Synthesis, characterization and antihypertensive activity of some new substituted pyridazine derivatives

Article abstract of DOI:10.4067/S0717-97072011000400006

Some new 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5- dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-i) were screened for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e and 4i showed appreciable antihypertensive activity.

Full text of DOI:10.4067/S0717-97072011000400006

J. Chil. Chem. Soc., 56, Nº 4 (2011)
SYNTHESIS, CHARACTERIZATION AND ANTIHYPERTENSIVE ACTIVITY OF SOME NEW SUBSTITUTED
PYRIDAZINE DERIVATIVES
RAVINESH MISHRA*a, ANEES A. SIDDIQUIb, ASIF HUSAINb, MOHD RASHIDb, ATISH PRAKASHa, MUKUL
TAILANGa, MUNEESH KUMARc, NEETI SRIVASTAVAc
*aInstitute of Pharmacy & Emerging Sciences, Baddi University of Emerging Science & Technology, Makhnumajra, Baddi, Distt. Solan, H.P.-173205, India.
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard, Hamdard Nagar, New Delhi 110 062, India.
cNKBR College of Pharmacy & Research Centre, Meerut-Hapur Road, Phaphunda, Meerut (U.P.)-245 206, India.
(Received: September 28, 2010 - Accepted: October 17, 2011)
ABSTRACT
Some new 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were
synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-i) were screened for antihypertensive activities by
non-invasive method using Tail Cuff method. The compounds 4e and 4i showed appreciable antihypertensive activity.
Key words: Pyridazine, Antihypertensive activity, Non invasive tail-cuff method.
To a solution of substituted β-aroyl propionic acids (0.01 mol) in ethanol
(30 mL) were added carbohydrazide (0.01 mol) and sodium acetate, and the
mixture was refluxed for 6 h. After completion of the reaction, ethanol was
distilled off and the residue was poured into cold water. The solid which
separated was filtered and washed with water. The product was dried in air and
crystallized from ethanol23.
Synthesis of 6-(substituted-phenyl)-2-(4-substituted-phenyl-5-thioxo-
4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one
derivatives 4(a-i)
A ethanolic solution of 6-oxo-3-substituted-phenyl-5,6-dihydropyridazine-
1(4H)-carbohydrazide (0.01 mole) and aromatic isothiocyanate (0.01 mole)
was refluxed for 4 hours. The contents were concentrated and poured into
crushed ice, filtered and dried to crude thiosemicabazide intermediates as
6-substituted-phenyl-2-(N-phenylthiosemicarbazido)-4,5-dihydropyridazin-
3(2H)-one derivatives 3(a-i). Crude thiosemicarbazide intermediates (0.005
mole) was refluxed in 2M sodium hydroxide solution (20 ml) for 5 hours,
cooled, poured into excess of water with continuous stirring and filtered to get
the final compound. The filtrate on acidification with glacial acetic acid yielded
a solid and recrystallized from ethanol.
INTRODUCTION
Hypertension is the most common cardiovascular disease and is the major
risk factor for coronary artery disease leading to myocardial infarction and
sudden cardiac death, heart failure, stroke and renal failure1. Great efforts
have been made on obtaining novel antihypertensive agents acting on different
mechanisms to control blood pressure2. The studies on the hydralazine
group drugs led to the synthesis of many pyridazine derivatives with a wide
activity spectrum on cardiovascular system3. Pyridazine derivatives, a class of
compounds containing the N-N bond, exhibit a wide range of pharmacological
activities such as antidepressant4, antihypertensive5-8
,
antithrombotic9,
anticonvulsant10, cardiotonic11, antibacterial12, diuretics13, antiHIV14 and
anticancer15. Some pyridazinone derivatives like indolidan16, bemoradan17,
primobendan18, levosimendan19 (antihypertensive), already approved in
the clinical market. The current work describes the synthesis of some new
substituted pyridazine derivatives with encouraging antihypertensive activity
by non-invasive method using Tail Cuff method.
