Synthesis, in vitro evaluation and molecular docking studies of biscoumarin thiourea as a new inhibitor of α-glucosidases

Article abstract of DOI:10.1016/j.bioorg.2015.09.004

Biscoumarin analogs 1-18 have been synthesized, characterized by EI-MS and ¹H NMR and evaluated for α-glucosidase inhibitory potential. All compounds showed variety of α-glucosidase inhibitory potential ranging in between 13.5 ± 0.39 and 104.62

Full text of DOI:10.1016/j.bioorg.2015.09.004

Bioorganic Chemistry 63 (2015) 36–44
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis, in vitro evaluation and molecular docking studies of
biscoumarin thiourea as a new inhibitor of a-glucosidases
a,b,
a,b
Nik Khairunissa Nik Abdullah Zawawi a,b, Muhammad Taha a,b, , Norizan Ahmat
,
⇑
⇑
, Nor Hadiani Ismail
Abdul Wadood d, Fazal Rahim c, Ashfaq Ur Rehman d
a Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA, Puncak Alam Campus, Malaysia
b Faculty of Applied Science, Universiti Teknologi MARA, 40450 Shah Alam, Selangor D.E., Malaysia
c Depatment of Chemistry, Hazara University, Mansehra 21120, Pakistan
d Department of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
a r t i c l e i n f o
a b s t r a c t
Biscoumarin analogs 1–18 have been synthesized, characterized by EI-MS and 1H NMR and evaluated for
-glucosidase inhibitory potential. All compounds showed variety of -glucosidase inhibitory potential
ranging in between 13.5 0.39 and 104.62 0.3 M when compared with standard acarbose having
IC50 value 774.5 1.94 M. The binding interactions of the most active analogs were confirmed through
molecular docking. The compounds showed very good interactions with enzyme. All synthesized com-
pounds 1–18 are new. Our synthesized compounds can further be studied to developed lead compounds.
Ó 2015 Elsevier Inc. All rights reserved.
Article history:
Received 27 July 2015
Revised 21 September 2015
Accepted 22 September 2015
Available online 25 September 2015
a
a
l
l
Keywords:
Biscoumarin
Thiourea
Synthesis
Molecular docking
a-Glucosidase inhibition
1. Introduction
Biscoumarin is a dimeric form of coumarin showed more potent
biological activities. Biscoumarins have been reported as anti-
Type-2 diabetes is characterized by chronic hyperglycemia and
the development of microangiopathic complications such as
retinopathy, nephropathy and neuropathy. Aggressive control of
blood glucose level is preliminary and effective therapy for diabetic
patients and reduces risk of complications [1].
urease agents [8]. Biscoumarin–chalcone hybrid molecules also
showed anti-inflammatory and antioxidant activities [9]. A new
dimeric biscoumarin, daphnoretin in which two coumarin linked
by ether has property to inhibit DNA polymerase b-lyase, and pro-
tein kinase C activation [10] and also exhibit antifungal activity
[11]. They were reported to show in vivo antineoplastic activity
against the Ehrlich ascites carcinoma in mice and used as inhibitor
in Ehrlich ascites cells to inhibit a number of enzymes involved in
DNA synthesis [12].
Thiourea is a versatile reagent in synthetic chemistry [13].
Thioureas manifest important multiple biological effects and are
the basis for target oriented synthesis. Moreover, ureas and
thioureas evaluate their plant growth-regulating activity mainly
on the herbicidal, root growth inhibitory and stimulatory and
cytokinin-like activities [14]. Thiourea and urea have attracted
much attention as drug candidates against a variety of diseases
due to their bioactivities and broad spectrum as pesticides and in
pharmacological activities [15]. A variety of thiourea derivatives
and their metal complexes exhibit analgesic, anti-inflammatory
[16], carbonic anhydrase inhibitors [17], b-glucuronidase [18], anti-
urease [19] and antimicrobial activities [20,21]. Thiourea deriva-
tives also possess anti-HCV [22], anti-HIV, antituberculosis, and
a
-Glucosidase (EC. 3.2.1.20) are membrane-bound enzymes
located at the epithelium of the small intestine [2], and is the
key enzymes of carbohydrate digestion [3]. It specifically hydro-
lyzed the
from the non-reducing end of the sugar.
found to contribute to the glycosylation of human immunodefi-
ciency virus type I [4], thus inhibitors of -glucosidase can block
the viral infection [5,6]. Clinical trials showed that the
-glucosidase inhibitor improved long-term glycemic control as
a-glucopyranoside bond, thereby releasing
a-D-glucose
a-Glucosidase had been
a
a
measured by decreased hemoglobin A1c (HbA1c) in patients with
type II diabetes and delay the development of type II diabetes in
patients with impaired glucose tolerance [7].
⇑
Corresponding authors at: Atta-ur-Rahman Institute for Natural Product
Discovery, Universiti Teknologi MARA, Puncak Alam Campus, Malaysia.
E-mail addresses: taha_hej@yahoo.com, muhamm9000@puncakalam.uitm.edu.
my (M. Taha), noriz118@salam.uitm.edu.my (N. Ahmat).
http://dx.doi.org/10.1016/j.bioorg.2015.09.004
0045-2068/Ó 2015 Elsevier Inc. All rights reserved.

Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
37
antileukemic activity [23]. Fluorinated thioureas constitute a novel
class of potent influenza virus neuraminidase inhibitors [24]. We
have reported that sulfur and nitrogen containing compounds
showed potent a-glucosidase inhibition [25] and we also reported
biscoumarin as potent glucosidase inhibitors [26]. On the bases of
that we synthesized hybrid molecules of both thiourea and
biscoumarin and evaluated for potent a-glucosidase inhibition.
be due to electron donating group on aromatic ring attached with
thiourea, if we compare compound 6 with 5 and 4 having meta and
ortho methoxy group respectively. The activity difference among
these analog might be due to the difference in position of sub-
stituents. Compound 18 a para nitro analog is found to be the next
most active analog among the series with IC50 value 24.69 0.68.
The activity of this compound might be due to the electron
withdrawing group on phenyl part of thiourea.
The binding interactions of the most active analogs were
confirmed through molecular docking studies.
2. Result and discussion
2.1. Chemistry
2.3. Molecular docking calculations
Synthesis of target compounds was prompted by the reaction of
4-hydroxycoumarin and 4-nitrobenzaldehyde in catalytic amount
of piperidine and product was further reduced to 4-amino-benzyli
dene-bis-(4-hydroxycoumarin). The synthesis of the thiourea
derivatives can be easily performed with good yield by condensa-
tion of 4-amino-benzylidene-bis-(4-hydroxycoumarin) with
various phenyl isothiocyanate derivatives (Scheme 1).
All the synthesized analogs of biscoumarin thiourea were
docked into the binding pocket of
a-glucosidase to find out the
binding interactions, docking fitness scores and their specificity
for enzyme. The docking scores and binding modes of most of
the analogs are well correlated with the experimental results. In
our docking study, all the docked compounds were analyzed from
the two aspects. (1) Analogs which have different groups bonded to
the same position (2) Analogs which have same groups on different
positions. Inhibition values (IC50) of all the analogs except bro-
mobenzene indicate that compounds with para substituted aryl
moiety are more active than other compounds (Table 1). Com-
2.2. Biological activity
In the continuation of our work on enzyme inhibition [27–32]
we synthesized biscoumarin analogs 1–18 and evaluated for
a-glucosidase inhibitory potential. All of the eighteen (18) analogs
pound 3 (IC5038.97 0.99 (lM)), with Br at para position of the
showed outstanding -glucosidase inhibitory potential with IC50
a
substituted aryl group, showed docking score (S) ꢀ14.1155 and
interactions with the residues Arg 312 and Glu 276. Arg 312
formed hydrogen bond with the oxygen (OH) of the compound
while Glu 276 was in a polar interaction with the bromobenzene
moiety of the ligand (Fig. 1a).
values, 38.97 0.99, 51.02 1.41, 91.29 0.27, 50.25 1.43,
25.31 0.73, 104.62 0.3, 35.85 0.91, 26.8 0.76, 37.41 0.95,
31.72 0.83, 53.4 1.58, 50.22 0.86, 13.5 0.39, 24.69 0.68,
28.47 0.54, 43.36 0.59, 55.12 1.63, 78.04 0.23,
lM respec-
tively so many folds better than standard acarbose 774.5 1.94.
The structure activity relationship has been established. The
activity difference among all the analogs is mainly due to the
different substitution pattern on thiourea moiety. Compound 6 a
para-methoxy analog was found to be the most active among the
Compound 6 (IC50 13.5 0.39 (lM)), with methoxy group at
para position of the substituted aryl group, showed docking score
(S) ꢀ14.9010 and interactions with the residues Asn 241, His 279
and Ser 281. Asn 241 and Ser 281 showed polar bonds with Sulfur
and oxygen of the compound respectively. His 279 was in a hydro-
gen bonding interaction with the lone pair of oxygen atom, as
series with IC50 value 13.5 0.39
lM many fold better than the
standard acarbose. The greater potential of the compound might
shown in (Fig. 1b). Compound 9 (IC50 53.4 1.58 (lM)), with F
Scheme 1. Synthesis of biscoumarin thiourea derivatives 1–18.

38
Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
Table 1
Prepared various analogs of biscoumarin thiourea and their
a-glucosidase Inhibition.
S. no.
R
IC50
(l
M)
S
S. no
R
IC50
(
lM)
S
1
37.41 0.95
ꢀ14.2100
ꢀ14.3935
10
50.25 1.43
ꢀ14.2773
Br
Cl
2
3
4
5
6
7
35.85 0.91
11
12
13
14
15
16
28.47 0.54
ꢀ14.4123
ꢀ14.4468
ꢀ12.999
Br
Cl
38.97 0.99
104.62 0.3
25.31 0.73
13.5 0.39
91.29 0.27
ꢀ14.1155
ꢀ13.0116
ꢀ14.4225
ꢀ14.9010
ꢀ13.2324
26.8 0.76
50.22 0.86
78.04 0.23
43.36 0.59
31.72 0.83
Br
Cl
Me
OMe
ꢀ12.6695
ꢀ13.2772
ꢀ14.3036
MeO
Me
Me
MeO
F
F
F
F
N
8
9
55.12 1.63
53.4 1.58
ꢀ14.4613
ꢀ14.5199
17
18
51.02 1.41
24.69 0.68
ꢀ13.2324
ꢀ14.5686
F
F
O2
N
O2
group at para position of the substituted aryl group, showed dock-
ing score (S) ꢀ14.5199 and interacts with the binding site residues
His 239 and Asn 241 (Fig. 1c). A polar interaction was found
between Asn 241 and the hydroxyl group of the compound and
arene arene interaction between His 239 and compound.
