Synthesis and evaluation of antioxidant, anti-inflammatory and antiulcer activity of conjugates of amino acids with nifedipine

Article abstract of DOI:10.1248/cpb.59.1153

A new series of novel (2S)-2-({2-[1,4-dihydro-3,5-bis(methoxycarbonyl)-2,6- dimethyl-4-(2-nitrophenyl)pyridin-1-yl]-2-oxoethyl}amino)-3-(4-hydroxyphenyl) propanoic acid (3a) and its analogues 3b-j has been synthesized. These compounds were evaluated for their in vitro antioxidant activity, anti-inflammatory activity and antiulcer activity. Compounds 3b and f exhibited significant antioxidant action comparable with that of standard. Efficacy against inflammation and ulceration was also found to be significant. The chemical structures of these compounds were confirmed on the basis of spectral data.

Full text of DOI:10.1248/cpb.59.1153

September 2011
Note
Chem. Pharm. Bull. 59(9) 1153—1156 (2011)
1153
Synthesis and Evaluation of Antioxidant, Anti-inflammatory and
Antiulcer Activity of Conjugates of Amino Acids with Nifedipine
b
Bharat Bhusan SUBUDHI ,a and Shakti Prasanna SAHOO
*
a School of Pharmaceutical Sciences, Siksha O Anusandhan University; Bhubaneshwar, Orissa–751003, India: b Alluri
Krishna Rao Govindamma College of Pharmacy; Nallajerla, West Godavari, Andhra Pradesh–534112, India.
Received December 27, 2010; accepted May 24, 2011; published online June 7, 2011
A new series of novel (2S)-2-({2-[1,4-dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridin-
1-yl]-2-oxoethyl}amino)-3-(4-hydroxyphenyl) propanoic acid (3a) and its analogues 3b—j has been synthesized.
These compounds were evaluated for their in vitro antioxidant activity, anti-inflammatory activity and antiulcer
activity. Compounds 3b and f exhibited significant antioxidant action comparable with that of standard. Efficacy
against inflammation and ulceration was also found to be significant. The chemical structures of these com-
pounds were confirmed on the basis of spectral data.
Key words nifedipine; amino acid; conjugate; antioxidant; anti-inflammatory; antiulcer
Gastric acid secretion is a calcium dependent process and DPPH was added and incubated in the dark room for 35 min.
calcium channel blockers including nifedipine have exhibited The absorbance was measured at 517 nm and percentage
good potential to reduce gastric secretion.1—3) The role of quenching of DPPH was calculated. For all the compounds
free radicals in inflammation of gastric mucosa and use of and standard half inhibition concentration (IC50) was calcu-
antioxidants for protection against ulceration has been widely lated and showed in Table 1. Conjugation of amino acids in-
suggested.4,5) Several amino acids6) and their conjugates with creased the antioxidant potential of nifedipine as evident
curcumin,7) pyrrole8) and 5H-dibenzazepine9) have been re- from the lower IC50 value of compounds. The IC50 value of
ported with significant antioxidant action. Inspired with anti- compound 3b was lowest among the test compounds fol-
secretory profiles of nifedipine and antioxidant properties of lowed by that of 3f indicating their good radical scavenging
amino acids and in connection with our research on the de- potential. The DPPH radical scavenging action of 3b was
sign and synthesis of biologically active and pharmacologi- found to be better than ascorbic acid (Fig. 1).