EXPERIMENTAL
6-Phenyl-2-[4-(4-methoxyphenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one, 4a, Yield: 80%;m.p. 182-184
ºC; Rf 0.45; IR (KBr) υmax (cm-1): 3323 (NH), 2930 (CH), 2368 (C=S), 1685
Melting points were determined by open tube capillary method and
are uncorrected. Purity of the compounds was checked by thin layer
chromatography (TLC) method. The FT-IR spectra were recorded on Bio-
rad FTS-135 spectrophotometer using KBr pellets; υmax values are given in
1
(C=O), 1607 (C=N), 1030; H-NMR (δ) CDCl3: 2.38 (s, 3H, OCH3), 2.54 (t,
2H, CH2), 2.99 (t, 2H, CH2), 7.13-7.93 (m, 9H, Ar-H), 10.78 (s, 1H, CSNH);
13C-NMR: 24.1, 32.6, 55.8, 114.6, 125.1, 128.2, 128.8, 131, 133.7, 143, 147.9
(C=N), 166.7 (C=S), 172.8 (C=O); Mass (m/z): 379/380 (M+/M++1); Anal
Calc. for C19H17N5O2S: C: 60.14; H: 4.52; N: 18.46. Found: C: 60.32; H: 4.22;
N: 18.26.
6-Phenyl-2-[4-(4-bromophenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one, 4b, Yield: 86%; m.p. 150-
152 ºC; Rf 0.48; IR (KBr) υmax (cm-1): 3330 (NH), 2922 (CH), 2365 (C=S), 1665
(C=O), 1612 (C=N), 1025, 817; 1H-NMR (δ) CDCl3: 2.48 (t, 2H, CH2), 2.99 (t,
2H, CH2), 7.13-7.93 (m, 9H, Ar-H), 10.82 (s, 1H, CSNH); 13C-NMR: 24.2, 32.5,
122.7, 128.2, 128.8, 129, 131, 131.8, 135.6, 136.4, 143, 147.8 (C=N), 166.7
(C=S), 172.5 (C=O); Mass (m/z): 428 (M+); Anal Calc. for C H14BrN5OS: C:
50.48; H: 3.29; N: 16.35. Found: C: 50.76; H: 3.56; N: 16.22.18
6-Phenyl-2-[4-(3-methylphenyl)-5-thioxo-4,5-dihydro-1H-1,2,4-
triazol-3-yl]-4,5 dihydropyridazin-3(2H)-one, 4c, Yield: 60%; m.p. 188-190
ºC; Rf 0.46; IR (KBr) υmax (cm-1): 3452 (NH), 2926 (CH), 2360 (C=S), 1648
(C=O), 1600 (C=N); 1H-NMR (δ) CDCl3: 2.40 (s, 3H, CH ), 2.62 (t, 2H, CH2),
3.2 (t, 2H, CH2), 7.2-7.80 (m, 9H, Ar-H), 10.76 (s, 1H,3 CSNH); 13C-NMR:
21.3, 24.1, 32.6, 125, 128.2, 128.8, 128.9, 130, 133.8, 136.4, 138.7, 143, 147.9
(C=N), 166.7 (C=S), 172.5 (C=O); Mass (m/z): 363/364 (M+/M++1). Anal
Calc. for C19H17N5OS: C: 62.79; H: 4.71; N: 19.27. Found: C: 62.78; H: 4.66;
N: 19.02.
cm-1. H-NMR spectra were recorded on Bruker Spectrospin DPX 300 MHz
1
using CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard.
Chemical shifts are given in δ (ppm) scale and coupling constants (J values)
are expressed in Hz. The FAB Mass spectra were obtained on JEOL-JMS-
DX 303 system, equipped with direct inlet probe system. Elemental analysis
was carried out on CHNS Elementar (Vario EL III) using sulphanilic acid as a
standard and tugsten (VI) oxide as a combusting agent and analyses for C, H,
and N were within ±0.4% of the theoretical values.
