New bioactive triaryl triglyceride esters: Synthesis, characterization and biological activities

Article abstract of DOI:10.3329/bjp.v13i4.37210

Four new bioactive aryl triester derivatives of glycerol and benzoic acids were synthesized. The synthetic compounds were studied for their antimicrobial and urease inhibition activities. Esterification was carried out by using carbonyldiimidazole to enhance the acyl elimination addition reaction with benzoic acid derivatives. The structure of triglycerides were studied by EI-MS,¹H,¹³C-NMR, FT-IR and elemental analysis. All synthetic compounds showed urease inhibition activity with highest value of IC₅₀ value 22.4 ± 0.45 μM which is nearest to standard thiourea IC₅₀ value (21.6 ± 0.12 μM). Except compound (3d), all other compounds exhibited antimicrobial activity against Streptococcus pneumoniae, Staphylococcus epidermidis, Bacillus pumilus, Escherichia coli, Pseudomonas aeruginosa and Candida albican.

Full text of DOI:10.3329/bjp.v13i4.37210

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Bangladesh Journal of Pharmacology
Research Article
New bioactive triaryl triglyceride es-
ters: Synthesis, characterization and
biological activities

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New bioactive triaryl triglyceride esters: Synthesis, characterization
and biological activities
Tanzila Arshad1, Hamdullah Khadim Sheikh1, Mehdi Hassan Kazmi1, Sadia Farheen2,
Tehmina Sohail2 and Mehreen Lateef3
1Department of Applied Chemistry, University of Karachi, Karachi 75270, Pakistan; 2Pakistan Council of Scientific
and Industrial Research Laboratories Complex, Karachi. Pakistan; 3Bahria University Medical and Dental College,
Karachi, Pakistan.
Article Info
Abstract
Received:
Accepted:
Available Online:
29 June 2018 Four new bioactive aryl triester derivatives of glycerol and benzoic acids were
12 October 2018
14 October 2018
synthesized. The synthetic compounds were studied for their antimicrobial
and urease inhibition activities. Esterification was carried out by using
carbonyldiimidazole to enhance the acyl elimination addition reaction with
benzoic acid derivatives. The structure of triglycerides were studied by EI-
DOI: 10.3329/bjp.v13i4.37210
Cite this article:
1
MS, H, 13C-NMR, FT-IR and elemental analysis. All synthetic compounds
Arshad T, Sheikh HK, Kazmi MH,
Farheen S, Sohail T, Lateef M. New
bioactive triaryl triglyceride esters:
showed urease inhibition activity with highest value of IC50 value 22.4 ± 0.45
μM which is nearest to standard thiourea IC50 value (21.6 ± 0.12 μM). Except
Synthesis, characterization and bio- compound (3d), all other compounds exhibited antimicrobial activity against
logical activities. Bangladesh
Pharmacol. 2018; 13: 302-08.
J
Streptococcus pneumoniae, Staphylococcus epidermidis, Bacillus pumilus, Escheri-
chia coli, Pseudomonas aeruginosa and Candida albican.
Szelag, 2004), triphenylphosphine dibromide (Saroja
and Kaimal, 1986) which are very expensive. In this
Introduction
Triglycerides are esterified products of glycerol with
fatty acids. They are the main constituents in human,
animals and plants as the form of oil, fats and lipids
(Nelson and Cox, 2000). In body, liver cell synthesizes
certain triglycerides and store the fatty acid as the
source of energy (White and Venkatesh, 2011). They are
also used as lubricants, emulsifiers and plasticizers in
cosmetic, food, chemical and pharmaceutical industry
(Macierzanka and Szelag, 2004). In literature, many
synthetic methods for synthesis of triglycerides have
been reported in which, the first step is the conversion
of fatty acid into fatty chloride by using thionyl
chloride, oxalyl chloride, phosphate pentachloride
(Quinn et al., 1967) (Mattson and Volpenhe, 1962).
These inorganic acids are not environment friendly
method. Another approach toward the synthesis of
triglyceride involves the use of certain enzymes as free
CALB (Ravelo et al., 2015; Ferreira and Tonetto, 2017),
and catalysts as zinc carboxylates (Macierzanka and
research work, synthesis of new triglyceride with
benzoic acid derivatives rather than fatty acid has been
reported through, an environmental friendly and
inexpensive, acyl addition elimination reaction by using
CDI reported by Sheikh et al. (2018).
