Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents

Article abstract of DOI:10.1016/j.bmcl.2020.127595

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD₅₀ activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD₅₀ > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).

Full text of DOI:10.1016/j.bmcl.2020.127595

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Synthesis and biological evaluation of imidazoline derivatives as potential
CNS and CVS agents
Vineet Malhotra, Monika Vats, Rajendra Nath, Simpi Mehta, Rakesh Kumar,
Manish Bhalla, J.N. Sinha, K. Shanker, Seeema R. Pathak
PII:
DOI:
Reference:
S0960-894X(20)30706-X
https://doi.org/10.1016/j.bmcl.2020.127595
BMCL 127595
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
29 June 2020
24 September 2020
26 September 2020
Please cite this article as: Malhotra, V., Vats, M., Nath, R., Mehta, S., Kumar, R., Bhalla, M., Sinha, J.N.,
Shanker, K., Pathak, S.R., Synthesis and biological evaluation of imidazoline derivatives as potential CNS and
CVS agents, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://doi.org/10.1016/j.bmcl.2020.127595
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Synthesis and biological evaluation of imidazoline
derivatives as potential CNS and CVS agents
Vineet Malhotrab , Monika Vatsa, Rajendra Nathb , Simpi Mehta a, Rakesh Kumara, Manish Bhallab ,
J N Sinhab, K Shankerb , Seeema R.Pathak a,
R HC
O
R HC
O
R HC
O
Epichorohydrin
Dioxane/NaOH
p Aminophenol
Abs Alcohol
N
N
O
N
O
N
N
OH
CH3
Arylamine
OH
CH3
Dioxane/NaOH
CH3
NH
Morpholine/
HCHO/Dioxane
R HC
O
N
Cl
N
OH
N
O
2

Bioorganic
&
Medicinal
Chemistry
Letters
journal homepage: www.elsevier.com
Synthesis and biological evaluation of imidazoline derivatives as potential CNS and
CVS agents
Vineet Malhotrab, Monika Vatsa, Rajendra Nathb, Simpi Mehtaa, Rakesh Kumara, Manish Bhallab, J N Sinhab, K Shankerb,
Seeema R.Pathak a,
aDepartment of Chemistry, Biochemistry & Forensic Science, Amity school of Applied Sciences, Amity University Haryana,
Gurugram,122413, India
bDepartment of Pharmacology & Therapeutics, KGMU, Lucknow, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of substituted imidazoline derivatives were synthesized and
characterized. Compounds were tested in-vivo for their antihypertensive,
analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The
compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central
nervous system activities and are potential candidate as drug among all fifteen
compounds tested. All these compounds have shown better activity for
antihypertensive, analgesic, antiaggressive, and depressant-antidepressant,
properties than reference compounds clonidine, morphine, diazepam, and
imipramine respectively. Most of the compounds have shown ALD50 > 500
mg/kg with maximum in 4a and 5a (>1000 mg/kg).
Revised
Accepted
Available online
Keywords:
Keyword_1 Imidazoline, oxazolone
Keyword_2 morpholine,
Keyword 3 CO, NE, hypotensive
Keyword_4 CNS, analgesics,
antiaggressive, depressants
-antidepressants
2009 Elsevier Ltd. All rights reserved.
Keyword_5 ALD50
———
 Corresponding author. Tel.: + 01242167853-1103; fax: + 01242167853-1106; e-mail: srpathak@ggn.amity.edu; seemarpathak@gmail.com
3

Imidazolines are partially reduced imidazoles and are
medicinally privileged scaffolds.1,2 2-Imidazolines are
widely recognized as pharmacophores having an affinity
for a class of biological targets.3 Derivatives of
imidazoline have been recognized as an important class
of drug which mediates their action by interacting with
α 2–adrenoceptors and have shown a variety of
physiological functions.4,5 Additionally, imidazolines
nucleus modulates adrenergic (a) receptors6, and binds
to them.7-12 The toxicological effects of imidazoline
receptor binding13 along with a/I receptors are also
reported.14
imidazole, pyrazolines, and quinazolines markedly
modulate antihypertensive activity and toxicity profiles.
These reports gave us an impetus to design and
synthesize some novel substituted imidazoline
derivatives having different pharmacophoric moieties at
1, 3, and 5 positions, and evaluate them for their CVS,
CNS and ALD50 activities.
In the present study, we have incorporated bulky
pharmacophoric groups at position-1 of imidazoline
nucleus with a view to studying the effect of these
substitutions on CVS, CNS, and ALD50 activities.
Imidazoline nucleus is constituent of a chemically
useful
antihypertensive
agent,
[2-(2,
6-
dichlorophenylamine)]-imidazoline named as Clonidine
I (Figure 1). Clonidine is an alpha-2 adrenergic agonist
and is used for centrally acting hypotensive agent and
have central nervous system activities,15-17 viz.
psychiatric disorders,18 obsessive-compulsive disorders,
schizophrenia, and panic states.19-26 In addition, there
are large number of compounds having an imidazoline
nucleus possessing antidepressant activities.27,28 The
derivatives of imidazole (BFI II, BU224 III, TRIM IV
(4-(2-ethylamino)-1H-imidazole) V, Figure 1) exhibit in
vivo neuronal nitric-oxide synthase (NOS) inhibition
The synthetic procedure to obtain the final compounds
is depicted in Scheme 1. Substitutions were made at 4
position of oxazolone nucleus by treating acetyl glycine
with substituted aldehyde35 and acetic anhydride leading
to 4-arylidene-2-methyl-5-(4H) oxazoline-5-one 2(a-c).
The compounds 2(a-c), on refluxing with para
aminophenol in ethanol resulted in 4-arylidene-1-(p-
activity
convulsions29,30, leading to antiaggresive, and analgesic
properties30,31
and
prevent
glufosinate
induced
hydroxy-phenyl)-2-methylimidazoline-5-ones
3(a-c).
.
Compounds 3(a-c) were undergone Manich reaction
with secondary amines and formaldehyde in the
presence of DMSO afforded 4-arylidene-1-(p–hydroxy-
phenyl)-2-[2-morpholino ethyl]-3-imidazoline-5-one
Earlier reports from our lab have elucidated that
incorporation of various pharmacophores like
morpholine, 32 substituted aryl group,33 and arylamine 34
at different positions of heterocyclic nucleus viz.
4