cally important new heterocycles, it was thought worthwhile
Anti-inflammatory Activity of Synthesized Compounds
to synthesize the amino acid conjugates of nifedipine with a Acute inflammation was produced by sub plantar injection of
view to obtain certain new chemical entities with potential to 0.1 ml of 1% suspension of carrageenin in normal saline in
reduce excess gastric acid secretion as well as protect gastric the right hind paw of the rats. Paw volume was measured
mucosa against inflammation and ulceration. On the other plethysmometrically11) at 0 and 4 h after carrageenin injec-
hand, to the best of our knowledge, previously there is no re- tion. The animals were treated with the synthesized com-
port, on the synthesis of (2S)-2-({2-[1,4-dihydro-3,5-bis(methoxy- pounds (50 mg/kg). Saline (3 ml/kg, orally) treated animals
carbonyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridin-1-yl]-2- served as control and acetyl salicylic acid (100 mg/kg, orally)
oxoethyl}amino)-3-(4-hydroxyphenyl)propanoic acid (3a) was administered as standard drug. The drugs were adminis-
and its analogues 3b—j.
tered simultaneously with carrageenin injection. Mean in-
The key intermediate dimethyl 1,4-dihydro-2,6-dimethyl- crease in paw volume was measured and reported in Table 1.
4-(2-nitrophenyl)pyridine-3,5-dicarboxylate (1) was prepared All the test compounds reduced the paw volume. The anti-
by Hansch pyridine synthesis by treating 2-nitrobenzalde- inflammatory activity was found to be significant (pꢀ0.001)
hyde with methyl acetoacetate in presence of ammonium hy- for compounds 3b, c and f (Fig. 2).
droxide. Dimethyl 1-(2-chloroacetyl)-1,4-dihydro-2,6-dimethyl-
Antiulcer Activity of Synthesized Compounds The
4-(2-nitrophenyl)pyridine-3,5-dicarboxylate (2) was prepared antiulcer activity of the synthesized compounds were evalu-
by reaction of nifedipine (1) in benzene with 3-chloroacetyl ated by pyloric ligature induced gastric ulcers in rat model
chloride in presence of triethylamine and continuous stirring. using parameters including volume, pH, ulcer index, free
Further treatment of compound 2 with amino acids in pres- acidity and total acididy.12) The test compounds exhibited
ence of K2CO3 in methanol followed by reflux yielded the variable antiulcer activity. Reduction in acid secretion was
title compounds 3a—j. The synthetic route leading to the more significant (pꢀ0.001) in animals administered with
title compounds is summarized in Chart 1. The chemical compounds 3b, c and f. The acid neutralizing ability of 3b
structures of all the newly synthesized compounds were con- and 3f were more significant (pꢀ0.001) and comparable with
1
firmed by their IR, H-NMR, elemental and mass spectra omeprazole. The reduction in free acidity by 3b and f was
analysis. The compounds were screened for their antioxidant, close to that of the standard. The reduction in total acidity by
anti-inflammatory and antiulcer activities.
both compounds was significant (pꢀ0.001) but less than
In-Vitro Antioxidant Study The free radical scavenging omeprazole. The ulcer healing capacity as indicated by ulcer
activity of synthesized compounds was evaluated by the index was significant (pꢀ0.001) for compounds 3a, d, f, h
method first employed by Blois10) using 1,1-diphenyl-2- and i. This study shows that antioxidant action complements
picrylhydrazyl (DPPH). To 1 ml of each compound of differ- the antisecretory properties of the compounds as evident
ent concentrations (1, 2, 3, 4, 5 mg/ml) 1 ml of 0.1 mmol from activities of compounds 3b and f. Compound 3b showed
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: bharatbhusans@gmail.com

1154
Vol. 59, No. 9
Chart 1
recorded on BRUKER AVANCE-II-400 MHz spectrometer for 1H-NMR.
The chemical shifts were reported as ppm down field using tetramethylsilane
(TMS) as an internal standard. Elemental analysis was carried out with
PERKIN ELMER-2400 analyser. Mass spectra were recorded on a MICRO-
MASS Q-TOF MICRO spectrometer operating at 70 eV.
better antioxidant action than 3f but the anti-inflammatory
and antiulcer actions were comparable. Thus it can be sug-
gested that antioxidant action of 3b has not been able to re-
markably potentiate its antisecretory properties. From this
study it can be proposed that conjugation of amino acids to
nifedipine enhanced the antioxidant action that comple-
mented the antisecretory action of the compounds resulting
in increased anti-inflammatory and antiulcer potential. This
improvement was more significant in phenyl alanine and
methionine conjugates of nifedipine.
