Synthesis and pharmacological activities of hydrazones, schiff and mannich bases of isatin derivatives

Article abstract of DOI:10.1248/bpb.24.1149

Schiff bases and phenyl hydrazone of isatins were prepared by reacting isatin and the appropriate aromatic primary amine/hydrazines. A new series of the corresponding N-mannich bases were synthesized by reacting them with formaldehyde and diphenylamine. T

Full text of DOI:10.1248/bpb.24.1149

October 2001
Biol. Pharm. Bull. 24(10) 1149—1152 (2001)
1149
Synthesis and Pharmacological Activities of Hydrazones, Schiff and
Mannich Bases of Isatin Derivatives
a
,b
*
Seshaiah Krishnan SRIDHAR and Atmakuru RAMESH
Department of Pharmaceutical Chemistry, Vel’s College of Pharmacy,a Chennai 600 117, India and Department of
Pesticide Chemistry, Fredrick Institute of Plant Protection and Toxicology,b Padappai 601 301, Chennai, India.
Received May 28, 2001; accepted July 6, 2001
Schiff bases and phenyl hydrazone of isatins were prepared by reacting isatin and the appropriate aromatic
primary amine/hydrazines. A new series of the corresponding N-mannich bases were synthesized by reacting
1
them with formaldehyde and diphenylamine. The chemical structures were confirmed by means of their H-
NMR, IR spectral data and elemental analysis. The compounds were screened for analgesic, antiinflammatory
and antipyretic activity. 1-Diphenylaminomethyl-3-(1-naphthylimino)-1,3-dihydroindol-3-one (4), 3-(1-naph-
thylimino)-5-bromo-1,3-dihydroindol-2-one (2) and 1-diphenylaminomethyl-3-(4-methylphenylimino)-1,3-dihy-
droindol-3-one (7) were found to exhibit the highest analgesic, anti-inflammatory and antipyretic activity respec-
tively. 1-Diphenylaminomethyl-3-(4-methylphenylimino)-1,3-dihydroindol-3-one (7) was found to be the most ac-
tive compound of the series.
Key words isatin; mannich base; schiff base; analgesic; anti-inflammatory; antipyretic
Schiff and mannich bases of isatin derivatives were re-
Synthesis of Mannich Bases of Isatin Equimolar quan-
ported to exhibit a wide range of CNS activities as potentia- tity (0.004 mol) of diphenylamine in 10 ml of ethanol was
tion of pentobarbitone induced narcosis,1) analgesic,2,3) anti- added to a slurry containing appropriate isatin and 0.3 ml of
convulsant,4—8) antidepressant9) and antiinflammatory activ- formaldehyde solution (37% v/v) in 10 ml of ethanol. The re-
ity.10) Therefore, it was envisaged that a new series of N- action mixture was stirred for 1 h at room temperature and
mannich bases of isatins containing diphenylamino methyl refrigerated for 48 h. The products were separated by suction
moiety would possess analgesic, anti-inflammatory and an- filtration, vacuum dried and recrystallized from ethanol.
tipyretic activity due to its structural resemblance with in-
TLC was carried out on SiO2 gel (HF254, 200 mesh). The
domethacin and aryl acetic acid NSAID. In continuation of solvent system employed was benzene : chloroform (55 : 45)
our work on some pharmacologically active Isatin deriva- and the spots were identified by placing the plate in Iodine
tives,11—13) we hereby report the synthesis of phenyl hydra- Chamber.
zone, schiff and mannich bases of isatins and their pharma-
3-(4-Bromophenylimino)-5-chloro-1,3-dihydroindol-2-one
cological activities. In the present study, aromatic primary (1): Yieldϭ88%, mp 234—236 °C, Rf valueϭ0.746, Rm
1
amines or phenyl hydrazine were subjected to reaction with valueϭϪ0.4679. H-NMR (CDCl3) d: 6.67—7.07 (s, 1H,
isatin and 5-substituted isatin to form schiff bases and hydra- NH), 7.13—7.73 (m, 7H, Ar–H). IR (KBr) cmϪ1: 3262 (eno-
zones respectively. A new series of the corresponding N- lic O–H), 1611 (CO), 1580 (CϭN), 1461 (CϭC), 829, 790,
mannich bases were synthesized by reacting them with 748 (Ar–H); 669 (C–Br), 614 (C–Cl). UV lmax (EtOH) nm:
formaldehyde and diphenylamine. The chemical structures of
the synthesized compounds were confirmed by means of
1
their H-NMR, IR spectral data and elemental analysis. The
synthesized compounds were tested for their analgesic activ-
ity by acetic acid induced writhing reflex method, anti-in-
flammatory activity by formalin induced pedal paw oedema
method and antipyretic activity by yeast induced pyrexia
method.