analgesic, antiaggressive and antidepressant
activities respectively.
4(a-c). Williamson O-alkylation of compounds 3(a-c)
with epichlorohydrine in presence of dioxane/NaOH
resulted with 4-arylidene-1-[p-(epoxy propoxy) phenyl]-
Substitutions were made at position 4 of the oxazolone
nucleus with different aryl groups resulting in
compound 2(a-c). Compound 2a produced moderated
hypotension of a long duration. Compound 2c has
shown only delayed fall. Compound 2a and 2c also
inhibited carotid occlusion (CO) and potentiated
norepinephrine (NE) induced pressor response. In
general, the oxazolone moiety having no substitution in
the phenyl ring of the arylidene group exhibited an
increase in hypotensive activity. Compound 2b could
not produce any change in mean arterial pressure
(MAP). Furthermore, 2b exhibited significant analgesic
activity whereas the other two compounds in this series
did not show any Central Nervous System (CNS)
activity.
2-methyl-3-imidazoline-5-ones
to
yield
5(a-c).
Compounds 5(a-c) were again condensed with aryl
amines in basic condition in presence of DMF yielded 4-
arylidene-1-[p-(2”-hydroxy-3’-arylamino
propoxy)
phenyl]-2-methyl-3-imidazoline-5-ones 6(a-c). All the
synthesized compounds were well characterized by
several spectroscopic methods such as mass, 1H NMR,
13C NMR and elemental analysis (SI). These compounds
were tested for their hypotensive, analgesic,
antiaggressive, antidepressant and ALD50 activities as
shown in Table-1, 2, 3, 4, Graph 1, 2, 3(SI).
Substitution of oxygen of the oxazolone nucleus with
para aminophenol resulted in compounds 3(a-c).
Compound 3a & 3c exhibited moderate hypotension and
3a inhibited both CO & NE pressor response. While 3c
inhibited CO response and potentiated NE pressor
response. Compound 3b exhibited only mild
hypotensive activity. It can be concluded that after
inserting the para aminophenol group at oxazolone
nucleus the extent and duration of hypotension become
more apparent for CVS activity. The compound 3a
exhibited mild analgesic as well as depressant activity
and 3c produced significant antiaggressive and
antidepressant activity while 3b only produced
antiaggressive activity.
Screening of all fifteen compounds for hypotensive
activity in a dose of 2.5 mg/kg & reference drug clonidine
in a dose of 10 mg/kg was performed. Morphine in a dose
of 5 mg/kg, Diazepam in a dose of mg/kg & Imipramine in
a dose of 15 mg/kg wereused as reference drugs for
5