thecompoundshavingelectronwithdrawinggroupsatparaposition
except for Flourine and almost the same results were observed in
docking analysis. On the basis of IC50 value, docking score and bind-
ing interaction compound 6 demonstrated high inhibitory potential
among the compounds of this series. The electron withdrawing
capability of the oxygen of methoxy group might be a reason for
the high activity of this compound and the same cause is reflected
in case of compound 18 (NO2 group) followed by compound 12 (Cl
group) and Compound 3 (Br group). In case of compound 9 the
electron withdrawing capability of F did not provide the results as
given away by the above mentioned groups, although it showed
good docking score (S) ꢀ14.5199. However, it may be attributed to
the smaller size of F and its low electron affinity. The substituted
methyl group with electron donating inductive effect in compound
15 was also observed with mild activity and docking score.
The biological activity and docking score (Table 1) of the ana-
logs which have same groups on different positions showed that
substitution at para position in the aryl group resulted in better
inhibition than ortho and meta position except in case of Br. From
the knowledge of chemistry it is apparent that para substituted
group may directly transfer their electronic effect over the rest of
the compound and might be a reason for the high activity of para
substituted compounds. However, the bromoaryl substituted
compounds 1, 2 and 3, contrast, showed better results at ortho
and meta position than para.
Compound 12 (IC50 26.8 0.76 (lM)), with Cl at para position of
the substituted aryl group, showed docking score (S) ꢀ14.4468 and
interactions with the residues Arg 312, Lys 155 and Asn 412. Arg
312 and Lys 155 formed hydrogen bonds with the oxygen (OH)
of the compound while Asn 412 was in a polar interaction with
the benzene moiety of the ligand (Fig. 1d). In case of Compound
15 (IC50 43.36 0.59 (lM)), with methyl group at para position
of the substituted aryl group, the docking score (S) observed was
ꢀ13.2772 with two binding interactions to the active site residues
His 239 and 279 (Fig. 1e). A polar interaction was found between
His 279 and the hydroxyl group of the compound and arene arene
interaction between His 239 and compound.
Some similar interactions were also found in compound
18-protein docked complex (Fig. 1f). Compound 18 (IC50
24.69 0.68 (lM)) has a nitro (NO2) at para position of the
substituted aryl ring and showed the docking score (S) ꢀ14.5686.
Here His 279 and Glu 276 were involved in binding interactions.
His 279 showed arene–arene and a polar interaction with the
compound and Glu 276 was found making a polar interaction with
the benzene group of the compound.
The structural differences among these compounds are based on
different groups at para position of the substituted aryl group. The
biological activity (Table 1) revealed better inhibitory activity for
In the docking study it was observed that most of the
compounds in this series showed good agreement between the
docking and experimental results. The good correlation between

Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
39
Fig. 1. Predicted binding mode of (a) compound 3, (b) compound 06, (c) compound 09, (d) compound 12, (e) compound 15 and (f) compound 18 within the binding pocket of
predicted homology model of -glucosidase enzyme.
a

40
Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
Fig. 2. Predicted binding mode of (a) compound 02, (b) compound 12 and (c) compound 10 within the binding pocket of predicted homology model of a-glucosidase enzyme.
experimental findings and docking results can be analyzed from
the IC50 values and docking scores given in Table 1.
a-glucosidase inhibitors that exert stronger inhibitory effects than
does acarbose.
As compared to compound02 having Br attachmentat orthoposi-
tion showed slightly poor interactions with the active site residues
(Fig. 2a). In case of compound 12 having Chlorine (Cl) attachment
at para position over the phenyl ring also showed good interaction
pattern (Fig. 2b) as compared to compound 10 which have Cl
attachment at ortho position showed poor interaction (Fig. 2c).
Overall the docking results showed that the compounds having
para substituted phenyl ring have good interactions with active
site residues and good inhibitory activities as compared to
compounds having either meta or ortho substituted phenyl ring.
The para position attachment might be one of the best clues for
good interaction network and good IC50 value.
4. Materials and method
4.1. General
Melting point was taken on Buchi M-560 melting point instru-
ment and was uncorrected. IR spectra were recorded on a Spec-
trum One FT-IR spectrometer (Perkin Elmer), using KBr discs and
values were signified in cmꢀ1. The 1H NMR and 13C NMR spectra
were measured on Bruker 500 Ultrashield Plus NMR (500 MHz)
in DMSO-d6 as solvent, using tetramethylsilane (TMS) as an inter-
nal standard, and chemical shifts are expressed as ppm. HR-ESI-MS
were determined on Agilent 6224 TOF-LC/MS using negative mode
at Faculty of Pharmacy, UiTM Puncak Alam, Malaysia
3. Conclusion
Synthesis of biscoumarin thiourea derivatives and their
4.2. Synthesis of 3,30-((4-nitrophenyl)methylene)bis(4-hydroxy-2H-
a
-glucosidase inhibitory potential was evaluated. Compound 6
showed the most potent -glucosidase inhibitory potential with
IC50 13.5 0.39 M. On the basis of in-vitro testing, we
demonstrated that biscoumarin derivatives are potential
chromen-2-one) (a)
a
l
Compound a was synthesized by stirring the mixture of
4-hydroxycoumarin
(26 mmol)
and
4-nitrobenzaldehyde

Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
41
(13 mmol) in EtOH and catalytic amount of piperidine overnight.
