Substituted imidazole derivatives as novel cardiovascular agents

Article abstract of DOI:10.1016/j.bmcl.2010.12.062

A series of novel substituted imidazole derivatives were synthesized and have been screened in vivo for their hypotensive and acute toxicity activities. Out of seventeen compounds eight compounds (2b, 2c, 3b, 3c, 3f, 4a, 4b and 4c) have shown good hypoten

Full text of DOI:10.1016/j.bmcl.2010.12.062

Bioorganic & Medicinal Chemistry Letters 21 (2011) 936–939
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Substituted imidazole derivatives as novel cardiovascular agents
Vineet Malhotra b, Seema R.Pathak a, , Rajendra Nath b, Devashish Mukherjee b, K Shanker c
⇑
a Applied Chemistry, ASET, Amity University, Haryana, India
b Department of Pharmacology & Therapeutics, CSJMMU, Lucknows, India
c NIC college of Engineering, Faizabad Rd, Lucknow, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel substituted imidazole derivatives were synthesized and have been screened in vivo for
their hypotensive and acute toxicity activities. Out of seventeen compounds eight compounds (2b, 2c,
3b, 3c, 3f, 4a, 4b and 4c) have shown good hypotensive & bradycardiac responses. Compounds 3b, 3c, 3f
& 4c have shown better activity than reference drug clonidine. All the compounds have shown
ALD50>1000mg/kg with maximum in 2e & 4c (>1200mg/kg).
Received 6 August 2010
Revised 9 December 2010
Accepted 15 December 2010
Available online 19 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arylidine hydrazides
Substituted oxadiazole
Imidazole
Hypotensive activity
Carotid occlusion
NE response
For a long time adrenoceptors (a1a2 &b)1 have been attractive
therapeutical target because they serve a large variety of physio-
logical action & functional processes namely cardiovascular regula-
tion. Alpha blockers are vasodilators (drugs that relax blood
vessels) and do not affect cardiac output. One of the major advan-
tage of alpha blockers is that they lower cholesterol especially LDL,
triglycerides and raises HDL. Studies have documented that abnor-
mal enlargement of left heart ventricle improves with use of alpha
blocker.2 These drugs may also help to control diabetes and relieve
the symptoms of benign prostate hypertrophy (enlarged pros-
tate).3 Imidazole nucleus exhibits broad spectrum cardiovascu-
lar4–6 activities. There are indeed a large number of compounds
pressure (BP) by reducing cardiac output, relaxation of capacitance
vessels with reduction in peripheral vascular resistance.12
The compounds having imidazole nucleus have shown to inter-
act with a2- adrenoceptors13,14 & lower systemic blood pressure.
Hence substituted aryl imidazoles have been extensively utilized
for the synthesis of compounds having cardiovascular activity.15
Earlier reports have elucidated that incorporation of various phar-
macophore at position-1 of heterocyclic compounds viz. imidaz-
ole16 and pyrazolines17 markedly modulate hypotensive activity.
Therefore it was thought worthwhile to synthesize some new
(Fig. 1) able to interact with a2- adrenoceptors having heterocyclic
HN
N
nucleus like imidazole and oxazole e.g. medetomidene [I], idazo-
xan [II], moxonidine [III], clonidine [V] & rilmenidine [IV].7 It has
been demonstrated that clonidine is a2 adrenoceptor agonist. Clo-
nidine and these agents stimulate a2 /imidazoline receptors pres-
ent in medulla oblongata of CNS.8–10 Subsequently it has been
elucidated that the central neurochemical modulation of barore-
ceptor reflex occurs at the level of various medullary nuclei of
HN
N
N
Cl
O
O
N
H
HN
N
N
Idazoxan
Medetomidene
[II]
[I]
Moxonidine
[III]
GRN which is rich in
a
- adrenoceptors and clonidine like drugs
N
NH
have been shown to interact with a2 receptors present at these
site.11 These a2 receptors present in central and peripheral nerve
endings reduce the nor-epinephrine release. They decrease blood
H
H
Cl
O
N
N
N
Cl
Rilmenidine
[IV]
Clonidine
[V]
⇑
Corresponding author. Tel.:+91 522 2721931; fax: +91 522 2721934.