Typical Procedure Dimethyl 1,4-Dihydro-2,6-dimethyl-4-(2-nitro-
phenyl)pyridine-3,5-dicarboxylate (1) A solution of 2-nitro benzalde-
hyde (0.2 mol), methyl acetoacetate (0.2 mol) and ammonium hydroxide
(8 ml) in ethanol (60 ml) was heated under reflux for 3 h. To the resulting
mixture warm water (40 ml) was added and then allowed to cool. The sepa-
rated product was filtered off, washed with 60% aqueous ethanol and recrys-
tallised from ethanol. The purity of the compound was checked with TLC.
Dimethyl-1-(2-chloroacetyl)-1,4-dihydro-2,6-dimethyl-4-(2-nitro-
phenyl)pyridine-3,5-dicarboxylate (2) Chloroacetyl chloride (2.2 mmol)
was added drop by drop for about 30 min to the well stirred solution of 1
(2 mmol) and triethylamine (2.2 mmol) in 50 ml benzene. The reaction mix-
ture was stirred at room temperature for about 6h. Progress of the reaction
was monitored by TLC using 9 : 1 (hexane : ethyl acetate) mixture as mobile
phase. After completion of reaction, the reaction mass was quenched in ice
Experimental
General All reagents and solvents were used as purchased without fur-
ther purification. Melting points were determined on a Sisco melting point
apparatus and are uncorrected. Crude products were purified by column
chromatography on silica gel of 60—120 mesh. IR spectra were obtained on
a JASCO FTIR-4100 spectrometer using KBr pellet. NMR spectra were

September 2011
1155
Table 1. Antioxidant, Anti-inflammatory and Antiulcer Activity of 2(S)-2-({2-[1,4-Dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridin-
1-yl]-2-oxoethyl}amino)-3-(4-hydroxyphenyl)propanoic Acid (3a) and Its Analogues 3b—j
RSA
Anti-inflammatory activity
Antiulcer activity
Ulcer index
Group
IC50 (mg/ml)
Increase PV
%
Volume (ml)
pH
FA (meq/l)
TA (meq/l)
Cont.
Standard
1
—
50
272
326
10
180
169
381
65
254
90
0.5833ꢃ0.03073
—
6.4ꢃ0.3141
2.167ꢃ0.283***
4.85ꢃ1.2
4.783ꢃ0.2587
2.383ꢃ0.25***
3.833ꢃ0.40***
5.850ꢃ0.37
4.817ꢃ0.365
2.233ꢃ0.2951*** 4.648ꢃ0.317***
4.500ꢃ0.2569*
3.983ꢃ0.5474**
4.533ꢃ0.5542
1.912ꢃ0.2693
5.050ꢃ0.3354***
2.29ꢃ0.453
3.300ꢃ0.2582
4.100ꢃ0.152***
2.962ꢃ0.3102
2.483ꢃ0.3833
2.383ꢃ0.2725
16.80ꢃ1.152
2.750ꢃ0.428***
14.2ꢃ0.541
46.17ꢃ3.655
6.867ꢃ0.5858***
39.5ꢃ0.89
38.33ꢃ4.295
8.817ꢃ0.8845***
39.83ꢃ3.400
26.33ꢃ2.290**
31.00ꢃ4.017
8.383ꢃ0.5770***
33.67ꢃ2.753
32.17ꢃ3.894
27.17ꢃ3.978**
35.17ꢃ2.455**
50.38ꢃ2.585
8.150ꢃ0.4682***
45.8ꢃ0.44
42.00ꢃ4.187
15.82ꢃ1.839***
43.83ꢃ3.936
31.67ꢃ2.801**
36.33ꢃ3.621
11.00ꢃ0.3907***
39.50ꢃ3.063
39.00ꢃ3.838
