Structure Activity
Relationship Studies of Synthesised Schiff Bases and Mannich Bases of Substituted 5-Methyl-1, 2-Dihydro-3H-Pyrazol-3-One
Derivatives Having Variable Electronegative Atoms for Antioxidant Screening
Urviben Yashodharbhai Patel, Ravi Natvarlal
Patel, Dhrubo Jyoti Sen and R. Badmanaban
Department of Pharmaceutical
Chemistry and Phytochemistry, Shri Sarvajanik Pharmacy College, Hemchandracharya
North Gujarat University, Arvind Baug,
Mehsana-384001, Gujarat, India,
ABSTRACT:
The proposed project has been designed for structure
activity relationship by the Schiff base and Mannich
base of substituted 5-methyl-1,2-dihydro-3H-pyrazol-3-one
derivatives for antioxidant screening.
The scheme for synthesis has been designed to synthesise 5-methyl-1,2-dihydro-3H-pyrazol-3-one molecule
is done by reacting ethyl acetoacetate with hydrazine
and then by benzoylation in basic medium produced
1,2-dibenzoyl derivative of the heterocyclic ring. Further condensation with
hydrazine with this heterocyclic ring produced Schiff base at three positions
where free ketone group is present. This tri-Schiff
base has been condensed with various ketone compounds
to produce Schiff base of R1/R2 at three positions as
well as the same tri-Schiff bas on condensation with benzaldehyde with urea/thiourea/guanidine produced Mannich
bases ath three positions for X=O/S/NH. The synthesised compounds have been characterized by N% and UV,
IR, NMR and Mass Spectra. The antioxidant screening is based on the iodine spot
activity of synthesised compounds by zone diameter
calculation. It has been observed that in Mannich
bases derivatives guanidine derivative (Compound-7) showed maximum antioxidant
activity. The profile for the antioxidant activity is:
Compound-7(X=NH)>Compound-6(X=S)>Compound-5(X=O). It happens due to the electronegativity: NH=3.1+2.2=5.3; S=2.4; O=3.5. Here “N”
has one lone pair of electrons whereas “O” and “S” has two lone pair of
electrons but the electronegativity of “NH” is
maximum in comparison to “S” and “O” which both have two lone pair of electrons
but the electronegativity of “S” is lower that “O” so
the antioxidant profile showed a very good satisfactory result. In case of
Schiff bases the butanone derivative (Compound-4) showed maximum antioxidant
activity. The profile for the antioxidant activity is: Compound-4(R1=CH3,R2=C2H5)>Compound-1(R1=R2=CH3)>Compound-3(R1=R2=C6H5)>Compound-2(R1=CH3,R2=C6H5).
It happens due to the presence of CH3+C2H5=3
carbons in alipahtic chain in case of Compound-4(R1=CH3,R2=C2H5)
but in case of Compound-1(R1=R2=CH3), here CH3+CH3=2
carbons in aliphatic chain, in Compound-3(R1=R2=C6H5),
here C6H5+C6H5=12 carbons in
aromatic ring and in Compound-2(R1=CH3,R2=C6H5),
here CH3+C6H5=7 carbons in alipahtic
and aromatic ring. Compound-4(R1=CH3,R2=C2H5)
of Schiff base is more active than Mannich base of
Compound-7(X=NH) in antioxidant activity.
KEYWORDS: Schiff
base, Mannich base, Pyrazol-3-one, Antioxidant study
The scheme for synthesis has been designed to synthesise 5-methyl-1,2-dihydro-3H-pyrazol-3-one molecule is done by reacting ethyl acetoacetate with hydrazine and then by benzoylation
in basic medium produced 1,2-dibenzoyl derivative of the heterocyclic ring.
Further condensation with hydrazine with this heterocyclic ring produced Schiff
base at three positions where free ketone group is
present. This tri-Schiff base has been condensed with various ketone compounds to produce Schiff base of R1/R2
at three positions as well as the same tri-Schiff bas on condensation with
benzaldehyde with urea/thiourea/guanidine produced Mannich bases ath three positions
for X=O/S/NH. The synthesised compounds have been
characterized by N% and UV, IR, NMR and Mass Spectra1-9.
Experimental
Part:
Compounds:
1-4: Ethyl acetoacetate
(ethyl-3-oxo-butanoate) has been condensed with hydrazine in 1:1 molar ratio in
heating condition to get the 5-methyl-1,2-dihydro-3H-pyrazol-3-one which has been crystallised
in aqueous ethanol to get 76.% yield (m.p. 219-219°C). This in basic medium
reacted with benzoyl chloride 1:2 molar ratio to get
1,2-dibenzoyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one, which has been crystallised by aqueous ethanol to get (81% yield; m.p.
