Rational Design and Synthesis of 1-(Arylideneamino)-4-aryl-1H-imidazole-2-amine Derivatives as Antiplatelet Agents

Article abstract of DOI:10.1002/cmdc.201700123

Based on previous studies indicating the pharmacophoric role of a hydrazone group and azole rings for antiplatelet aggregation activity, a few series of compounds with both hydrazone and an azole (imidazole) ring in their structures were synthesized, and their platelet aggregation inhibitory effects were evaluated. Two of these 1-(arylideneamino)-4-aryl-1H-imidazole-2-amine derivatives, compounds 4 a [(E)-1-(benzylideneamino)-4-phenyl-1H-imidazol-2-amine] and 4 p [(E)-4-phenyl-1-((thiophen-2-ylmethylene)amino)-1H-imidazol-2-amine], exhibited IC₅₀ values similar to that of acetylsalicylic acid against collagen as a platelet aggregation inducer. Structural comparison of the synthesized compounds revealed that those with a para-substituted phenyl ring on the imidazole were among the most active compounds against platelet aggregation induced by arachidonic acid (AA), and the presence of a thiophene ring in these compounds maximized their antiplatelet activity.

Full text of DOI:10.1002/cmdc.201700123

Accepted Article
Title: Rational design and synthesis of 1-(arylideneamino)-4-aryl-1H-
imidazole-2-amine derivatives as antiplatelet agents
Authors: Salimeh Amidi, Marjan Esfahanizadeh, Kimia Tabib, Zohreh
Soleimani, and Farzad Kobarfard
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To be cited as: ChemMedChem 10.1002/cmdc.201700123
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10.1002/cmdc.201700123
ChemMedChem
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Rational design and synthesis of 1-(arylideneamino)-4-aryl-1H-
imidazole-2-amine derivatives as antiplatelet agents
Salimeh Amidi[a], Marjan Esfahanizadeh[a], Kimia Tabib[a], Zohreh Soleimani[a] and Farzad Kobarfard*[a,b]
[a]
[b]
*
Dr. S. Amidi, Dr. M. Esfahanizadeh, K. Tabib, Z. Soleimani, Prof. F. Kobarfard
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, No. 2660 Vali-e-Asr Ave,Tehran (Iran)
E-mail: kobarfard@sbmu.ac.ir
Prof. F. Kobarfard
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, No. 2660 Vali-e-Asr Ave,Tehran (Iran)
E-mail: kobarfard@sbmu.ac.ir
Corresponding author
Abstract: Based on the previous studies indicating the
pharmacophoric role of hydrazone group and azole rings for
antiplatelet aggregation activity, a few series of compounds with both
hydrazone and azole (imidazole) ring in their structures were
synthesized and their platelet aggregation inhibitory effect was
evaluated. Two compounds among the 1-(arylideneamino)-4-aryl-
1H-imidazole-2-amine derivatives compound 4a and 4p showed IC50
values comparable to that of aspirin against collagen as platelet
aggregation inducer. Structural comparison of the synthesized
compounds revealed that those compounds with para-substituted
phenyl ring on imidazole ring are among the most active compounds
against the platelet aggregation induced by arachidonic acid (AA)
and the presence of thiophene ring in these compounds (6b, 6c and
6d) will maximize their antiplatelet activity.
aggregation activity on the thrombin and ADP-induced platelet
aggregation by Momin et al.[10]
A review among the compounds with antiplatelet aggregation
activity reveals that hydrazone moiety plays a pharmacophoric
role in many of these compounds. Chelucci et al reported drugs
that hybrid with N-acyl hydrazone subunit show antiplatelet and
antithrombotic activities.[11] Todeschini et al. reported a series of
2-pyridylhydrazones in 1998 with moderate inhibitory activity
against arachidonic acid (AA).[12] Todeschini et al. disclosed the
synthesis and pharmacological profile of N-phenylpyrazole
arylhydrazones derivatives and described the pharmacophoric
contribution of both the functionalized arylhydrazone units and
the N-heterocyclic moiety in antiplatelet aggregation activities.[12]
Jordao et al have also introduced
a
group of N-
acylheteroarylhydrazones efficient inhibitors of AA, ADP and/or
adrenaline pathways.[13] It was reported by Watala et al. that
resorcylidene aminoguanidine showed unique antithrombotic
activity in vivo.[14]
Introduction
In our previous works we synthesized
hydrazone derivatives (Figure 1) with efficient platelet
aggregation inhibitory Classic bioisosteric
effect.[15-17]
replacement of phenyl ring with heteroaromatic rings gave us
compound 2 (Figure 1) with IC50 = 2.2 µM against the platelet
aggregation induced by AA.[18]
a group of indole
Cardiovascular diseases (CVDs) such as coronary heart disease
(heart attack), cerebrovascular disease (stroke) and deep vein
thrombosis are one of the main causes of death in the world. It is
estimated that CVDs are responsible for 17.5 million deaths
(31%) every year. Over 75% of CVD deaths occur in low- and
middle-income countries.[1]
1
Platelet activation and aggregation play a pivotal role in CVDs
and their complications. Antiplatelet drugs are widely used in the
treatment of CVDs and prevention of heart attack and stroke.
Platelet activation can be initiated upon exposure to various
endogenous agonists such as thrombin, thromboxane A2 (TXA2),
collagen and/or adenosine 5’-diphosphate (ADP).[2]
H
H
N
N
N
N
N
N
O
S
N
H
Many antiplatelet drugs have been developed based on different
mechanisms of action such as: aspirin (TXA2 pathway blocker),
clopidogrel and ticlopidine (ADP receptor antagonist)[3], tirofiban
(GPIIa/IIIb antagonist), cilostazol (phosphodiesterase inhibitor)[3],
dipyridamole,[4] ozagrel and dazoxiben (TXA2 synthase
inhibitors).[5,6]
1
2
R
H
5
4
H
Alongside the advantages of antiplatelet drugs, they have some
limitations such as gastric erosion, bleeding, variable response
in patients, drug resistance and interaction.[3,7] Therefore,
attempts to develop new efficient antiplatelet drugs is ongoing.[8]
Recently several imidazole derivatives were also synthesized as
antiplatelet agents. Rehse and steege have reported imidazole-
4-carboxylic acid derivatives with antiplatelet activity in a low
micromolar range.[9] A series of fluorinated imidazole-2-thiones
were prepared with concentration dependent antiplatelet
1
3
N
N
Ar
N
2
NH2
Designed Derivatives
Figure 1. Structure of 1, 2 and designed derivatives.
1
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In continuation of our quest to find new structures with potent
antiplatelet aggregation activity we decided to take advantage of
the possible pharmacophoric contribution of both hydrazone unit
and N-heterocyclic rings by molecular hybridization of the two
moieties. Therefore we designed and synthesized a new series
of hydrazinic group of 1-(arylideneamino)-4-aryl-1H-imidazole-2-
amine.
The compounds 5a-g and 6a-g with substituent on phenyl ring at
position 4 of imidazole ring were prepared by reaction of 3a and
3p with different phenacyl bromide derivatives.
Pharmacology: Antiplatelet activity
The antiplatelet activity of synthesized compounds were
evaluated according to Born method[22] by using ADP, collagen
and AA as platelet aggregation inducers. The obtained IC50
values are reported in Table 1 and 2 as mean ± SE (n=3).
Structure activity relationships
Results and Discussion
As shown in Table 1 all guanylhydrazone compounds displayed
poor antiplatelet activity against ADP with the exception of 3f, 3i
and 3j which showed a moderate activity (IC50 = 230-240 μM).
In order to investigate the pharmacophoric contribution of azole
ring in exerting antiplatelet activity, guanylhydrazone derivatives
were converted to imidazole derivatives via a ring closure
reaction. Thus compound 4a-q were synthesized and their
antiplatelet activity was evaluated (Table 1). The obtained data
demonstrated that antiplatelet activity against the aggregation
induced by ADP did not improve after ring closure.
As presented in Table 1, among the guanylhydrazone
compounds when collagen was used as platelet aggregation
inducer, only 2-fluorophenyl derivative 3b exhibited good
antiplatelet activity (IC50 = 23.98 μM). Compounds 3f, 3g, 3i, 3j,
3m and 3p with IC50 values range between 50 to 90 μM, show
moderate activities. Ring closure and converting the
guanylhydrazones to imidazole derivatives resulted in
improvement in activity of compounds 4a (IC50 = 11.9 μM) and
4p (IC50 = 10.65 μM) against the platelet aggregation induced by
collagen. These IC50 values are comparable to that of aspirin
(9.7 μM). This result showed that replacement of phenyl ring
with the bioisostere ring, thienyl, did not affect the activity
against collagen. Compounds 4f, 4g, 4i and 4l exhibited modest
activity against the platelet aggregation induced by collagen
(IC50 = 33-74 μM). Most of the imidazole derivatives exhibited an
antiplatelet activity very similar to their corresponding
guanylhydrazone compounds.