General procedure for the synthesis of β-aroylpropionic acids 1(a-c)
To liquid aromatic hydrocarbon (30 mL), anhydrous aluminum chloride
(16.6 g, 0.125 mol) was added. The mixture was stirred using a magnetic
stirrer at room temperature for 30 min. To this, succinic anhydride (5 g, 0.05
mol) was added in five portions with continuous stirring. Vigorous reaction
started with the evolution of HCl gas. Stirring was continued for another 6 h at
room temperature. The mixture was left at room temperature for 48 h and then
decomposed by adding ice-cold hydrochloric acid (50%, 100 mL). The excess
solvent was removed by steam distillation. The precipitated solid was treated
with saturated sodium bicarbonate solution, filtered, washed with cold water,
dried, and crystallized from the appropriate solvent to give 1a-c21,22
General procedure for the synthesis of 6-Oxo-3-substituted-phenyl-
5,6-dihydropyridazine-1(4H)-carbohydrazide 2(a-c)
.
e-mail: ravi_kcp@rediffmail.com
856

J. Chil. Chem. Soc., 56, Nº 4 (2011)
6-(4-Methylphenyl)-2-(4-methoxyphenyl-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one, 4d, Yield: 90%; m.p.
194-196 ºC; Rf 0.52; IR (KBr) υmax (cm-1): 3426 (NH), 3094 (CH), 2365 (C=S),
acetate (20 mg/kg/wk) for 2 weeks as per method reported by Krakoff et al.24.
Measurement of mean blood pressure of rats
Mean arterial blood pressure was measured in conscious rats using
CODA Non Invasive Blood Pressure Recorder by Tail–Cuff method (Kent
Scientific Corporation, USA). The restrainer carrying the rat was placed in the
BP instrument with tail protruding out. The tail was gently placed in contact
with a transducer membrane, which was connected to the digital BP display
panel. The instrument was then turned on and allowed to stabilize until steady
pulse rate was observed. Once the ‘‘pulse level ready’’ signal appeared, the BP
recording button was pressed and the mean arterial BP was recorded. Albino
rats (body weight 200–250 g) were used in present study. Rats were assigned
to groups of four animals in each. Each compound (20 mg/kg body weight)
was injected intraperitoneally after suspending in 1% carboxymethyl cellulose
(CMC) solution. The mean arterial blood pressure was recorded after 1 h.
Statistical analysis of data
The statistical analysis was performed using GRAPHPAD INSTAT 3
software (Graph Pad Software Inc, San Diego, CA). Data obtained from animal
experiments were expressed as arithmetic mean ± SEM. The comparison
between various groups was performed by one-way analysis of variance
(ANOVA), and the effect in treatment groups were compared with toxic
control group by Dunnet multiple comparison test. p < 0.05 was considered to
be significant [*p < 0.05; **p < 0.01]. The percentage reduction in MABP for
all the treatment groups was also calculated and compared.
1
1658 (C=O), 1612 (C=N), 809, 699; H-NMR (δ) CDCl : 2.30 (s, 3H, CH3),
2.40 (s, 3H, OCH ), 2.44 (t, 2H, CH2), 2.96 (t, 2H, CH23), 7.21-7.64 (m, 8H,
Ar-H), 10.82 (s, 13H, CSNH); 13C-NMR: 21.2, 24.1, 32.6, 55.8, 114.6, 125.1,
127, 128.2, 128.8, 128.9, 129.3, 130, 133.4, 136.4, 138.7, 140.7, 142.9, 147.6
(C=N), 159.3, 166.6 (C=S), 172.4 (C=O); Mass (m/z): 393/394 (M+/M++1);
Anal Calc. for C20H19N5O2S: C: 61.05; H: 4.87; N: 17.80. Found: C: 59.84; H:
4.62; N: 17.56.
6-(4-Methylphenyl)-2-[4-(4-bromophenyl)-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one, 4e, Yield: 88%; m.p.