108°C). This on reaction with hydrazine in 1:3 molar ratio in heating obtained
Tri-Schiff base (70% yield; m.p. 118°C) to go for two synthetic route for desigining final Compounds:
1-4 of Schiff base moiety and Compounds:
5-7 of Mannich base moiety. Tri-Schiff base has
been refluxed with acetone for Compound-1,
with acetophenone for Compound-2, with benzophenone for Compound-3 and with methyl-ethyl ketone for Compound-4
in 1:3 molar ratio to get the product. The products
have been cryslattised in aqueous ethanol to get the
pure product Compound-1: 70% yield
(mp 112-113°C), Compound-2: 81%
yield (mp 89-90°C), Compound-3: 75%
yield (mp 59-60°C), Compound-4: 40%
yield (mp 183-184°C).
Compounds:
5-7: Tri-Schiff base has been refluxed
with benzaldehyde and urea for Compound-5,
with thiourea for Compound-6 and with guanidine for Compound-7 in 1:3 molar ratio and the synthesised
products have been crystallised with aquous ethanol to get Compound-5:
76% yield (mp 118-119°C), Compound-6:
55% yield (mp 115-118°C), Compound-7: 75% yield (mp 70-72°C).
Molecular Design
COMPOUND-1: Acetone Derivative: R1=R2=CH3 3-D
structure\
COMPOUND-2: Acetophenone
Derivative: R1=CH3, R2=C6H5 3-D
structure
COMPOUND-3: Benzophenone
Derivative: R1=R2=C6H5 3-D structure
COMPOUND-4: Methyl ethyl ketone Derivative: R1=CH3, R2=C2H5
3-D structure
COMPOUND-5: Urea Derivative: X=O 3-D
structure
COMPOUND-6: Thiourea
Derivative: X=S 3-D
structure
COMPOUND-7: Guanidine Derivative: X-NH 3-D
structure
Table-1: PHYSICOCHEMICAL PARAMETERS
|
Compounds |
% Yield |
Melting Point °C |
Molecular Formula |
N% Found |
N% Calcd |
|
COMPOUND-1 (R1=R2=CH3) |
70 |
112-113 |
C27H32N8 |
23.87 |
23.91 |
|
COMPOUND-2 (R1=CH3,
R2=C6H5) |
81 |
89-90 |
C42H38N8 |
17.09 |
17.11 |
|
COMPOUND-3 (R1=R2=C6H5) |
75 |
59-60 |
C57H44N8 |
13.29 |
13.32 |
|
COMPOUND-4 (R1=CH3,
R2=C2H5) |
40 |
183-184 |
C30H38N8 |
21.91 |
21.94 |
|
COMPOUND-5 (X=O) |
76 |
118-119 |
C42H44N14O3 |
24.69 |
24.73 |
|
COMPOUND-6 (X=S) |
55 |
115-118 |
C42H44N14S3 |
23.28 |
23.31 |
|
COMPOUND-7 (X-NH) |
75 |
70-72 |
C42H47N17 |
30.11 |
30.14 |
Histogram of Physicochemical parameters
UV Spectras:
Ultraviolet Spectras have been recorded in instrument
and λmax of all the synthesized compounds are
given in the Table-2
Table-2
|
Compounds |
λ max (nm) |
|
COMPOUND-1 (R1=R2=CH3) |
277 |
|
COMPOUND-2 (R1=CH3, R2=C6H5) |
299 |
|
COMPOUND-3 (R1=R2=C6H5) |
250 |
|
COMPOUND-4 (R1=CH3, R2=C2H5) |
272 |
|
COMPOUND-5 (X=O) |
264 |
|
COMPOUND-6 (X=S) |
266/299 |
|
COMPOUND-7 (X-NH) |
300 |
HISTOGRAM OF λmax
COMPOUND-1
COMPOUND-2
COMPOUND-3
COMPOUND-4
COMPOUND-5
COMPOUND-6
COMPOUND-7
IR Spectras: Infra-Red Spectras have been recorded in Shimadzu FT-IR instrument
and υ values in cm-1 have been recorded.