Chemistry
The guanylhydrazones 3a-q were prepared by the reaction of
aminoguanidine with appropriate aromatic aldehydes. The
obtained hydrazone derivatives 3a-q were converted to
compounds 4a-q in the presence of phenacyl bromide in ethanol
at room temperature according to the synthetic route shown in
scheme 1.[19,20]
O
R'
Br
H
O
R'
H
H
N
a
N
N
NH2
NH
b
Ar
N
Ar
H
Ar
N
NH2
3a-q
4a-q, 5a-g, 6a-g
Scheme 1. Reagents and conditions: a) Aminoguanidine
bicarbonate, HCl, 1 h; b) NaOH, EtOH, 40-45 °C, 24 h.
The double bond geometry of 4a was characterized by nuclear
overhauser effect (NOE) experiments. The stereochemistry
determined to be E according to the strong NOE effect between
the HC=N and proton of imidazole ring.(Figure 2) This finding
was also consistent with previous studies.[20,21]
Guanylhydrazone compounds 3g (IC50 = 153.7 μM) and 3m
(IC50 = 155.4 μM) showed the highest antiplatelet activity against
AA among other guanylhydrazone derivatives. Interestingly, the
presence of imidazole ring improves the antiplatelet activity
against AA induced platelet aggregation. The antiplatelet activity
induced by AA of all imidazole derivatives with halogen
substituent (4b-j) at ortho, meta and para position of the phenyl
ring decreases as the size of the halogen increases from fluorine
to bromine. Moreover, addition of methoxy and methyl group at
para position of phenyl ring in 4l and 4k improve the antiplatelet
activity against the AA pathway, whereas introduction of
hydroxyl groups at the C-4 position of phenyl group decreased
the antiplatelet activity. The antiplatelet activity of imidazole
derivatives with a thienyl group 4p improved when compared to
imidazole derivatives with furanyl 4o and 2-pyridyl 4q groups.
Compound 4e (IC50 = 27.00 μM) and 4p (IC50 = 26.61 μM) with
phenyl and thienyl ring were the most active compounds against
the platelet aggregation induced by AA.
As Compound 4p was the most active compound against the
platelet aggregation induced by both collagen and AA and
compound 4a showed activity against collagen comparable to
that of 4p, we decided to investigate the importance of
substitution at the phenyl ring attached to imidazole ring for
Figure 2. NOE spectrum of compound 4a. The off-diagonal
signal which correlate peaks at 8.0 and 8.57 ppm indicates the
spacial correlation of HC=N and H-5 of imidazole ring.
2
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these series of compounds. Compounds 5a-g with various
substituted phenyl on the imidazole ring were synthesized and
their antiplatelet activity was evaluated. As indicated in Table 2,
the antiplatelet activity of phenyl imidazole derivatives 5a-g
didn’t improve against ADP but the activity decreased
significantly against collagen (4a against 5a-g, P < 0.001).
Introduction of methyl 5c and methoxy 5d group onto the para
position of phenyl ring of imidazole led to a significant increase
in antiplatelet activity against AA (4a against 5c-d; P < 0.005).
However the compounds containing fluoro 5a at para position of
phenyl ring show moderate activity (IC50 = 41.9 µM). The
compounds with a chlorine group at the ortho and meta position
5e-g show no improvement in activity.
Thienylimidazole derivatives 6a-g were synthesized with
different substituents on phenyl ring at position 4 of imidazole as
shown in Table 2. All the synthesized compounds show no
activity against ADP and the activity decreased significantly
against collagen (4p against 6a-g; P < 0.01). Compounds 6b, 6c
and 6d with chlorine, methyl and methoxy at the para position of
phenyl ring showed increased activity against AA. The IC50 of 6b,
6c and 6d were between 2.68 to 3.36 µM and comparable to
that of indomethacin with IC50 value of 1.67 µM (Figure 3).
Table 1: In vitro antiplatelet activity using arachidonic acid (AA), adenosine diphosphate (ADP) and Collagen as platelet aggregation
inducers. The obtained IC50 values are reported as mean (n=3).
H
H
H
N
NH2
N
N
Ar
N
Ar
N
NH
NH2
3a-q
4a-q
IC50 (µM)
Collagen
(2.5 µg/ml)
>100
IC50 (µM)
ADP
AA
(1.35 mM)
>500
>500
>500
>500
>500
241.0±8.7
153.70±5.9 4g
>500 4h
383.0±10.0 4i
219.0±10.6 4j
>500
474.0±11.6 4l
155.40±3.7 4m
>500
>500
>500
>500
ADP
Collagen
(2.5 µg/ml)
11.90±2.18
>100
76.7±7.8
>100
AA
Compd
Ar
Compd
(5 µM)
>500
>500
(5 µM)
>500
>500
>500
>500
(1.35 mM)
177.9±10.2
112.1±4.1
145.0±4.3
375.3±7.0
27.00±4.0
>500
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
phenyl
4a
4b
4c
4d
4e
4f
2-fluorophenyl
2-chlorophenyl
2-bromophenyl
3-fluorophenyl
3-chlorophenyl
3-bromophenyl
4-fluorophenyl
4-chlorophenyl
4-bromophenyl
4-methylphenyl
4-metoxyphenyl
4-hydroxyphenyl
3,4,5-trimethoxyphenyl
2-furanyl
2-thienyl
2-pyridyl
23.98±6.42
473.8±7.7 >100
>500
>500
>100
>100
458.0±8.8 >100
231.9±5.5 89.1±4.4
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
51.3±5.7
65.3±7.5
>100
74.2±9.4
>100
>100
33.1±4.0
>100
>100
>100
10.65±0.63
>100
>500
>500
81.3±1.5
>100
241.7±8.3 57.5±3.9
230.4±8.3 66.1±4.8
>500
40.0±2.5
109.8±7.8
>500
254.8±7.1
91.4±1.6
>500
>500
>500
>500
>500
>500
>500
>500
>500
>500
>100
>100
56.2±2.8
>100
>100
70.0±4.3
>100
1.2±0.3
9.7±0.7
4k
4n
4o
4p
4q
>500
210.0±7.6
26.61±3.26
260.8±2.7
Indomethacin
Aspirin
1.67±0.67
0.24±0.05
3
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Table 2: In vitro antiplatelet activity using arachidonic acid (AA), adenosine
diphosphate (ADP) and Collagen as platelet aggregation inducers. The obtained
IC50 values are reported as mean (n=3).
R'
R'
H
H
N
N
N
N
N
N
NH2
NH2
S
5a-g
6a-g
IC50 (µM)
ADP
Collagen
(2.5 µg/ml)
>500
AA
Compd
R′
(5 µM)
>1000
>1000
226.0±7.4
496.0±7.7
>1000
>1000
>1000
>1000
>1000
>1000
402.0±11.8
>1000
>1000
>1000
>500
(1.35 mM)
41.9±1.9
310.0±11.2
10.76±1.02
15.78±2.69
152.8±5.2
>500
295.4±7.8
311.0±8.4
2.78±0.46
2.68±0.22
3.36±0.40
42.6±4.2
316.0±7.9
94.1±3.9
1.67±0.67
0.24±0.05
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
6g
4 -F
4- Cl
4- CH3
4- OCH3
2- Cl
2- Br
3- Cl
4 -F
4- Cl
4- CH3
4- OCH3
2- Br
3- Cl
3- Br
>500
73.3±3.3
60.7±3.8
396.0±8.5
>500
>500
96.6±8.1
264.0±15.4
125.2±4.9
166.5±7.1
103.0±6.1
445.0±12.8
262.0±5.8
1.2±0.3
Indomethacin
Aspirin
>500
9.7±0.7
4
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R'
H
N
N
NH NH2
NH
N
N
cyclization
N
N
N
NH2
NH2
3a
4a
5c R' :-CH3
5d R': -OCH3
R'
H
NH NH2
NH
N
N
N
N
cyclization
N
N
N
S
NH2
S
NH2
S
3p
4p
6b R': -Cl
6c R': -CH3
6d R': -OCH3
Increased antiplatelet activity against AA inducer
Increased antiplatelet activity
against collagen inducer
Decreased antiplatelet activity
against collagen inducer
Figure 3. Structure activity relationship (SAR) of synthesized compounds.
Lipinski rule of five
(clog P between 2.85-3.53), they might be able to pass through
the biological membranes. The results of calculating Lipinski’s
criteria of drug likeness for the most active derivatives (Table 3)
indicate that all of these compounds fall within the rule of five
and thus have properties which would make them kinetically
proper drug candidates.
To predict if a chemical compound could be used orally, the
most active derivatives 5c, 5d and 6b–d against AA were
analyzed according to the Lipinski "rule of five"[23] using OSIRIS
Datawarrior (version 4.2.2)[24] (Table 3). In lipinski rule of five the
clogP is an indicator for the lipophilicity of compounds. Based on
the calculated clogP values of compounds 5c, 5d and 6b–d
Table 3: The calculated parameters of Lipinski rule of five for the most active
derivatives against arachidonic acid (AA).