31.67ꢃ3.499**
38.33ꢃ2.124***
0.1500ꢃ0.02236*** 74.3
0.3124ꢃ0.02108*** 33.4
0.3333ꢃ0.02108*** 42.8
0.1833ꢃ0.01667*** 68.6
0.3667ꢃ0.04216**
0.3500ꢃ0.02236**
0.3167ꢃ0.04773*** 45.7
0.2000ꢃ0.02582*** 65.1
0.400ꢃ0.06009*
0.353ꢃ0.03651
0.3167ꢃ0.04773
3a
3b
3c
3d
3e
3f
3g
3h
3i
13.083ꢃ0.5016
4.250ꢃ0.295***
8.250ꢃ0.676**
7.267ꢃ0.518***
12.883ꢃ0.4191
3.200ꢃ0.646***
11.333ꢃ0.4807
6.283ꢃ0.426***
5.817ꢃ0.451***
14.100ꢃ0.663***
37.1
39.9
34.2
31.4
28.5
2.983ꢃ0.3591
2.903ꢃ0.3795
3.117ꢃ0.3745
3.233ꢃ0.4863
81
332
3j
0.5833ꢃ0.03073*** 51.4
4.083ꢃ0.2344**
RSA: Radical (DPPH) scavenging activity. Data are represented as meanꢃS.E.M. Statistical analysis was done with one way analysis of variance (ANOVA). ∗∗∗ pꢀ0.001,
∗∗ pꢀ0.05 and ∗ pꢀ0.01 as compared to control (nꢄ6 in each group).
propanoic Acid (3a) Tyrosine (1.2 mmol) in methanol (25 ml) was neu-
tralized with triethylamine (1.2 mmol). To this K2CO3 (600 mg) was added.
Later the solution of 2 (1 mmol) in methanol (50 ml) was added drop by drop
for 30 min. The reaction mixture was refluxed for 8 h. The progress of the re-
action was monitored by TLC. The reaction mixture was then desolventized
and compound was extracted in ethyl acetate. The ethyl acetate layer was
washed with water and dried over anhydrous Na2SO4. The product was fur-
ther recrystallised from ethanol. Other compounds of the series 3a—j were
obtained in a similar manner.
Dimethyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicar-
boxylate (1): Yellow solid, yield 71%, mp 172—174 °C. IR (KBr) cmꢁ1
:
3339, 3089, 2985, 1689, 1125. 1H-NMR (CDCl3) d: 7.2—7.6 (m, Ar-H), 6.2
(s,1H, NH), 5.2 (s, 1H, –CH–), 3.8 (s, 6H, –CH3), 2.3 (s, 6H, –CH3). MS
m/z: 346 (Mꢂ).
Fig. 1. IC 50 of Compounds
Dimethyl-1-(2-chloroacetyl)-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-3,5-dicarboxylate (2): Pale yellow solid, yield 65%, mp 154—
156 °C. IR (KBr) cmꢁ1: 3076, 2974, 1711,1688, 1125. 1H-NMR (CDCl3) d:
7.5—7.9 (m, Ar-H), 4.5 (s, 1H, –CH–), 3.7(s, 6H,–CH3), 2.3 (s, –CH3),
2.4—3.3 (m, Alk-H).
(2S)-2-({2-[1,4-Dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-ni-
trophenyl)pyridin-1-yl]-2-oxoethyl}amino)-3-(4-hydroxyphenyl)propanoic
Acid (3a): Light yellow solid, yield 64%, mp 108—110 °C. IR (KBr) cmꢁ1
:
1
3458, 3131, 3023, 2925, 1728, 1689, 1143. H-NMR (CDCl3) d: 11 (s, 1H,
OH), 6.2—7.9 (m, Ar-H), 5.8 (s, 1H, OH), 4.7 (s, 1H, –CH–), 2.2—2.8 (m,
–CH2–), 3.6 (s, OH, –CH3). Anal. Calcd for C28H30N3O10: C, 59.25; H, 5.32.