E-mail address: seemarpathak@yahoo.com (S. R.Pathak).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.12.062

V. Malhotra et al. / Bioorg. Med. Chem. Lett. 21 (2011) 936–939
937
substituted imidazole derivatives by incorporating hydrazides,18
arylidine hydrazide & oxadiazole moieties19 at 1-position of imid-
azole with a hope to get better novel antihypertensive agent.
The substituted imidazoles 1(a-e) were synthesized by treating
benzyl group with substituted aryl aldehydes and ammonium ace-
tate as ammonia source, in the presence of catalytic amount of
NiCl2ꢀ6H2O supported onto acidic alumina.20 Michael condensation
of 1(a-e) with ethylchloroacetate in the presence of dry K2CO3 and
subsequent treatment of reaction mixture with hydrazine hydrate
in the presence of DMF afforded compounds 2(a-e) which were
further reacted with different aromatic aldehydes to undergo man-
nich reaction furnishing substituted benzylidene-1H-imidazole-(1-
yl) acetohydrazide 3(a-f). These compounds were further reacted
(Scheme 1) with PTSA/ZnCl2# in the presence of DMF or with warm
glacial acetic acid & ferric chloride to afford final compounds 4 (a-
f). All the synthesized compounds were well characterized by spec-
troscopic data like IR, mass, NMR and elemental analysis.21 These
compounds were tested for their hypotensive activities Table-1 &
ALD50 activities.
The active compounds were investigated for approximate lethal
dose (ALD50). Mice (either sex) weighing 20-25 grams were used
for this study. They have been fasted overnight (about 18 hr), were
given water adlibitum & maintained at the temperature of 24
2
°C. In this acute toxicity test, performed for determination of LD
50 value (the dose which will kill 50%of the animals) single dose
of compounds were used in each animal on one occasion only. Val-
ues were determined by obscuring mortality within 25 hours after
oral drug administration with the help of feeding cannula accord-
ing to the methods observed by Smith.22 In the present study all
the active compounds have shown ALD50>1000mg/kg with maxi-
mum in 2e & 4c (>1200mg/kg).
Screening of all seventeen compounds, in dose of 2.5 mg/kg &
reference drug clonidine in dose of 10 mg/kg respectively was per-
formed (Table 1). First series of compounds 2 (a-e) have shown
hypotension and bradycardia in immediate and delayed phases ex-
cept compounds 2c and 2e both of which exhibited tachycardia in
delayed phase. Maximum effect was shown by compound 2b
which produced immediate & delayed hypotension each -30 &
change in heart rate -18 in immediate & -27 delayed phase. In sec-
ond series of compounds 3(a-f), compound 3b, 3c, 3f have shown
good hypotensive response and bradycardia except 3d & 3e which
exhibited slight hypotension in immediate & delayed phases and
have shown no change in heart rate. In last series of compounds
4(a-f) again all the compounds except 4d & 4e produced hypoten-
sion & bradycardia. Maximum cardiovascular activity was exhib-
ited by 4c. Most of the compounds have shown decrease in
carotid occlusion response (; which shows that they have central
action as well. The reference drug clonidine has produced hypoten-
sion & bradycardia (in 10 mg/kg dose) of similar range. Compounds
2b, 2c, 3b, 3c, 3f, 4a, 4c have shown even better hypotensive
response than reference drug in efficacy. It was observed that
compound 2b having R1 as N (CH3)2 showed maximum immediate
& delayed fall in blood pressure -30 each. It is clear that conversion
of these compounds to substituted arylidine acetohydrazides
3(a-f) enhanced the activity. Compound 3b having R1 as N-(CH3)2
and R2 as p- OCH3 (C6H4) and 3c having R1 as N (CH3)2 and R2as
3-(OCH3)4-OH(C6H3) have shown immediate and delayed
responses -45, -50 and -80 & -55 respectively. It is clear from the
All these new compounds 2(a-e), 3(a-f), 4(a-f) were tested
in vivo in order to evaluate their hypotensive activity according
to following standard method discussed below.