Lipinski rule of five[a]
Compound
5c
5d
6b
6c
6d
IC50 (μM)
10.76
15.78
2.78
2.68
3.36
HBA
HBD
Mw
276
292
302
282
298
357
clog P
3.40
2.99
3.53
3.27
2.85
4.00
4
5
4
4
5
5
1
1
1
1
1
1
Indomethacin
1.67
[a] number of hydrogen bond acceptors (HBA) ≤ 10, number of hydrogen bond
donors (HBD) ≤ 5, clog P ≤ 5 and Molecular weight (Mw) ≤ 500
Docking studies
lowest energy calculated by AutoDock version 4.2 was selected
On the basis of the antiplatelet aggregation test, the most active
derivatives 6b, 6c and 6d against AA were selected for
molecular docking studies on their possible potential target i.e.
cyclooxygenase 1 (COX-1). The best docked pose with the
and analyzed with PyMol and Ligplot software.
The position of compounds 6b, 6c and 6d in the binding site was
shown in Figure 4. It was observed that all of the 6b, 6c and 6d
displayed strong hydrogen bound between the NH2 group of
5
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imidazole ring and hydroxyl oxygen of Ser530. In compounds 6b
and 6c another hydrogen bond was established between the
imidazole nitrogen atom and the hydroxyl group of Ser530.
In the compounds 6b and 6c the thiophene rings were in the
same position and oriented toward Tyr355, Leu359 and Val116.
On the contrast, in 6d with methoxy substituent the thiophene
ring is directed to the opposite site and display hydrophobic
contacts with Trp387, Leu384 and Met522.
Figure 4. Interaction of Compounds 6b, 6c and 6d with COX-1 active site. The residues are showed in green lines. Picture was
generated with PyMOL (A). Schematic diagram of interactions of 6b, 6c and 6d with COX-1 active site generated by Ligplot.
Hydrogen bonds are showed with green dashed lines. Residues involved in hydrophobic interaction with the ligands are shown with
red rays. The red cycles showed the same residues which interact with ligands (B).
antiplatelet activity on platelet rich plasma (PRP) was evaluated
by using ADP, collagen and AA as platelet aggregation inducers.
The obtained data demonstrated that synthesized derivatives did
not show significant activity against ADP. The structure activity
Conclusions
relationship studies showed that compounds 4a and 4p with
phenyl ring at position 4 of imidazole were active against
collagen as platelet aggregation inducer while, substitutions at
A series of guanylhydrazone and 1-(arylideneamino)-4-aryl-1H-
imidazole-2-amine derivatives were synthesized and their
6
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Yellow solid. Yield: (172.5 mg, 88%); mp: 145-146 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.58 (s, 2H, NH2), 5.97 (s, 2H, NH2), 7.23 (m, 2H, H-4, H-
5), 7.34 (dd, J=7.5 Hz, J=1.7 Hz, 1H, H-3), 8.08 (dd, J=7.5 Hz, J=1.9 Hz,
1H, H-6), 8.23 ppm (s, 1H, HC=N); IR (KBr): ϋ=3455, 3327, 3284, 1628,
1600, 1544, 1162, 748 cm-1; ESI-MS m/z [M+H+] = 197.1; Anal. Calcd for
C8H9ClN4: C 48.87, H, 4.61, N 28.49, found C 48.86, H, 4.62, N 28.47.
para position of phenyl at position 4 of imidazole ring decreased
the antiplatelet activity against collagen. As for the activity
against collagen, substitution on the phenyl ring attached to
imidazole ring could not be tolerated. Whereas derivatives with
substituents such as chlorine, methyl and methoxy at para
position of phenyl at position 4 of imidazole ring were the most
active compounds against AA. The presence of thiophene ring in
these compounds will maximize their anitplatelet activity. The
compound 6c has an IC50 comparable to indomethacin. The
results of this study are helpful for our ongoing studies to design
and obtain promising compounds with antiplatelet effects.
(E)-2-(2-bromobenzylidene)hydrazine-1-carboximidamide (3d)
Cream solid. Yield: (216.0 mg, 90%); mp: 161-168 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.57 (s, 2H, NH2), 5.97 (s, 2H, NH2), 7.13 (t, J=7.5 Hz, 1H,
H-5), 7.27 (t, J=7.6 Hz, 1H, H-4), 7.52 (d, J=7.6 Hz, 1H, H-3), 8.067 (dd,
J=8.0 Hz, J=1.5 Hz, 1H, H-6), 8.18 ppm (s, 1H, N=CH); IR (KBr): ϋ=3472,
3394, 3317, 1638, 1608, 1573, 1439, 1169, 760 cm-1; ESI-MS m/z
[M+H+] = 241, 243; Anal. Calcd for C8H9BrN4: C 39.86, H 3.76, N 23.24,
found C 39.85, H 3.75, N 23.22.
Experimental Section
General methods
All the chemicals and solvents were purchased from Merck (Darmstadt,
Germany). The 1H-NMR spectra were recorded on a 500 MHz Bruker
spectrometer. NOE spectrum was recorded on a 600 MHz Bruker
spectrometer. The positive ESI-MS mass spectra were recorded on an
Agilent 6410 triple quadrupole mass spectrometer. IR spectra were
recorded on Perkin Elmer IR spectrophotometer as potassium bromide
discs. The melting points of the compounds were obtained on 9100
Electrothermal melting point apparatus. Elemental analyses were
(E)-2-(3-fluorobenzylidene)hydrazine-1-carboximidamide (3e)
White solid. Yield: (162.0 mg, 90%); mp: 153-156 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.48 (s, 2H, NH2), 5.94 (s, 2H, NH2), 6.99 (t, J=7.7 Hz;1H,
H-5), 7.30 (dd, J=14.0 Hz, J=7.7 Hz, 1H, H-4), 7.37 (d, J=7.3 Hz; 1H, H-
6), 7.54 (d, J=10.0 Hz, 1H, H-2), 7.92 ppm (s, 1H, N=CH); IR (KBr):
ϋ=3377, 3209, 3163, 1688, 1636, 1599, 1274, 1137, 942, 799, 686 cm-1;
ESI-MS m/z [M+H+] = 181; Anal. Calcd for C8H9FN4: C 53.33, H 5.03, N
31.09, found C 53.30, H 5.02, N 31.11.
performed by
a Costech ECS 4010 CHNS analyzer. For all the
compounds the calculated values agreed with the measured values to
within 0.4%. All the compounds used in platelet aggregation assay were
> 98% pure as determined by 1H NMR spectroscopy.
(E)-2-(3-chlorobenzylidene)hydrazine-1-carboximidamide (3f)
General procedure for the synthesis of guanylhydrazones
White solid. Yield: (172.5 mg, 88%); mp: 164-166 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=6.2 (bs, 4H, NH2), 7.29 (d, J=7.9 Hz, 1H, H-4), 7.35 (t,
J=7.7 Hz, 1H, H-5), 7.58 (d, J=7.6 Hz, 1H, H-6); 7.83 (s, 1H, H-2), 7.97
ppm (s, 1H, N=CH); IR (KBr): ϋ=3475, 3443, 1643, 1595, 1349, 1148,
937, 789, 682 cm-1; ESI-MS m/z [M+H+] = 197.1; Anal. Calcd for
C8H9ClN4: C 48.87, H 4.61, N 28.49, found C 48.89, H 4.60, N 28.50.
The guanylhydrazones 3a-q were prepared by the procedure described
in the literature.[19,20,25] In Brief, a mixture of aminoguanidine bicarbonate
(1 mmol) and appropriate aromatic aldehydes in the presence of HCl
(37%) was stirred for 30 min at room temperature. Then a solution of 5%
aqueous NaOH (7 mL) was added. The obtained precipitate was
collected by filtration.
(E)-2-benzylidenehydrazine-1-carboximidamide (3a)
White solid. Yield: (137.7 mg, 85%); mp: 180-182 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=6.16 (bs, 4H, NH2), 7.28 (t, J=7.2 Hz, 1H, H-4); 7.35 (t,
J=7.6 Hz, 2H, H-3,H-5), 7.71 (d, J=7.2 Hz, 2H, H-2, H-6), 8.02 ppm (s,
1H, HC=N); IR (KBr): ϋ=3465, 3423, 3312, 1648, 1580, 1480, 1437, 1144,
1016, 936, 758, 686 cm-1; ESI-MS m/z [M+H+] = 163.1; Anal. Calcd for
C8H10N4: C 59.24, H 6.21, N 34.54, found: C 59.31, H 6.21, N 34.48.
(E)-2-(3-bromobenzylidene)hydrazine-1-carboximidamide (3g)
White solid. Yield: (220.8 mg, 92%); mp: 178-180 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.54 (s, 2H, NH2), 6.00 (s, 2H,NH2), 7.27 (t, J=7.8 Hz, 1H,
H-5), 7.40 (d, J=7.7 Hz, 1H, H-4), 7.60 (d, J=7.6 Hz, 1H, H-6), 7.94 ppm
(s, 2H, H-2, N=CH); IR (KBr): ϋ=3452, 3295, 3187, 1652, 1531, 1338,
1150, 933, 801, 682 cm-1; ESI-MS m/z [M+H+] = 241.3, 243; Anal. Calcd
for C8H9BrN4: C 39.86, H 3.76, N 23.24, found C 39.84, H 3.76, N 23.25.
