prop-2-yn-1-yloxy)ben-
zene 3 (1.0 equiv) was dissolved in dry THF (10 ml) and
catalytic amount of copper iodide was added. To this,
azido- chalcones (6a–6k) (1.0 equiv), in dry THF, were
added slowly while stirring at room temperature under
nitrogen atmosphere after 12 h after the monitoring of
the reaction the solvent was removed under reduced
pressure and the residue was diluted with distilled water
and extracted thrice with ethyl acetate. The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated to get the product. The crude product was
purified by column chromatography with ethyl acetate in
hexane.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-phenylprop-2-en-1-one (7a)
Yellow solid, yield: 94%, m.p. 90–92 C, IR (KBr): 3138,
3069, 3002, 2936, 2834, 1738, 1659, 1603, 1511, 1453,
1415, 1336, 1260, 1222, 1137, 1022, 986, 913, 834, 765,
694, 666 cm
1; 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.33
(d, 2H), 3.93 (s, 3H), 5.10 (m, 2H), 5.36 (s, 2H), 5.96 (m,
1H), 6.73 (d, 2H), 7.00 (d, 1H), 7.43 (m, 2H), 7.55 (m, 2H),
7.84 (m, 2H), 7.89 (m, 2H), 7.91 (m, 1H), 8.17 (s,
2H), 8.19 (s, 1H). 13C NMR (125 Hz, DMSO-d6) δ (ppm):
39.84, 55.89, 63.37, 112.41, 114.52, 115.78, 120.20, 120.60,
120.89, 121.44, 128.60, 129.06, 130.27, 130.27, 130.90,
134.16, 134.64, 137.43, 138.13, 139.79, 145.78, 145.81,
149.59, 188.95. ESI-MS (m/z) 452 (M+ 1) observed for
C28H25N3O3.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(4-fluorophenyl)prop-2-en-
1-one (7b)
Pale yellow solid, yield: 81%–83%, m.p. 109–111 C, IR
(KBr): 3135, 3072, 2934, 1740, 1659, 1600, 1510, 1463,
1415, 1331, 1223, 1138, 1023, 986, 912, 820, 784 cm
1; 1H
NMR (CDCl3, 300 MHz) δ (ppm): 3.33 (d, 2H), 3.93 (s,
3H), 5.10 (m, 2H), 5.36 (s, 2H), 5.97 (m, 1H), 6.74 (d, 2H),
7.00 (d, 1H), 7.44 (s, 1H), 7.48 (s, 1H), 7.67 (m, 2H), 7.83
10
(m, 2H), 7.91 (m, 2H), 8.16 (m, 2H), 8.18 (s, 1H). 13C
NMR (125 Hz, DMSO-d6) δ (ppm): 39.83, 55.89, 63.37,
112.40, 114.49, 115.81, 116.18, 116.36, 120.20, 120.59,
120.85, 121.11, 130.24, 130.50, 130.57, 130.90, 134.15,
137.46, 138.01, 139.85, 144.41, 145.82, 145.87, 149.58,