The study was carried in cats of either sex, the weight of cats were
between the ranges of 2.5 to 4 kg, anaesthetized with alpha –chloral-
ose (80 mg /kg, i.v.) and maintained on artificial respiration. The
femoral vein and artery of one side were cannulated with polyethyl-
ene tubing. The venous catheter was used for the stathum P 23 db
pressure transducer for recording the blood pressure on one channel
of polygraph (polyrite, India). Heart rate was calculated either from
the pressure pulse recording or from the electrocardiogram (ECG
lead II) recorded on another channel of the polygraph. The effect of
the synthesized compounds & reference drug clonidine were stud-
ied on the blood pressure & heart rate and on the pressure response
evoked either by carotid occlusion (CO) for 10 sec or by i.v. injection
of nor epinephrine (1-2
lg). Changes observed in blood pressure
were classified as immediate and delayed. Any changes which oc-
curred from the control level within 5 minutes were taken as imme-
diate and changes after a period of 5 minutes were taken as delayed
following the administration of test compounds.
CHO
O
R1
a
N
R1
N
N
+
R1
O
N
H
Where R1=
1a-H
CH2CONHNH2
1(a-e)
2(a-e)
WhereR
1b-p-N(CH3)2
1c-3OCH3.4OH
1d-p-(OCH3)
1e-o-(OH)
b
1
2a-H
=
2b-p-N(CH3)2
2c-3OCH3.4OH
2d-p-(OCH3)
2e-o-(OH)
N
R1
R1
N
N
c
N
CH2CONHN=CHR2
N
3(a-f)
Where R2=
N
4(a-f)
R1=
O
Where R2
=
R=
3a-H
R2
3a-p-C6H4(OCH3)
3b-p-C 6H4(OCH3)
3c-3(OCH3).4(OH).C6H3
3d-p-C6H4(OCH3)
3e-p-C6H4(OCH3)
3f-p-C6H4(NCH3)2
4a-p-C6H4(OCH3)
4b-p-C 6H4(OCH3)
4c-3(OCH3).4(OH).C6H3
4d-p-C6H4(OCH3)
4e-p-C6H4(OCH3)
4f-p-C6H4 (NCH3)2
4a-H
3b-p-N(CH3)2
3c-p-N(CH3)2
3d-3(OCH3)4(OH)
3e-p-OCH3
3f-o-OH
4b-p-N(CH3)2
4c-p-N(CH3)2
4d-3(OCH3)4(OH)
4e-p-OCH3
4f-o-OH
Scheme 1. Reagents and conditions: (a) ClCH2COOEt/dry K2CO3, NH2NH2.H2O/DMF reflux 6 hr; (b) R0CHO, few drops of glacial acetic acid, MeOH reflux, 3 h; (c) PTSA/ZnCl2,
DMF or warm glacial acetic acid & ferric chloride refluxed 3 hr.