Completion of reaction was monitored by periodic TLC. After com-
pletion of reaction, it was filtered and then washed with distilled
water affording a pure product in high yields. Yield 93%. m.p.
(C), 116.6 (C), 115.9 (CH), 103.9 (C), 36.3 (CH). HREI-MS:
641.0220 (Mꢀ).
4.3.4. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
235.6 °C; IR(KBr) (m
max, cmꢀ1): 3445, 3083, 1649, 1596, 1536,
3-(2-chlorophenyl)-thiourea (4)
1441, 1357, 1133, 1054. 1H NMR (500 MHz, DMSO) d 8.23 (s,
1H), 8.07 (d, J = 8.8 Hz, 2H), 7.82 (dd, J = 7.8, 1.5 Hz, 2H), 7.53 (m,
2H), 7.37 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.25 (m, 2H),
6.36 (s, 1H). EI-MS: 456.0724 (Mꢀ).
Yield 82%. m.p. 195.4 °C. IR(KBr) (m
max, cmꢀ1): 3358, 1664, 1608,
1530, 1186, 1059. 1H NMR (500 MHz, DMSO) d 9.89 (s, 1H), 9.23 (s,
1H), 7.85–7.79 (m, 2H), 7.64 (d, J = 7.4 Hz, 1H), 7.49 (ddd, J = 11.0,
9.0, 4.0 Hz, 3H), 7.25 (ddd, J = 12.2, 11.6, 6.4 Hz, 8H), 7.08 (d,
J = 8.3 Hz, 2H), 6.26 (s, 1H). 13C NMR (126 MHz, DMSO) d 180.5
(C), 168.2 (C), 165.0 (C), 153.0 (C), 139.8 (C), 137.0 (C), 136.4 (C),
131.4 (CH), 130.0 (CH), 129.7 (CH), 127.6 (CH), 127.4 (CH), 127.4
(CH), 124.6 (CH), 124.0 (CH), 123.3 (CH), 120.4 (C), 115.9 (CH),
103.9 (C), 36.3 (CH). HREI-MS: 595.0742 (Mꢀ).
4.3. Synthesis of 3,30-((4-aminophenyl)methylene)bis(4-hydroxy-2H-
chromen-2-one) (b)
In a round-bottomed flask (500 ml) equipped with a magnetic
stirrer, a solution of compound a (11.425 g, 25 mmol) in EtOH–
H2O (375:0.375 ml) was prepared. To the resulting solution, Ni
(OAc)ꢁ4H2O (1.225 g, 5 mmol) was added and the mixture was
then stirred for 5 min. Afterwards, NaBH4 (3.775 g, 100 mmol)
was added to the reaction mixture and a fine black precipitate
was immediately deposited. The mixture continued to be stirred
for 45 min and the progress of the reaction was monitored by
TLC. At the end of reaction, distilled water (125 ml) was added to
the reaction mixture and stirred for 10 min. The mixture was
extracted with CH3Cl (3 ꢂ 300 ml) and the CH3Cl extract was evap-
orated under reduced pressure to give compound b. Yield 82%. m.p.
4.3.5. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(3,4-dichlorophenyl) thiourea (5)
Yield 83%. m.p. 207.3 °C. IR(KBr) (m
max, cmꢀ1): 3357, 1657, 1608,
1531, 1185, 1031. 1H NMR (500 MHz, DMSO) d 9.89 (s, 1H), 9.79 (s,
1H), 7.89 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 7.8, 1.3 Hz, 3H), 7.55–7.49
(m, 4H), 7.44 (dd, 1H), 7.27–7.22 (m, 8H), 7.07 (d, J = 8.2 Hz, 2H),
6.26 (s, 1H). 13C NMR (126 MHz, DMSO) d 179.9 (C), 168.2 (C),
165.0 (C), 153.0 (C), 140.5 (C), 139.9 (C), 136.3 (C), 131.4 (CH),
130.8 (CH), 130.5 (CH), 127.4 (CH), 126.2 (C), 125.3 (CH), 124.6
(CH), 124.1 (CH), 124.0 (CH), 123.3 (CH), 120.4 (C), 115.9 (CH),
103.8 (C), 36.3 (CH). HREI-MS: 629.0350 (Mꢀ).
176.2 °C; IR(KBr) (m
max, cmꢀ1): 3358,3027, 1665, 1605, 1536, 1509,
1399, 1182, 1032. 1H NMR (500 MHz, DMSO) d 7.82 (dd, J = 7.7,
1.1 Hz, 2H), 7.52–7.46 (m, 2H), 7.23 (dd, J = 12.7, 7.7 Hz, 4H), 6.76
(d, J = 8.1 Hz, 2H), 6.39 (d, J = 8.4 Hz, 2H), 6.12 (s, 1H), 4.64
(s, 2H). EI-MS: 426.0988 (Mꢀ).