Found: C, 59.08; H, 5.12. MS m/z: 567 (Mꢂ). [a]D25 ꢁ11.
Fig. 2. Reduction in Paw Volume (%) by Compounds
(2S)-2-((3-(3,5-Bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-1(4H)-3-oxoacetyl)amino)-3-phenylpropanoic Acid (3b): Light
yellow solid, yield 48%, mp 158—160 °C. IR (KBr) cmꢁ1: 3444, 3145,
3045, 2931, 1734, 1691, 1125. 1H-NMR (CDCl3) d: 10.2 (s, 1H, OH), 7.3—
7.9 (m, Ar-H), 4.5 (s, 1H, –CH–), 3.3—3.5 (m,–CH2–), 3.78 (s, 6H, –CH3),
2.2—2.7 (m, –CH2–). Anal. Calcd for C28H30N3O9: C, 60.97; H, 5.48.
Found: C, 61.1; H, 5.89. MS m/z: 551 (Mꢂ). [a]D25 ꢁ6.
(2S)-2-((3-(3,5-Bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-1(4H)-3-oxoacetyl)amino)-3-(3R)-hydroxybutanoic Acid (3c): Yel-
low solid, yield 44%, mp 123—125 °C. IR (KBr) cmꢁ1: 3395, 3125, 3043,
2961, 1721, 1687, 1145. 1H-NMR (CDCl3) d: 10 (s, 1H, OH), 7.5—7.8 (m,
Ar-H), 4.3 (s, 1H, –CH–), 3.9 (s, 1H, OH), 2.1—2.6 (m, –CH2–), 3.4 (s, 6H,
–CH3). Anal. Calcd for C23H28N3O10: C, 54.65; H, 5.58. Found: C, 54.02; H,
5.11. MS m/z: 505 (Mꢂ). [a]D25 ꢁ62.
(2R)-2-((3-(3,5-Bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-1(4H)-3-oxoacetyl)amino)-3-hydroxypropanoic Acid (3d): Brown-
ish yellow solid, yield 49%, mp 155—157 °C. IR (KBr) cmꢁ1: 3445, 3132,
Fig. 3. Antiulcer Activity of Compounds
ꢀ: Total acidity, ꢁ: free acidity, ꢀ: ulcer index.
1
1723, 1695, 2922, 1145. H-NMR (CDCl3) d: 1.8 (s, 1H, NH), 2.1 (s, 6H,
–CH3), 2.3—2.8 (m, –CH2–), 3.6 (s, 6H, –CH3–), 3.7—4.1 (m, –CH2), 4.6 (s, 1H,
–CH–), 7.4—7.8 (m, Ar-H). Anal. Calcd for C22H26N3O10: C, 53.76; H, 5.33.
Found: C, 53.86; H, 5.98. [a]D25 138.
(2R)-2-((3-(3,5-Bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-1(4H)-3-oxoacetyl)amino)-3-methylbutanoic Acid (3e): Yellow
solid, yield 47%, mp 151—153 °C. IR (KBr) cmꢁ1: 3388, 3043, 2946, 1709,
cold water and extracted in diethyl ether. The ether layer was washed twice
with 5% NaHCO3 and twice with distilled water. Finally the ether layer was
dried with anhydrous Na2SO4.
(2S)-2-({2-[1,4-Dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-
nitrophenyl)pyridin-1-yl]-2-oxoethyl}amino)-3-(4-hydroxyphenyl)-

1156
Vol. 59, No. 9
1678,1132 . 1H-NMR (CDCl3) d: 10.4 (s, 1H, OH), 7.6—7.8 (m, Ar-H), 4.3
(3j): Deep yellow solid, yield 53%, mp 127—129 °C. IR (KBr) cmꢁ1: 3390,
3167, 3032, 2960, 1732, 1134. 1H-NMR (CDCl3) d: Anal. Calcd for
(s, 1H, –CH–), 3.5 (s, 1H, OH), 2.1—2.6 (m, –CH2–), 3.4 (s, 6H, –CH3).