938
V. Malhotra et al. / Bioorg. Med. Chem. Lett. 21 (2011) 936–939
Table 1
Cardiovascular effects for compounds 2(a–e), 3(a–f), 4(a–f)
Comp
Resting BP (mmHg)
Change in blood pressure (mmHg)
Change in heart rate (bpm)
Co* response
NE** response
Immediate
Delayed
Immediate
Delayed
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
3f
4a
120
110
122
134
140
128
132
116
126
136
130
112
110
130
134
128
132
126
ꢁ25
ꢁ30
ꢁ30
ꢁ20
ꢁ22
ꢁ15
ꢁ45
ꢁ80
ꢁ10
ꢁ5
ꢁ15
ꢁ30
ꢁ20
ꢁ5
ꢁ6
ꢁ18
–
ꢁ16
ꢁ21
ꢁ8
ꢁ12
ꢁ14
–
ꢁ6
ꢁ27
"
–
;
;
–
–
–
;
;
;
;
;
;
;
;
–
;
–
;
–
–
"
ꢁ21
"
–
–
–
–
–
"
ꢁ17
ꢁ
ꢁ11
ꢁ14
ꢁ20
–
ꢁ50
ꢁ55
–
ꢁ5
–
–
–
–
–
;
–
–
;
ꢁ60
ꢁ50
ꢁ15
ꢁ50
ꢁ10
ꢁ10
ꢁ15
ꢁ15
ꢁ35
ꢁ10
ꢁ10
ꢁ20
ꢁ10
+10
+5
ꢁ8
ꢁ11
–
–
4b
4c
4d
4e
ꢁ6
ꢁ6
–
ꢁ10
ꢁ14
–
–
–
4f
ꢁ5
ꢁ5
–
;
Clonidine
ꢁ26
ꢁ8
ꢁ15
+ indicates rise in and ꢁ indicates fall in blood pressure and heart rate, respectively, " indicates potentiation and ; indicates inhibition of pressor
response, –indicates no effect on CO &NE response. Decrease/increase in responses—we have taken more than 20–25 mm Hg of decrease or
10 mm Hg of increase as decrease or increase in BP and 6–12 beats per minute of decrease or increase was taken as decrease/increase in heart
rate (HR)
*
Note: Carotid Occlusion (CO) response—when we occluded both the carotid arteries for 10 s there was a rise in BP. Hypotensive drugs which
act centrally to block or reduce this CO response.
**
Nor-epinephrine response; Nor-epinephrine (NE) response—showed the peripheral action of NE on BP. Peripheral acting antihypertensive
agents decrease this response.
6. Robinson, K. A.; Robinson, C. P.; Castaner, J. Drugs of Future 1996, 21(11), 1129.
7. Eglen, R. M.; Hudson, A. L.; Kendall, D. A.; Nutt, D. J.; Morgan, N. G.; Wilson, V.
G.; Dillon, M. P. TIPS 1998, 19, 381.
8. Schmidt, H. Eur.J.of Pharmacol 1969, 6, 8.
9. Schmidt, H. Actual Pharmacol 1971, 24, 93.
10. Sinha, J. N.; Tangri, K. K.; Bhargava, K. P.; Schmitt, H. Recent advances in
hypertension 1975, 1, 97.
11. Nath, R.; Mukherjee, D.; Khattri, S.; Pant, K. K.; Saxena, A. K.; Mishra, N.; Shina,
J. N. Asia pacific Journal of Pharmacology 2001, 15, 1.
12. 12. B.G. Katzung, Basic & Clinical Pharmacology, nineth ed., Mc Graw-Hill,New
York, 2004 (Chapter 11), pp. 160-183.
results obtained that cyclization of substituted arylidine acetohyd-
razides 3(a-f) into their corresponding oxadiazole derivatives in
general reduced the hypotensive activity of compounds 4(a-f),
however compounds 4a & 4c showed maximum hypotensive
activity within this series of compounds. Compound 3c i.e. 2-(5-
(4-dimethylamino) phenyl)-2, 4-Diphenyl -1H–imidazole-1yl) N0-
(4- hydroxyl-3-methoxy-benzylidene) - acetohydrazide was found
to be most active compound of this series.
In conclusion, seventeen compounds 2(a-e), 3(a-f), 4(a-f) were
synthesized as a novel series of substituted imidazole analogues.
These compounds are showing promising anti-hypertensive activ-
ity in cat models weighing 2.5-4 kg and having ALD50 dose > 1000
mg/kg in mice (either sex) weighing 20-25 grams which is safe.
Out of the seventeen synthesized compounds eight compounds
have shown good hypotensive activity. Compounds 2b, 2c, 3b, 3c
3f, 4a & 4c have shown better efficacy than reference drug cloni-
dine. Compound 3c was found to be most active compound of this
series. All the active compounds have shown ALD50>1000mg/kg
with maximum in 2e & 4c (>1200mg/kg). The present study sug-
gested that the newly synthesized imidazole derivatives are new
lead for blood pressure lowering. These molecules can be very use-
ful for further optimization work in anti-hypertensive activity.
