Med Chem Res (2016) 25:70–82
71
et al., 2012). The present study aimed at conjugating quer-
cetin, a naturally occurring polyphenolic flavonoid with
ACF to obtain ACF-quercetin mutual prodrug. Quercetin is
well known for anti-ulcer activity due to its antioxidant
properties (Martin et al., 1998; Cotelle, 2001). Although
linking of quercetin with ACF in 1:1 ratio is difficult due to
the presence of a number of hydroxyl groups, an attempt has
been made to conjugate this in the form of its derivative,
quercetin tetramethyl ether (QTME) with ACF.
Synthesis of aceclofenac-quercetin mutual prodrug (Martin
et al. 1998)
Step 1: Synthesis of aceclofenac acid chloride: Aceclofe-
nac (1) (2.12 g, 0.01 mM) was added to thionyl chloride
(1.44 g, 0.96 ml, 0.012 M) and stirred at room temperature
for 18 h. The excess of thionyl chloride was removed under
reduced pressure to give aceclofenac acid chloride (1a) as
yellow amorphous solid.
0
0
Literature survey reveals that many efforts had been
made to synthesize amino acid ester, glycolamide ester and
amide prodrugs using various amines. But few attempts
were made to develop ester prodrugs using antioxidants and
amide prodrugs using amino acids. With this background, an
attempt has been made to synthesize aceclofenac–vanillin
and aceclofenac-L-tryptophan mutual prodrugs. With this
approach, it is expected to get non-toxic prodrugs with
minimal GIT disturbance but maintaining the useful
physicochemical and pharmacological properties.
Step 2: Synthesis of quercetin 5, 7, 3 , 4 tetramethyl
ether : To a fine solution of rutin hydrate (1b) (2 g,
0.003 M) in dry acetone (20 ml), anhydrous potassium
carbonate (8 g, 0.056 M) and dimethyl sulfate (8 ml,
0.059 M) were added and the reaction mixture was
refluxed for 60 h. The solution was filtered, and insoluble
potassium salts were washed with acetone. The washings
were combined with the filtrate, and the solvent was
removed under reduced pressure to obtain methylated
glycoside as semisolid residue. The product was refluxed
with ethanolic sulfuric acid (2 %, 50 ml) for 2 h. The
solvent was removed under reduced pressure, and the
residue obtained was recrystallized from ethanol to give
Materials
0
0
quercetin 5, 7, 3 , 4 tetramethyl ether (QTME) (1d).
Step 3: Aceclofenac-QTME mutual prodrug (ACF-Q):
QTME (1.74 g, 0.005 M) was dissolved in dichlor-
omethane (20 ml) containing triethyl amine (5 drops) and
4-dimethyl amino pyridine (1 pinch). The reaction mixture
was cooled to -10 °C, and aceclofenac acid chloride
(2.057 g, 0.01 M) dissolved in dichloromethane (30 ml)
was added dropwise over a period of 1 h. The reaction
mixture was stirred overnight, and the solvent was removed
under reduced pressure and recrystallized from ethanol to
obtain ACF-Q.
Quercetin, vanillin and tryptophan were obtained from M/s
Sigma-Aldrich, Mumbai, India, and aceclofenac was obtained
as gift sample from Alkem Laboratories, Mumbai, India. The
other reagents and solvents used were of analytical grade. The
melting points were recorded using melting point determi-
nation apparatus by Sigma Instrument, Chennai, and are
uncorrected. The elemental analysis was performed using
Carlo-Erba Model 1108 Analyzer, Italy. The infrared and
mass spectra were recorded on IR spectrophotometer (Shi-
madzu 8201 PC) and mass spectrophotometer (Jeol SX-102
1
13
(
FAB), Japan), respectively. H NMR and C NMR spectra
Characterization of 2-(5-(5,7-dimethoxy-4-oxochro-
man-2-yl)-2,3-dimethoxy-phenoxy)-2-oxoethyl-2-(2-(2,6-
dichlorophenyl) amino) phenyl acetate (ACF-Q): brown-
ish needles (from EtOH) (it was obtained as a brown
solid); mp 198 °C; UV (MeOH) kmax 300 (SGF), 324
(SIF), 287 (PBS) nm; IR (KBr) mmax: 3424 (NH Stretch),
1580, 1498 (aromatic ring stretch), 1309, 1231 (primary
or secondary, OH in plane bend), 1188, 1146 (secondary
amine, NH bend), 1084 (primary amine), 766 (1,2 dis-
were recorded in DMSO on a Bruker DRX 400 Fourier
transform spectrometer with TMS as internal standard.
Chemical shifts are expressed as d (ppm) values. The
hydrolysis data and drug content determination were per-
formed by UV spectrophotometer (Shimadzu, Japan) at a
range of 200–400 nm. The pharmacological evaluation was
carried out in Department of Pharmacology, Alshifa College
of Pharmacy, Kerala. The histopathological studies were
carried out using Primostar Carl Zeiss trinocular microscope
in Department of Pathology, Al Shifa hospital, Kerala.
-
1 1
ubstitution (ortho, meta)) cm ; H NMR (DMSO): d = 4
(1H, aromatic C–NH), 7.28 (2H, Ar–H), 6.48 (1H, Ar–H),
1
3
.72 (2H, OCH ), 2.50 (1H, CH in ring); C NMR
3
3
0
(
DMSO): d = 169.4 (ester C=O), 171 (C-4 ), 164 (C-7),
0
0
Experimental procedures
Synthesis of prodrugs
159 (C-9), 149 (C-2), 141.3 (C-4 ), 140.7 (C-4 ), 140.2
C-3), 135 (C-3), 132.4, 130, 128.7, 127.2, 126.9
(12-C Ar–C biphenyl compound) 56.1 (OCH ); Mass
m/z) 695.13 [M] ? (100); C H Cl NO ; (calcd.
(
3
(
3
5
31
2
10
The study involves synthesis of aceclofenac with quercetin
tetramethyl ether, vanillin and L-tryptophan and shown in
Schemes 1, 2 and 3, respectively.
696.43); Anal. Calcd. for C35H31Cl NO10 : C, 60.35; H,
2
4.49; N, 2.01; O, 22.97. Found: C, 60.11; H, 4.45; N,
1.98; O, 22.86.
123