COMPOUND-1
IR (KBr): Aromatic (Ar-, 3051), C-N streching (C=N-, 1645, 1660), tertiary N (=N-, 1190, 1290)
COMPOUND-2
IR (KBr): Aromatic (Ar-, 3051), C-N streching (C=N-, 1645, 1626), tertiary N (=N-, 1210)
COMPOUND-3
IR (KBr): Aromatic (Ar-, 3014, 3086, 3055, 3082), C-N streching
(C=N-, 1645), tertiary N (=N-, 1276, 1311)
COMPOUND-4
IR (KBr): Aromatic (Ar-, 3055), C-N streching (C=N-, 1645, 1660, 1676, 1691), tertiary
N (=N-, 1100)
COMPOUND-5
IR (KBr): Aromatic (Ar-, 3024, 3051), Ketone (-C=O-, 1645, 1700, 1758), -NH- streching (-NH-, 1290, 1180, 1190), tertiary N (=N-, 1190, 1290)
COMPOUND-6
IR (KBr): Aromatic (Ar-, 3026, 3051), C-N streching (-C=N-, 1627, 1645), -NH- streching (-NH-, 1305, 1213), -CS- streching (-C=S-, 1213, 1072)
COMPOUND-7
IR (KBr): Aromatic (Ar-, 3028, 3055, 3082, 3097), C-N
streching (-C=N-, 1627, 1645), -NH-
streching (-NH-, 1170, 1211, 1290,
1303, 1319), -CN- streching (-C=S-,
2210, 2320, 2350)
NMR Spectras: NMR
COMPOUND-2: Acetophenone Derivative: R1=R2=CH3
Compound-2: 1H-NMR: δ: 8.66 (5, H, pyrazole-H), 7.82-7.84 (m, 4H, CH3), 7.0-7.44 (m, 7H, Ar-H)
COMPOUND-7: Guanidine Derivative: X-NH
Compound-7:
1H-NMR: δ: 7.2 (5, 2H, NH2),
7.39-7.44 (m, 10H, NH-NH2),
7.82-7.85 (m, 5H, Ar-H), 8.66 (s, H, pyrazole-H)
Mass Spectras:
COMPOUND-2: Acetophenone
Derivative: R1=R2=CH3
Compound-2:
M+=654.80, (M+1: 654.32, M-77: 577.0, M-15: 636.9, M-60: 593.0,
M-118: 537.0, M-65: 587.0)
COMPOUND-7: Guanidine Derivative: X-NH
Compound-7:
M+=789.41, (M-77: 715, M-58: 731, M-135: 654, M-15: 774, M-93: 696,
M-65: 724.0)
Antioxidant Screening:
The
antioxidant screening is based on the iodine spot activity of synthesised compounds by zone diameter calculation. Iodine solubilised in potassium iodide has been spotted in the
Whatman filter paper as 1000 µg/ml
concentration and the test samples have been spotted in various conectrations 100, 200, 300, 400 µg/ml concentrations and
zone diameter for antioxidant activity have been recorded in the Table-3 along
with the histogram10-11.
Table-3
|
Compounds |
Concentration
(µg/ml) |
Zone diameter for oxidation (mm) |
|
COMPOUND-1 (R1=R2=CH3) |
100 |
20 |
|
200 |
27 |
|
|
300 |
38 |
|
|
400 |
41 |
|
|
1000 (stock) |
50 |
|
|
COMPOUND-2 (R1=CH3,
R2=C6H5) |
100 |
20 |
|
200 |
25 |
|
|
300 |
31 |
|
|
400 |
37 |
|
|
1000 (stock) |
45 |
|
|
COMPOUND-3 (R1=R2=C6H5) |
100 |
21 |
|
200 |
27 |
|
|
300 |
32 |
|
|
400 |
39 |
|
|
1000 (stock) |
46 |
|
|
COMPOUND-4 (R1=CH3,
R2=C2H5) |
100 |
26 |
|
200 |
37 |
|
|
300 |
42 |
|
|
400 |
52 |
|
|
1000 (stock) |
58 |
|
|
COMPOUND-5 (X=O) |
100 |
18 |
|
200 |
25 |
|
|
300 |
32 |
|
|
400 |
38 |
|
|
1000 |
44 |
|
|
COMPOUND-6 (X=S) |
100 |
21 |
|
200 |
28 |
|
|
300 |
40 |
|
|
400 |
42 |
|
|
1000 (stock) |
50 |
|
|
COMPOUND-7 (X-NH) |
100 |
25 |
|
200 |
35 |
|
|
300 |
45 |
|
|
400 |
48 |
|
|
1000 (stock) |
60 |
RESULTS AND DISCUSSION:
Antioxidant
Screening: It has been observed that
in Mannich bases derivatives guanidine derivative
(Compound-7) showed maximum antioxidant activity. The profile for the
antioxidant activity is:
Compound-7(X=NH)>Compound-6(X=S)>Compound-5(X=O). It happens due to the electronegativity: NH=3.1+2.2=5.3; S=2.4; O=3.5. Here “N”
has one lone pair of electrons whereas “O” and “S” has two lone pair of
electrons but the electronegativity of “NH” is
maximum in comparison to “S” and “O” which both have two lone pair of electrons
but the electronegativity of “S” is lower that “O” so
the antioxidant profile showed a very good satisfactory result. In case of
Schiff bases the butanone derivative (Compound-4) showed maximum antioxidant
activity. The profile for the
antioxidant activity is: Compound-4(R1=CH3,R2=C2H5)>Compound-1(R1=R2=CH3)>
Compound- 3(R1=R2=C6H5)> Compound-2(R1=CH3,R2=C6H5).