CHEMISTRY
Melting points were determined in open capillaries and are
uncorrected. IR spectra was recorded (in KBr) on Bomem
1
FT-IR spectrophotometer MB Serial II. H-NMR spectra
were recorded on 300 MHz–Bruker DPX 200 using tetra-
methylsilane as Internal standard. Elemental analysis was
performed in Heraeus CHN Rapid Analyzer.
Synthesis of Schiff Bases of Isatin Equimolar quantity
(0.004 mol) of 5-substituted isatin and the aromatic primary
amine or hydrazine were dissolved in 10 ml of warm ethanol
and refluxed for 30 min. After standing for approximately
24 h at room temperature, the products were separated by fil-
Chart 1
tration, vacuum dried and recrystallized from warm ethanol.
To whom correspondence should be addressed. e-mail: fippat@giasmd01.vsnl.net.in
© 2001 Pharmaceutical Society of Japan

1150
Vol. 24, No. 10
208, 244, 258, 314, 374. Anal. Calcd for C14H8BrClN2O: C, Calcd for C27H22N4O: C, 77.52; H, 5.33; N, 13.41. Found: C,
50.06; H, 2.43; N, 8.39. Found: C, 50.10; H, 2.40; N, 8.35.
77.49; H, 5.30; N, 13.39.
3-(1-Naphthylimino)-5-bromo-1,3-dihydroindol-2-one (2):
1-Diphenylaminomethyl-3-(4-bromophenylimino)-5-
Yieldϭ27%, mp 222—224 °C, Rf valueϭ0.922, Rm valueϭ chloro-1,3-dihydroindol-3-one (9): Yieldϭ42%, mp 247—
1
Ϫ1.0726. H-NMR (CDCl3) d: 6.40—6.94 (s, 1H, NH), 249 °C, Rf valueϭ0.880, Rm valueϭϪ0.8657. 1H-NMR
7.05—8.11 (m, 10H, Ar–H). IR (KBr) cmϪ1: 3200 (enolic (CDCl3) d: 1.07—1.36 (s, 2H, –CH2–), 6.37—7.95 (m, 17H,
O–H), 1615 (CO), 1578 (CϭN), 1457 (CϭC), 864, 813, 771, Ar–H). IR (KBr) cmϪ1: 1748 (CϭO), 1615 (CϭN), 1458
751 (Ar–H), 650 (C–Br). UV lmax (EtOH) nm: 252, 276, (CϭC), 1390 (–CH2–), 689, 623 (Ar–H), 613 (C–Br), 579
315. Anal. Calcd for C18H11BrN2O: C, 61.58; H, 3.20; N, (C–Cl). UV lmax (EtOH) nm: 244, 309, 350. Anal. Calcd for
8.01. Found: C, 61.55; H, 3.16; N, 7.98.
C27H19BrClN3O: C, 62.73; H, 3.74; N, 8.16. Found: C, 62.74;
3-(4-Methoxy-phenylimino)-5-bromo-1,3-dihydroindol-2- H, 3.71; N, 8.13.
one (3): Yieldϭ23%, mp 264—266 °C, Rf valueϭ0.917, Rm
1-Diphenylaminomethyl-3-(4-methoxyphenylimino)-5-
valueϭϪ1.0433. 1H-NMR (CDCl3) d: 3.50—4.10 (s, 3H, 4Ј- bromo-1,3-dihydroindol-3-one (10): Yieldϭ48%, mp 200—
OCH3), 6.42—7.34 (m, 7H, Ar–H), 7.34—7.73 (s, 1H, NH). 201 °C, Rf valueϭ0.499, Rm valueϭ0.0017. 1H-NMR
IR (KBr) cmϪ1: 3222 (enolic O–H), 1609 (CO), 1594 (CDCl3) d: 1.40—1.75 (s, 2H, –CH2–), 3.65—4.04 (s, 3H,
(CϭN), 1460 (CϭC), 1291 (C–H), 1254 (C–O), 819, 751 4Ј-OCH3), 6.59—7.58 (m, 7H, Ar–H). IR (KBr) cmϪ1: 1736
(Ar–H), 603 (C–Br). UV lmax (EtOH) nm: 212, 277, 378. (CϭO), 1609 (CϭN), 1503 (CϭC), 1459 (–CH2–), 1291
Anal. Calcd for C15H11BrN2O2: C, 54.42; H, 3.33; N, 8.50. (O–CH3), 1253 (C–O), 838, 750, 700 (Ar–H), 602 (C–Br).