#end note- PTSA/ZnCl2 gave better yield than glacial acetic acid
& ferric chloride.
13. Pigini, M.; Quaglia, W.; Gentili, F.; Marucci, G.; Cantalamessa, F.; Frranchini, S.;
Sorbi, C.; Brasili, L. Bioorg. Med. Chem. 2000(8), 883.
14. Francesco, G.; Francesco, G.; Mario, G.; Alessandro, P., et al J.Med. Chem.
2004(47), 6160.
15. Matier, W. L.; Owens, D. A.; Comer, W. T.; Deitchman, D.; Ferguson, H. C.;
Seidehamel, R. J.; Young, J. R. J. Med. Chem. 1973, 16(8), 901.
16. Francesco, G.; Pascal, B.; Livio, B.; Mariangela, C.; Antonio, C., et al J.Med. Chem.
2002, 45, 32.
17. Malhotra, V.; Pathak, S. R.; Nath, R.; Mukherjee, D.; Shanker, K. Indian journal of
Chemistry 2002, 41B, 1310.
18. Sanchez-Salvatoria, M. D. L. A.; Rieos, C.; Vidrio, H. Cardiovascular Research
1998, 37(3), 748.
19. Deshmukh, A. A.; Sattur, P. B.; Sheth, U. K. Indian Journal of Exp.Biol 1976, 4, 166.
20. Heravi, Majid M.; Bakhtiari, Khadijeh; Oskooie, Hossein A.; Taheri, Shima
Journal of Molecular Catalysis A: Chemical 2007, 263(1-2), 279.
21. Compound 1a. Yield 72%; mp 182 °C;MS (FAB) (M+1): 296; IR (KBr)
t :
in cmꢁ1
3421 (–NH, imidazole ring), 1596 (C@N cyclic 1460, 1490 (C@C stretching),
2781 (C–H stretching);1H NMR (CDCl3) d in ppm: 7.22–7.48 (m, 15H, ArH), 10.4
(1H, NH exchangeable); Anal. Calcd for C12H16N2: C, 85.13; H, 5.4; N, 9.45.
Found: C, 85.10; H, 5.3; N, 9.40. Compound 1b.Yield, 80%; mp 210 °C; MS (FAB)
(M+1): 338, IR(KBr)
t : 3421 (NH imidazole ring), 1596 (C@N
in cmꢁ1
cyclic),1460, 1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d in ppm:
6.65–7.48 (m,14H, ArH),10.4 (1H, NH exchangeable), 2.8 (s, 6H, N(CH3)2); Anal.
Calcd for C23H20N3: C, 81.65; H, 5.91; N, 12.42. Found; C, 81.63; H, 5.90; N,
Acknowledgements
12.40. Compound 1c: Yield, 56%; mp 156 °C; MS (FAB) (M+1): 342, IR(KBr)
t in
Authors, Seema R.Pathak & Rajendra Nath are thankful to CSIR
for financial support and are also thankful to SAIF division, CDRI,
Lucknow for instrumental and elemental analysis.
cmꢁ1: 3421 (NH imidazole ring),1596 (C@N cyclic),1460, 1490 (C@C str), 2781
(C–H str); 1H NMR (CDCl3) d in ppm: 6.65–7.48 (m, 13H, ArH), 10.4 (1H, NH
exchangeable with D2O), 3.73 (s, 3H, NCH3), 5.0 (1H, OH); Anal. Calcd for
C22H18N2O2: C, 80.98; H, 5.52; N, 8.58. Found: C, 80.80; H, 5.42; N, 8.52.