(E)-2-(2-fluorobenzylidene)hydrazine-1-carboximidamide (3b)
White solid. Yield: (158.4 mg, 88%); mp: 183-185 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.59 (s, 2H, NH2), 5.98 (s, 2H, NH2), 7.18 (m, 2H, H-4, H-
5); 7.29 (dd, J=14.1 Hz, J=8.5 Hz,1H, H-3), 8.06 (dt, J=8.0 Hz, J=1.5 Hz,
1H, H-6), 8.12 ppm (s,1H, HC=N); IR (KBr): ϋ=3488, 3447, 3373, 1648,
1600, 1522, 1239, 1156, 767 cm-1; ESI-MS m/z [M+H+] = 181; Anal.
Calcd for C8H9FN4: C 53.33, H 5.03, N 31.09, found C 53.35, H 5.02, N
31.10.
(E)-2-(4-fluorobenzylidene)hydrazine-1-carboximidamide (3h)
White solid. Yield: (162.0 mg, 90%); mp: 182-186 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.41 (s, 2H, NH2), 5.86 (s, 2H, NH2), 7.11 (t, J=8.9 Hz, 2H,
H-3, H-5), 7.67 (dd, J=8.8 Hz, J=5.8 Hz, 2H, H-2, H-6), 7.93 ppm (s, 1H,
N=CH); IR (KBr): ϋ=3495, 3449, 1650, 1595, 1245, 1163, 847, 682 cm-1;
ESI-MS m/z [M+H+] = 181; Anal. Calcd for C8H9FN4: C 53.33, H 5.03, N
31.09, found C 53.36, H 5.03, N 31.08.
(E)-2-(2-chlorobenzylidene)hydrazine-1-carboximidamide (3c)
7
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10.1002/cmdc.201700123
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FULL PAPER
(E)-2-(4-chlorobenzylidene)hydrazine-1-carboximidamide (3i)
White solid. Yield: (184.2 mg, 94%); mp: 206-208 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.52 (s,2H, NH2), 5.94 (s, 2H, NH2), 7.37 (d, J=8.5 Hz, 2H,
H-3, H-5), 7.69 (d, J=8.5 Hz, 2H, H-2 ,H-6), 7.96 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3471, 3435, 3357, 1643, 1595, 1151, 1090, 824 cm-1; ESI-MS
m/z [M+H+] = 197.1; Anal. Calcd for C8H9ClN4: C 48.87, H 4.61, N 28.49,
found C 48.90, H 4.61, N 28.48.
(E)-2-(furan-2-ylmethylene)hydrazine-1-carboximidamide (3o)
Orange solid. Yield: (118.6 mg, 78%); mp: 175-178 °C; 1H NMR (500
MHz, [D6]DMSO): δ= 5.50 (s, 2H, NH2), 5.76 (s, 2H, NH2), 6.52 (dd,
J=3.1 Hz, J=1.6 Hz, 1H, H-4), 6.61 (d, J=3.2 Hz, 1H, H-5), 7.64 (s, 1H, H-
3), 7.85 ppm (s, 1H, N=CH); IR (KBr): ϋ=3448, 3301, 3119, 1611, 1547,
1486, 1336, 1162, 944, 729 cm-1; ESI-MS m/z [M+H+] = 153; Anal. Calcd
for C6H8N4O: C 47.36, H 5.30, N 36.82, found C 47.36, H 5.29, N 36.83.
(E)-2-(4-bromobenzylidene)hydrazine-1-carboximidamide (3j)
White solid. Yield: (220.8 mg, 90%); mp: 207-209 °C; 1H NMR (500 MHz,
[D6]DMSO): δ=5.50 (s, 2H, NH2), 5.91 (s, 2H, NH2), 7.45 (d, J=8.4 Hz, 2H,
H-3, H-5), 7.58 (d, J=8.4 Hz, 2H, H-2, H-6), 7.90 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3466, 3321, 1639, 1627, 1590, 1390, 1164, 932, 819 cm-1; ESI-
MS m/z [M+H+] = 241.3, 243; Anal. Calcd for C8H9BrN4: C 39.86, H 3.76,
N 23.24, found C 39.85, H 3.75, N 23.24.
(E)-2-(thiophen-2-ylmethylene)hydrazine-1-carboximidamide (3p)
Yellow solid. Yield: (146.2 mg, 87%); mp: 107-109 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.51 (s, 2H, NH2), 5.70 (s, 2H, NH2), 7.03 (dd, J=4.3 Hz,
J=3.5 Hz, 1H, H-4), 7.14 (d, J=5.0 Hz, 1H, H-5), 7.37 (d, J=5.0 Hz, 1H, H-
3), 8.14 ppm (s, 1H, N=CH); IR (KBr): ϋ=3488, 3449, 3353, 1648, 1597,
1159, 932, 773, cm-1; ESI-MS m/z [M+H+] = 169; Anal. Calcd for
C6H8N4S: C 42.84, H 4.79, N 33.31, S 19.06, found C 42.81, H 4.80, N
33.32, S 19.07.
(E)-2-(4-methylbenzylidene)hydrazine-1-carboximidamide (3k)
Yellow solid. Yield: (153.12 mg, 87%); mp: 202-206 °C; 1H NMR (500
MHz, [D6]DMSO): δ=2.30 (s, 3H, CH3), 5.42 (s, 2H, NH2), 5.83 (s, 2H,
NH2), 7.14 (d, J=8.0 Hz, 2H, H-3, H-5), 7.56 (d, J=8.0 Hz, 2H, H-2, H-6),
7.95 ppm (s, 1H, N=CH); IR (KBr): ϋ=3473, 3432, 3357, 3092, 1646,
1584, 1349, 1147, 930, 817 cm-1; ESI-MS m/z [M+H+] = 177; Anal. Calcd
for C9H12N4: C 61.34, H 6.86, N 31.79, found C 61.38, H 6.85, N 31.77.
(E)-2-(pyridin-2-ylmethylene)hydrazine-1-carboximidamide (3q)
Yellow solid. Yield: (156.5 mg, 96%); mp: 219-221 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.68 (s, 2H, NH2), 6.06 (s, 2H, NH2), 7.20 (dd, J=6.7 Hz,
J=5.1 Hz,1H, H-5), 7.69 (t, J=7.8 Hz, 1H, H-4), 7.96 (s, 1H, N=CH), 8.06
(d, J=7.9 Hz, 1H, H-3), 8.45 ppm (d, J=5.1 Hz, 1H, H-6); IR (KBr):
ϋ=3439, 3335, 1646, 1562, 1143, 962, 822 cm-1; ESI-MS m/z [M+H+] =
164; Anal. Calcd for C7H9N5: C 51.52, H 5.56, N 42.92, found C 51.50, H
5.57, N 42.93.
(E)-2-(4-methoxybenzylidene)hydrazine-1-carboximidamide (3l)
White solid. Yield: (161.3 mg, 84%); mp: 187-191 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 3.72 (s, 3H, OCH3), 5.32 (s, 2H, NH2), 5.77 (s, 2H, NH2),
6.85 (d, J=8.7 Hz, 2H, H-3, H-5), 7.55 (d, J=8.7 Hz, 2H, H-2, H-6), 7.90
ppm (s, 1H, N=CH); IR (KBr): ϋ=3475, 3350, 1662, 1597, 1248, 1176,
1026, 829 cm-1; ESI-MS m/z [M+H+] = 193; Anal. Calcd for C9H12N4O: C
56.24, H 6.29, N 29.15, found C 56.25, H 6.30, N 29.14.
General procedure for the synthesis of 2-amino-4-aryl-1-
arylideneaminoimidazoles
A solution of NaOH (1 mmol) in ethanol was added dropwise to a solution
of phenacylbromide or phenacylbromide derivatives (1 mmoL) and
benzilydene aminoguanidine (1 mmoL) in ethanol. The mixture was
warmed to 40-45°C and stirred at room temperature overnight.[25] The
obtained precipitate 4-6 was filtered off and purified by plate
chromatography or recrystallization in ethanol.
(E)-2-(4-hydroxybenzylidene)hydrazine-1-carboximidamide (3m)
Yellow solid. Yield: (154.9 mg, 87%); mp (as HCl): 245-250 °C; 1H NMR
(500 MHz, [D6]DMSO): δ= 6.79 (d, J=9.7 Hz, 2H, H-3, H-5), 7.5 (bs, 2H,
NH2), 7.62 (d, J=9.1 Hz, 2H, H-2, H-6), 7.8 (bs, 2H, NH2), 8.01 (s, 1H,
N=CH), 11.80 ppm (s, 1H, OH); IR (KBr): ϋ=3424, 3280, 1680, 1636,
1509, 1425, 1264, 1094, 833 cm-1; ESI-MS m/z [M+H+] = 179; Anal.