In the next series, H of CH3 group was replaced by CH2-
N-morpholine group resulted in compounds 4(a-c). All
the compounds 4(a-c) of this series exhibited moderate
hypotension and inhibited CO induced pressor response.
It was observed that when H of the CH3 group was
replaced by CH2-N-morpholine, the compounds 4(a-c)
lost their CVS activity. In addition, 4a have shown mild
analgesic and antidepressant activity while 4c exhibited
antiaggressive and antidepressant activity. However
compound 4b did not show any significant CNS
activity.
6b exhibited significant analgesic activity while 6a has
not shown any CNS activity.
The results suggest that compounds 2a and 2c showed
better hypotension, CO inhibition, NE pressor response
than 2b. Compound 3a showed NE inhibition while 3c
potentiated it. Compounds 4(a-c) showed moderate
hypotension and inhibited CO response. Compound 4c
also exhibited mild antiaggressive and antidepressant
activity. Compound 5a exhibited moderate hypotension
of longer duration, potentiated NE induced pressor
response, and inhibited CO induced pressor response.
Compounds 5b and 5c produced mild hypotension of
short duration. Compound 5b potentiated NE induced
pressor response. In addition, compound 5a and 5b
exhibited significant analgesic as well as antigressive
activity while 5c did not possess any CNS activity. The
compounds 6b and 6c induced severe initial fall in
blood pressure while 6a exhibited a prolonged fall as
well. Compounds 6a and 6c potentiated NE induced
pressor response, whereas, compound 6b was not able to
modify CO and NE response. In addition, 6c have
shown significant antiaggresive and antidepressant
activity. Compound 6b exhibited significant analgesic
activity while 6a has not shown any CNS activity. Form
the above observation it is clear that substituting 1-
position of oxazolone ring with para aminophenyl group
increases cardiovascular and central nervous system
activities of the compounds. Further substitution in the
imidazoline ring has shown variable grades of
hypotensive and CNS activity. All the compounds
which displayed significant hypotensive activity (25-50
mm Hg) also showed bradycardia of varying grade (-6
Replacement of phenolic hydrogen of 4(a-c) compounds
by epichlorohydrin moiety resulted in compounds 5(a-
c). Compounds 5a exhibited moderate hypotension of
longer duration, potentiated NE induced pressor
response, and inhibited CO induced pressor response.
Compound 5b and 5c produced mild hypotension of
short duration. However, compound 5b potentiated NE
induced pressor response. In addition, compounds 5a
and 5b exhibited significant analgesic as well as
antiaggressive activity while 5c did not possess any
CNS activity.
In the last series, epoxy ring was opened and further
substituted by the arylamino group resulting in
compounds 6 (a-c). All the compounds of this series 6a,
6b, and 6c induced severe initial fall in blood pressure.
The compound 6a also exhibited prolonged fall in BP.
Compounds 6a and 6c potentiated NE induced pressor
response, whereas compound 6b did not modify CO and
NE responses. In addition, 6c has shown significant
antiaggressive and antidepressant activity. Compound
6

to -30 beats per minute). The most promising
compounds having cardiovascular as well as central
nervous system activities are 3a, 3c, 4c, 5a, and 6c. The
present study suggested that the newly synthesized
imidazoline derivatives are good candidates for blood
pressure-lowering along with analgesic, antiaggressive,
Table 1. Cardiovascular effects and ALD50 activitties
of compounds 2(a-c) to 6(a-c) (Dose-2.5 mg/kg)
Co
Effect on
Effect
NE
CO
Resp
onse
ALD50
mg/kg
mp B.P (mmHg)
on
Resp
onse
d
HR,
Imme Del
Beats
/min.
diate
aye
d
2a
2b
2c
3a
3b
3c
>500
>500
>500
>200
>500
>500
>500
>1000
>500
-25
--
-40
-36
↑
--
↑
↓
--
↓
--
--
depressant,
antiantidepressant
activities.
These
--
-15
-70
-20
-50
--
molecules can be very useful for further optimization
work in antihypertensive and CNS activities. ALD50
values are much higher for most of the compounds
which indicate that they are safe to be used as a drug.
-15
-20
-25
-12
-18
-27
↓
↓
--
↑
--
↓
4a
4b
4c
-35
-35
-15
-15
-20
-37
-15
-18
-30
--
↑
↓
↓
↓
Acknowledgments
The authors would like to acknowledge the
support provided under the DST-FIST Grant No.
SR/FST/PS-I/2019/68 of Govt. of India. Seema R.
Pathak & Rajendra Nath are thankful to CSIR for
providing financial support under the grant number
37(0932)/97/EMR-II and to SAIF division, CDRI,
Lucknow for instrumental and elemental analysis.
↑
5a
5b
-25
-30
-45
-20
-21
-6
↑
↓
↓
>500
↑↑
>1000
5c
-60
-28
to
-24
↓
↓
>500
-35
6a
6b
6c
-50
-25
-15
-18
-17
-6
↑↑
--
↓
--
↓
>200
>500
>500
-20
-30
-28
-27
-21
-18
↑↑
↓
CL
↓
Note: Compd: Compound numbers, CL: Clonidine (10 mg /kg);
+ indicates rise & - indicates fall in blood pressure and heart rate,
respectively; ↑ indicates potentiation and ↓ indicates Inhibition of
pressor response, - indicates no effect on CO & NE response; more
than 20-25 mm Hg of decrease or 10 mm Hg increase as decrease or
increase in B. P. and 6-12 beats per minute of decrease or increase was
taken as decrease/increase in heart rate (HR);
7