Urease (urea amidohydrolase, E.C.3.5.1.5) enzyme
catalyzes the hydrolysis of urea and converts it into CO2
and NH3. Urease catalyzed urea enzymatic hydrolysis
is 1014 times faster than non-enzymatic hydrolysis
(Backert and Clyne, 2011). High urease activity increa-
ses NH3 concentration and resultant toxicity (Bremner
and Krogmeier, 1989). High concentration of NH3 can
cause many human diseases like ulcer, urolithiasis,
pyelonephritis, NH3 and hepatic encephalopathy, heap-
tic coma, and urinary catheter encrustation (Amtul et
al., 2002). In addition, almost 90% of the world
population is suffering from Gram negative bacterium
Helicobacter pylori which cause urinary tract stones and
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Bangladesh J Pharmacol 2018; 13: 302-308
303
1
peptic ulcer by using urease mechanism (Blaser, 1998).
Because of these reasons, in recent year’s urease inhibi-
tion studies have fascinated researchers and increasing
concentration towards this problem caused by urease
enzyme. Several urease inhibitors have been reported
including hydroxamate derivatives, phosphoramidites,
benzimidazole derivatives, urea derivatives, polyphe-
nol, thiols, heavy metal ions, boric acid and phosphate
(Arshad et al., 2017; Kafarski and Talma, 2018).
spectrometers. H-NMR, 13C-NMR, IR, elemental ana-
lysis and EI-MS were done in International Center for
Chemical and Biological Sciences, University of Kara-
chi, Karachi, Pakistan. For all compounds, mass
spectroscopic analysis data were collected through EI-
MS using JEOL USA JMS600S instrument.
The mass spectra were taken under electron impact (EI)
on MAT 312 and MAT 113D mass spectrometers. Thin
layer chromatography technique was used to monitor
the reactions and purity, carried out on Merck pre-
coated silica gel 60 F254 20 x 20 cm aluminum sheets and
spots were seen under UV light at 254 and 366 nm.
Many glycerol derivatives such as fatty acid glycerides
have been reported as bioactive against Gram positive,
Gram negative, yeast and protozoa. Examples include
monolaurin and monocaprin against Helicobacter pylori
(Bergsson et al., 2002), E. coli (Kabara, 1978), Staphylo-
coccus aureus, S. epidermidis, Streptococcus beta-hemolytic
and alpha hemolytic, Corynebacterium, Giardia lamblia
(Moanta and Radu, 2008) and Candida (Jarrahpour et al.,
2004). Benzoic acid and benzoate ester derivatives are
reported for their antibacterial (Friedman et al., 2003),
antifungal (Terreaux et al., 2010), anti-inflammatory
(Chen et al., 2007) and anti-protozoal (Kashif et al.,
2017) activities. In recent years, benzoic acid derivatives
have been reported for their inhibitory activities against
different enzymes like urease (Rauf et al., 2014),
acetylcholinesterase (Yildiz et al., 2016), tyrosinase
(Khan et al., 2010) and Trypanosoma cruzi trans-sialidase
(TcTS) (Kashif et al., 2017).
Synthesis of triaryl triglycerides (3a-3d)
Organic acid (1a-1d) (5 mmol) and carbonyldiimidazole
(5 mmol) were dissolved in THF (30 mL). After 2 hours
of stirring, the glycerol (5) (1.25 mmol) was added into
the vessel along with triethylamine base (0.52 mL). The
reaction mixture was left stirring for 48 hours after
which the solvent was dried off. The solid reaction
mixture was poured into 0.05 M solution of Na2CO3.
Obtained precipitate of the product was filtered, wash-
ed again with water, extracted with dichloromethane
and was dried over sodium sulfate. Evaporation of
solvent gave the triaryl triglyceride ester (3a-3d) which
was further purified through column chromatography
(Scheme 1).
Propane-1,2,3-triyl tribenzoate (3a)(Figure 1)
In the current study, we synthesized four new triaryl
triglycerides (3a-3d) with benzoic acid and evaluated
their urease inhibitory and antimicrobial activities
which were found to be comparable to previously
reported monoglyceride analogs (Sheikh et al., 2018).