Calcd for C8H10N4O: C 53.92, H 5.66, N31.44, found C 53.92, H 5.67, N
31.42.
(E)-1-(benzylideneamino)-4-phenyl-1H-imidazol-2-amine (4a)
Yellow solid. Yield: (11.3 mg, 4.3%); mp: 197 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.17 (s, 2H, NH2); 7.19 (t, J=7.3 Hz, 1H, H-4’), 7.35 (t,
J=7.7 Hz, 2H, H-3, H-5), 7.5 (m, 3H, H-4, H-3’, H5’), 7.71 (d, J=7.4 Hz,
2H, H-2’, H-6’), 7.93 (d, 2H, H-2, H-6), 8.00 (s, 1H, H-imidazole), 8.56
ppm (s, 1H, N=CH); IR (KBr): ϋ=3433, 3295, 3135, 3066, 1644, 1469,
764, 689 cm-1; ESI-MS m/z [M+H+] = 263; Anal. Calcd for C16H14N4: C
73.26, H 5.38, N 21.36, found C 73.24, H 5.39, N 21.37.
(E)-2-(3,4,5-trimethoxybenzylidene)hydrazine-1-carboximidamide
(3n)
Pale yellow solid. Yield: (219.2 mg, 87%); mp: 175-178 °C; 1H NMR (500
MHz, [D6]DMSO): δ= 3.61 (s, 3H, OCH3), 3.75 (s, 6H, OCH3), 5.35 (s, 2H,
NH2), 5.87 (s, 2H, NH2), 6.93 (s, 2H, H-2, H-6), 7.86 ppm (s, 1H, N=CH);
IR (KBr): ϋ=3496, 3412, 3381, 3152, 1653, 1577, 1230, 1126, 936, 824,
792 cm-1; ESI-MS m/z [M+H+] = 253; Anal. Calcd for C11H16N4O3: C
52.37, H 6.39, N 22.21, found C 52.42, H 6.37, N 22.20.
(E)-1-((2-fluorobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4b)
Yellow solid. Yield: (7.6 mg, 2.7%); mp: 190 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.23 (s, 2H, NH2), 7.15 (t, J=7.3 Hz, 1H, H-4’), 7.3 (m, 4H,
8
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10.1002/cmdc.201700123
ChemMedChem
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H-3’, H-5’, H-4, H-5), 7.49 (dd, J=13.2, J=6.5 Hz, 1H, H-3), 7.69 (d, J=7.4
Hz, 2H, H-2’, H-6’), 8.13 (s, 1H, H-imidazole), 8.25 (t, J=7.3 Hz, 1H, H-6),
8.57 ppm (s, 1H, N=CH); IR (KBr): ϋ=3403, 3064, 1632, 1469, 1237, 768
cm-1; ESI-MS m/z [M+H+] = 281; Anal. Calcd for C16H13FN4: C 68.56, H
4.67, N 19.99, found C 68.57, H 4.68, N 19.98.
Yellow solid. Yield: (207.0 mg, 61%); mp: 203 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.61 (s, 2H, NH2), 7.23 (t, J=7.2 Hz, 1H, H-4’), 7.37 (t,
J=7.3 Hz, 2H, H-3’, H-5’), 7.46 (t, J=7.7 Hz, 1H, H-5), 7.67 (d, J=8.1 Hz,
1H, H-4), 7.70 (d, J=7.7 Hz, 2H, H-2’, H-6’), 7.84 (d, J=7.5 Hz, 1H, H-6),
8.01 (s, 1H, H-imidazole), 8.25 (s, 1H, H-2), 8.57 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3425, 3295, 3051, 1648, 1482, 1074, 799, 705 cm-1; ESI-MS
m/z [M+H+] = 341, 343; Anal. Calcd for C16H13BrN4: C 56.32, H 3.84, N
16.42, found C 56.34, H 3.85, N 16.41.
(E)-1-((2-chlorobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4c)
Yellow solid. Yield: (22.2 mg, 7.5%); mp: 207 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.28 (s, 2H, NH2); 7.19 (t, J=7.3 Hz, 1H, H-4’), 7.34 (t,
J=7.8 Hz, 2H, H-3’, H- 5’), 7.45 (t, J=7.4 Hz, 1H, H-5), 7.49 (t, J=7.8 Hz,
1H, H-4), 7.57 (dd, J=5.7 Hz, J=1.2 Hz, 1H, H-3), 7.72 (d, J=7.6 Hz, 2H,
H-2’, H-6’), 8.15 (s, 1H, H-imidazole), 8.35 (dd, J=7.7 Hz, J=1.7 Hz, 1H,
H-6), 8.65 ppm (s, 1H, N=CH); IR (KBr): ϋ=: 3412, 933, 1635, 1470, 1127,
764 cm-1; ESI-MS m/z [M+H+] = 297; Anal. Calcd for C16H13ClN4: C 64.76,
H 4.42, N 18.88, found C 64.78, H 4.41, N 18.87.
(E)-1-((4-fluorobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4h)
Yellow solid. Yield: (16.8 mg, 6%); mp: 210 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.16 (s, 2H, NH2), 7.15 (t, J=7.3 Hz, 1H, H-4’), 7.3 (m, 4H,
H-2’, H-6’, H-3’, H-5’), 7.66 (d, J=8.0 Hz, 2H, H-2 H-6), 7.92 (s, 1H, H-
imidazole), 7.95 (t, J=7.5 Hz, 2H, H-3, H-5), 8.52 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3425, 3291, 3221, 3133, 3079, 1648, 1468, 835, 698 cm-1; ESI-
MS m/z [M+H+] = 281; Anal. Calcd for C16H13FN4: C 68.56, H 4.67, N
19.99, found C 68.55, H 4.67, N 20.00.
(E)-1-((2-bromobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4d)
(E)-1-((4-chlorobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
Yellow solid. Yield: (23.8 mg, 7.5%); mp: 192 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.28 (s, 2H, NH2), 7.20 (t, J=7.3 Hz, 1H, H-4’), 7.34 (t,
J=7.7 Hz, 2H, H-3’, H-5’), 7.41 (t, J=7.4 Hz, 1H, H-5), 7.49 (t, J=7.6 Hz,
1H, H-4), 7.74 (d, J=7.9 Hz, 1H, H-3), 7.77 (d, J=8.2 Hz, 2H, H-2’, H-6’),
8.10 (s, 1H, H-imidazole), 8.31 (dd, J=7.8 Hz, J=1.6 Hz, 1H, H-6), 8.57
ppm (s, 1H, N=CH); IR (KBr): ϋ=3400, 3268, 3140, 2931, 1630, 1454,
763 cm-1; ESI-MS m/z [M+H+] = 341, 343; Anal. Calcd for C16H13BrN4: C
56.32, H 3.84, N 16.42, found C 56.33, H 3.83, N 16.43.
(4i)
Yellow solid. Yield: (35.5 mg, 12%); mp: 211 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.23 (s, 2H, NH2), 7.19 (t, J=7.8 Hz, 1H, H-4’), 7.35 (t,
J=9.5, 2H, H-3’, H-5’), 7.56 (d, J=8.4 Hz, 2H, H-3, H-5), 7.70 (d, J=8.1 Hz,
2H, H-2’, H-6’), 7.94 (d, J=8.4 Hz, 2H, H-2, H-6), 7.96 (s, 1H, H-
imidazole), 8.55 ppm (s, 1H, N=CH); IR (KBr): ϋ=3419, 3286, 3214, 3128,
1644, 1461, 1085, 824, 693 cm-1; ESI-MS m/z [M+H+] = 297; Anal. Calcd
for C16H13ClN4: C 64.76, H 4.42, N 18.88, found C 64.62, H 4.43, N 19.00.
(E)-1-((3-fluorobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4e)
(E)-1-((4-bromobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4j)
Yellow solid. Yield: (9.2 mg, 3.3%); mp: 193 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.25 (s, 2H, NH2), 7.14 (t, J=7.3 Hz, 1H, H-4’), 7.3 (m, 3H,
H-3’, H-5’, H-5), 7.50 (dd, J=14.0 Hz, J=7.6 Hz, 1H, H-4), 7.62 (d, J=7.6
Hz, 1H, H-6), 7.66 (d, J=7.3 Hz, 2H, H-2’, H-6’), 7.84 (d, J=9.9 Hz, 1H, H-
2), 7.92 (s, 1H, H-imidazole), 8.51 ppm (s, 1H, N=CH); IR (KBr): ϋ=3422,
3083, 1655, 1592, 1486, 812, 716, 692 cm-1; ESI-MS m/z [M+H+] = 281;
Anal. Calcd for C16H13FN4: C 68.56, H 4.67, N 19.99, found C 68.61, H
4.66, N 19.97.