163.28, 188.69. ESI-MS (m/z) 470 (M+ 1) observed for
C28H24 FN3O3.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(p-tolyl)prop-2-en-1-one (7c)
Yellow solid, yield: 95%, m.p.135–137 C, IR (KBr):
3137, 3070, 3002, 2918, 1741, 1656, 1600, 1512, 1460,
1412, 1258, 1226, 1135, 1026, 988, 842, 810, 668 cm
1;
1
H NMR (CDCl3, 500 MHz) δ (ppm): 2.43 (s, 3H), 3.37
(d, 2H), 3.90 (s, 3H), 5.10 (m, 2H), 5.39 (s, 2H), 5.98
(m, 1H), 6.76 (d, 2H), 7.03 (d, 1H), 7.28 (s, 1H), 7.50
(m, 2H), 7.58 (m, 2H), 7.88 (m, 2H), 7.93 (m, 2H), 8.19
(s, 1H), 8.21 (s, 1H), 13C NMR (125 Hz, DMSO-d6) δ
(ppm): 21.59, 39.84, 55.90, 63.39, 112.41, 114.52,
115.79, 120.18, 120.44, 120.61, 120.88, 128.65, 129.82,
130.23, 131.93, 134.15, 137.46, 138.31, 141.55, 145.89,
145.88, 149.60, 189.04. ESI-MS (m/z) 466 (M+ 1)
observed for C29H27N3O3.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(4-methoxyphenyl)prop-2-en-
1-one (7d)
Yellow solid, yield: 96%, m.p.125–127 C, 1H NMR
(CDCl3, 300 MHz) δ (ppm): 3.37 (d, 2H), 3.77 (s, 3H),
3.88 (s, 3H), 5.10 (m, 2H), 5.36 (s, 2H), 5.96 (m, 1H), 6.75
(d, 2H), 7.00 (d, 1H), 7.51 (m, 2H), 7.62 (m, 2H), 7.88 (m,
2H), 7.90 (m, 2H), 8.11 (m, 1H), 8.17 (m, 1H), 8.18 (s,
1H), 13C NMR (125 Hz, DMSO-d6) δ (ppm): 40.11, 55.55,
55.74, 63.65, 112.68, 113.98, 114.51, 114.81, 116.07,
119.38, 120.29, 120.43, 120.59, 120.87, 121.13, 123.07,
127.66, 130.15, 130.43, 130.71, 130.90, 137.74, 138.46,
139.64, 145.90, 149.59, 162.27, 189.22. ESI-MS (m/z)
482 (M+ 1) observed for C29H27N3O4.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(2,3-dichlorophenyl)prop-
2-en-1-one (7e)
Yellow solid, yield: 88%, m.p. 149–151 C, 1H NMR
(CDCl3, 300 MHz) δ (ppm): 3.35 (d, 2H), 3.90 (s, 3H),
5.10 (m, 2H), 5.39 (s, 2H), 5.96 (m, 1H), 6.75 (d, 2H),
7.01 (d, 1H), 7.50 (m, 2H), 7.68 (m, 2H), 7.93 (m, 2H),
8.19 (m, 2H), 8.22 (m, 1H), 8.25 (s, 1H). 13C NMR
(125 Hz, DMSO-d6) δ (ppm): 39.83, 55.89, 63.36,
112.41, 114.49, 115.81, 120.23, 120.59, 120.83, 125.28,
125.97, 127.47, 130.43, 131.92, 133.64, 134.16, 134.26,
135.41, 137.45, 137.56, 140.02, 141.37, 145.82, 145.91,
149.59, 188.61. ESI-MS (m/z) 520 (M+ 1) observed for
C28H23Cl2N3O3.