Yield: 68%; off white solid; m.p.: 56-58°C; Rf: 0.42 (ethyl
acetate: n-hexane 2:1); IR (KBr) νmax (cm-1): 3066
(aromatic) 2934 (C-H aliphatic), 1692 (C=O ester), 1614
(C=C aromatic), 1277 (C-O ester), 1105 (C-O ether) cm-1;
1H-NMR (CDCl3, 300 MHz, 25 °C, TMS) δ (ppm): 4.53
(4H, d, J = 6.19 Hz, C1H2-O-, C3H2-O), 4.95 (1H, m, C2H-
O-), 7.22(6H, m, C7H, C9H, C7'H, C9'H, C7"H, C9"H), 7.46
(3H, m, C8H,C8'H, C8"H), 8.02 (6H, m, C6H, C10H, C6'H,
C10'H, C6"H, C10"H),; 13C NMR: (75 MHz, DMSO-d6):
165.9, 133.2, 130.1,128.6, 68.9, 62.9,; EIMS: m/z (rel.
abund. %), 404.41 (M+,27), 403.1(70), 165.05 (100), 148
(28), 122 (4); Anal. Calcd for C24H20O6: C, 71.28; H, 4.98;
O, 23.74; Found: C, 71.30; H, 4.95; O, 23.72.
Materials and Methods
Solvents and reagents that were used in the synthesis
were of analytical grade and purchased from the Sigma
-Aldrich Chemical Company, USA and Merck Milli-
pore. Jasco-320-A spectrophotometer was used for the
IR spectroscopy by using KBr discs in the range of 400-
1
4000 cm-1. H-NMR and 13C-NMR spectra were recor-
Propane-1,2,3-triyltris(4-(dimethylamino)benzoate)
(3b)
ded in the solvent CDCl3 and DMSO with Si(Me)4 as the
internal standard at 300 on Bruker Avance AM
Scheme 1: Synthesis of triaryl triglycerides (3a-3d)

304
Bangladesh J Pharmacol 2018; 13: 302-308
Figure 1: 1H-NMR chemical shifts of compound 3a
Yield: 56%; white solid; m.p.: 69-71°C; Rf: 0.32 (ethyl
acetate : n-hexane 2:1); IR (KBr) νmax (cm-1): 3140 (C-H
aromatic), 2931 (C-H aliphatic), 1690 (C=O ester), 1604
(C=C aromatic), 1274 (C-O ester), 1185 (C-N amine),
1099 (C-O ether) cm-1; 1H-NMR (CDCl3, 300 MHz, 25 °C,
TMS) δ (ppm): 3.02 (18H, s, -C11H3, -C12H3, -C11'H3, -
C12'H3, -C11"H3, -C12"H3), 3.77(1H, m, C1H2-O-), 4.12 (1H,
m, C1H2-O-), 4.36 (2H, d, J = 5.1 Hz, C3H2-O-), 4.42 (1H,
m, C2H-O-), 6.67 (6H, m, C7H, C9H, C7'H, C9'H, C7"H,
C9"H), 7.91 (6H, m, C6H, C10H, C6'H, C10'H, C6"H, C10"H),;
13C NMR: (75 MHz, DMSO-d6): 165.7, 154.7, 130.9,
119.8.9, 112.0, 67.8, 62.9,40.8.; EIMS: m/z (rel. abund. %),
533.25 (M+,27),; Anal. Calcd for C30H35N3O6: C, 67.52; H,
6.61; N, 7.87; O, 17.99; Found: C, 67.55; H, 6.59; N, 7.88;
O, 18.00.
(4H, d, J = 8.6 Hz, C1H2-O-, C3H2-O-), 4.44 (1H, m, C2H-
O-), 6.63 (6H, d, J = 9 Hz, C8H, C10H, C8'H, C10'H, C8"H,
C10"H), 7.91 (6H, d, J = 9 Hz, C7H, C11H, C7'H, C11'H, C7"H,
C11"H),; 13C NMR: (75 MHz, DMSO-d6): 172.4, 154.3,
131.5, 127.9, 115.3, 68.6, 63.2, 39.8, 41.8; EIMS: m/z (rel.
abund. %), 536.59 (M+,27),; Anal. Calcd for C30H32O9: C,
67.15; H, 6.01; O, 26.84; Found: C, 67.16; H, 6.00; O,
26.86.