Yellow solid. Yield: (33.2 mg, 9.8%); mp: 214 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.19 (s, 2H, NH2), 7.15 (t, J=7.3 Hz, 1H, H-4’), 7.31 (t,
J=7.7, 2H, H-3’, H-5’), 7.66 (m, 4H, H-3, H-5, H-2’, H-6’), 7.83 (d, J=8.4
Hz, 2H, H-2, H-6), 7.92 (s, 1H, H-imidazole), 8.50 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3436, 3313, 3140, 3085, 1654, 1474, 1075, 830, 703 cm-1; ESI-
MS m/z [M+H+] = 341, 343; Anal. Calcd for C16H13BrN4: C 56.32, H 3.84,
N 16.42, found C 56.32, H 3.82, N 16.44.
(E)-1-((3-chlorobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(E)-1-((4-methylbenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4f)
(4k)
°
Yellow solid. Yield: (29.6 mg, 10%); mp: 199 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.31 (s, 2H, NH2), 7.20 (t, J=7.3 Hz, 1H, H-4’), 7.35 (t,
J=7.7, 2H, H-3’, H-5’), 7.52 (d, J=5.1 Hz, 2H, H-4, H-6), 7.7 (d, J=7.3 Hz,
2H, H-2’, H-6’),7.79 (t, J=4.8 Hz, 1H, H-5), 7.94 (s, 1H, H-imidazole), 8.10
(s, 1H, H-2) 8.54 ppm (s, 1H, N=CH); IR (KBr): ϋ=3426, 3069, 1639,
1466, 936, 796, 683 cm-1; ESI-MS m/z [M+H+] = 297; Anal. Calcd for
Yellow solid. Yield: (8.0 mg, 3%); mp: 218 C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 2.37 (s, 3H, CH3), 6.12 (s, 2H, NH2), 7.15 (t, J=7.3 Hz, 1H,
H-4’), 7.31 (d, J=8.0 Hz, 2H, H-3, H-5), 7.34 (t, J=7.5 Hz, 2H, H-3’, H-5’),
7.70 (d, J=7.7 Hz, 2H, H-2’, H-6’), 7.81 (d, J=8.0, 2H, H-2, H-6), 7.98 (s,
1H, H-imidazole), 8.52 ppm (s, 1H, N=CH); IR (KBr): ϋ=3414, 3154, 3071,
1648, 1483, 1332, 827, 710 cm-1; ESI-MS m/z [M+H+] = 276.9; Anal.
Calcd for C17H16N4: C 73.89; H, 5.84, N, 20.27, found C 73.87; H, 5.85, N,
20.28.
C
16H13ClN4: C 64.76, H 4.42, N 18.88, found C 64.74, H 4.41, N 18.89.
(E)-1-((3-bromobenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4g)
(E)-1-((4-methoxybenzylidene)amino)-4-phenyl-1H-imidazol-2-amine
(4l)
9
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10.1002/cmdc.201700123
ChemMedChem
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Brown solid. Yield: (5.3 mg, 2%); mp: 198 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 3.84 (s, 3H, OCH3), 6.91 (bs, 2H, NH2), 7.08 (d, J=8.7 Hz,
2H, H-3, H-5), 7.27 (t, J=7.3, 1H, H-4’), 7.41 (t, J=7.7 Hz, 2H, H-3’, H-5’),
7.70 (d, J=7.4 Hz, 2H, H-2’, H-6’), 7.91 (d, J=8.7 Hz, 2H, H-2, H-6), 8.16
(s, 1H, H-imidazole), 8.62 ppm (s, 1H, N=CH); IR (KBr): ϋ=3399, 3352,
3198, 3070, 1664, 1601, 1478, 1256, 1171, 837, 703 cm-1; ESI-MS m/z
[M+H+] = 293; Anal. Calcd for C17H16N4O: C 69.85, H 5.52, N 19.17,
found C 69.81, H 5.53, N 19.18.
(E)-4-phenyl-1-((pyridin-2-ylmethylene)amino)-1H-imidazol-2-amine
(4q)
Brown solid. Yield: (10.0 mg, 3.8%); mp: 197 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 7.23 (t, J=6.9 Hz, 1H, H-4’), 7.51 (t, J=7.3 Hz, 2H, H-3’,
H-5’), 7.56 (t, J=5.8 Hz, 1H, pyridine H-5), 7.73 (d, J=7.5 Hz, 2H, H-2’, H-
6’), 8.01 (t, J=7.5 Hz, 1H, pyridine H-4), 8.35 (bs, 2H, NH2), 8.47 (d,
J=7.8 Hz, 1H, pyridine H-3), 8.63 (s, 1H, H-imidazole), 8.74 (s, 1H,
pyridine H-6), 8.78 ppm (s, 1H, N=CH); IR (KBr): ϋ=3364, 3261, 3209,
3082, 2880, 1662, 1522, 1220, 1182, 765 cm-1; ESI-MS m/z [M+H+] =
264; Anal. Calcd for C15H13N5: C 68.42, H, 4.98, N, 26.60, found C 68.31,
H, 4.99, N, 26.70.
(E)-4-(((2-amino-4-phenyl-1H-imidazol-1-yl)imino)methyl)phenol (4m)
Yellow solid. Yield: (4.7 mg, 1.7%); mp: 197 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.97 (bs, 2H, NH2), 6.83 (d, J=8.5 Hz, 2H, H-3, H-5), 7.13
(t, J=7.3 Hz, 1H, H-4’), 7.29 (t, J=7.7 Hz, 2H, H-3’, H-5’), 7.65 (d, J=7.4
Hz, 2H, H-2’, H-6’), 7.71 (d, J=8.6 Hz, 2H, H-2, H-6), 7.91 (s, 1H, H-
imidazole), 8.40 ppm (s, 2H, N=CH, OH); IR (KBr): ϋ=3352, 3247, 2968,
1642, 1599, 1235, 1107, 841 cm-1; ESI-MS m/z [M+H+] = 279; Anal.
Calcd for C16H14N4O: C 69.05, H 5.07, N 20.13, found C 69.06, H 5.08, N
20.12.
(E)-1-(benzylideneamino)-4-(4-fluorophenyl)-1H-imidazol-2-amine
(5a)
Yellow solid. Yield: (14.0 mg, 5%); mp: 183-186 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.14 (s, 2H, NH2), 7.14 (t, J=6.7 Hz, 2H, H-2’, H-6’), 7.46
(m, 3H, H-3, H-4, H-5), 7.68 (dd, J=8.5 Hz, J=5.6 Hz, 2H, H-3’, H-5’),
7.88 (d, J=6.7 Hz, 2H, H-2 ,H-6), 7.94 (s, 1H, H-imidazole), 8.50 ppm (s,
1H, N=CH); IR (KBr): ϋ=3400, 3278, 3078, 1638, 1563, 1493, 1218, 839
cm-1; ESI-MS m/z [M+H+] = 281 Anal. Calcd for C16H13FN4: C 68.56, H
4.67, N 19.99, found C 68.55, H 4.68, N 19.98.
(E)-4-phenyl-1-((3,4,5-trimethoxybenzylidene)amino)-1H-imidazol-2-
amine (4n)
Brown solid. Yield: (9.9 mg, 2.8%); mp: 145 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 3.6 (s, 3H, OCH3), 3.8 (s, 6H, OCH3), 6.22 (s, 2H, NH2),
7.14 (t, J=7.1 Hz, 1H, H-4’), 7.19 (s, 2H, H-2, H-6), 7.32 (t, J=7.5 Hz, 2H,
H-3’, H-5’), 7.65 (d, J=7.6 Hz, 2H, H-2’, H-6’), 7.90 (s, 1H, H-imidazole),
8.44 ppm (s, 1H, N=CH); IR (KBr): ϋ=3352, 2939, 1686, 1465, 1128, 783,
702 cm-1; ESI-MS m/z [M+H+] = 353; Anal. Calcd for C19H20N4O3: C
64.76, H 5.72, N 15.90, found C 64.72, H 5.73, N 15.91.
(E)-1-(benzylideneamino)-4-(4-chlorophenyl)-1H-imidazol-2-amine
(5b)
Brown solid. Yield: (8.9 mg, 3%); mp: 195 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.17 (s, 2H, NH2), 7.35 (d, J=8.5 Hz, 2H, H-3’, H-5’), 7.47
(m, 3H, H-3, H-4, H-5), 7.66 (d, J=8.5 Hz, 2H, H-2’, H-6’) 7.9 (d, J=7.8 Hz,
2H, H-2, H-6), 8.02 (s, 1H, H-imidazole), 8.59 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3399, 3276, 3125, 3080, 1638, 1469, 1090, 833 cm-1; ESI-MS
m/z [M+H+] = 297; Anal. Calcd for C16H13ClN4: C 64.76, H 4.42, N 18.88,
found C 64.72, H 4.43, N 18.89.
