2-{2"-carbomyl-5"-[3′-amino-2′-methylmono/ dihalosubstituted quinazolin-4′(3'h)-onomethylene]- 1",3",4"-oxadiazol-2"-yl}-4,5-dihydroimidazolines as potential antihypertensive agents

Article abstract of DOI:10.13005/ojc/300243

Twelve new 2- {2"-carbomyl - 5" - [3′-amino-2′ - methylmono / dihalosubstituted quinazolin- 4′ (3'H) - onomethylene] - 1",3",4" - oxadiazol-2"-yl} -4, 5- dihydroimidazolines were prepared and evaluated for their cardiovascular activity. The most active compound of this series is 2-{2"- carbomyl-5"-[3′-amino-2′-methyl-6-bromoquinazolin-4′(3'H)-onomethylene]-",3",4"-oxadiazol-2"- yl}-4,5-dihydroimidazolines i.e. compound VIc.

Full text of DOI:10.13005/ojc/300243

ISSN: 0970-020 X
CODEN: OJCHEG
2014, Vol. 30, No. (2):
Pg. 713-721
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
2-{2"-carbomyl-5"-[3'-amino-2'-methylmono/
Dihalosubstituted Quinazolin-4'(3’h)-onomethylene]-
1",3",4"-oxadiazol-2"-yl}-4,5-dihydroimidazolines
as Potential Antihypertensive Agents
MIRDULATYAGI
Medicinal Chemistry Lab, Department of Chemistry Meerut College, Meerut - 250 004, India.
*Corresponding author E-mail: mirdulatyagi@gmail.com
http://dx.doi.org/10.13005/ojc/300243
(Received: March 08, 2014; Accepted: April 12, 2014)
ABSTRACT
‘Twelve new 2- {2"-carbomyl - 5" - [3’-amino-2' – methylmono / dihalosubstituted quinazolin-
4' (3’H) - onomethylene] – 1",3",4" - oxadiazol-2"-yl} -4, 5- dihydroimidazolines were prepared and
evaluated for their cardiovascular activity. The most active compound of this series is 2-{2"-
carbomyl-5"-[3'-amino-2'-methyl-6-bromoquinazolin-4'(3’H)-onomethylene]-”,3",4"-oxadiazol-2"-
yl}-4,5-dihydroimidazolines i.e. compound VIc.
Key words: Quinazolinonyl oxadiazoles, acute toxicity studies, hypotensive activity, dogs,
synthesis Quinazolinonyloxadiazolyl-imidazolines, acute toxicity studies,
hypotensive activity dogs, synthesis.
INTRODUCTION
moieties, plays a pivotal role in delineating the
cardiovascular Moreover,
activity7-8
.
Research in the field of imidazoline
derivatives has yielded a number of clinically useful
anti-hypertensive drugs. Imidazoline derivatives of
different heterocyclic nucleus have shown potent
pharmacological properties like antiinflammatory1.
analgesic2, CNS-depressant3, anticonvulsant4 and
hypotensive5-6.Importantly, substitution at 2-position
of imidazoline nucleus plays pivotal role in
molecular designing of some cardiovascular
agents like clonidine, which lowered the blood
pressure. Furthermore, substitution at 2-position of
imidazoline nucleus by different heterocyclic
quinazolinones9-10 and oxadiazoles11-12 have also
been reported to possess potent antihypotensive
activity. With an aim to develop better hypotensive
agents, it was thought worthwhile to synthesize a
new series of 2-substituted imidazoline derivatives
bearing oxadiazolyl and quinazolinonyl moieties.
All the newly synthesized compounds (synthetic
route is given in scheme) were evaluated for their
cardiovascular activity and acute toxicity studies.
Moreover structures of all the compounds were
delineated by spectral analysis.