In vitro urease assay and antimicrobial activity
A mixture of 25 μL of enzyme (jack bean urease) and
100 mm urea containing 55 μL of buffer was incubated
with 5 μL of compound (3a-3d) which concentration
was 1 mM. Incubation process was carried out at 30°C
for 15 min in 96-well plates. Indophenol method is
described in the literature (Weatherburn, 1967), in
which the activity was measured through the NH3
production. In brief, 45 μL each of 1% w/v phenol and
0.005% w/v sodium nitroprusside (phenol reagent) and
70 μL of 0.5% w/v NaOH and 0.1 % active chloride
NaOCl (alkali reagent) were added to each well. The
increasing absorbance at 630 nm was measured after 50
min, using a microplate reader (molecular device,
USA). All the assays were performed at pH 8.2 (0.01 m
Propane-1,2,3-triyltris(4-chlorobenzoate) (3c)
Yield: 75%; white solid; m.p.: 83-85°C; Rf: 0.37 (ethyl
acetate : n-hexane 2:1); IR (KBr) νmax (cm-1): 3156 (C-H
aromatic), 2981 (C-H aliphatic), 1691 (C=O ester), 1599
(C=C aromatic), 1275 (C-O ester), 1079 (C-O ether) cm-1;
1H-NMR (CDCl3, 300 MHz, 25 °C, TMS) δ (ppm): 3.92
(4H, d, J = 8.6 Hz, C1H2-O-, C3H2-O-), 4.44 (1H, m, C2H-
O-), 7.65 (6H, m, C7H, C9H, C7'H, C9'H, C7"H, C9"H), 7.99
(6H, d, J = 8.2 Hz, C6H, C10H, C6'H, C10'H, C6"H, C10"H),;
13C NMR: (75 MHz, DMSO-d6): 166.2, 139.7, 133.6,
130.4, 128.5, 127.9, 67.6, 63.5.; EIMS: m/z (rel. abund. %),
506.00 (M+,100), 508.1(M+2, 95), 510.03 (M+4, 30),; Anal.
Calcd for C24H17Cl3O6: C, 56.77; H, 3.37; Cl, 20.95; O,
18.91; Found: C, 56.76; H, 3.39; Cl, 20.94; O, 18.93.
K2HPO4.3H2O,
1 mm EDTA and 0.01 m LiCl2).
Percentage inhibition was calculated from the formula
given as follows:
100–(ODtestwell/ODcontrol) x 100
Thiourea was used as the standard inhibitor of urease.
Antimicrobial activity
Propane-1,2,3-triyltris(2-(4-methoxyphenyl)acetate)
(3d)
The agar well diffusion method was used to determine
the antibacterial activity by plant extract and its
fractions (Ahmed et al., 1998). In this procedure, 100 μL
of inoculums (diluted to 106 CFU/mL) of test culture
was mixed with 20 mL of molten sterile tryptic soya
agar. This mixture was poured into pre-sterilized petri
dishes under sterile condition. Plates were allowed to
Yield: 68%; white solid; m.p.: 5-77°C; Rf: 0.49 (ethyl
acetate : n-hexane 2:1); IR (KBr) νmax (cm-1): 2931 (C-H
aliphatic), 1691 (C=O ester), 1607 (C=C aromatic), 1275
1
(C-O ester), 1102 (C-O ether) cm-1; H-NMR (CDCl3, 300
MHz, 25 °C, TMS) δ (ppm): 3.56 (6H, s, -C5H2-, -C5'H2-, -
C5"H2-), 3.77 (9H, s, -O-C12H3, -O-C12'H3, -O-C12"H3), 3.92

Bangladesh J Pharmacol 2018; 13: 302-308
305
set at 4ºC for 30-40 min. Holes (6 mm diameter) were
made in the center of each seeded plate. 0.1 mL of the
test solution i.e. compound (3a-3d) was then filled in
holes with two concentrations (0.1 and 0.05%). Standard
disc of antibiotic gentamicin (10 μg) served as positive
antibacterial control. DMSO was used as negative
control. All plates were then incubated at 37 ± 1ºC for
24 hours. The zone of inhibition around the wall was
observed for the evaluation of the antibacterial activity.