(E)-1-((furan-2-ylmethylene)amino)-4-phenyl-1H-imidazol-2-amine
(4o)
Brown solid. Yield: (10.1 mg, 4%); mp: 134 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.92 (s, 2H, NH2), 6.67 (moderately broad singlet, 1H,
furan H-4), 7.0 (d, J=3.3 Hz, 1H, furan H-5), 7.16 (t, J=8.7 Hz, 1H, H-4’),
7.30 (t, J=7.5 Hz, 2H, H-3’, H-5’), 7.64 (d, J=7.8 Hz, 2H, H-2’, H-6’), 7.88
(s, 1H, furan H-3), 7.93 (s, 1H, H-imidazole), 8.41 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3453, 3308, 2945, 1636, 1482, 1158, 699 cm-1; ESI-MS m/z
[M+H+] = 253; Anal. Calcd for C14H12N4O: C 66.65, H 4.79, N 22.21,
found C 66.68, H 4.77, N 22.20.
(E)-1-(benzylideneamino)-4-(p-tolyl)-1H-imidazol-2-amine (5c)
Yellow solid. Yield: (5.5 mg, 2%); mp: 210-212 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 2.25 (s, 3H, CH3), 6.10 (s, 2H, NH2), 7.12 (d, J=8.0 Hz,
2H, H-3’, H-5’), 7.46 (m, 3H, H-3, H-4, H-5), 7.56 (d, J=8.0 Hz, 2H, H-2’,
H-4’), 7.88 (dd, J=7.7 Hz, J= 1.9 Hz, 2H, H-2, H-6), 7.9 (s, 1H, H-
imidazole), 8.5 ppm (s, 1H, N=CH); IR (KBr): ϋ=3410, 3293, 3082, 1645,
1472, 1381, 832 cm-1; ESI-MS m/z [M+H+] = 277; Anal. Calcd for
C17H16N4: C 73.89, H 5.84, N 20.27, found C 73.97, H 5.83, N 20.20.
(E)-4-phenyl-1-((thiophen-2-ylmethylene)amino)-1H-imidazol-2-
amine (4p)
(E)-1-(benzylideneamino)-4-(4-methoxyphenyl)-1H-imidazol-2-amine
(5d)
Yellow solid. Yield: (10.7 mg, 4%); mp: 188 °C dec; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.95 (s, 2H, NH2), 7.2 (m, 2H, H-4’, thiophene H-4), 7.34
(t, J=7.6 Hz, 2H, H-3’, H-5’), 7.56 (d, J=3.4 Hz, 1H, thiophene H-5), 7.68
(d, J=7.5 Hz, 2H, H-2’, H-6’), 7.77 (d, J=4.9 Hz, 1H, thiophene H-3), 7.95
(s, 1H, H-imidazole), 8.78 ppm (s, 1H, N=CH); IR (KBr): ϋ=3457, 3311,
3153, 3095, 1660, 1483, 1332, 788, 708 cm-1; ESI-MS m/z [M+H+] = 269;
Anal. Calcd for C14H12N4S: C 62.66, H 4.51, N 20.88, S 11.95, found C
62.09, H 4.50, N 20.87, S 11.94.
Yellow solid. Yield: (5.8 mg, 2%); mp: 198-200 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 3.72 (s, 3H, OCH3), 6.14 (s, 2H, NH2), 6.9 (d, J=6.9 Hz,
2H, H-3’, H-5’), 7.45 (m, 3H, H-3, H-4, H-5), 7.59 (d, 2H, J=6.8 Hz, H-2’,
H-6’), 7.83 (s, 1H, H-imidazole), 7.71 (dd, J=7.7 Hz, J=1.9 Hz; 2H, H-2,
H-6), 8.48 ppm (s, 1H, N=CH); IR (KBr): ϋ=3439, 3298, 3093, 1643, 1510,
1483, 1254, 1185, 1042, 955, 850 cm-1; ESI-MS m/z [M+H+] = 293; Anal.
Calcd for C17H16N4O: C 69.85, H 5.52, N 19.17, found C 69.89, H 5.53, N
19.10.
10
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(E)-1-(benzylideneamino)-4-(2-chlorophenyl)-1H-imidazol-2-amine
(5e)
(E)-1-((thiophen-2-ylmethylene)amino)-4-(p-tolyl)-1H-imidazol-2-
amine (6c)
Yellow solid. Yield: (8.9 mg, 3%); mp: 190-191 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.18 (s, 2H, NH2), 7.18 (t, J=7.6 Hz, 1H, H-5’), 7.32 (t,
J=7.7 Hz, 1H, H-4’), 7.42 (d, J=7.9 Hz, 1H, H-6’), 7.46 (m, 3H, H-3, H-4,
H-5), 7.94 (dd, J=7.6 Hz, J=1.6 Hz, 2H, H-2, H-6), 8.06 (dd, J=7.9 Hz,
J=1.4 Hz, 1H, H-3’), 8.08 (s, 1H, H-imidazole), 8.67 ppm (s, 1H, N=CH);
IR (KBr): ϋ=3455, 3307, 3104, 1657, 1476, 1327, 781, 693 cm-1; ESI-MS
m/z [M+H+] = 297; Anal. Calcd for C16H13ClN4: C 64.76, H 4.42, N 18.88,
found C 64.72, H 4.41, N 18.90.
Yellow solid. Yield: (8.5 mg, 3%); mp: 202-203 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 2.25 (s, 3H, CH3), 5.89 (s, 2H, NH2), 7.11 (d, J=7.9 Hz,
2H, H-3’, H-5’), 7.16 (dd, J=4.9 Hz, J=1.3 Hz, 1H, thiophene H-4), 7.51 (d,
J=3.1 Hz, 1H, thiophene H-5), 7.53 (d, J=8.0 Hz, 2H, H-2’, H-6’), 7.72 (d,
J=5.0 Hz, 1H, thiophene H-3), 7.85 (s, 1H, H-imidazole), 8.71 ppm (s, 1H,
N=CH); IR (KBr): ϋ=3409, 3032, 1644, 1479, 827 cm-1; ESI-MS m/z
[M+H+] = 283; Anal. Calcd for C15H14N4S: C 63.81, H 5.00, N 19.84, S
11.35, found C 63.80, H 5.01, N 19.83, S 11.36.
(E)-1-(benzylideneamino)-4-(2-bromophenyl)-1H-imidazol-2-amine
(5f)
(E)-4-(4-methoxyphenyl)-1-((thiophen-2-ylmethylene)amino)-1H-
imidazol-2-amine (6d)
Yellow solid. Yield: (6.8 mg, 2%); mp: 180 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.19 (bs, 2H, NH2), 7.12 (t, J=6.6 Hz, 1H, H-5’), 7.36 (t,
J=7.9 Hz, 1H, H-4’), 7.46 (m, 3H, H-3, H-4, H-5), 7.62 (d, J=7.6 Hz, 1H,
H-6’), 7.95 (m, 3H, H-2, H-6, H-3’), 8.11 (s, 1H, H-imidazole), 8.64 ppm (s,
1H, N=CH); IR (KBr): ϋ=3441, 3307, 1650, 1478, 1218, 743, 699 cm-1;
ESI-MS m/z [M+H+] = 341, 343; Anal. Calcd for C16H13BrN4 : C 56.32, H
3.84, N 16.42, found C 56.30, H 3.85, N 16.41.
Yellow solid. Yield: (9.5 mg, 3.2%); mp: 192 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 3.72 (s, 3H, OCH3), 5.89 (s, 2H, NH2), 6.89 (d, J=8.8 Hz,
2H, H-3’, H-5’), 7.15 (dd, J=4.9 Hz, J=1.3 Hz, 1H, thiophene H-4), 7.50 (d,
J=3.5 Hz, 1H, thiophene H-5), 7.57 (d, J=8.7 Hz, 2H, H-2’, H-6’), 7.71 (d,
J=5.0 Hz, 1H, thiophene H-3), 7.77 (s, 1H, H-imidazole), 8.69 ppm (s, 1H,
N=CH); IR (KBr): ϋ=3424, 3104, 1653, 1488, 1260 cm-1; ESI-MS m/z
[M+H+] = 299; Anal. Calcd for C15H14N4OS: C 60.38, H 4.73, N 18.78, S
10.75, found C 60.40, H 4.72, N 18.79, S 10.74.
(E)-1-(benzylideneamino)-4-(3-chlorophenyl)-1H-imidazol-2-amine
(5g)
Brown solid. Yield: (6.5 mg, 2.2%); mp: 197-200 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 6.19 (s, 2H, NH2), 7.2 (dd, J=7.8 Hz, J=1.3 Hz, 1H, H-6’),
7.34 (t, J=7.8 Hz, 1H, H-5’), 7.47 (m, 3H, H-3, H-4, H-5), 7.60 (d, J=7.8
Hz, 1H, H-4’), 7.68 (s, 1H, H-2’), 7.88 (dd, J=7.3 Hz, J=1.5 Hz, 2H, H-2,
H-6), 8.1 (s, 1H, H-imidazole), 8.52 ppm (s, 1H, N=CH); IR (KBr): ϋ=3398,
3057, 1636, 1471, 1208, 1068, 760, 684 cm-1; ESI-MS m/z [M+H+] = 297;
Anal. Calcd for C16H13ClN4: C 64.76, H 4.42, N 18.88, found C 64.84, H
4.42, N 18.81.