4.3.6. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(4-chlorophenyl)-thiourea (6)
Yield 81%. m.p. 197.2 °C. IR(KBr) (m
max, cmꢀ1): 3319, 1675, 1607,
1541, 1183, 1043. 1H NMR (500 MHz, DMSO) d 9.74 (s, 1H), 9.67 (s,
1H), 7.85–7.82 (m, 2H), 7.53–7.51 (m, 3H), 7.35 (m, 2H), 7.27–7.23
(m, 7H), 7.07 (d, J = 8.3 Hz, 2H), 6.26 (s, 1H). 13C NMR (126 MHz,
DMSO) d 180.0 (C), 168.2 (C), 165.1 (C), 153.0 (C), 140.0 (C),
139.2 (C), 136.6 (C), 131.4 (CH), 128.8 (CH), 128.6 (CH),
127.3 (CH), 125.9 (CH), 125.8 (CH), 124.6 (CH), 123.9 (CH), 123.4
(CH), 120.4 (C), 115.9 (CH), 103.9 (C), 36.31 (CH). HREI-MS:
595.0742 (Mꢀ).
4.3.1. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(2-bromophenyl)-thiourea (1)
Yield 81%. m.p. 219.2 °C. IR(KBr) (m
max, cmꢀ1): 3348, 1671, 1615,
1523, 1185, 1047.1H NMR (500 MHz, DMSO) d 9.88 (s, 1H), 9.16 (s,
1H), 7.83 (dd, J = 7.8, 1.3 Hz, 2H), 7.61 (ddd, J = 15.6, 8.0, 1.0 Hz,
2H), 7.51 (m, 2H), 7.35 (m, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.24 (dd,
J = 16.7, 8.0 Hz, 4H), 7.15 (td, J = 8.0, 1.4 Hz, 1H), 7.08 (d,
J = 8.1 Hz, 2H), 6.26 (s, 1H). 13C NMR (126 MHz, DMSO) d 180.5
(C), 168.2 (C), 165.0 (C), 153.0 (C), 139.8 (C), 138.5 (C), 136.3 (C),
132.9 (CH), 131.4 (CH), 130.4 (CH), 128.1 (CH), 127.4 (CH), 124.6
(CH), 124.0 (CH), 123.3 (CH), 121.3 (C), 120.4 (CH), 115.9 (CH),
103.9 (C), 36.3 (CH). HREI-MS: 641.0217 (Mꢀ).
4.3.7. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(2-fluorophenyl)-thiourea (7)
Yield 81%. m.p. >400 °C. IR(KBr) (m
max, cmꢀ1): 3363, 1668, 1603,
1533, 1270, 1185, 1042. 1H NMR (500 MHz, DMSO) d 9.85 (s, 1H),
9.31 (s, 1H), 7.84 (dd, J = 7.8, 1.3 Hz, 2H), 7.64 (t, J = 7.9 Hz, 1H),
7.51 (m, 2H), 7.25 (ddd, J = 19.9, 9.8, 5.7 Hz, 8H), 7.15 (ddd,
J = 8.5, 5.5, 3.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.27 (s, 1H). 13C
NMR (126 MHz, DMSO) d 180.8 (C), 168.2 (C), 165.1 (C), 157.7
(C), 153.0 (C), 139.6 (C), 136.5 (C), 131.4 (CH), 129.0 (CH), 127.8
(C), 127.7 (C), 127.5 (CH), 127.4 (CH), 127.3 (CH), 124.6 (CH),
124.4 (2CH), 123.9 (CH), 123.4 (CH), 120.4 (C), 116.1 (CH), 115.9
(CH), 103.9 (C), 36.3 (CH). HREI-MS: 579.1031 (Mꢀ).
4.3.2. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(3-bromophenyl)-thiourea (2)
Yield 79%. m.p. 252 °C. IR(KBr) (m
max, cmꢀ1): 3360, 1664, 1615,
1527, 1180, 1028.1H NMR (500 MHz, DMSO) d 9.82 (s, 1H), 9.72
(s, 1H), 7.86–7.81 (m, 3H), 7.54–7.49 (m, 2H), 7.43 (dd, J = 6.7,
2.2 Hz, 1H), 7.29–7.21 (m, 8H), 7.07 (d, J = 8.3 Hz, 2H), 6.26 (s,
1H). 13C NMR (126 MHz, DMSO) d 179.9 (C), 168.2 (C), 165.0 (C),
153.0 (C), 141.9 (C), 139.7 (C), 136.4 (C), 131.4 (CH), 130.6 (CH),
127.3 (CH), 127.1 (CH), 126.3 (CH), 124.6 (CH), 123.9 (CH), 123.3
(CH), 122.8 (CH), 121.2 (C), 120.4 (C), 115.9 (CH), 103.8 (C), 36.3
(CH). HREI-MS: 641.0215 (Mꢀ).