Found: C, 54.39; H, 3.35; N, 8.46.
UV lmax (EtOH) nm: 234, 262, 375. Anal. Calcd for
1-Diphenylaminomethyl-3-(1-naphthylimino)-1,3-dihy- C28H22BrN3O2: C, 65.60; H, 4.32; N, 8.19. Found: C, 65.63;
droindol-3-one (4): Yieldϭ88%, mp 236—238 °C, Rf H, 4.33; N, 8.20.
valueϭ0.835, Rm valueϭϪ0.7029. 1H-NMR (CDCl3) d:
1.30—1.95 (s, 2H, –CH2–), 6.79—7.78, 7.84—8.12 (m, 21H, PHARMACOLOGY
Ar–H). IR (KBr) cmϪ1: 1748 (CϭO), 1613 (CϭN), 1461
(CϭC), 1383 (–CH2–); 799, 767, 750, 731, 689 (Ar–H). UV
The synthesized compounds were evaluated for analgesic,
l
max (EtOH) nm: 239, 314, 375. Anal. Calcd for C31H23N3O: antiinflammatory and antipyretic activity. Acute toxicity test
C, 82.07; H, 5.08; N, 9.13. Found: C, 82.09; H, 5.11; N, 9.27. was performed for all the synthesized compounds to ascer-
1-Diphenylaminomethyl-3-(4-bromophenylimino)-1,3-di- tain the LD50 values by Karber’s arithmetical method14) and
hydroindol-3-one (5): Yieldϭ75%, mp 202—204 °C, Rf the data are presented in Table 1. The experimental doses
valueϭ0.742, Rm valueϭϪ0.4592. 1H-NMR (CDCl3) d: were selected between the minimum effective dose and mini-
1.37—1.79 (s, 2H, –CH2–), 6.65—8.49 (m, 18H, Ar–H). IR mum non lethal dose. Student-t-test was performed for all the
(KBr) cmϪ1: 1739 (CϭO), 1610 (CϭN), 1460 (CϭC), 1477, activities to ascertain the significance of the exhibited activi-
1393 (–CH2–), 830, 811, 749, 688, 670 (Ar–H), 582 (C–Br). ties. The test compounds and the standard drugs were admin-
UV lmax (EtOH) nm: 204, 241, 259, 315, 375. Anal. Calcd istered in the form of a suspension (1% Carboxy Methyl Cel-
for C27H20BrN3O: C, 67.19; H, 4.21; N, 8.68. Found: C, lulose as vehicle) in the same route of administration. Each
67.22; H, 4.18; N, 8.71.
group consisted of six animals. All the pharmacological ex-
1-Diphenylaminomethyl-3-(4-methoxyphenylimino)-1,3- perimental protocols were performed according to the rec-
dihydroindol-3-one (6): Yieldϭ84%, mp 218—219 °C, Rf ommendation of the Institutional ethics committee (Fredrick
valueϭ0.645, Rm valueϭϪ0.2591. 1H-NMR (CDCl3) d: Institute of Plant Protection and Toxicology, Padappai 601
1.46—1.74 (s, 2H, –CH2–), 3.75—3.99 (s, 3H, 4Ј-OCH3), 301, Chennai, India).
6.66—7.49 (m, 18H, Ar–H). IR (KBr) cmϪ1: 1748 (CϭO),
Animals The animals were maintained in colony cages
1613 (CϭN), 1461 (CϭC), 1326 (–CH2–), 1280 (O–CH3), at 25Ϯ2 °C, relative humidity of 45—55%, maintained under
1268 (C–O), 799, 769, 689 (Ar–H). Anal. Calcd for 12 h light and dark cycle and were fed with standard animal
C28H23N3O2: C, 77.60; H, 5.33; N, 9.68. Found: C, 77.58; H, feed. All the animals were acclimatized for a week before
5.35; N, 9.70. UV lmax (EtOH) nm: 237, 244, 262, 290, 374.