210-212 ºC;, Rf 0.62; IR (KBr) υm1ax (cm-1): 3215 (NH), 2929 (CH), 2364 (C=S),
1682 (C=O), 1615 (C=N), 760; H-NMR (δ) CDCl : 2.34 (s, 1H, CH ), 2.48
(t, 2H, CH2), 2.96 (t, 2H, CH2), 3.20 (t, 2H, CH2), 37.13-7.93 (m, 8H,3Ar-H),
10.74 (s, 1H, CSNH); 13C-NMR: 21.3, 24.3, 32.6, 122.7, 128.3, 128.8, 129.2,
131, 131.7, 135.5, 136.6, 143.1, 147.7 (C=N), 166.8 (C=S), 172.8 (C=O); Mass
(m/z): 442 (M+); Anal Calc. for C19H16BrN5OS: C: 51.59; H: 3.65; N: 15.83.
Found: C: 51.25; H: 3.96; N: 15.52.
6-(4-Methylphenyl)-2-[4-(3-methylphenyl)-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one, 4f, Yield: 72%; m.p.
202-204 ºC; Rf 0.48; IR (KBr) υmax (cm-1): 3450 (NH), 2924 (CH), 2352 (C=S),
1662 (C=O), 1602 (C=N); 1H-NMR (δ) CDCl3: 2.30 (s, 3H, CH3), 2.40 (s, 3H,
CH3), 2.52 (t, 2H, CH2), 2.96 (t, 2H, CH ), 7.21-7.23 (dd, 2H, J=7.8, H-3’,
H-5’), 7.34-7.40 (m, 4H, Ar-H), 7.61-7.642(dd, 2H, J=7.8, H-2’, H-6’), 10.84
(s, 1H, CSNH); 13C-NMR: 21.3, 24.1, 32.6, 125, 127, 128.9, 129.2, 130, 134,
133.8, 138.7, 143, 166.7, 172.5; Mass (m/z): 377/378 (M+/M++1). Anal Calc.
for C H19N5OS: C: 63.64; H: 5.07; N: 18.55. Found: C: 63.58; H: 4.88; N:
18.462.0
6-(4-Methoxyphenyl)-2-(4-methoxyphenyl-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one, 4g, Yield: 92%; m.p.
172-174 ºC, Rf 0.54; IR (KBr) υmax (cm-1): 3471 (NH), 2926 (CH), 2374 (C=S),
1647 (C=O), 1612 (C=N), 1092, 794; 1H-NMR (δ) CDCl : 2.40 (s, 3H, OCH3),
2.58 (t, 2H, CH2), 2.96 (t, 2H, CH2), 3.67 (s, 3H, CH33O), 7.0-7.94 (m, 8H,
Ar-H), 10.86 (s, 1H, CSNH); 13C-NMR: 24.1, 32.6, 55.8, 114.4, 114.6, 125.1,
128.7, 133.7, 143, 147.9, 159.3, 162.9, 166.7; Mass (m/z): 409/410 (M+/M++1);
Anal Calc. for C20H19N5O3S: C: 58.67; H: 4.68; N: 17.10. Found: C: 58.42; H:
4.48; N: 17.40.
RESULTS AND DISCUSSION
Chemistry
The synthesis of some new 1,2,4-triazole derivatives of 4,5-dihydro-
3(2H)-pyridazinone has been carried out according to the steps shown in the
Figure 1.
6-(4-Methoxyphenyl)-2-[4-(4-bromophenyl)-5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one, 4h, Yield: 85%;
º
m.p. 188-190 C; Rf 0.56; IR (KBr) υmax (cm-1): 3499 (NH), 2920 (CH), 2360
(C=S), 1638 (C=O), 1562 (C=N), 801; 1H-NMR (δ) CDCl3: 2.62 (t, 2H, CH2),
2.94 (t, 2H, CH2), 3.82 (s, 3H, CH3O), 7.12-7.96 (m, 8H, Ar-H), 10.72 (s, 1H,
CSNH); 13C-NMR: 24.2, 32.5, 55.8, 122.7, 128.2, 128.8, 129, 131, 131.8,
135.6, 136.4, 143, 147.8 (C=N), 166.7 (C=S), 172.5 (C=O); Mass (m/z): 458
(M+); Anal Calc. for C19H16ClN5O2S: C: 49.79; H: 3.52; N: 15.28. Found: C:
50.02; H: 3.84; N: 14.94.