Table 3. Antiaggressive Effects of compounds 2(a-c)
to 6(a-c) (Dose-10 mg/kg, I.P.) on foot shock induced
fighting behavior showing antiaggressive activity
Table 2. Analgesic Activity:
Showing
mean
maximum change in Tail flick latencies for analgesic
activity of compounds 2(a-c) to 6(a-c) (Dose-10
mg/kg)
Compd
Mean Fighting Count ± SE
(Treated)
Compd
Mean Maximum
Specific
Change in Tail Time (Duration) of
(Control)
Flick Latency
max
change
in
2a
8.0 ± 1.52
7.6 ± 3.18
12.0 ± 2.00
13.3 ± 2.96
8.3 ± 3.80
8.3 ± 2.88
24.3 ± 5.45
7.0 ± 2.08
6.6 ± 4.75
9.3 ± 2.18
18.3 ± 3.99
17.3 ± 6.43
14.0 ± 4.98
16.6 ± 0.88
7.6 ± 0.3
6.0 ± 2.88
6.0 ± 2.51
7.3 ± 1.76
8.6 ± 2.20
4.6 ± 0.33
1.6 ± 2.88**
21.6 ± 6.76
6.6 ± 0.88
4.5 ± 2.2
6.3 ± 3.28
5.0 ± 2.5**
10.3 ± 0.88*
11.3 ± 4.7
10.6 ± 1.85
4.8 ± 0.5
latencies (in minutes)
(in second)
2b
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
+1.3 ± 4.5
At 60’
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
+8.8 ± 0.68**
+1.8 ± 7.5
+6.4 ± 0.65*
+1.3 ± 8.4
+0.1 ± 4.9
+4 ± 1.73
At 15’
At 60’
At 60’
At 60’
At 30’
At 60’
At 30’
At 60’
At 60’
At 60’
At 30’
At 60’
At 30’
At 30’
At 60’
+5.2 ± 3.8
+2.6 ± 4.75
+8.5 ± 0.57**
+6.4 ± 0.92*
+3.8 ± 1.5
+4.5 ±.4.6
+6.9 ± 1.02*
+0.9 ± 0.75
6c
Diazepam (2.5
mg/kg, IP)
PG (0.1 ml/rat,
IP)
10.3 ± 1.5
1.1 ± 0.22**
PG (0.1 ml +0.7 ± 4.6
rat)
15.6 ± 2.3
16.6 ± 2.3
/
Morphine
(5 mg/kg)
+19.4± 0.2**
At 60’
*P< 0.05, ** P< 0.01 using Chi square test
b*P< 0.05, ** P< 0.01 using Chi square test
Graph 2. Antiaggresive effect of compounds 2(a-c)
to 6(a-c) (10 mg/kg, I.P.) with control data of
propylene glycol (PG) and standard drug Diazepam
(2.5 mg/kg) on foot shock induced fighting behaviour
Graph 1. The analgesic activity of compounds 2(a-c)
to 6(a-c) (10 mg/kg) along with control data of
propylene glycol (PG) and standard drug Morphine
(5 mg/kg) measured as tail flick latency time (in
seconds).
8

Table 4. Showing the total mean swimming
time (in min) of control and treated groups for
antidepressant effect of compounds 2(a-c) to
6(a-c) (Dose- 5 mg/kg):
Compd
Dose
Total
mean
swimming
time in minutes
Control
Treated
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
5 mg/kg
15 mg/kg
0.1
2.46
3.12
2.60
2.35
2.84
2.74
2.86
2.94
2.95
2.90
2.08
2.57
2.70
3.04
3.00
2.98
2.86
1.72
2.64
1.50
2.74*
2.52
0.42**
0.84*
1.30
0.50**
1.68
1.14
1.31
1.60
2.83
0.84**
2.33
0.12**
Graph 3. Antidepressant effect of compounds
2(a-c) to 6(a-c) (5 mg/kg, I.P.) with control
data of propylene glycol (PG) and standard
drug imipramine(15mg/kg), total mean
immobility time (in minutes) of control and
treated group
Imipramin
e
PG
ml/mice
*P< 0.05, ** P< 0.01 using Chi square test;
compound
3a
showing increase in mean swimming time
9

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Related
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Critical Care Toxicology 2016, 1-19.
23. Holman R. B.; Shillito E. E.; Vogt M., Sleep
Produced by Clonidine (2-6 dichlorophenyl
amino)-2-imidazoline hydrochloride, Br. J.
Pharmacol, 1971, 43; 685-695.
31. Pathak S. R.; Malhotra V.; Nath R.; Shanker K.,
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M.; Shanker K., Bioorg & Med.Chem.Lett. 2011,
21(3): 936-939.
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2002, 14: 1310-1313.
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37. Porsolt R. D.; Pichon M. Le.; Jalfre M.,
Depression: a new animal model sensitive to
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38. Porsolt R. D.; Bertin A.; Jalfre M., Behavioral
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327–36
Supporting Information
1. Experimental
1.1. General Chemistry
Leave this area blank for abstract info.
Synthesis and biological evaluation of imidazoline
derivatives as potential CNS and CVS agents
Vineet Malhotrab , Monika Vatsa, Rajendra Nathb , Simpi Mehta a, Rakesh Kumara, Manish Bhallab ,
J N Sinhab, K Shankerb , Seeema R.Pathak a,
R HC
O
R HC
O
R HC
O
Epichorohydrin
Dioxane/NaOH
p Aminophenol
Abs Alchohol
N
N
O
N
O
N
N
OH
CH3
Arylamine
OH
CH3
Dioxane/NaOH
CH3
NH
Morpholine/
HCHO/Dioxane
R HC
O
Cl
N
N
OH
12
N
O