1-Diphenylaminomethyl-3-(4-methylphenylimino)-1,3-di-
use.
Analgesic Activity The analgesic activity14) was deter-
hydroindol-3-one (7): Yieldϭ66%, mp 222—224 °C, Rf mined by the acetic acid induced writhing method using Wis-
valueϭ0.867, Rm valueϭϪ0.8168. 1H-NMR (CDCl3) d: tar albino mice (25—30 g) of either sex selected by random
1.37—1.80 (s, 3H, 4Ј-CH3), 2.09—2.62 (s, 2H, –CH2–), sampling technique. Paracetamol at a dose level of 100
6.55—7.56 (m, 18H, Ar–H). IR (KBr) cmϪ1: 1715 (CϭO), mg/kg was administered as standard drug for comparison.
1645 (CϭN), 1458 (CϭC), 1390 (C–H), 1325 (–CH2–), 819, The test compounds at 3 dose levels (25, 50, 100 mg/kg)
775, 746, 691 (Ar–H). Anal. Calcd for C28H23N3O: C, 80.51; were administered intraperitoneally 15 min prior to adminis-
H, 5.53; N, 10.10. Found: C, 80.55; H, 5.55; N, 10.07. UV tration of the writhing agent (0.6% v/v aqueous acetic acid,
l
max (EtOH) nm: 236, 261, 375.
1-Diphenylaminomethyl-indole-2,3-dione-3-phenyl hydra- served for 30 min and percentage protection was calculated
zone (8): Yieldϭ80%, mp 254—256 °C, Rf valueϭ0.499, for analgesic activity. The results are presented in Table 1.
1 ml/100 g). The writhings produced in the animal were ob-
1
Rm valueϭϪ0.0893. H-NMR (CDCl3) d: 1.43—1.81 (s,
Anti-inflammatory Activity The anti-inflammatory ac-
2H, –CH2–), 6.30—6.74, 6.80—6.99, 7.00—8.05 (m, 17H, tivity15) was determined by formalin induced pedal paw
Ar–H). IR (KBr) cmϪ1: 1785 (CϭO), 1685 (CϭN), 1480 edema method in Wistar albino rat (150—200 g) of either sex
(CϭC), 1465 (–CH2–), 1243 (N–H), 789, 779, 746, 689, 662 by using Plethysmograph. Diclofenac sodium (50 mg/kg)
(Ar–H). UV lmax (EtOH) nm: 234, 248, 285, 354. Anal. was administered as standard drug. The test compounds were

October 2001
1151
Table 1. Analgesic Activity (Writhing Reflex Method) and LD50 Data
Table 2. Anti Inflammatory Activity (Formalin Induced Paw Edema
Method)
Dose
Mean
%
LD50
(mg/kg)
Compd.
(mg/kg) WrithingsϮS.E.M. Protection
% Reduction of edema
Dose
Compd.