Vernier caliper was used to measure the diameter (in
mm) of inhibition zone. Readings were made repeated-
ly to minimize test error.
gentamycin (10 μg) was used as standard while syn-
thetic compounds (3a-3d) were used in two concentra-
tions 0.1 and 0.05%. The antimicrobial activity results
are listed in Table II.
Discussion
In the synthesis of triaryl triglyceride (3a-3d), glycerol
was esterified with only once with one benzoic acid.
The esterification was carried out by CDI which
incorporated the imidazole as leaving group in place of
basic group –OH. Being an aromatic ring, the imidazole
anion is highly stable (closed bonding shell and
resonance) (Verma et al., 2012), hence elimination step
of acyl addition elimination reaction becomes
energetically facile. Acyl addition elimination is
facilitated by the same scheme of the replacement of the
leaving group usually by reaction of the acid with an
inorganic acid such as SOCl2, oxalyl chloride, PCl3 and
PCl5 (Roy et al. 2016). Glycerol being a triol polyhydric
alcohol (Bieleski, 1982) wields three Lewis basic OH
sites for bonding with bioactive moieties, in this
research work these OH sites bonds with C=O of three
benzoic acids. Other than glycerol, higher polyol sugar
alcohols can also be used on the same pattern with even
higher number of Lewis basic sites in them to be
bonded with aryl rings.
Results
Urease inhibition activity
All compounds (3a-3d) were evaluated for inhibition
activity. Standard (thiourea) was used with IC50 value
21.6 ± 0.12 μM. All compounds were showed inhibition
activity with the IC50 values between 22.4 ± 0.45 to 41.2
± 0.16 μM. Compound (3c) was the most active
compound with the IC50 value near to the standard that
is 22.4 ± 0.45 μM, while the least active compound was
(3d) with the IC50 value two times less than (3c). All the
values were listed in Table I.
Antimicrobial activity
Some bonded benzoic acid rings had activating and
deactivating (resonating and inductive) groups on the
aryl ring inducing an overall electron rich or deficient
character on the bonded aryl ring respectively. Hence,
substitution on the aryl ring had an impact on the
All synthetic compounds (3a-3d) were evaluated for
their antimicrobial activity against Gram positive (S.
pneumoniae, S. epidermidis and Bacillus pumilus), Gram
negative (Escherichia coli and Pseudomonas aeruginosa)
and yeast (Candida albican). In the current study,
Table I
Urease inhibition results of compounds (3a-3d)
SL. No.
1
Compound
R
Urease inhibition
Substituents
(IC50 ± SEM μM)a
3a
3b
26.4 ± 0.5
2
36.5 ± 0.3
22.4 ± 0.5
41.2 ± 0.2
21.6 ± 0.1
3
4
3c
3d
Standard
Thiourea
a = (Mean ± Standard error of mean)

306
Bangladesh J Pharmacol 2018; 13: 302-308
Table II
Antimicrobial activity of compounds (3a-3d)
Zone inhibition (mm)
Yeast
Gram positive
Gram negative
Candida
albican
Streptococcus
pneumoniae
Staphylococcus
epidermidis
Bacillus
pumilus
Escherichia
Pseudomonas
aeruginosa
coli
Conc.
0.1 0.05 Std.
0.1 0.05 Std.
0.1 0.05 Std.
0.1 0.05 Std.
0.1 0.05 Std.
0.1 0.05 Std.
%
3a 18.2 15.4
20 17.5
16
20
21
18
15
16
20 17.5 19.6
20
22
20
12 15.6
22 18.3
17
20
3b
3c
19 17.3
20 19.6
20 18.3 16.6
-
20 18.3 13.6
21 18.7 17.6
20 22.3 23.5
18 12.6 19.3
24 17.6 16.7 20
21
20
19 18.5
14
20 18.9 14.6
20
23 22.3
3d
16
-
-
-
-
21
14.
-
20 16.3
-
22
14
-
20
position in all three aryl rings. The least active com-
pound was (3d) with the IC50- value 41.2 ± 0.16 μM.