All reactions were performed according to
conditions as under at ambient temperature, and
thus obtained were filtered, washed with water and
dried.
reagents
were
used
without
further
4- Arylidine -1-(4-hydroxyphenyl)-2-methyl-1H-
imidazol-5(4H)-one, 3 (a-c)
purification.Melting points were taken in open
capillary tubes and are uncorrected. Thin layer
chromatography (TLC) was performed on silica gel
G plates, Proton magnetic resonance (PMR) spectra
in CDCl3 were recorded on an JEOL AL 300 and
AL500 FT-NMR spectrometer (300 and 500 MHz),
A
mixture
of
4-arylidine-2-methyl-5(4H)
2(a-c) (0.1 mol) and
oxazoline-5-one
paraminophenol (0.1 mol) was refluxed in absolute
alcohol (100 ml) for 12 hrs. The excess of solvent
was distilled off. The resulting solution was cooled
using trimethylsilane (TMS) as internal standard and poured over crushed ice. The solid thus
(Chemical Shift in δ ppm) and mass spectra on a obtained was recrystallized from alcohol/water to
JMSD 300 instrument fitted with JMS 2000 data
system 70 ev.
give title compounds.
4-Arylidene-1(p–hydroxyl-phenyl)-2-[2-
morpholino-ethyl]-3-imidazolines-5-ones, 4(a-c)
1.2. General Procedure for Preparation of
Compounds
4-Arylidine-1-(p-hydroxy
phenyl)-2-methyl
Acetyl Glycine (1)
imidazoline-5-ones 3(a-c) (0.1 mol) and
morpholine (a secondary amine) (0.1 mol) was
refluxed in dioxane (50 ml) in the presence of
formaldehyde (0.05 mol) for 10 hrs. The excess of
solvent was distilled off. The residue was cooled
and poured into ice cold water. The solid separated
out, was filtered off and recrystallized from
dioxane/water.
Acetyl glycine was prepared by method of Vogel et
al [34], M.P. 2080C, yield 85%.
4-Arylidine -2-Methyl-5(4H)-Oxazoline-5- ones ,
2 (a-c)
Actyl glycine (1) (0.1 mol) and aryl aldehyde (0.1
mol) were dissolved in acetic anhydride (100 ml),
sodium acetate (anhydrous) was added to the
reaction mixture. It was refluxed for 10 hrs. The 4-Arylidine
-1-[p-(epoxy-propoxy)-phenyl]-2-
excess of solvent was distilled off. The solid mass
obtained on cooling was stirred with little methanol
and poured over ice cold water. The compounds
methyl-3-imidazoline-5-ones, 5(a-c)
4-Arylidine-1-(p-hydroxy-phenyl)-2methyl-
imidazoline-5-ones 3(a-c) (0.1 mol) was dissolved
13

in dioxane (150) ml and
a
solution of
1.8 (s,3H,C-CH3), 5.0 (s,1H,-OH); 13CNMR
epichlorohydrine (0.01 mol) in dioxane was added
(CDCl3) δ: 16.9, 160, 162, 137.6, 134.3, 131.9,
drop wise. Simultaneously sodium hydroxide 126.2, 128.4, 127.7, 150.9, 114.9, 121.5, 132, Anal
(0.1mol) was also added to this solution. The
reaction mixture was refluxed for 6-8 hrs. The
excess of solvent was distilled off. The residue was
cooled and poured into ice cold water. The solid
separated out was filtered and crystallized from
dioxane/water to give desired compounds.
for C17H13N2O2, calcd C: 73.64, H: 4.69, N: 10.10;
found C: 73.23, H: 4.32, N: 10.42.
3b:
5-Furan-2-yl-methylene-3-(4-hydroxy-
phenyl)-methyl-3,5-dihydroimidazole-4-one,
Yield: 58%; mp: 122, MS: expected 268.0,
obtained 269.0 (M+1); 1HNMR (CDCl3) δ: 6.65-7.8
4-Arylidines-1-[p-(2”-hydroxy-3’-aryl-amino-
propoxy)-phenyl]-2-methyl-3-imidazoline-5-
ones, 6(a-c)
(m,3H,oxazole),H),
6.71
(d,2H,ArH),
7.47
(d,2H,ArH), 6.5 (s,1H,=CH), 1.6 (s,3H,CCH3), 5.0
(s,1H,OH); 13C NMR (CDCl3) δ: 16.9, 160, 162,
141.5, 133.3, 112.7, 111.8, 143.0, 155.3, 150.9,
114.9, 121.8, 130.6; Anal for C15H12N2O3; calcd: C:
67.16, H: 4.47, N, 10.4; found C: 67.23, H: 4.32, N:
10.32.
A mixture of 4-arylidine-1-[p-(epoxy-propoxy)-
phenyl]-2-methyl-3-imidazoline-5-ones 5(a-c) (0.1
mol), aryl amine (0.1 mol) and sodium hydroxide
(0.1 mol) was refluxed in dioxane for 8-10 hrs. The
solvent was distilled off and the residue was poured 3c:
5-(4-Dimethylamino-benzylidene)-3-(4-
into ice cold water. The solid separated out was
neutralized with dil HCl and was recrystallized
from dioxane/water to give title compounds.
hydroxy- phenyl)-2-methyl-3,5-dihydro-
imidazol-4-one, Yield: 69%; mp: 158; MS:
1
expected 321.0, obtained 322.0 (M+1); H NMR
The characterization data of the synthesized (CDCl3) 6.54 (d,2H,ArH), 7.12 (d,2H,ArH), 6.71
compounds are given below. (d,2H,ArH), 7.47 (d,2H,ArH), 6.5 (s,1H,=CH), 1.6
3a:
5-Benzylidene-3-(4-hydroxy-phenyl)-2- (s,3H,C-CH3), 2.85 (s,6H,N-CH3) 5.0 (s,1H,-OH );
methyl-3,5-dihydroimidazole-4-one, Yield: 70%; 13C NMR (CDCl3) δ: 16.9, 160, 162, 137.6, 134.3,
mp: 112; MS: MS: expected 277.0, obtained 278.0
125.5, 127, 115, 140.5, 130, 121.2, 115.5, 150.9,
42.6; Anal for C19H19N3O2; calcd C: 71.02, H:
5.91, N: 13.08; found C: 71.23, H: 5.32, N: 13.42.
1
(M+1); H NMR (CDCl3) δ: 7.1-7.5 (m,5H,Ar-H),
6.71 (d,2H,ArH), 7.47 (d,2H,ArH), 6.5 (s,1H,=CH),
14