(mg/kg)
1
25
50
100
40.3Ϯ1.347
30.5Ϯ1.307
25.5Ϯ0.3903
0
675
663
830
783
718
715
700
863
878
675
15 min
30 min
45 min
60 min
120 min
23.75*
36.25
1
100
200
400
6.6
40†
6.6*
51.1†
55.6†
15.5***
55.6†
60†
6.6*
51.1†
55.6†
6.6*
51.1†
55.6†
64.4†
66.7†
71.1†
2
3
25
50
100
22.3Ϯ1.2172
17.8Ϯ0.4357
12.2Ϯ0.7233
44.18*
55.43*
69.58*
40†
2
100
200
400
23.3**
40†
48.9†
60†
60†
60†
64.4†
66.7†
64.4†
66.7†
25
50
100
30Ϯ0.527
21.8Ϯ1.0386
17.67Ϯ0.4513
25*
45.43*
55.83*
40†
66.7†
3
100
200
400
23.3**
26.6***
26.6***
42.2†
44.4†
51.1†
51.5†
55.5†
64.4†
44.4†
51.1†
60†
48.9†
55.5†
66.7†
51.1†
60†
4
25
50
100
24.3Ϯ1.0453
17Ϯ0.3333
12Ϯ0.527
39.18*
57.5*
70*
66.7†
4
100
200
400
16.7***
40†
55.5†
55.5†
60†
60†
60†
64.4†
71.1†
5
25
50
100
39.83Ϯ0.984
39.83Ϯ0.984
38.66Ϯ1.24
0.425
0.425
3.35
46.7†
66.7†
66.7†
5
100
200
400
0
0
0
0
4.1
4.4
4.4
4.4
4.4
0
4.2
4.2
4.3
4.4
4.4
6
25
50
100
40Ϯ0.527
40.33Ϯ1.045
39.5Ϯ0.391
0
0
1.25
6
100
200
400
0
6.6
6.6
4.2
3.8
4.2
4.4
3.8
4.4
55.6†
64.4†
66.7†
42.2†
48.9†
48.9†
42.2†
66.7†
66.7†
3.6
4.4
3.4
4.1
4.2
4.4
64.4†
66.7†
71.1†
42.2†
51.1†
55.6†
42.2†
66.7†
66.7†
7
25
50
100
24.2Ϯ0.7964
16.8Ϯ0.9255
12.8Ϯ0.5486
39.58*
57.93*
67.93*
7
100
200
400
23.3**
33.3†
56.6†
60†
60†
64.4†
66.7†
8
25
50
100
29Ϯ1.0541
22.5Ϯ1.0737
17.8Ϯ0.4357
27.5*
43.75*
55.43*
53.3†
64.4†
8
100
200
400
6.6
6.6
13.3***
37.8†
44.4†
48.9†
42.2†
48.9†
51.1†
44.4†
71.1†
71.1†
44.4†
48.9†
66.7†
9
25
50
100
23Ϯ0.6236
16.5Ϯ0.9654
13.8Ϯ0.6419
42.5*
58.75*
65.43*
9
10
100
200
400
13.3***
13.3***
13.3***
42.2†
60†
10
25
50
100
22.5Ϯ0.3909
18.2Ϯ0.8949
13Ϯ0.6666
43.75*
54.5*
67.5*
60†
100
200
400
6.7
6.7
6.7
33†
42.2†
44.4†
55.6†
42.2†
44.4†
64.4†
42.2†
44.4†
64.4†
Paracetamol
Control
100
—
07Ϯ0.666
40Ϯ0.626
82.5*
—
Diclofenac
50
75†
75†
75†
75†
Significance level: pϽ0.005 compared to control.
†
Significance levels: pϽ0.1,
control.
pϽ0.01,
pϽ0.05 and pϽ0.001 compared to
administered at 3 dose levels (100, 200, 400 mg/kg) intra-
peritoneally 30 min prior to administration of formalin
(0.1 ml of 1% w/v) in the plantar region of the paw. The paw gesic, antiinflammatory and antipyretic agent respectively.
volumes were measured at 15, 30, 60, 120 min after formalin Compounds 3 and 8 were inactive at the does of 50 mg/kg as
administration. The results are presented in Table 2.
an antipyretic agent. The compounds 3-(4-bromophenylim-
Antipyretic Activity The Antipyretic activity16) was de- ino)-1,3-dihydroindol-3-one and 3-(4-methoxyphenylimino)-
termined by experimentally induced pyrexia in rabbits 1,3-dihydroindol-3-one13) previously reported by us pos-
(0.95—1.1 kg) of either sex. Paracetamol (100 mg/kg) was sessed significant analgesic, antiinflammatory and antipyretic
administered as standard drug for comparison. The com- activity. 1-Substitution (diphenylamino methyl group) of the
pounds at 3 dose levels (50, 100 and 200 mg/kg) were admin- corresponding compounds to yield 5 and 6 were devoid of
istered subcutaneously prior to administration of 12% w/v of activity. This suggests that 1-substitution in isatin Schiff
suspended Brewer’s yeast (1 ml/100 g) subcutaneously. The bases (isatinϩprimary aromatic amine) may lead to decrease
normal rectal temperature of each animal was recorded be- or complete absence of activity if the amine is substituted
fore the administration of the compounds using telether- with strongly electrophilic or nucleophilic groups.
mometer. After administration of yeast, the rectal tempera-
1-Diphenylaminomethyl-3-(1-naphthylimino)-1,3-dihy-
ture of the rabbits were recorded at 30, 60, 90, 120, 150 and droindol-3-one (4), 3-(1-naphthylimino)-5-bromo-1,3-dihy-
180 min intervals. The results are presented in Table 3.