Compound 1d: Yield, 80%; mp 210 °C; MS (FAB) (M+1): 326; IR (KBr) t :
in cmꢁ1
References
3421 (NH imidazole ring),1596 (C@N cyclic),1460, 1490 (C@C str), 2781 (C–H
str); 1H NMR (CDCl3) d in ppm: 6–7.8 (m, 14H, ArH), 12.5 (br s, 1H, –NH), 3.8 (s,
3H, OCH3; Anal. Calcd for C22H18N2O: C, 80.98; H, 5.52; N, 8.58. Found: C,
80.92; H, 5.56; N, 8.50. Compound 1e. Yield, 67%, mp 180 °C; MS (FAB) (M +1):
1. Hieble, J. P.; Bondinell, W. E.; Ruffolo, R. R. J.Med. Chem. 1995, 38, 3415.
2. Toja, Hong. I.; Kaplan, Norman M. JAMA 1990, 264(8), 1015.
3. Khoury, A. F.; Kalpana, Norman M. The JAMA 1991, 266(3), 394.
4. Stephen, A.Munk; Dales, A.; Harcourt, Premilla N.Arasasingham, James, A.
Bruke; J. Med. Chem. 1997,40,18.
312, IR (KBr)
t
in cmꢁ1: 3421 (NH imidazole ring), 1596 (C@N cyclic), 1460,
1490 (C@C str), 2781 (C–H str), 1H NMR (CDCl3) d in ppm:6.83–7.48 (m, 14H,
ArH), 10.4 (1H, NH exchangeable with D2O), 5.0 (1H, OH); Anal. Calcd for
C
21H16N2O: C, 80.76; H, 5.12; N, 8.97. Found: C, 80.71; H, 5.10; N, 8.95.
5. Mealy, N.; Castaner, J. Drug of Future 1996, 21(2), 139.

V. Malhotra et al. / Bioorg. Med. Chem. Lett. 21 (2011) 936–939
939
Compound 2a. Yield, 70%; mp 210 °C; MS (FAB) (M+1): 368; IR(KBr) 74.80; H, 5.65; N, 12.80. Compound 3d. Yield, 68%; mp 156 °C; MS (FAB) (M+1):
t
in cmꢁ1
:
3421 (NH imidazole ring), 1596 (C@N cyclic), 1460, 1490 (C@C str), 2781 (C–H
str); 1H NMR (CDCl3) d in ppm: 7.2–7.4 (m,15H, ArH), 4.6 (s, 2H, N–CH2CO), 8.0
(br s, 1H, NH), 2.0 (br s, 2H, NH2); Anal. Calcd for C23H20N4O: C, 75.00; H, 5.43;
N, 15.21. Found: C, 74.80; H, 5.40; N, 15.18. Compound 2b.Yield, 72%; mp
532; IR (KBr) t
in cmꢁ1: 3421 (NH imidazole ring), 1596 (C@N cyclic), 1460,
1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d in ppm: 6.8–7.5 (m, 17H,
ArH), 3.7 (s, 6H, OCH3), 5.0 (s, 1H, OH), 4.6 (s, 2H, N–CH2–CO), 8.1 (s, 1H,
N@CHAr); Anal. Calcd for C32H28N4O4: C, 72.18; H, 5.26; N, 10.52. Found: C,
72.14; H, 5.21; N, 10.50. Compound 3e. Yield, 63%; mp 205 °C; MS (FAB) (M+1):
198 °C; MS (FAB) (M+1): 411; IR (KBr)
t
in cmꢁ1: 3421 (NH imidazole ring),
1596 (C@N cyclic), 1460, 1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d in
ppm: 6.6–7.4 (m, 14H, ArH), 2.8 (s, 6H, N–CH3), 4.6 (s, 2H, N–CH2–CO), 8.0 (br s
1H, NH), 2.0 (br s, 2H, NH2); Anal. Calcd for C25H25N5O: C, 72.99; H, 6.08; N,
17.03. Found: C, 72.94; H, 6.02; N, 17.00. Compound 2c. Yield: 52%; mp 170 °C;
516; IR (KBr) t
(cmꢁ1): 3421 (NH imidazole ring), 1596 (C@N cyclic), 1460,
1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d (ppm): 6.8–7.5 (m, 18H,
ArH), 3.7 (s, 6H, OCH3), 4.6 (s, 2H, NCH2CO), 8.1 (s, 1H, N@CHAr); Anal. Calcd
for C32H28N4O3: C, 74.41; H, 5.42; N, 10.85. Found: C, 74.38; H, 5.38; N, 10.80.