4.3.8. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(3-fluorophenyl)-thiourea (8)
Yield 83%. m.p. 311 °C. IR(KBr) (
m
max, cmꢀ1): 3366, 1671, 1611,
9.78 (d,
1530, 1180, 1035. 1H NMR (500 MHz, DMSO)
d
4.3.3. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
J = 12.4 Hz, 2H), 7.83 (dd, J = 7.8, 1.4 Hz, 2H), 7.53 (ddd, J = 13.9,
8.2, 4.5 Hz, 3H), 7.32 (dd, J = 15.0, 8.1 Hz, 1H), 7.24 (dd, J = 8.3,
6.6 Hz, 7H), 7.06 (d, J = 8.1 Hz, 2H), 6.91 (td, J = 8.4, 2.1 Hz, 1H),
6.25 (s, 1H). 13C NMR (126 MHz, DMSO) d 179.8 (C), 168.2 (C),
165.1 (C), 163.2 (C), 153.0 (C), 139.7 (C), 136.5 (C), 131.4 (CH),
130.3 (CH), 130.2 (CH), 127.3 (CH), 124.6 (CH), 124.0 (CH), 123.4
(CH), 120.4 (C), 119.5 (CH), 115.9 (CH), 111.1 (CH), 110.9
(CH), 110.5 (CH), 110.3 (CH), 103.8 (C), 36.3 (CH). HREI-MS:
579.1033 (Mꢀ).
3-(4-bromophenyl)-thiourea (3)
Yield 81%. m.p. 236.3 °C. IR(KBr) (m
max, cmꢀ1): 3366, 1668, 1533,
1186, 1012. 1H NMR (500 MHz, DMSO) d 9.74 (s, 1H), 9.67 (s, 1H),
7.83 (dd, J = 7.8, 1.2 Hz, 2H), 7.51 (dd, J = 10.0, 3.2 Hz, 2H), 7.47–
7.46 (m, 3H), 7.27–7.23 (m, 7H), 7.06 (d, J = 8.2 Hz, 2H), 6.26 (s,
1H). 13C NMR (126 MHz, DMSO) d 179.9 (C), 168.2 (C), 165.1 (C),
153.0 (C), 139.6 (C), 139.6 (C), 136.5 (C), 131.5 (CH), 131.4 (CH),
127.3 (CH), 126.1 (CH), 124.6 (CH), 123.9 (CH), 123.3 (CH), 120.4

42
Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
4.3.9. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
4.3.14. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(4-fluorophenyl)-thiourea (9)
3-(2-methoxyphenyl)-thiourea (14)
Yield 80%. m.p. 205.2 °C. IR(KBr) (
m
max, cmꢀ1): 3358, 1671, 1607,
Yield 88%. m.p. 186.2 °C. IR(KBr) (m
max, cmꢀ1): 3344, 1664, 1609,
1530, 1213, 1183, 1042. 1H NMR (500 MHz, DMSO) d 9.67 (s, 1H),
9.57 (s, 1H), 7.83 (dd, J = 7.8, 1.0 Hz, 2H), 7.54–7.48 (m, 2H), 7.46
(dd, J = 8.8, 5.0 Hz, 2H), 7.25 (dd, J = 16.8, 8.2 Hz, 6H), 7.13 (t,
J = 8.8 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.26 (s, 1H). 13C NMR
(126 MHz, DMSO) d 180.3 (C), 168.1 (C), 165.0 (C), 160.5 (C),
158.6 (C), 153.0 (C), 139.5 (C), 136.6 (C), 136.4 (C), 136.4 (C),
131.4 (CH), 127.3 (CH), 126.7 (2CH), 124.6 (CH), 123.9 (CH),
123.4 (CH), 120.4 (C), 115.9 (CH), 115.4 (CH), 115.2 (CH), 103.9
(C), 36.3 (CH). HREI-MS: 579.1028 (Mꢀ).
1538, 1234, 1100. 1H NMR (500 MHz, DMSO) d 9.85 (s, 1H), 8.96 (s,
1H), 8.04 (dd, J = 7.9, 1.1 Hz, 1H), 7.83 (dd, J = 7.8, 1.4 Hz, 2H), 7.51
(td, 1H), 7.29–7.22 (m, 6H), 7.11 (td, 1H), 7.08 (d, J = 8.0 Hz, 2H),
7.02 (d, 1H), 6.90 (t, 1H), 6.26 (s, 1H), 3.81 (s, 3H). 13C NMR
(126 MHz, DMSO) d 179.5 (C), 168.2 (C), 165.1 (C), 153.0 (C),
151.8 (C), 139.7 (C), 136.4 (C), 131.4 (CH), 128.4 (CH), 127.3 (CH),
125.8 (CH), 125.4 (CH), 124.6 (CH), 124.1 (CH), 123.3 (CH), 120.4
(CH), 120.2 (C), 115.9 (CH), 111.7 (CH), 103.9 (C), 56.2 (OCH3),
36.3 (CH). HREI-MS: 591.123 (Mꢀ).
4.3.10. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
4.3.15. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(4-(trifluoromethyl)-phenyl) thiourea (10)
3-(3-methoxyphenyl)-thiourea (15)
Yield 83%. m.p. 270.7 °C. IR(KBr) (m
max, cmꢀ1): 3363, 1660, 1615,
Yield 84%. m.p. 300 °C. IR(KBr) (m
max, cmꢀ1): 3333, 1671, 1610,
1533, 1324, 1167, 1111, 1067. 1H NMR (500 MHz, DMSO) d 9.95,
9.992 (s, 2H), 7.84 (dd, J = 7.8, 1.3 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H),
7.65 (d, J = 8.6 Hz, 2H), 7.54–7.49 (m, 2H), 7.35–7.13 (m, 6H),
7.09 (d, J = 8.1 Hz, 2H), 6.28 (s, 1H). 13C NMR (126 MHz, DMSO) d
179.9 (C), 168.3 (C), 165.1 (C), 153.0 (C), 144.1 (C), 139.8 (C),
136.5 (C), 131.4 (CH), 127.3 (CH), 125.9 (CH), 125.8 (CH), 124.6
(CH), 123.9 (CH), 123.4 (CH), 123.3 (CH), 120.4 (C), 115.9 (CH),
113.5 (CH), 103.9 (C), 36.3 (CH). HREI-MS: 629.1 (Mꢀ).