Anal. Calcd for C24H30N3O9: C, 57.25; H, 6.0. Found: C, 57.25; H, 6.0. C25H28N5O9: C, 50.38; H, 4.73. Found: C, 50.02; H, 4.11. 567 MS m/z: 596
Found: C, 57.88; H, 5.69. MS m/z: 503 (Mꢂ). [a]D25 42.
(Mꢂ). [a]D25 ꢁ3.
(2R)-2-((3-(3,5-Bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-1(4H)-3-oxoacetyl)amino)-4-(methylthio)butanoic Acid (3f): Deep
Acknowledgement The authors are thankful to Director, sophisticated
yellow solid, yield 51%, mp 153—155 °C. IR (KBr) cmꢁ1: 3415, 3122, analytical instrument facility, Punjab University, Chandigarh for their kind
1
3025, 2955, 7748, 1128. H-NMR (CDCl3) d: 11 (s, 1H, OH), 7.5—7.8 (m,
Ar-H), 4.6 (s, 1H, –CH), 3.8 (s, 6H, –CH3), 2.1—2.7 (m, –CH2–). Anal. Calcd
for C24H30N3O9S: C, 53.82; H, 5.64. Found: C, 53.87; H, 5.47. [a]D25 85.
(2S)-2-((3-(3,5-Bis(methoxycarbonyl)-2,6-dimethyl-4-(2-nitrophenyl)-
pyridine-1(4H)-3-oxoacetyl)amino)-3-(1H-indol-3-yl)propanoic Acid (3g):
Brownish yellow solid, yield 56%, mp 122—124 °C. IR (KBr) cmꢁ1: 3426,
help in analysis.
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3125, 3045, 1731, 2960. H-NMR (CDCl3) d: 2 (1H, s, NH), 2.28 (s, 6H,
CH3), 2.3—2.8 (m, –CH2), 3.6 (s, 6H, –CH3), 3.1—3.3 (m, –CH2–), 4.8 (s,
1H, –CH–), 7.2—7.9 (m, Ar-H), 11 (s, 1H, OH). Anal. Calcd for
C30H31N4O9: C, 61.01; H, 5.29. Found: C, 60.561; H, 5.12. MS m/z: 590
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(2S)-2-({2-[1,4-Dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-ni-
trophenyl)pyridin-1-yl]-2-oxoethyl}amino)-4-carbamoylbutanoic Acid (3h):
Brown solid, yield 56%, mp 150—152 °C. IR (KBr)cmꢁ1: 3437, 3245, 3160,
3046, 2950, 1748, 1148. 1H-NMR (CDCl3) d: 11 (s, 1H, OH), 7.1 (1H, NH),
7.4—7.8 (m, Ar-H), 4.7 (s, 1H, –CH), 3.8 (s, 6H, CH3), 2.2—2.8 (m, –CH2).
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[a]D25 ꢁ44.
(2R)-2-({2-[1,4-Dihydro-3,5-bis(methoxycarbonyl)-2,6-dimethyl-4-(2-ni-
trophenyl)pyridin-1-yl]-2-oxoethyl}amino)-3-mercaptopropanoic Acid (3i):
Brown solid, yield 54%, mp 129—131 °C. IR (KBr) cmꢁ1: 3418, 3116, 10) Blois M. S., Nature (London), 26, 1199—1205 (1958).
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(m, Ar-H), 10.6 (s, 1H, OH). 1H-NMR (CDCl3) d: Anal. Calcd for
C25H31N4O11S2: C, 47.91; H, 4.98. Found: C, 48.08; H, 5.32. [a]D25 ꢁ65.
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trophenyl)pyridin-1-yl]-2-oxoethyl}amino)-2-(1H-imidazol-4-yl)acetic Acid
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