6-(4-Methoxyphenyl)-2-[4-(3-methylphenyl)-5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yl]-4,5-dihydropyridazin-3(2H)-one, 4i, Yield: 78%;
º
m.p. 182-184 C; Rf 0.54; IR (KBr) υmax (cm-1): 3458 (NH), 2940 (CH), 2372
(C=S), 1672 (C=O), 1618 (C=N); 1H-NMR (δ) CDCl : 2.40 (s, 3H, CH ), 2.56
(t, 2H, CH ), 2.96 (t, 2H, CH2), 3.67 (s, 1H, CH3O),37.0-7.94 (m, 8H,3Ar-H),
10.84 (s, 12H, CSNH); 13C-NMR: 21.3, 24.2, 32.5, 55.8, 122.7, 128.2, 128.8,
129, 131, 131.8, 135.6, 136.4, 143, 147.8 (C=N), 166.7 (C=S), 172.5 (C=O);
Mass (m/z): 393/394 (M+/M++1). Anal Calc. for C H19N5O2S: C: 61.05; H:
4.87; N: 17.80. Found: C: 60.98; H: 3.94; N: 17.64. 20
Antihypertensive activity
Procurement, identification, and housing of animals
Albino rats (body weight 200–250 g) were supplied by Central Animal
House facility (Registration Number: 173/CPCSEA and Date of Registration:
28, JAN-2000), Jamia Hamdard and kept under standard laboratory conditions
in 12 h light/dark cycle at 25 ºC ± 2 ºC. Animals were provided with pellet
diet (Lipton, Calcutta, India) and water ad libitum. They were marked for easy
identification.
Figure 1. Synthesis of 6-(substituted phenyl)-2-(4-substituted phenyl-5-
thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one
derivatives.
Conditioning/training of animals
For conducting the BP measurement studies, the animals were kept in a
restrainer for 10 min every day for one week. This exercise was done to avoid
the fluctuation in blood pressure due to aggressive behavior of animal while
keeping into the restrainer for measuring the activity.
In the initial step, b-aroyl propionic acids (1a-c) were synthesized by
Friedel-Crafts acylation of appropriate hydrocarbons with succinic anhydride
in the presence of anhydrous aluminium chloride.The intermediates (2a–c)
were synthesized by reacting b-aroyl propionic acids with carbohydrazide in
absolute ethanol. The thiosemicarbazides (3a-3i) conveniently synthesized
Induction of hypertension in normotensive rats
After recording the initial BP of rats, the animals were divided into groups
of 5 animals each. One group was taken as control. Hypertension was induced
in the remaining groups by subcutaneous injection of methyl prednisolone
857

J. Chil. Chem. Soc., 56, Nº 4 (2011)
by refluxing carbohydrazide derivatives (2a-2c) with aryl isothiocyanate in
ethanol. Intermediate thiosemicarbazide (0.05 M) was refluxed in 2M sodium
hydroxide solution (reaction time varies from 4 to 5 h), cooled and poured
into excess of water containing crushed ice which on acidification with glacial
acetic acid yielded a solid, crystallized from ethanol to give final compounds
(4a-4i). The purity of the compounds was checked by single-spot TLC, and
the compounds were characterized on the basis of spectral data (IR, 1H-NMR,
Mass and elemental analysis). Spectral data of all the newly synthesized
compounds were in full agreement with proposed structures. In general, Infra
Red Spectra (IR) revealed NH, CH, C=S, C=O and C=N peak at 3323, 2926,
2368, 1685 and 1607 cm-1, respectively. In the Nuclear Magnetic Resonance
Spectra (1H-NMR) the signals of the respective protons of the prepared titled
compounds were verified on the basis of their chemical shifts, multiplicities, and
coupling constants. The two triplets at δ 2.54 and 2.99 confirmed the presence
of methylene group at 4 and 5 position of pyridazinone ring respectively. The
multiplets at δ 7.13-7.93 are indicative of aromatic protons. The singlet at δ
10.78 is due to CSNH group flanked by two nitrogen atoms. The structure
is also supported by elemental analysis data and 13C NMR data. The other
compounds are also identified in a similar manner. The mass spectrum shows
the presence of peak at definite m/z value in accordance to the molecular
formula. The elemental analysis results were within ±0.4% of the theoretical
values.