From the results, it was found that urease inhibition
activity depends on the number of aryl rings and
substituents on it. As the number of aryl ring increases,
the probability of π-π stacking of aryl rings with the
active sites of enzyme or its side chain which contains
cysteine or methionine groups also increase (Rego et al.,
2018). As a result, good urease inhibition activity was
shown by the synthesized triaryl triglycerides (3a-3d),
compared to the monoglycerides reported by Sheikh et
al., (2018). Taha et al. (2016) reported that the incor-
poration of electron-withdrawing groups on aryl ring
increase the polarizbility and inhibition activity
towards urease enzyme. As results showed that the
most active compound (3c) also contains three Cl at
para position of all aryl rings and was found most
active among rest.
bioactivity and also on the interaction with substrates.
The 1H-NMR of all compounds were studied at 300
1
MHz. In H-NMR of (3a), alkyl protons of C1, C2 and
C3 appeared between 4 to 5 ppm, due to the deshiel-
ding effects of sp2 O atom which is in conjugation with
the C=O bond of the ester. Aryl protons are deshielded
by sp2 carbonyl carbon of ester, appearing between 7 to
8 ppm.
Because of the presence of the symmetry element in (3a-
3d) half of the resonance spectra were achieved. All aryl
ring proton showed 2nd order coupling with AA’BB’C
system. This system referred to as Pople notation spin
spitting designation protocol (Pople et al., 1957),
otherwise in 1st order spectra of aryl ring spin splitting
3
system would at least doublet of doublet (dd) with J
4
and J. Similarly, the beta carbon (C2) proton should
have been doublet of doublet (dd) but there was also
2nd order interaction between the mutually spin
splitting protons in the alkyl aliphatic range. The higher
vicinal coupling constant means (sp3-1s) σ orbital is
parallel to the 1s σ orbital, this implies that the orbital-
orbital overlap is strong according to Dirac modal and
electronic spin interaction is facile (Minch, 1994). This
orbital overlap is possible when angle is either 0º or
180º. In case of 180º the interaction is in between σ and
σ* orbital. The alkyl aliphatic system is deshielded by
the sp2 O which is in conjugation with the C=O bond of
ester. Aryl section is deshielded by sp2 carbonyl carbon
of ester group. Whether the symmetry was axial or
planer can be verified by the stereochemical analysis
such as NOE, NOESY.
All compounds showed activity against all micro-
organisms the most active molecule was (3c), it
exhibited good activity against all bacteria and yeast at
both concentrations and its zone inhibition values was
very close to standard values. The least active com-
pound was (3d) which showed moderate level activity
at 1% concentration and inactive at 0.05%. It was also
inactive against S. epidermidis at both concentrations. As
compared to the previously reported fatty glycerides
and monoglycerides (Sheikh et al., 2018), the synthe-
sized triaryl triglycerides exhibited good to excellent
level bioactivity against the given microbes.
Limited structural activity relationship showed that
compound (3c) was the most active compound with the
IC50 value 22.4 ± 0.45 μM and it had Cl at para position
of the aryl ring in all three substituents R. The next
active most compound was (3a) with IC50 value 26.4 ±
0.47 μM, it had unsubsituted aryl ring. Compound (3b)
also showed good activity with the IC50- value 36.5 ±
0.33 μM, it had N,N-dimethyl substituents on para
Conclusion
Potent bioactive triaryl triglyceride esters (3a-3d) were
synthesized with benzoic acid derivatives through
facile one-step and environmental friendly synthesis.
All synthetic triglycerides (3a-3d) inhibit the enzyme
urease and show the good antimicrobial activity even
better than previously reported monoglycerides.

Bangladesh J Pharmacol 2018; 13: 302-308
Molecules 2017; 22: 1863.
307
Conflict of Interest
Khan SB, Khan MT, Jang ES, Akhtar K, Seo J, Han H.
Tyrosinase inhibitory effect of benzoic acid derivatives and
their structure-activity relationships. J Enzyme Inhib Med
Chem. 2010: 25: 812-17.
Authors declare no conflict of interest.
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Author Info
Tanzila Arshad (Principal contact)
e-mail: tanzila_arshad2000@yahoo.com