1538, 1180, 1043. 1H NMR (500 MHz, DMSO) d 9.64 (s, 1H), 9.61
(s, 1H), 7.84 (dd, J = 7.8, 1.3 Hz, 2H), 7.51 (dt, J = 11.9, 2.5 Hz, 2H),
7.23 (ddd, J = 18.1, 16.9, 8.3 Hz, 9H), 7.07 (d, J = 8.3 Hz, 1H), 7.03
(d, J = 7.4 Hz, 1H), 6.68 (dd, J = 8.2, 2.1 Hz, 1H), 6.27 (s, 1H), 3.73
(s, 3H). 13C NMR (126 MHz, DMSO) d 179.8 (C), 168.3 (C), 165.2
(C), 159.7 (C), 153.0 (C), 141.2 (C), 139.4 (C), 136.7 (C), 131.4
(CH), 129.6 (CH), 127.2 (CH), 124.6 (CH), 124.0 (CH), 123.4 (CH),
120.4 (C), 116.1 (CH), 115.9 (CH), 110.2 (CH), 109.6 (CH), 103.9
(C), 55.5 (OCH3), 36.3 (CH). HREI-MS: 591.1232 (Mꢀ).
4.3.11. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(o-tolyl)thiourea (11)
4.3.16. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
Yield 81%. m.p. 202 °C. IR(KBr) (m
max, cmꢀ1): 3354, 1668, 1605,
3-(4-methoxyphenyl)-thiourea (16)
1525, 1182, 1037. 1H NMR (500 MHz, DMSO) d 9.55 (s, 1H), 9.15
(s, 1H), 7.83 (d, J = 7.0 Hz, 2H), 7.53–7.49 (m, 2H), 7.25
(dd, J = 17.9, 7.8 Hz, 8H), 7.17–7.13 (m, 2H), 7.07 (d, J = 8.3 Hz,
2H), 6.26 (s, 1H), 2.22 (s, 3H). 13C NMR (126 MHz, DMSO) d 180.7
(C), 168.2 (C), 165.1 (C), 153.0 (C), 139.4 (C), 138.5 (C), 136.7 (C),
135.3 (C), 131.4 (CH), 130.7 (CH), 128.5 (CH), 127.3 (CH),
126.8 (CH), 126.4 (CH), 124.6 (CH), 123.9 (CH), 123.4 (CH), 120.4
(C), 115.9 (CH), 103.9 (C), 36.3 (CH), 18.3 (CH3). HREI-MS:
575.1279 (Mꢀ).
Yield 85%. m.p. 225.1 °C. IR(KBr) (m
max, cmꢀ1): 3359, 1664, 1519,
1180, 1032. 1H NMR (500 MHz, DMSO) d 9.49 (s, 1H), 9.42 (s, 1H),
7.84 (d, J = 7.7 Hz, 2H), 7.54–7.49 (m, 1H), 7.32 (d, J = 8.6 Hz, 1H),
7.25 (dd, J = 16.7, 8.0 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.88 (d,
J = 8.9 Hz, 2H), 6.26 (s, 1H), 3.74 (s, 3H). 13C NMR (126 MHz, DMSO)
d 180.3 (C), 168.2 (C), 165.1 (C), 157.0 (C), 153.0 (C), 139.3 (C),
136.8 (C), 132.8 (C), 131.4 (CH), 127.2 (CH), 126.5 (CH), 124.6
(CH), 123.9 (CH), 123.4 (CH), 120.4 (C), 115.9 (CH), 114.1 (CH),
103.9 (C), 55.7 (OCH3), 36.3 (CH). HREI-MS: 591.1233 (Mꢀ).
4.3.12. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
4.3.17. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(m-tolyl)thiourea (12)
Yield 86%. m.p. 222 °C. IR(KBr) (m
max, cmꢀ1): 3356, 1668, 1608,
3-(3-nitrophenyl)-thiourea (17)
Yield 85%. m.p. 193.7 °C. IR(KBr) (m
max, cmꢀ1): 3357, 1660, 1609,
1538, 1186, 1042. 1H NMR (500 MHz, DMSO) d 9.60 (s, 1H), 9.54
(s, 1H), 7.83 (dd, J = 7.8, 1.3 Hz, 2H), 7.56–7.45 (m, 2H), 7.22
(ddd, J = 26.2, 14.8, 7.9 Hz, 9H), 7.05 (d, J = 8.2 Hz, 2H), 6.92 (d,
J = 7.5 Hz, 1H), 6.25 (s, 1H), 2.28 (s, 3H). 13C NMR (126 MHz, DMSO)
d 179.9 (C), 168.2 (C), 165.1 (C), 153.0 (C), 139.9 (C), 139.4 (C),
138.1 (C), 136.8 (C), 131.4 (CH), 128.6 (CH), 127.2 (CH),
125.5 (CH), 124.6 (CH), 123.9 (CH), 123.3 (CH), 121.3 (CH), 120.4
(C), 115.9 (CH), 103.9 (C), 36.3 (CH), 21.5 (CH3). HREI-MS:
575.1282 (Mꢀ).