Antihypertensive activity
The final compounds (4a-4i) were evaluated for antihypertensive activity
by non-invasive method using Tail Cuff method. The results were shown in
Table 1 and compared with standard drug, hydralazine20 and propranolol.
Compound 4e and 4i were found to show highly significant reduction in mean
arterial blood pressure but at higher dose in comparison to standard drugs. The
mechanism of action of pyridazine (similar to vasodilators) derivatives has
been shown in Figure 2.
Table 1- Mean arterial blood pressure (mm Hg) and substituents of compounds 4(a-i)
General structure of 4(a-e)
MABP
Compound (20mg/kg)
% Reduction in MABP
R
R1
(Mean ± SEM)
101.33±4.64
162.33±4.02**
95.12±4.68**
96.16±4.70**
113.6±7.78**
122±4.85**
107.4±5.54**
118±7.56**
94.41±7.32**
111.6±10.28**
109.6±6.17**
136.2±2.9**
Control
Toxic control
Propranolola
Hydralazineb
41.40
41.76
30.01
24.84
38.83
27.30
41.84
31.25
32.48
16.09
40.98
4a
4b
4c
4d
4e
4f
H
H
p-OCH3
p-Br
H
m-CH3
p -OCH3
p-Br
CH3
CH3
CH3
OCH3
OCH3
OCH3
m-CH3
p-OCH3
p-Br
4g
4h
4i
95.8±3.93**
m-CH3
aDose of Propranolol was taken as 14 mg/kg. bDose of hydralazine was taken as 2.6 mg/kg. All values were expressed as Mean ±SEM (*p ≤ 0.05), each group
comprised of four animals (i.e. n=4). Toxic control group was compared with control group. All the treatment groups were compared with toxic control group and
p < 0.05 was considered to be significant. **P < 0.01, *P < 0.05.
Figure 2. Angiotensin and bradykinin interact to induce angiogenesis.
Bradykinin (BK), a potent vasodilator involved in regulation of blood pressure,
induces angiogenesis. BK upregulates angiogenic molecules such as basic
fibroblast growth factor (bFGF), via the BK B1 receptor25, or VEGF and NO,
via the BK B2 receptor26. The BK B2 receptor can also activate the VEGF
receptor on endothelial cells. ACE inhibition results in BK accumulation
and promotion of neovascularization. Moreover, angiotensin II activates the
AT2 receptor during AT1 receptor blockade, thereby upregulating BK and
contributing to an angiogenic response27. ATR, angiotensin receptor.
858