4a:
5-Benzylidene-3-(4-hydroxy-phenyl)-2-(2-
4c:
5-(4-Dimethylamino-benzylidene)-3-(4-
morpholine-4-yl-ethyl)-3,5-dihydro-imidazole-4-
hydroxy-phenyl)-2-(2-morpholin-4-yl-ethyl)-3,5-
one), Yield: 72%; mp: 180; MS: expected 377.0,
dihydro-imida-zol-4-one, Yield: 62%; mp: 192;
1
obtained 378.0 (M+1); 1H NMR (CDCl3) δ: 7.1-7.5 MS: expected 417.0, obtained 416 (M+1) ; H
(m,5H,ArH), 6.71(d,2H,ArH), 7.47 (d,2H,ArH), 6.5
(s,1H,=CH), 5.0 (s,1H,-OH), 2.9 (t,2H,CH-N of
morpholine), 2.5 (t,2H,CH2 attached to imidazoline
nucleus), 2.37-3.67 (m,4xCH2 ,8H); 13C NMR
(CDCl3) δ: 160, 162, 137.6, 134.3, 131.9, 126.2,
128.4, 127.7, 150.9, 114.9, 121.5, 132, 32.0, 44.5,
56.2, 70.9; Anal for: C22H23N3O3; calcd C: 70.02,
H: 6.10, N: 11.14; found C: 70.23, H: 6.32, N:
11.42.
NMR (CDCl3) δ: 6.54 (d,2H,ArH), 7.12
(d,2H,ArH), 6.71 (d,2H,ArH), 7.47 (d,2H,ArH), 6.5
(s,1H,=CH), 2.85 (s,6H,N-CH3) 2.9 (t,2H,CH-N of
morpholine), 2.5 (t,2H,CH2 attached to imidazoline
nucleus), 2.37-3.67 (m,4xCH2,8H), 5.0 (s,1H,-OH);
13C NMR (CDCl3) δ: 160, 162, 137.6, 134.3, 125.5,
127.7, 115, 140.5, 42.6, 130, 121.2, 115, 150.9,
32.0, 44.5, 56.2, 70.9; Anal for: C24H28N4O3; calcd
C: 69.39, H: 6.74, N:13.49: found C:69.23, H: 6.32,
N:13.42.
4b:
5-Furan-2-yl-methylene-3-(4-hydroxy-
phenyl)-2-(2-morpholin-4-yl-ethyl)-3,5-dihydro-
5a:5-Benzylidene-2-methyl-3-(4-oxiranyl-
imidazole-4-one, Yield: 60%; mp: 164; MS:
methoxy-phenyl)-3,5-dihydro-imidazol-4-one,
Yield: 68%; mp: 102; MS: expected 334.0,
obtained 330.0 (M+1); 1H NMR (CDCl3) δ: 7.0-7.5
(m,5H,Ar-H), 6.71 (d,2H,ArH), 7.47 (d,2H,ArH),
6.5 (s,1H,=CH), 1.6 (s,3H,C-CH3), 4.04 (d,2H,-
CH2), 3.04 (m,1H,CH), 2.5 (d,2H,-CH2, cyclic); 13C
NMR (CDCl3) δ: 16.5, 160, 162, 136.6, 134.3,
1
expected 367.0, obtained 368.0 (M+1); H NMR
(CDCl3) δ: 6.65-7.8 (m,3H,oxazole), 6.71
(d,2H,ArH), 7.47 (d,2H,ArH), 6.5 (s,1H,=CH), 5.0
(s,1H,-OH), 2.9 (t,2H,N-CH attached morpholine),
2.5 (t,2H,CH2 attached to imidazoline nucleous),
2.37-3.67 (m,4xCH2,8H) .13C NMR (CDCl3) δ: 160,
162, 141.5, 133.3, 112.7, 111.8, 143.0, 155.3, 131.9, 126.2, 128.4, 127.7, 150.9, 114.9, 121.5,
150.9, 114.9, 121.8,130, 32.0, 44.5, 56.2, 70.9; 132, 75.5, 50.5, 43.2; Anal for: C20H18N2O3; calcd:
Anal for: C20H21N3O4; calcd C: 65.39, H: 5.72, N:
11.44; found C: 65.23, H, 5.32, N: 11.40.
C: 72.94, H: 5.47, N: 8.51; found C: 72.23, H: 5.32,
N: 8.42.
15