RESULTS AND DISCUSSION
droindol-2-one (2) and 1-diphenylaminomethyl-3-(4-methyl-
phenylimino)-1,3-dihydroindol-3-one (7) was found to ex-
hibit the highest analgesic, anti-inflammatory and antipyretic
activity respectively. 1-Diphenylaminomethyl-3-(4-methyl-
All the compounds except 5 and 6 exhibited analgesic, phenylimino)-1,3-dihydroindol-3-one (7) was found to be the
anti-inflammatory and antipyretic activities. It was observed most active compound of the series. The exhibited analgesic,
that the Mannich bases (9, 10) possess greater activity than anti-inflammatory and antipyretic activity of the compounds
the corresponding Schiff bases (1, 3). All the active com- may be probably due to its structurally similarity with In-
pounds exhibited graded dose response. Compound 1 was in- domethacin.
active at the does of 25, 100, and 50 to 100 mg/kg as an anal-

1152
Vol. 24, No. 10
Table 3. Antipyretic Activity (Yeast Induced Pyrexia Method)
Mean rise in body temperature (°C) ϮS.E.M.
Compd.
Dose (mg/kg)
30 min
60 min
90 min
120 min
150 min
180 min
1
50
100
200
0.5Ϯ0.0653
0.5Ϯ0.0839
0.5Ϯ0.0745
0.9Ϯ0.0509
0.9Ϯ0.0761
0.9Ϯ0.0694
1.5Ϯ0.0842
1.5Ϯ0.1072
1.2Ϯ0.0962***
2.2Ϯ0.0903
2.2Ϯ0.0965
1.8Ϯ0.0831**
2.4Ϯ0.1305
2.4Ϯ0.0965
1.7Ϯ0.077‡
2.9Ϯ0.1466
2.7Ϯ0.1074
2.0Ϯ0.0965‡
2
3
50
100
200
0.5Ϯ0.085
0.5Ϯ0.0694
0.5Ϯ0.1155
0.9Ϯ0.1269
0.9Ϯ0.0984
0.9Ϯ0.1363
1.3Ϯ0.1394
1.1Ϯ0.0943‡
0.9Ϯ0.1321‡
1.9Ϯ0.1434‡
1.4Ϯ0.1054‡
1.1Ϯ0.1558‡
1.6Ϯ0.1256‡
1.2Ϯ0.1321‡
1.3Ϯ0.1866‡
2.0Ϯ0.1571‡
1.6Ϯ0.1442‡
1.4Ϯ0.1447‡
50
100
200
0.5Ϯ0.0667
0.5Ϯ0.0408
0.6Ϯ0.0495
0.9Ϯ0.0471
0.9Ϯ0.0816
1.0Ϯ0.0304
1.5Ϯ0.0925
1.3Ϯ0.0796†
1.2Ϯ0.0761**
2.2Ϯ0.1217
1.6Ϯ0.1743**
1.6Ϯ0.085‡
2.4Ϯ0.1388
1.4Ϯ0.1575‡
1.4Ϯ0.0782‡
2.7Ϯ0.1484
1.8Ϯ0.1558‡
1.8Ϯ0.1054‡
4
50
100
200
0.5Ϯ0.0925
0.5Ϯ0.0561
0.5Ϯ0.0385
0.9Ϯ0.1247
1.0Ϯ0.0697
0.9Ϯ0.0408
1.3Ϯ0.1247*
1.3Ϯ0.0733***
0.9Ϯ0.0408***
1.7Ϯ0.1553