J. Chil. Chem. Soc., 56, Nº 4 (2011)
14. D. G. H. Livermone, R. C. Bethell, N. Cammack, J. Med. Chem., 36, 3784,
1993
CONCLUSIONS
15. W. Malinka, A. Redzicka, O. Lozach, Il Farmaco, 59, 457, 2004
16. K. Abouzid, M. A. Hakeem, O. Khalil, Y. Maklad, Bioorg. Med. Chem.,
16, 382, 2008
17. D. W. Combs, M. S. Rampulla, S. C. Bell, D. H. Klaubert, A. J. Tobia, R.
Falotico, B. Haertlein, C. L. Weiss, J. B. Moore, J. Med. Chem., 22, 380,
1990
18. D. W. Robertson, N. D. Jones, J. H. Krushinski, G. D. Pollock, J. K.
Swartzendruber, J. S. Hayes, J. Med. Chem., 30, 623, 1987
19. S. Archan, W. Toller, Curr. Opin. Anesthesiol., 21 (1), 78, 2008
20. M. S. Y. Khan, A. A. Siddiqui, Ind. J. Chem., 39B, 614, 2000
21. A. A. Siddiqui, R. Mishra, M. Shaharyar, Eur. J. Med. Chem., 45, 2283,
2010
22. R. Mishra, A. A. Siddiqui, R. Kumar, S. Kumar, Molbank, M 652, 2010.
23. R. E. Borchard, C. D. Barnes, L. G. Eltherington, Drug Dosage in
Laboratory Animals: A Handbook, third ed. The Telford Press Inc., New
Jersey, 1991
Various 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-
dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one
derivatives
can be further modified to exhibit better potency than the standard drugs.
Further studies to acquire more information about Quantitative Structure
Activity Relationships (QSAR) are in progress in our laboratory. The
substituted pyridazine derivatives discovered in this study may provide
valuable therapeutic intervention for the treatment of hypertension.
REFERENCES
1. A. D. Williams, L. T. Lemke, Foye’s Principles of Medicinal Chemistry,
David Troy (Ed.), fifth ed. Lippincott Williams & Wilkins, Baltimore, 824,
2002
2. P. J. Johansen, in: A.E. Doyle (Ed.), Handbook of Hypertension, vol. 5,
Elsevier, New York, (Chapter 2), 1984
3. G. Heinisch, H. K. Frank, Prog. Med. Chem., 29, 141, 1992
4. A. Coelho, E. Sotelo, E. Ravina, Tetrahedron, 59, 2477, 2003
5. S. Demirayak, A. C. Karaburun, R. Beis, Eur. J. Med. Chem., 39, 1089,
2004
24. L. R. Krakoff, R. Selvadurai, E. Sytter, Effect of methylprednisolone
upon arterial pressure and the renin angiotensin system in the rat. Am. J.
Physiol., 228, 613, 1975
25. L. Morbidelli, A. Parenti, L. Giovannelli, H. J. Granger, F. Ledda, M.
Ziche Br J Pharmacol 124, 1286, 1998
26. A. Parenti, L. Morbidelli, F. Ledda, H. J. Granger, M. Ziche FASEB J 15,
1487, 2001
27. A. J. Knox, L. Corbett, J. Stocks, E. Holland, Y. M. Zhu, L. Pang FASEB
J 15, 2480, 2001.
6. A. A. Siddiqui, S. M. Wani, Ind. J. Chem., 43B, 1574, 2004
7. S. G. Lee, J. J. Kim, D. H. Kweon, Y. J. Kang, S. D. Cho, S. K. Kim, Y. J.
Yoon, Curr. Med., Chem., 8, 1463, 2004
8. L. Betti, M. Floridi, G. Giannaccini, F. Manetti, G. Strappaghetti, A. Tafi,
M. Botta, Bioorg. Med. Chem. Lett., 13, 171, 2003
9. A. Monge, P. Parrado, M. Font, E. F. Alvarez, J. Med. Chem., 30 (6), 1029,
1987
ACKNOWLEDGEMENTS
10. C. Rubat, P. Coudert, B. Refouvelet, P. Tronche, P. Bastide, Chem. Pharm.
Bull., 38 (11), 3009, 1990
One of the authors (Ravinesh Mishra) expresses sincere thanks to the
University Grant Commission (UGC), New Delhi, India, for the award of
Research Fellowship in Science for Meritorious Students (RFSMS). The
authors are also thankful to Jamia Hamdard, New Delhi, India for providing
facility for the research work.
11. I. Sircar, R. E. Weishaar, D. Kobylarz, W. H. Moos, J. A. Bristol, J. Med.
Chem., 30, 1955, 1987
12. J. G. Longo, I. Verde, M. E. Castro, J. Pharm. Sci., 82, 286, 1993
13. A. Akahane, H. Katayama, T. Mitsunaga, J. Med. Chem., 42, 779, 1999
859