BUDUMA ET AL.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(4-chlorophenyl)prop-2-en-
1-one (7f )
Pale yellow solid, yield: 84%, m.p. 121–123 C, IR (KBr):
3158, 3072, 3003, 2937, 1740, 1665, 1609, 1511, 1254,
1219, 1137, 1014, 912, 847, 806, 660 cm
1; 1H NMR
(CDCl3, 300 MHz) δ (ppm): 3.33 (d, 2H), 3.88 (s, 3H),
5.07 (m, 2H), 5.36 (s, 2H), 5.96 (m, 1H), 6.73 (d, 2H), 6.99
(d, 2H), 7.52 (m, 4H), 7.83 (m, 1H), 7.88 (m, 2H), 8.15 (m,
2H), 8.23 (s, 1H). 13C NMR (125 Hz, DMSO-d6) δ (ppm):
39.83, 55.89, 63.37, 112.41, 114.50, 115.81, 120.21, 120.60,
120.84, 121.89, 125.22, 129.91, 130.27, 132.33, 133.55,
134.16, 137.45, 137.89, 139.91, 144.27, 145.82, 145.89,
149.59, 188.61. ESI-MS (m/z) 486 (M+ 1) observed for
C28H24ClN3O3.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(2-nitrophenyl)prop-2-en-
1-one (7g)
yellow solid, yield: 86%, m.p. 97–99 C, IR (KBr): 3144,
3080, 2937, 1658, 1603, 1513, 1418, 1341, 1258, 1221,
1138, 1017, 798, 753, 703, 667 cm
1; 1H NMR (CDCl3,
300 MHz) δ (ppm): 3.35 (d, 2H), 3.90 (s, 3H), 5.10 (m,
2H), 5.39 (s, 2H), 5.96 (m, 1H), 6.74 (d, 2H), 6.98 (d, 1H),
7.60 (m, 4H), 7.79 (m, 1H), 7.93 (m, 2H), 8.13 (m, 2H),
8.20 (s, 1H) 8.22 (s, 1H). 13C NMR (125 Hz, DMSO-d6) δ
(ppm): 39.83, 55.89, 63.37, 112.44, 114.54, 115.80, 120.24,
120.60, 120.83, 125.11, 126.52, 126.82, 129.30, 130.45,
130.61, 131.16, 133.41, 133.66, 134.17, 137.46, 140.06,
141.11, 145.82, 145.91, 148.58, 149.61, 189.03. ESI-MS (m/
z) 497 (M+ 1) observed for C28H24N4O5.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(benzo[d][1,3]dioxol-4-yl)
prop-2-en-1-one (7h)
Yellow solid, yield: 94%, m.p. 119–121 C, 1H NMR
(CDCl3, 300 MHz) δ (ppm): 3.33 (d, 2H), 3.88 (s, 3H),
5.10 (m, 2H), 5.36 (s, 2H), 5.98 (m, 1H), 6.04 (d, 2H),
6. 74 (m, 2H), 6.98 (d, 1H), 7.23 (m, 2H), 7.35 (m, 4H),
7.79 (m, 1H), 8.16 (m, 2H), 8.17 (s, 1H). 13C NMR
(125 Hz, DMSO-d6) δ (ppm): 39.83, 55.89, 63.38, 101.74,
106.72, 108.77, 112.41, 114.52, 115.80, 119.42, 120.17,
120.60, 120.85, 125.58, 129.13, 130.16, 134.14, 137.47,
138.33, 139.70, 145.60, 145.82, 148.53, 149.60, 150.26,
188.77. ESI-MS (m/z) 496 (M+ 1) observed. for
C28H25N3O5.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(naphthalen-1-yl)prop-2-en-
1-one (7i)
Yellow solid, yield: 89%, m.p. 87–89 C, 1H NMR (CDCl3,
300 MHz) δ (ppm): 3.32 (d, 2H), 3.87 (s, 3H), 5.10 (m,
2H), 5.35 (s, 2H), 5.95 (m, 1H), 6.73 (m, 3H), 6.99
BUDUMA ET AL.
(m, 4H), 7.85 (m, 3H), 8.23 (m, 6H), 8.25 (s, 1H). 13C NMR
(125 Hz, DMSO-d6) δ (ppm): 39.83, 55.88, 63.35, 112.41,
114.49, 115.80, 120.10, 120.59, 120.83, 130.10, 134.15, 136.92,
137.45, 140.04, 145.82, 145.85, 149.58, 196.54. ESI-MS (m/z)
502 (M+ 1) observed for C32H27N3O3.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(furan-2-yl)prop-2-en-
1-one (7j)
Pale yellow solid, yield: 94%, m.p. 111–113 C, IR (KBr):
3134, 3002, 2918, 2863, 1738, 1654, 1601, 1513, 1259,
1229, 1137, 1021, 911, 834, 743, 668 cm
1; ESI-MS (m/z)
442 (M+ 1) observed for C26H23N3O4.