5b:
5-Furan-2-yl-methylene-2-methyl-3-(4- methyl-3,5-dihydro-imidazol-4-one, Yield: 73%;
oxiranyl-methoxy-phenyl)-3,5-dihydro-imidazol-
mp: 238; expected 461.5, obtained 462.0 (M+1; 1H
NMR (CDCl3) δ: 7.1-7.5 (m,5H,ArH), 6.71
4-one, Yield: 54%; mp: 126; MS: expected 324.0,
1
obtained 325.0 (M+1); H NMR (CDCl3) δ: 6.65-
(d,2H,ArH), 7.53 (d,2H,ArH), 7.05 (d,2H,ArH),
6.37 (d,2H,ArH), 6.5 (s,1H,=CH), 1.6 (s,3H,CCH3),
3.94 (d,2H,OCH2), 3.09 (m,2H,CCH2), 4.35
(t,1H,CH-OH), 4.8 (brs,1H,C-NH), 5.1(s,1H,-OH);
13C NMR (CDCl3) δ: 16.5, 160, 162, 137.6, 134.3,
7.8 (m,3H,oxazole), 6.71 (d,2H,ArH), 7.47
(d,2H,ArH), 6.5 (s,1H,=CH), 1.6 (s,3H,C-CH3),
4.04 (d,2H,-CH2), 3.04 (m,1H,CH), 2.5 (d,2H,-CH2,
cyclic), 13C NMR (CDCl3) δ: 16.5, 160, 162,
141.5, 133.3, 112.7, 111.8, 143.0, 155.3, 150.9, 131.9, 126.2, 128.4, 127.7, 150.9, 114.9, 121.5,
114.9, 121.8, 130, 75.5, 50.5, 43.2; Anal for: 132, 63.5, 39.7, 79.5, 113.7, 129.7, 122.2; Anal for:
C18H16N2O4; calcd C: 66.66, H: 4.93, N: 8.64;
found C: 66.23, H: 4.32, N: 8.42.
C26H24N3O3Cl; calcd C: 67.60; H: 5.20; N: 9.10;
found C: 67.23, H: 5.32, N: 9.22.
5c: 5-(4-Dimethylamino-benzylidene)-2-methyl-
3-(4-oxiranyl-methoxy-phenyl)-3,5-dihydro
6b: 3-{4-[3-(4-Chloro-phenylamino)-3-hydroxy-
propoxyl]-phenyl}-5-furan-2-yl-methylene-2-
imidazol-4-one, Yield: 59%; mp: 164; MS: methyl-3,5-dihydro-imidazol-4-one, Yield: 56%;
1
expected 378.0, obtained 378.0 (M+1); H NMR
(CDCl3) δ: 6.54 (d,2H,ArH), 7.12 (d,2H,ArH), 6.71
(d,2H,ArH), 7.47 (d,2H,ArH), 6.5 (s,1H,=CH), 2.85
(s,6H,N-CH3), 5.0 (s,1H,-OH), 1.6 (s,3H,C-CH3),
4.04 (d,2H,-CH2), 3.04 (m,1H,CH), 2.5 (d,2H,-CH2,
mp: 180; expected 451.5, obtained 452.0 (M+1); 1H
NMR (CDCl3) δ: 6.65-7.8 (m,3H,oxazole), 6.71
(d,2H,ArH), 7.47 (d,2H,ArH), 6.5 (s,1H,=CH), 1.6
(s,3H,C-CH3), 7.05 (d,2H,Ar-H), 6.37 (d,2H,ArH),
3.94 (d,2H,OCH2), 3.09 (m,2H,CCH2), 4.35
(t,1H,CH-OH) 4.8 (brs,1H,C-NH) 5.1 (s,1H,-OH),
13C NMR (CDCl3) δ: 16.5 160, 162, 141.5, 133.3,
13
cyclic), C NMR (CDCl3) δ: 6.5, 160, 162, 137.6,
134.3, 125.5, 127.7, 115, 140.5, 42.6, 130, 121.2,
115.5, 150.9, 75.5, 50.5, 43.2; Anal for: 112.7, 111.8, 143.0, 155.3, 150.9, 114.9, 121.8,
C22H23N3O3; calcd C: 70.02, H: 6.10, N: 11.14;
found C: 70.23, H: 6.32, N: 11.42.
130, 141.6, 113.7, 129.7, 122.2, Anal for:
C24H22N3O4Cl, calcd C: 63.78, H: 4.87, N: 9.30;
found C: 63.23, H: 4.32, N:9.42.
6a:
5-Benzylidene-3-{4-[3-(4-chloro-
phenylamino)-3-hydroxy-propoxy]-phenyl}-2-
16