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TYAGI, Orient. J. Chem., Vol. 30(2), 713-721 (2014)
MATERIALS AND METHODS 3250 (NH), 3060 (C-H aromatic), 2918 (methyl C-H
Chemistry
stretch), 2845 (CH2), 1740 (C=O), 450 (C-I stretch).
1H-NMR (CDC13): d 9.60 (ss, 1H, NHCH2), 7.25-
All melting points are uncorrected. The 7.80 (m, 3H, Ar-H), 4.40 (d, 2H, CH2NH), 4.10 (q,
purity of the compounds were checked by TLC on 2H, J=7Hz, COOCH2CH3), 2.48 (s, 3H, CH3), 1.22 (t,
silica gel-G plates and spots were located by iodine. 3H, J=7Hz, COOCH2CH3) (ppm).
IR spectra were recorded on Beckman-Acculab-10- [MS]:[M]+m/z 387.
1
spectrophotometer (max in cm-1) H-NMR spectra
was recorded on Bruker-400-FT instrument. Mass Synthesis of l-[3'- amino-2'- methylmono/
spectra were recorded on Jeol- JMS D-300 dihalosubstituted- quinazoIin-4-(3’H)-onoacetyl]-
spectrophotometer.
Synthesis
semicarbazides (IIIa-HId)
A mixture of 3-(ethylacetylamino)- 2-
The required 3-amino - 2- methylmono / methyl- mono /dihalosubsti tutedquina zolin-4 (3H)-
dihalosubstitutedquinazolin - 4 (3H) - ones la-Id, ones (0.075 mole) and semicarbazide (0.075 mole)
were synthesized according to the reported in methonal (70ml) were refluxed on a steam bath
method13, which on reaction with ethylchloroacetate, for about 8 hr. The excess of the solvents were
in the presence of anhydrous K2Co3 gives ethyl-3- distilled off and the viscous mass poured into ice
amino-2-methylmono/dihalosubstituted-quinazolin- cold water, filtered and recrystallised from
4(3H)-onoacetates (Ila-IId). Com-pound Ila-IId on appropriate solvents. Physical and analytical data
treatment with semicarbazide in methanol gave l- of compounds IIIa-IIId are given in table 1.
[3'-amino-2'-
dihalosubstitutedquinazolin -4' (3’H) - onoacetyl]-
methylmono
/
Compound IIIa: IR (cm-1, selected lines);
semicarbazides (IIIa-IIId). These compounds were 3200 (NH), 3050 (aromatic C-H), 2918 (methyl C-H
reacts with conc. H2SO4 and then neutrallized with stretch), 2853 (CH2), 1700 (C=O), 1600 (C=N), 1580
liquid ammonia to yield cyclized products i.e. 2- (C….C of aromatic ring), 500 (C-I stretch). 1H-NMR
amino-5-
[3'-amino-2'-
methyl-mono
/
(CDC13): d 9.55 (ss, 1H, NHCH2), 8.80 (m, 4H,
dihalosubstitedquinazolin - 4' (3’H)-onomethylene] NHNHCONH2), 7.52-6.80 (m, 3H, Ar-H), 4.30 (d,
- l,3,4- oxadiazoles IVa-IVd.2 - Aminochloroacetyl- 2H, NHCH2), 2.52 (s, 3H, CH3) (ppm). MS: [M]+m/
5-
[3'-amino
-
2-
methylmono/ z416
(3’H)-
dihalosubstitutedquinazolin-4'
onomethylene]-l,3,4-oxadiazoles i.e. Va-Vd were Synthesis of 2-amino-5- [3'-amino-2'-
prepared by the addition of chloroacetylchloride methylmono/dihalo- sub- stitutedquinazolin-
drop by drop into the solution of compound IVa-IVd, 4'(3’H)- onomethylene] 1,3,4- oxadiazoles (IVa-
these compounds were cyclized to imidazolinesVla- IVd).
VId, by the addition of ethylenediamine and sulphur.