(E)-1-(4-(4-([5-allyl-2-methoxyphenoxy]methyl)-1H-
1,2,3-triazol-1-yl)phenyl)-3-(thiophen-2-yl)prop-2-en-
1-one (7k)
Yellow solid, yield: 84%, m.p. 117–119 C, IR (KBr): 3142,
3077, 2999, 2936, 2834, 1652, 1585, 1511, 1416, 1256, 1224,
1140, 1019, 819, 706 cm
1; 1H NMR (CDCl3, 300 MHz) δ
(ppm): 3.35 (d, 2H), 3.90 (s, 3H), 5.08 (m, 2H),5.37 (s, 2H)
5.94 (m, 1H), 6.7 (m, 1H), 7.01 (m, 2H), 7.33 (m, 1H), 7.41
(m, 2H), 7.47 (m, 1H), 7.90 (m, 2H), 7.99 (s, 1H), 8.19 (m,
2H), 8.21 (s, 1H). 13C NMR (125 Hz, DMSO-d6) δ (ppm):
39.84, 55.89, 63.37, 112.41, 114.51, 115.80, 120.07, 120.18,
120.60, 120.85, 128.50, 129.30, 130.10, 130.16, 132.60, 134.14,
137.47, 138.07, 139.79, 140.17, 145.83, 149.59, 188.26. ESI-
MS (m/z) 458 (M+ 1) observed for C26H23N3O3S.
4.3 | In silico molecular docking
Molecular docking and visualization studies of eugenol
derivatives series were performed through FlexX docking
program available in Lead IT 2.1.8 version of (Bio Solve IT
Germany). FlexX is a fast algorithm for flexible docking of
small ligands into the active protein-binding site using an
incremental construction process. During docking standard
parameters were kept in the FlexX program as implemented
in LeadIT v2.1.8. Chemical structure designing, energy min-
imization, and geometry cleaning were done through
ChemDraw and Chem3D 15.0.0.16 version (PerkinElmer
Informatics). The protein 3D crystallographic structures for
docking were retrieved through RCSB Protein Data Bank
(PDB) (www.rcsb.org/). To find the possible bioactive con-
formations of eugenol derivatives series of compounds, these
softwares were used.
4.4 | In silico pharmacokinetic screening
Pharmacokinetic screening of eugenol derivatives with
control molecules was performed by Discovery Studio
11
v3.5 software (Accelrys), ADMET module. Mathematical
predictive ADMET QSAR models for different pharmaco-
kinetic parameters were used, namely, aqueous solubil-
ity, BBB penetration, cytochrome P450 2D6 inhibition,
hepatotoxicity, human intestinal absorption, and plasma
protein binding. These ADMET descriptors allow us to
eliminate compounds with unfavorable ADMET charac-
teristics early, to avoid expensive reformulation, prefera-
bly before synthesis and also help to evaluate proposed
structural refinements that are designed to improve
ADMET properties. The studied compounds were also
evaluated against the Lipinski's rule of five. The toxicity
that is often used in drug development was calculated for
all designed compounds, all the predictions were calcu-
lated by DS_TOPKAT module of Discovery Studio 3.5
software (Accelrys).
ACKNOWLEDGMENTS
The authors thank the director, CSIR-CIMAP, Lucknow,
for his constant encouragement and support. Author
Komuraiah Buduma is thankful to CSIR, New Delhi, for
providing financial assistance in the form of a Senior
Research Fellowship.
DA TA AVAI LA BI LI TY S T ATE ME NT
Data available in article supplementary material
ORCID
Kotesh Kumar J https://orcid.org/0000-0001-8294-2234
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SU PP O R TI N G I N F O RMA TI O N
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How to cite this article: K. Buduma,
N. Kumar A, S. Srinivas KVN, K. Kumar J,
S. Chinde, A. K. Domatti, Y. Kumar, P. Grover,
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