1.4Ϯ0.0451‡
1.0Ϯ0.0408‡
1.5Ϯ0.1551‡
1.5Ϯ0.0192‡
1.1Ϯ0.0471‡
1.9Ϯ0.1661‡
1.7Ϯ0.0304‡
1.3Ϯ0.0723‡
5
50
100
200
0.5Ϯ0.0745
0.5Ϯ0.0408
0.5Ϯ0.113
0.9Ϯ0.0191
0.9Ϯ0.0684
0.9Ϯ0.1363
1.5Ϯ0.108
1.5Ϯ0.0903
1.6Ϯ0.1409
2.2Ϯ0.1491
2.2Ϯ0.0962
2.3Ϯ0.1939
2.4Ϯ0.1472
2.3Ϯ0.1575
2.5Ϯ0.1743
2.7Ϯ0.1667
2.6Ϯ0.1442
2.7Ϯ0.1498
6
50
100
200
0.5Ϯ0.0761
0.5Ϯ0.0707
0.5Ϯ0.0782
0.9Ϯ0.0723
0.9Ϯ0.0495
0.9Ϯ0.0913
1.5Ϯ0.0863
1.5Ϯ0.0436
1.5Ϯ0.1028
2.2Ϯ0.0653
2.2Ϯ0.0549
2.2Ϯ0.1321
2.4Ϯ0.0903
2.4Ϯ0.0656
2.4Ϯ0.1368
2.7Ϯ0.1388
2.7Ϯ0.0863
2.7Ϯ0.1571
7
50
100
200
0.5Ϯ0.0882
0.5Ϯ0.0527
0.5Ϯ0.0451
0.9Ϯ0.1333
0.9Ϯ0.0495
0.9Ϯ0.0609
1.2Ϯ0.1606*
1.2Ϯ0.0624‡
0.9Ϯ0.0723‡
1.4Ϯ0.1862‡
1.1Ϯ0.0882‡
0.8Ϯ0.0642‡
1.5Ϯ0.1616‡
1.1Ϯ0.0831‡
0.7Ϯ0.0642‡
1.8Ϯ0.1472‡
1.3Ϯ0.0863‡
0.9Ϯ0.0925‡
8
50
100
200
0.5Ϯ0.0624
0.5Ϯ0.0694
0.5Ϯ0.0955
0.9Ϯ0.0782
0.9Ϯ0.085
0.9Ϯ0.1141
1.5Ϯ0.0850
1.2Ϯ0.0871**
1.2Ϯ0.113***
2.2Ϯ0.1072
1.7Ϯ0.1217‡
1.5Ϯ0.0984‡
2.5Ϯ0.0903
1.3Ϯ0.1347‡
1.1Ϯ0.085‡
2.8Ϯ0.0773
2.1Ϯ0.13‡
1.8Ϯ0.1141‡
9
50
100
200
0.5Ϯ0.0609
0.5Ϯ0.0863
0.6Ϯ0.0561
0.9Ϯ0.0658
0.9Ϯ0.0984
1.0Ϯ0.0842
1.3Ϯ0.0697***
1.1Ϯ0.1045
1.8Ϯ0.0612‡
1.4Ϯ0.1262‡
1.0Ϯ0.0509‡
1.2Ϯ0.1748‡
1.2Ϯ0.1347‡
0.8Ϯ0.0565‡
1.7Ϯ0.1832‡
1.6Ϯ0.1347‡
1.1Ϯ0.0656‡
0.9Ϯ0.0451‡
10
50
100
200
100
—
0.5Ϯ0.0304
0.5Ϯ0.0327
0.5Ϯ0.0408
0.1Ϯ0.0667‡
0.5Ϯ0.0882
0.9Ϯ0.0385
0.9Ϯ0.0385
0.9Ϯ0.0408
0.2Ϯ0.066‡
0.9Ϯ0.1106
1.3Ϯ0.0871†
1.1Ϯ0.0597‡
0.8Ϯ0.0597‡
0.2Ϯ0.1‡
1.7Ϯ0.0805‡
1.2Ϯ0.0863‡
0.7Ϯ0.0723‡
0.1Ϯ0.0408‡
2.2Ϯ0.1667
1.6Ϯ0.0656‡
1.0Ϯ0.1018‡
0.6Ϯ0.1018‡
0.2Ϯ0.0782‡
2.4Ϯ0.1155
1.8Ϯ0.1194‡
1.5Ϯ0.0913‡
1.1Ϯ0.0991‡
0.3Ϯ0.0781‡
2.7Ϯ0.0782
Paracetamol
Control
1.5Ϯ0.1564
†
‡
Significance levels: pϽ0.1, pϽ0.01,
pϽ0.025, pϽ0.05 and pϽ0.005 compared to control.
8) Popp F. D., Pajouhesh H., J. Pharm. Sci., 71, 1052—1054 (1982).
9) Singh G. S., Singh T., Lakhan R., Indian J. Chem., 36B, 951—954
(1997).
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