It happens due to the presence of CH3+C2H5=3
carbons in alipahtic chain in case of Compound-4(R1=CH3,R2=C2H5)
but In case of Compound-1(R1=R2=CH3), here CH3+CH3=2
carbons in aliphatic chain, in Compound-3(R1=R2=C6H5),
here C6H5+C6H5=12 carbons in
aromatic ring and in Compound-2(R1=CH3,R2=C6H5),
here CH3+C6H5=7 carbons in alipahtic
and aromatic ring. Compound-4(R1=CH3,R2=C2H5)
of Schiff base is more active than Mannich base of
Compound-7(X=NH) in antioxidant activity.
ACKNOWLEDGEMENT:
The
authors Urviben Y. Patel and Ravi Natvarlal
Patel are thankful to the project guide Prof. Dr. Dhrubo
Jyoti Sen and the staff
members of Shri Sarvajanik
Pharmacy College, Mehsana, Gujarat to fulfil the project successfully. All the authors are thankful
to the Quality Assurance Department of Shri Sarvajanik Pharmacy College, Mehsana
for UV and IR spectrals datas,
Oxygen Healthcare, Ahmedabad for Mass spectral data and Panjab
University, Chandigarh for NMR spectral datas.
REFERENCES:
1.
Akbari J. D, Mehta K.B., Pathak
S.J. and Joshi, H.S., Synthesis and antimicrobial activity of some new pyrazolo[3,4-d]pyrimidines and thiazolo[4,5-d]pyrimidines, Indian J. Chem-B,
47B(03), 477-480, 2008.
2.
Nirmal R., Prakash C.R., Meenakshi K. and Shanmugapandiyan
P., Synthesis and pharmacological evaluation of novel schiff
base analogues of 3-(4-amino) phenylimino)
5-fluoroindolin-2-one, Journal of Young
Pharmacists, 2(2), 162-168, 2010.
3.
Hou H., Zhu
J., Yi Y. and Li Q., Antibacterial Activity of a Kind of Novel Schiff Base
and Its 3d,4f Complexes, Acta Physico-Chimica Sinica, 23(7), 987-992, 2007.
4.
Pandeya S.N., Sriram D., Nath G. and De E.C., Synthesis, Antibacterial, Antifungal
and Anti-HIV activity of Schiff and Mannichbases of Isatin with N-[6-Chlorobenzothiazol-2-yl]Thiosemicarbazide, Indian
Journal of Pharmaceutical Sciences, 61(6), 358-361, 1999.
5.
Pandeya S.N., Yogeeshwari P., Sriram D. and Nath G., Synthesis,
Antibacterial and Antifungal Activities Of N-Mannich Bases Of 3-(N2- Pyrimethaminylimino)
Isatin, Indian
Journal of Pharmaceutical Sciences 64(3), 209-212, 2002.
6.
Patel D.M. and
Sen D.J., Synthesis and antimicrobial screening by
SAR studies of synthesized chalcone derivatives
having heterocyclic rings: International
Journal of Pharmaceutical Sciences; 1(1),
35-41, 2009.
7.
Prajapati M.K. and Sen D.J.,
Synthesis and SAR study of some new 2-Imino-3-[carboxamido
p-hydroxyphenyl]-5-arylidene-4-thiazolidinone as
antimicrobial agents: International
Journal of Pharmaceutical Sciences; 1(1),
83-90, 2009.
8.
Prajapati P.M. and Jyoti Sen D.J., Synthesis and antimicrobial screening of piperidone derivative with pyrazolone
substituents: The
Manufacturing Pharmacist; 02(07), 37-44, 2010.
9.
Patel H.R., Patel P.K., Sen D.J. and Patel
A.H., Growth inhibition of microorganism by bioisosterism: International
Journal of Drug Development and Research: 2(1), 190-196, 2010.
10. Shah
Y.R. and Sen D.J., Schiff’s bases of piperidone derivatives as fungal growth inhibitors: The Manufacturing Pharmacist: 2(09),
37-44, 2010.
11. Chavda D.R., Modiya
P.R., Marvaniya H.M. and Sen
D.J.; Synthesis and chemistry of pyrazolone with pyrimidine ring and screening of antioxidant activity of synthesised heterocyclic nucleus having urea/thiourea/guanidine linkages: International Journal of Drug Development and Research; 2(2): 348-355, 2010.
Received on 30.12.2010
Accepted on 12.01.2011
© A&V Publication all right reserved
Research
J. Science and Tech. 3(2): Mar.-April.
2011: 99-110