Conc. H2SO4 (15ml) and
a mixture
of l-[3'-amino -2'- methyl - mono/ dihalosubstituted
Synthesis of ethyl-3- amino- 2- methyImono/ quinazolin- 4 (3H) - oneacetyl] semicarbazides (0.05
dihalosubstituted- quinazoIin - 4 (3H) - mole) were kept overnight at room temperature,
onoacetates (Ila-IId)
poured into ice cold water, neutrallised with liquid
A mixture of 3-Amino-2-methyl-mono / NH3 and filtered. The product obtained were
dihalosubstitutedquinazolin-4 (3H)-one (0.01 mole), recrystallised from appropriate solvents. Physical
ethylchloroacetate (0.01 mole) and anhydrous and analytical data of compounds IVa-IVd are given
K2CO3 (5g) in dry acetone (80 ml) were refluxed for in table-I.
15 hours on a steam bath.The excess of the solvents
were distilled off and the resulting solid mass poured Compound IVa
into ice cold water, filtered and recrystallised from
appropriate solvents. Physical and analytical data (aromatic C-H), 2920 (methyl C-H stretch), 2845
IR (cm-1, selected lines; 3355 (NH2), 3053
of compounds are given in table I.
(CH2), 1790 (CO), 1600 (C=N), 1580 (C….C of
aromatic ring), 1080 (C-O-C). H-NMR (CDC13): d
1
Compound IIa: IR (cm-1; selected lines); 9.40 (ss, 1H, NHCH2), 8.20 (s, 2H, NH2), 7.58-7.70

TYAGI, Orient. J. Chem., Vol. 30(2), 713-721 (2014)
715
(m, 3H, Ar-H), 4.30 (d, 2H, NHCH2), 2.70 (s, 3H,
CH3) (ppm).
MS: [M]+ m/z 398
(m, 4H, CH2-CH2 of 4,5-dihydroimidazoline ring),
2.48 (s, 3H, CH3) (ppm).
MS: [M]+m/z 494.
Synthesis of 2- [aminochloroacetyI- 5- (3'-amino-
2'- methyI-mono/dihalosubstitutedquinazolin-
4(3’H)-onomethylene]-l,3,4-oxadiazoles Va-Vb
To a well stirred solution of compounds
IVa-IVd (0.01 mole) in dry chloroform (40 ml)
chloroacetylchloride (0.02 mole) was added at 0°C
dropwise during 1 hr. The reaction mixtures were
stirred for 5 hr more cooled and poured into ice
water. The resulting mixtures were filtered and
recrystallised from appropriate solvents. Physical
and analytical data of compounds Va-Vd are
mentioned in table-I
Biological activities
The present study was carried out on adult
normotensive mongrel dogs (10-20 kg) or on cats
(3-4 kg) and charles foster albino mice (18-25gm).
The dogs/cats were divided into two groups of 5
animal each. One of the groups was treated as
control group while another group was treated as
test group. Dogs/cats were anaesthetized with
-
chloralose (80 mg/kg i.p.) injected intravenously
and maintained on positive pressure artificial
respiration by cannulation of the trachea in order to
avoid reflex change in respiration.The right femoral
vein was cannulated in each case with on
indevelling polyethene tube. The blood pressure
was recorded either from the left common carotid
artery by means of a mercury manometer on
smoked Kymography paper or from femoral artery
on one channel of “Encardiorite” (India) polygraph
using stathus P23 transducer. Electrocardiogram
(Lead II) was recorded on one channel of
“Encardiorite” (India) polygraph in some of the
experiments. The heart rate was calculated from
the pressure pulse tracing in all the experiments.
The newly synthesized compounds (test drugs)
were administered intravenously through an
indevelling polyethylene cannula by dissolving
them in propylene glycol and the effect on blood
pressure (B.P.), heart rate (H.R.) and pressor
responses evoked either by carotid occlusion (CO)
or intravenous noradrenaline (NA) 1-2 mg/kg
injection was studied. 0.25 ml of propyleneglycol
was injected as vehicle to see the effect of vehicle
on the parameters in the control group of animals.