MS (FAB) (M+1): 414; IR (KBr)
t
in cmꢁ1: 3421 (NH imidazole ring), 1596 (C@N
Compound 3f. Yield, 58%; mp 140 °C; MS (FAB) (M+1): 384; IR (KBr) t
(cmꢁ1):
cyclic), 1460, 1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d in ppm: 6.6–7.4
(m, 13H, ArH), 3.7 (s, 3H, OCH3), 5.0 (br, 1H, OH), 4.6 (s, 2H, NCH2CO), 8.0 (br s
1H, NH), 2.0 (br s, 2H, NH2); Anal. Calcd for C24H22N4O3: C, 69.56; H, 5.31; N,
13.5. Found: C, 69.51; H, 5.28; N, 13.0. Compound 2d. Yield: 69%; mp 184 °C;
3421 (NH imidazole ring), 1596 (C@N cyclic), 1460, 1490 (C@C str), 2781 (C–H
str), 1H NMR (CDCl3) d (ppm): 6.5–7.4 (m, 18H, ArH), 5.0 (br s, 1H, OH) 4.6 (s,
2H, NCH2CO), 8.0 (br s, 1H, NH), 2.0 (br s, 2H, NH2), 2.85 (s, 6H, N(CH3)2); Anal.
Calcd for C32H29N5O2: C, 74.56; H, 5.63; N, 13.59. Found: C, 74.51; H, 5.58; N,
13.51. Compound 4a. Yield, 52%; mp 175 °C; MS (FAB) (M+1): 484, 1H NMR
(CDCl3) d in ppm: 6.8–7.4 (m, 19H, ArH), 4.9 (s, 2H, NCH2CO), 3.7 (s, 3H, CH3);
Anal. Calcd for C31H26N4O2: C, 76.85; H, 4.95; N, 11.57. Found: C, 76.81; H,
4.91; N, 11.50. Compound 4b.Yield, 58%; mp 180 °C; MS (FAB) (M+1): 527, 1H
NMR (CDCl3) d in ppm: 6.4–7.4 (m, 18H, ArH), 2.8 (s, 6H, NCH3), 3.7 (s, 3H,
OCH3), 4.9 (s, 2H, NCH2CO); Anal. Calcd for C33H29N5O2: C, 75.14; H, 5.50; N,
13.2. Found: C, 75.10; H, 5.43; N, 13.0. Compound 4c.Yield, 61%; mp 140 °C; MS
(FAB) (M+1): 543; 1H NMR (CDCl3) d in ppm: 6.6–7.4 (m, 17H, ArH), 2.8 (s, 6H,
NCH3), 4.9 (s, 2H, NCH2CO), 3.7 (s, 3H, OCH3), 5.0 (s, 1H, OH); Anal. Calcd for
MS (FAB) (M+1): 398; IR(KBr)
t
in cmꢁ1: 3421 (NH imidazole ring), 1596 (C@N
cyclic), 1460, 1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d in ppm: 6.8–7.4
(m, 14H, ArH), 3.7 (s, 3H, OCH3), 4.6 (s, 2H, N–CH2–CO), 8.0 (br s, 1H, NH), 2.0
(br s, 2H, NH2); Anal. Calcd for C24H22N4O2: C, 72.36; H, 5.52; N, 14.07. Found:
C, 72.30, H, 5.50; N, 14.00. Compound 2e. Yield: 64%; mp 153 °C; MS (FAB)
(M+1): 384; IR (KBr)
t
in cmꢁ1: 3421 (NH imidazole ring), 1596 (C@N cyclic),
1460, 1490 (C@C str), 2781 (C–H str), 1H NMR (CDCl3) d in ppm: 6.7–7.4 (m,
14H, ArH), 5.0 (br s, 1H, OH), 4.6 (s, 2H, N–CH2–CO), 8.0 (br s 1H, NH), 2.0 (br s,
2H, NH2); Anal. Calcd for C23H20N4O2: C, 71.87; H, 5.20; N, 14.50. Found: C,
71.30; H, 5.19; N, 14.00. Compound 3a. Yield, 57%; mp 243 °C; MS (FAB) (M+1):
C33H29N5O3: C, 72.9; H, 5.34; N, 8.83. Found: C, 72.4; H, 5.30; N, 8.74.