6c: 3-{4-[3-(4-Chloro-phenylamino)-3-hydroxy-
propoxyl]-phenyl}-5-(dimethylamino-
injection of alpha chloralose (80 mg/kg) solution
prepared in propylene glycol. A femoral artery was
cannulated and the blood pressure was recorded by
connecting through p23 db pressure transducer to
two channel polygraphs. Test compounds (dose of
benzylidene)-2-methyl-3,5-dihydro-imidazol-4-
one, Yield: 62%; mp: 205; MS: expected 504.5,
1
obtained 505.0 (M+1); H NMR (CDCl3) δ: 6.54
(d,2H,ArH), 7.12 (d,2H,ArH), 6.71 (d,2H,ArH), 2.5 mg/kg body weight) and normal saline were
7.47 (d,2H,ArH), 6.5 (s,1H,=CH), 2.85 (s,6H,N-
CH3), 1.6 (s,3H,C-CH3), 7.05 (d,2H,Ar-H), 6.37
(d,2H,ArH), 3.94 (d,2H,OCH2), 3.09 (m,2H,CCH2),
administrated through cannulated femoral vein. The
animals were kept on positive pressure artificial
respiration throughout the experiment with the help
4.35 (t,1H,CH-OH), 4.8 (brs,1H,C-NH), 5.1(s,1H,- of artificial respirator. The both side (left and right)
OH); 13CNMR (CDCl3) δ: 16.5, 160,162, 137.6,
carotid arteries were also traced for occlusion (10-
134.3, 125.5,127.7, 115, 140, 150.9, 114.9, 121.8, 15sec). Exogenously administered norepinephrine
130, 63.5, 39.6, 79.5, 141.6, 113.7, 129.7, 122.2; induced pressor and carotid occlusion responses
Anal for: C28H29N4O3Cl; calcd C: 66.60, H: 5.74,
N: 11.10; found C: 66.23, H: 5.32, N: 11.22.
were taken as control. Transient effects appearing
just after administering test compound taken as
immediate while the effect which persisted for
longer period were termed as delayed. The
cardiovascular profile of compounds is shown in
Table-1.
2.1. Biological Studies
All these new compounds 2(a-c), 3(a-c), 4(a-c),
5(a-c), 6(a-c) were tested in vivo in order to
2.1.2. Approxiamte leathel dose
evaluate
their
hypotensive,
analgesic,
Compounds of the series 2(a-c) to 6(a-c) were
investigated for Approximate Lethal Dose (ALD50).
For evaluating ALD50, swiss albino mice (either
sex, of weight from 20 to 25 gm) were used for the
study. The test compounds were injected intra-
peritoneally at various doses in group of ten mice.
The percent mortality within 24 hrs of oral drug
antiaggressive, and antidepressant and ALD50
activities according to following standard methods.
2.1.1. Cardiovascular activities
The cardiovascular activities were carried out on
cats of either sex weighing between 2.5-4.0 kg. The
cats were anaesthetized by giving intravenous
17

administration determined ALD50 values36 (mg/kg-
1). The results are summarized in Table 1.
2.2.1. Central nervous system activities
2.2.1.1. Analgesic activity
along with standard drug Diazepam has also been
taken. The results are summarized in Table 3 &
Graph 2.
2.2.2.3. Depressant & antidepressant activity
Analgesic activity of compounds 2(a-c) to 6(a-c) Compounds 2(a-c) to 6(a-c) were also evaluated for
have been done by tail flick method (Columbus
Instruments). Albino rats of 150-200 gm of either
antidepressant effect with help of swimming
despair test according to the reported method.38 The
sex, which have been given food and water ad adult albino mice weighing 20-25 gm (male or
libitum and maintained the temperature at 24 ±2ºC.
A set of 6 rats were taken for each compound and
measured tail flick latency time (in seconds) with
female) was taken and total mean swimming time
of control as well as of drug treated group was
calculated. The significance of the result was
the help of electronic timer fitted in machine. analyzed by Chi square test. The results for
Student’s t test was performed to find out
significance of values of latencies (in seconds) of
different compounds at specific time interval along
with control data of propylene glycol (PG) and
standard drug Morphine. The results are
summarized in Table-2 & Graph 1.
antidepressant effect are summarized in Table 4 &
Graph 3.
2.2.2.2. Anti aggressive activity
Antiaggressive Activity of compounds 2(a-c) to
6(a-c) have been conducted on only male albino
rats weighing between 100-150 gm, according to
reported method.37 Fights were counted between
the rat’s group and mean fighting count was
calculated for each group. The significance of mean
values of the different groups was determined by
chi square test. Control data of propylene glycol
Image of In-vivo Cardiovascular
Activity
13
18

13 C spectra of Compound 3a
1 H Spectra of Compound 3a
19

1H Spectra of Compound 5a
13 C spectra of
Compound 4a
20

1H Spectra
of Compound 6a
Declaration of interests
☐ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
☐ The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
21