Injection of 0.25ml of propylene glycol induced a
mild and transient decrease of 5 mmHg in blood
pressure without affecting the CO and NA
responses. The toxicity study was carried out on
mice of either sex. Approximate 50% lethal dose
(ALDso) of the all the compounds was determined
in albino mice. The mice of either sex weighing
between 18-25 gm were used for the study. The
drugs were injected by intraperitonial (i.p.) route at
different dose levels in separate groups of animals.
From the data obtained ALD5o was calculated
according to the method14. The results were
analysed by using student’s t-test.
Compound Va
IR (cm-1, selected lines); 3045 (aromatic
C-H), 2870 (CH2), 1770 (C=0), 1635 (C=N), 1550
(C….C of aromatic ring), 1010 (C-O-C), 690 (C-
C1). 1H-NMR (CDC13): d 9.40 (ss, IK, NHCH2), 8.49
(hump, 1H, NHCO), 7.10-8.20 (m, 3H, Ar-H), 4.72
(s, 2H, CH2C1), 4.35 (d, 2H, NHCH2), 2.50 (s, 3H,
CH3) (ppm).
MS: [M]+m/z474.
Synthesis of 2-{2"-carbomyl-5"-[3'-amino-2'-
methylmono/ dihalosubstitutedquinazolin-
4'(3’H)-onomethylene]-l”,3",4"-oxadiazol -2"-yI}-
4,5-dihydroimidazolines Vla-VId
To a mixture of compounds Va-Vd (0.01
mole) in toluene (dry 100 ml) and sulphur (0.02
mole), ethylenediamine (0.01 mole) was added
dropwise at 110°C during Ihr.The reaction mixtures
were refluxed for 4 hrs. till the evolution of hydrogen
sulphide ceased. It is filtered hot and the filterate
concentrated and poured into crushed ice. The
resulting solids were recrystallised from
appropriate solvents. Physical and analytical data
of compounds Vla-VId are given in table-I
Compound VIa
IR (cm-1, selected lines); 3240 (NH), 3040
(aromatic C-H), 2930 (methyl C-H stretch), 2850
(CH2), 1700 (C=O of NHCO), 1620 (C=N), 1510
1
(C…..C of aromatic ring), 1040 (C-O-C). H-NMR
(CDC13): 5 9.55 (ss, 1H, NHCH2), 8.40 (bs, 1H,
NHCO), 7.45-8.10 (m, 3H, Ar-H), 5.65 (bs, 1H, NH
of imidazoline ring), 4.30 (d, 2H, NHCH2), 3.80-3.58

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on the smooth muscles of blood vessels (direct
Toxicity Studies: ALD50
Approximate ALD50 values of all the vasodilators). Compounds (Va-Vd; table 3) of stage
compounds were determined by observing 50% II exhibited better cardiovascular activity than their
mortality after 24 hours.
parent compounds (IVa-IVd; table-2). These
compounds exhibited hypotensive activity of
varying degree (20-70 mmHg) of duration (20-30
minutes) without affecting CO and NA responses
RESULTS
Hypotensive activity was determined and heart rate.CompoundVc showed an immediate
according to the reported method15. Cardiovascular fall in blood pressure 70 mmHg followed by a
activities of these compounds are presented in table delayed fall of 30mmHg.The hypotensive activity of
(2, 3, & 4). All the four 2-amino-5- (3'-amino-2'- this compound lasted for 20 minutes without
memylmono/ dihalosubstitutedquinazolin-4' (3’H)- affecting the pressor responses (CO and NA) and
onomethylene]- l,3,4-oxadiazoles (IVa-IVd; table 2) heart rate (HR). Further, the cyclization of these
exhibited mild hypotensive activity of varying degree above2-aminochloroacetyl-5-(2-methylmono/
(10-30 mmHg) and duration (10-22 minutes) without d i h a l o s u b s t i t u t e d - q u i n a z o l i n - 4 ( 3 H ) -
affecting the carotid occlusion (CO) and onomethylene)-l,3,4-oxadiazoles into their
noradrenaline (NA) pressor responses. Compound corresponding carbomyl (CONH) imidazolines i.e.