486, IR (KBr)
t
in cmꢁ1: 3421 (NH imidazole ring), 1596 (C@N cyclic), 1460,
Compound 4d. Yield 53%; mp 179 °C, MS (FAB) (M+1): 530; 1H NMR (CDCl3) d
in ppm: 6.8–7.5 (m, 17H, ArH), 3.7 (s, 6H, OCH3), 5.0 (s, 1H, OH), 4.9 (s, 2H,
NCH2CO); Anal. Calcd for C32H26N4O4: C, 72.45; H, 4.90; N, 10.56. Found: C,
72.40; H, 4.83; N, 10.50. Compound 4e. Yield, 57%; mp 152 °C; MS (FAB) (M+1):
514; 1H NMR (CDCl3) d in ppm: 6.8–7.5 (m, 18H, ArH), 3.7 (s, 6H, OCH3), 4.9 (s,
2H, NCH2CO); Anal. Calcd for C32H26N4O3: C, 74.70; H, 5.05; N, 10.89. Found: C,
74.67; H, 5.00; N, 10.80. Compound 4f. 2-(1((5-(4-Dimethyl amino)phenyl)-
1,3,4-oxadiazole-2-yl)methyl)-2,4-diphenyl-1H-imidazole-5-yl)phenol: Yield,
46%; mp 160 °C; MS (FAB) (M+1): 499; 1H NMR (CDCl3) d in ppm: 6.7–7.4
(m, 18H, ArH), 5.0 (br s, 1H, OH), 4.9 (s, 2H, NCH2CO), 2.8 (s, 6H, N(CH3)2); Anal.
Calcd for C32H27N5O2: C, 76.95; H, 5.41; N, 11.22. Found: C, 76.90; H, 5.32; N,
11.18.
1490 (C@C str), 2781 (C–H str); 1H NMR (CDCl3) d (ppm): 6.8–7.4 (m, 19H,
ArH), 4.6 (s, 2H, N–CH2–CO), 8.1 (s, 1H, CH@N), 3.73 (s, 3H, CH3); Anal. Calcd for
C
31H26N4O2: C, 71.87; H, 5.20; N, 14.50. Found: C, 71.30; H, 5.19; N, 14.00.
Compound 3b. Yield, 65%; mp 210 °C; MS (FAB) (M +1): 529; IR (KBr)
t
(cmꢁ1):
3421 (NH imidazole ring), 1596 (C@N cyclic), 1460, 1490 (C@C str), 2781 (C–H
str), 1H NMR (CDCl3) d (ppm): 6.8–7.5 (m, 18H, ArH), 2.8 (s, 6H, NCH3), 3.7 (s,
3H, OCH3), 4.6 (s, 2H, NCH2CO), 8.0 (br s, 1H, NH), 8.1 (s, 1H, N@CHAr); Anal.
Calcd for C33H31N5O2: C, 74.86; H, 5.86; N, 13.23. Found: C, 74.80, H, 5.82; N,
13.20. Compound 3c.Yield 70%; mp 117 °C; MS (FAB) (M+1): 545; IR (KBr)
t
(cmꢁ1): 3421 (NH imidazole ring), 1596 (C@N cyclic), 1460, 1490 (C@C str),
2781 (C–H str), 1H NMR (CDCl3) d in ppm 6.6–7.4 (m, 17H, ArH), 2.8 (s, 6H,
NCH3), 4.6 (s, 2H, NCH2CO), 8.1 (s, 1H, N@CHAr), 3.1 (s, 3H, OCH3), 5.0 (s, 1H,
OH); Anal. Calcd for C33H31N5O3: [Calcd, C, 74.85; H, 5.68; N, 12.84. Found: C,
22. Smith, C. C. J. Pharmacol. Exp. Ther. 1950, 100(4), 408.