(E)-4-(2-bromophenyl)-1-((thiophen-2-ylmethylene)amino)-1H-
imidazol-2-amine (6e)
°
Yellow solid. Yield: (5.2 mg, 1.5%); mp: 189-190 C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.94 (s, 2H, NH2), 7.10 (t, J=7.6 Hz, 1H, H-5’), 7.16 (t,
J=4.9 Hz, 1H, thiophene H-4), 7.35 (t, J=7.1 Hz, 1H, H-4’), 7.57 (d, J=3.4
Hz, 1H, thiophene H-5), 7.60 (d, J=7.5 Hz, 1H, H-6’), 7.74 (d, J=5.0 Hz,
1H, thiophene H-3), 7.97 (dd, J=7.9 Hz, J=1.7 Hz, 1H, H-3’), 8.06 (s, 1H,
H-imidazole), 8.86 ppm (s, 1H, N=CH); IR (KBr): ϋ=3444, 1654, 1484,
1225, 746 cm-1; ESI-MS m/z [M+H+] = 347, 349; Anal. Calcd for
C14H11BrN4S: C 48.43, H 3.19, N 16.14, S 9.23, found C 48.42, H 3.19, N
16.15, S 9.24.
(E)-4-(4-fluorophenyl)-1-((thiophen-2-ylmethylene)amino)-1H-
imidazol-2-amine (6a)
Yellow solid. Yield: (5.7 mg, 2%); mp: 148-150 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.93 (s, 2H, NH2), 7.15 (m, 3H, thiophene H-4, H-2’, H-6’),
7.51 (d, J=3.4 Hz, 1H, thiophene H-5), 7.66 (dd, J=7.6 Hz, J=4.7 Hz, 2H,
H-3’, H-5’), 7.72 (d, J=5.0 Hz, 1H, thiophene H-3), 7.90 (s, 1H, H-
imidazole), 8.72 ppm (s, 1H, N=CH); IR (KBr): ϋ=3391, 3125, 3062, 1636,
1562, 1470, 1210 cm-1; ESI-MS m/z [M+H+] = 287; Anal. Calcd for
(E)-4-(3-chlorophenyl)-1-((thiophen-2-ylmethylene)amino)-1H-
imidazol-2-amine (6f)
Yellow solid. Yield: (5.4 mg, 2%); mp: > 300 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.97 (s, 2H, NH2), 7.18 (m, 2H, thiophene H-4, H-4’), 7.33
(t, J=7.8 Hz, 1H, H-5’), 7.52 (d, J=3.1 Hz, 1H, thiophene H-5), 7.58 (d,
J=8.0 Hz, 1H, H-6’), 7.65 (s, 1H, H-2’), 7.75 (d, J=5.0 Hz, 1H, thiophene
H-3), 8.07 (s, 1H, H-imidazole), 8.75 ppm (s, 1H, N=CH); IR (KBr):
ϋ=3409, 3032, 1644, 1479, 1471, 1445, 827 cm-1; ESI-MS m/z [M+H+] =
303; Anal. Calcd for C14H11ClN4S: C 55.54, H 3.66, N 18.50, S 10.59,
found C 55.54, H 3.65, N 18.51, S 10.58.
C
14H11FN4S: C 58.73, H 3.87, N 19.57, S 11.20, found C 58.72, H 3.88,
N 19.58, S 11.19.
(E)-4-(4-chlorophenyl)-1-((thiophen-2-ylmethylene)amino)-1H-
imidazol-2-amine (6b)
Yellow solid. Yield: (6.6 mg, 2.2%); mp: 208-210 °C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.97 (s, 2H, NH2), 7.16 (dd, J=4.9 Hz, J=1.3 Hz, 1H,
thiophene H-4), 7.37 (d, J=8.5 Hz, 2H, H-2’, H-6’); 7.52 (d, J=3.1 Hz, 1H,
thiophene H-5), 7.64 (d, J=8.5 Hz, 2H, H-3’, H-5’), 7.73 (d, J=5.0 Hz, 1H,
thiophene H-3), 7.97 (s, 1H, H-imidazole), 8.73 ppm (s, 1H, N=CH); IR
(KBr): ϋ=3395, 3120, 1634, 1470, 1085, 829, 694 cm-1; ESI-MS m/z
[M+H+] = 303; Anal. Calcd for C14H11ClN4S: C 55.54, H 3.66, N 18.50, S
10.59, found C 55.54, H 3.67, N 18.49, S 10.60.
(E)-4-(3-bromophenyl)-1-((thiophen-2-ylmethylene)amino)-1H-
imidazol-2-amine (6g)
°
Yellow solid. Yield: (5.2 mg, 2%); mp: 189-193 C; 1H NMR (500 MHz,
[D6]DMSO): δ= 5.97 (s, 2H, NH2), 7.17 (t, J=3.7 Hz, 1H, thiophene H-4),
7.27 (t, J=7.9 Hz, 1H, H-5’), 7.32 (d, J=7.9 Hz, 1H, H-6’), 7.52 (d, J=3.6
Hz, 1H, thiophene H-5), 7.62 (d, J=7.1 Hz, 1H, H-4’), 7.74 (d, J= 4.8 Hz,
11
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10.1002/cmdc.201700123
ChemMedChem
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[9]
K. Rehse, J. Steege, Arch. Pharm. 2005, 338, 539–547.
1H, thiophene H-3), 7.81 (s, 1H, H-2’), 8.04 (s, 1H, H-imidazole), 8.73
ppm (s, 1H, N=CH); IR (KBr): ϋ=3401, 3100, 2933, 1634, 1471, 1206 cm-
1; ESI-MS m/z [M+H+] = 347, 349; Anal. Calcd for C14H11BrN4S: C 48.43,
H 3.19, N 16.14, S 9.23, found C 48.44, H 3.19, N 16.13, S 9.22.
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Koorbanally, Med. Chem. Res. 2015, 24, 2075–2084.
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Cunha, Bioorg. Med. Chem. 2009, 17, 3713–3719.
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Zitnanova, O. Ulicna, Z. Durackova, I. Waczulíková, J. Carsky, et al., Vascul.
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Platelet aggregation studies
Platelet aggregation studies were performed on APACT-4004
aggregometer (LABiTec, Ahrensburg, Germany) according to Born
method as described before.[16,22,26]
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M. E. Tehrani, F. Kobarfard, S. Mohebbi, Bull. Korean. Chem. Soc. 2015, 36,
2632–2639.
[16] V. Mashayekhi, K. Haj Mohammad Ebrahim Tehrani, S. Amidi, F.
Kobarfard, Chem. Pharm. Bull. 2013, 61, 144–150.
Briefly, platelet rich plasma (PRP) was obtained by centrifugation of
human citrated blood at 100 g for 10 min. To obtain platelet poor plasma
(PPP) the residual blood was centrifuged at 1500 g for 15 min. PRP (200
μL) and synthesized compounds were incubated at 37°C for 5 min before
activation by the addition of ADP, collagen and AA.
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Kobarfard, A. Shafiee, Med. Chem. Res. 2016, 25, 1–18.
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The final concentrations of ADP, collagen and AA were 5 µM, 2.5 µg/mL
and 1.35 mM, respectively. DMSO used as solvent of synthesized
compounds and blank sample (0.5% v/v) in aggregation studies. The
stock solutions of synthesized compounds (5 mM) were prepared. These
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[16,22,26]
calculated by Graphpad Prism Version 3.02.
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Docking studies
The crystal structure of COX-1 complex (PDB code: 3N8Y[27]) was
obtained from the RCSB Protein Data Bank. The docking studies were
performed with AutoDock version 4.2[28] (autodock.scripps.edu). Protein
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polar hydrogens and Gasteiger partial charges. The structure of
compounds was generated and minimized using molecular mechanic
AMBER method with the algorithm Polak-Ribiere through Hyperchem 8.0
software (Gainesville, FL, USA).
The grid box of 40 × 40 × 40 Å with a spacing of 0.375 Å was chosen.
Center of the native ligand in active site was selected as center of grid
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Keywords: 2-Aminoimidazole, Antiplatelet, Cyclization,
Hydrazone
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10.1002/cmdc.201700123
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Entry for the Table of Contents
R'
H
N
N
NH NH2
NH
N
N
Ar
N
Ar
N
Ar
N
NH2
NH2
3a-q
4a-q
5c-d
6b-d
Increased antiplatelet activity against AA inducer
Increased antiplatelet activity
against collagen inducer
Decreased antiplatelet activity
against collagen inducer
Cyclization of aromatic guanylhydrazones with phenacyl bromide increased antiplatelet activity against arachidonic acid (AA) and
collagen as platelet aggregation inducers. The substituents phenyl ring at position 4 of imidazole decreased the activity against
collagen while the phenyl ring with para substituent increased the activity against AA. These changes did not affect the antiplatelet
activity against adenosine diphosphate (ADP) as platelet aggregation inducers.
13
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