1532, 1347, 1186, 1039. 1H NMR (500 MHz, DMSO) d 10.00 (s, 2H),
8.57 (s, 1H), 7.93 (dd, J = 8.2, 1.6 Hz, 1H), 7.91–7.87 (m, 1H), 7.84
(dd, J = 7.8, 1.4 Hz, 2H), 7.58 (t, J = 8.2 Hz, 1H), 7.54–7.49 (m, 2H),
7.29–7.21 (m, 7H), 7.10 (d, J = 8.2 Hz, 2H), 6.28 (s, 1H). 13C NMR
(126 MHz, DMSO) d 180.1 (C), 168.2 (C), 165.1 (C), 153.0 (C),
147.9 (C), 141.6 (C), 140.0 (C), 136.2 (C), 131.4 (CH), 130.1 (CH),
129.9 (CH), 127.4 (CH), 124.6 (CH), 124.1 (CH), 123.4 (CH), 120.4
(C), 118.9 (CH), 118.1 (CH), 115.9 (CH), 103.8 (C), 36.3 (CH).
HREI-MS: 606.0985 (Mꢀ).
4.3.13. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
3-(p-tolyl)thiourea (13)
4.3.18. 1-(4-(bis(4-Hydroxy-2-oxo-2H-chromen-3-yl)methyl)phenyl)-
Yield 80%. m.p. 218.5 °C. IR(KBr) (
m
max, cmꢀ1): 3356, 1668, 1607,
3-(4-nitrophenyl) thiourea (18)
1534, 1184, 1040. 1H NMR (500 MHz, DMSO) d 9.57 (s, 1H), 9.53
(s, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.1 Hz, 2H), 7.34
(d, J = 8.2 Hz, 2H), 7.25 (dd, J = 16.4, 8.5 Hz, 6H), 7.11
(d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.26 (s, 1H), 2.27 (s,
3H). 13C NMR (126 MHz, DMSO) d 180.0 (C), 168.3 (C), 165.1 (C),
153.0 (C), 139.3 (C), 137.4 (C), 136.8 (C), 134.0 (C), 131.4 (CH),
129.3 (CH), 127.2 (CH), 124.6 (CH), 124.4 (CH), 123.9 (CH), 123.4
(CH), 120.4 (C), 115.9 (CH), 103.9 (C), 36.3 (CH), 21.0 (CH3).
HREI-MS: 575.1283 (Mꢀ).
Yield 72%. m.p. 225.6 °C. IR(KBr) (m
max, cmꢀ1): 3358, 1664, 1608,
1509, 1335, 1183, 1043. 1H NMR (500 MHz, DMSO) d 10.25 (s, 1H),
10.15 (s, 1H), 8.18 (d, J = 9.0 Hz, 2H), 7.91–7.78 (m, 4H), 7.51
(t, J = 7.7 Hz, 2H), 7.35–7.17 (m, 6H), 7.09 (d, J = 8.4 Hz, 2H), 6.27
(s, 1H). 13C NMR (126 MHz, DMSO) d 179.6 (C), 168.2 (C), 165.1
(C), 153.0 (C), 146.9 (C), 142.7 (C), 140.0 (C), 136.3 (C), 131.6 (C),
131.4 (CH), 127.4 (CH), 126.8 (CH), 124.7 (CH), 124.6 (CH), 123.9
(CH), 123.4 (CH), 122.0 (CH), 120.4 (C), 115.9 (CH), 112.9 (CH),
103.8 (C), 36.3 (CH). HREI-MS: 606.0973 (Mꢀ).

Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
43
4.4. Baker’s Yeast a-glucosidase inhibition assay
Acknowledgements
The enzyme inhibition was evaluated according to the method
previously reported by Taha et al. [25] with slight modification.
Authors would like to acknowledge the Ministry of Education
Malaysia and Universiti Teknologi MARA for the financial support
under RAGS Grant 600-RMI/ERGS/5/3/(4/2013).
Various concentration of test compounds (10
in DMSO (ranging from 200 to 6.25 g/mL) and premixed with
95 L of 50 mM phosphate buffer (pH 6.8). Then, 25 L of enzyme
(0.0625 U/mL) in phosphate buffer saline was added into each well
and the plate was incubated at 37 °C for 10 min. Afterward, 25
lL) were dissolved
l
l
l
Appendix A. Supplementary material
lL
of PNPG in phosphate buffer saline (5 mM) were added and
pre-read of the plate was taken by using a microplate reader (Spec-
trostar Nano BMG Labtech, Germany). The reaction mixture was
then incubated at 37 °C for 30 min and change in absorbance at
405 nm was monitored up to 30 min. For negative control, the test
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bioorg.2015.09.
004.
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Nik Khairunissa Nik Abdullah Zawawi et al. / Bioorganic Chemistry 63 (2015) 36–44
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