Ic i.e. 2-amino-5-(3'-amino-2'-methyl-6'-bromo- 5-membered ring structure (Vla-VId; table-4)
quinazolin-4'(3’H)-onomethylene]-l,3,4-oxadiazole exhibited potent cardiovascular activity of varying
showed an immediate fall in blood pressure of degree (10-60 mmHg) of duration (30-50 minutes).
l0mmHg followed by a delayed fall of 30 mmHg. All these compounds Vla-VId showed more’ potent
The hypotensive activity of this compound lasted cardiovascular activity than their parent compounds
for 22 minutes. As these compounds IVa-IVd did not (Va-Vd; table-3) due to the presence of imidazoline
affect the CO and NA responses and had very short ring. Compound VIc i.e. when quinazolinone was
duration of action, therefore, they appear to be acting substituted with Br at 6-position, showed an
Scheme 1:

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TYAGI, Orient. J. Chem., Vol. 30(2), 713-721 (2014)
immediate fall in blood pressure (60 mmHg),
followed by gradual fall in blood pressure (40
mmHg) at a dose of 2.5 mg/kg i.v. The hypotensive
DISCUSSION
It is interesting to point out that compounds
activity of this compound lasted for about 50 of third stage have shown different pharmacological
minutes. As this compound (compound VIc) profile (clonidine like centrally acting as compound
exhibited the promising activity at a dose of 2.5 mg/ VIa, VIb & VIc, secondly a purely peripheral
kg i.v., it was therefore thought worthwhile to study adrenergic blocking type as compound VId.
this compound at three graded doses (1.25, 2.5 Furthermore, all the compounds i.e.Vla-VId of stage
and 5.0 mg/kg i.v.).Interestingly this compound was third exhibited the more potent antihypertensive
associated with either inhibition or blockade of CO activity than their parent compounds (IVa-IVd and
without affecting the NA response, which might be Va-Vd). On the contrary, all the compounds of stage
suggestive of central site of action of this compound. first (IVa-IVd) and stage second (Va-Vd) did not affect
However, compound VIc has shown tachycardia the CO and NA responses and had short duration
(increase in heart rate) 1-2 beats per minutes, 2-3 of action. They appear to be acting directly on the
beats per minutes and 3-4 beats per minutes at a smooth muscles of the blood vessels (direct
dose of 1.25,2.5 and 5.0mg/kg i.v. respectively.The vasodilators). Moreover, it is also evident from the
results of the cardiovascular activity are mentioned results that presence of imidazoline ring with
in table (4). Compound VId has also exhibited a oxadiazolyl and quinazolinonyl moieties is
potent hypotensive fall of 50 mmHg. The beneficial for cardiovascular activity. Moreover, the
hypotensive activity of this compound lasted for 30 cyclisation of compound Va-Vd to Vla-VId i.e.
minutes with inhibition of both CO and NA. Such imidazolines increases the cardiovascular activity
cardiovascular profile is suggestive of peripheral in terms of magnitude as well as duration.
site of action of this compound. Compound VIa
exhibited an immediate fall of blood pressure 40
mmHg followed by a delayed fall of 30mmHg. The
hypotensive activity of compound VIa was lasted
ACKNOWLEDGEMENTS
We are thankful to the CDRI, Lucknow for
for 35 minutes with potentiation of CO without the elemental and spectral analysis. The
affecting the NA response, which might be contribution of Dr. Atul Kumar and Dr. P.M.S.
suggestive of central site of action of this compound. Chauhan, Scientist, Medicinal Chemistry Division,
CDRI, Lucknow is also gratefully acknowledged.
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