Synthesis of stable aromatic and heteroaromatic sulfonyl-amidoximes and evaluation of their antioxidant and lipid peroxidation activity

Article abstract of DOI:10.1016/j.ejmech.2014.04.040

We describe herein the synthesis of stable aromatic and heteroaromatic sulfonyl-amidoximes, from the reaction of amidoximes with the corresponding sulfonyl chlorides, in low to excellent yields. Evaluation of their antioxidant activity has shown that 17 o

Full text of DOI:10.1016/j.ejmech.2014.04.040

European Journal of Medicinal Chemistry 80 (2014) 145e153
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of stable aromatic and heteroaromatic sulfonyl-amidoximes
and evaluation of their antioxidant and lipid peroxidation activity
Ismini Doulou a, Christos Kontogiorgis b, Alexandros E. Koumbis c, Eleni Evgenidou c,
,
Dimitra Hadjipavlou-Litina b, Konstantina C. Fylaktakidou a
*
a Laboratory of Organic, Bioorganic and Natural Products Chemistry, Molecular Biology and Genetics Department, Democritus University of Thrace,
68100 Alexandroupolis, Greece
b Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
c Laboratory of Organic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the synthesis of stable aromatic and heteroaromatic sulfonyl-amidoximes, from the
reaction of amidoximes with the corresponding sulfonyl chlorides, in low to excellent yields. Evaluation
of their antioxidant activity has shown that 17 out of 28 compounds highly compete DMSO for hydroxyl
radicals, while five of them inhibit lipid peroxidation. Combining the reducing and anti-lipid peroxi-
dation ability it seems that compounds 13 and 31 could be used as lead molecules.
Ó 2014 Elsevier Masson SAS. All rights reserved.
Received 16 December 2013
Received in revised form
26 March 2014
Accepted 11 April 2014
Available online 13 April 2014
Keywords:
Antioxidant
Hydroxyl radicals
Lipid peroxidation
Amidoximes
Sulfonyl-amidoximes
1. Introduction
Amidoximes (I, Fig. 1) are bi-functional molecules exhibiting a
rich and fertile chemistry, which provides one of the shortest ways
Cell metabolism of aerobic organisms has as an unavoidable
consequence the formation of Reactive Oxygen Species (ROS).
Normally, the organism defense against these highly reactive spe-
cies involve enzymes, like superoxide dismutase and glutathione
peroxidase, and naturally occurring antioxidants such as ascorbic
to reach various heterocycles [2e5]. They possess varied and
diverse biological activities, which makes them an important and
attractive pharmacophore in medicinal chemistry. A plethora of
publications refers to individual amidoximes bearing anticoagu-
lanteantiaggregatory, antimicrobial, antituberculotic, anthel-
minthic, herbiside, insecticide, antihistaminic, antineoplastic,
antiarrythmic, anxiolyticeantidepressant, antihypertensive, hypo-
glycemic, antiamnesia and antiinflammatory biological properties
[6]. Others were found to inhibit glycosidase, squalene hopene
cyclise, gastric juice secretion and thrombin, to regulate plant
growth and to complex with metals and, thus, act as radiophar-
maceuticals and anti-pollutants [6]. Some of the above activities are
related to their recently discovered ability to release NO [6e8] or to
act as prodrugs of amidines.
Surprisingly, although known for many decades, sulfonyl-
amidoximes (II, Fig. 1) have received limited biological attention
[9,10] comparing to other O-substituted derivatives of amidoximes.
In one of the two cases studied, an O-methanosulfonyl-amidoxime
derivative exhibited the best antimalarial activity, in a nanomolar
range, comparing with other amidoxime derivatives [9]. Sulfonyl-
amidoximes are known synthones for various organic scaffolds,
acid (vitamin C),
a-tocopherol (vitamin E), b-carotene and poly-
phenolic flavonoids. Nevertheless, in many pathophysiological
conditions the excessive production of ROS overwhelms the natural
antioxidant defense mechanisms and essentially biological mole-
cules, such as lipids, proteins and DNA can be modified by those
persistently high levels of ROS. This imbalance is termed oxidative
stress (OS) and has been associated with several human diseases
such as cancer, neurodegenerative syndromes and inflammation. It
is consistent that rates of ROS production are increased in most
diseases [1]. As a result, natural and synthetic small molecules
possessing antioxidant activity are becoming increasingly impor-
tant in this kind of disease prevention and therapy.
* Corresponding author.
E-mail address: kfylakta@mbg.duth.gr (K.C. Fylaktakidou).
http://dx.doi.org/10.1016/j.ejmech.2014.04.040
0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved.

146
I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
which was relatively unstable, compared to the rest of the
compounds.
Spectroscopic data unambiguously verified the proposed
structures. In IR spectra all compounds gave absorptions in around
1360 and 1180 cmꢁ1, characteristic of the SO2 bond [9,13,17,18]. In
the negative electrospray LCeMS spectra a single fragment corre-
sponding to [ReSO3]ꢁ was observed in all but one cases (in com-
pound 31 the main peak corresponded to the [MꢁH]ꢁ.fragment).
Additionally, the majority of the positive electrospray LCeMS
spectra exhibited as the main fragment (100%) the one corre-
sponding to m/z 166 for p-nitrophenyl amidoxime derivatives and
122 for the pyridine amidoxime derivatives ([Mþ2HeRSO3]þ). The
hydroxyl-imino structure of these amidoxime derivatives was
verified in their 1H NMR spectra from the existence of a broad
singlet peak, at 6e7 ppm integrated for two protons (NH2). In
accordance to the literature, these chemical shifts are found rela-
tively downfield compared to their corresponding parent amidox-
imes [18]. Additionally, we observed the corresponding two
absorptions at the IR spectra for the NH2 group, as well as ab-
sorptions around 1630e1670 cmꢁ1 due to the C]N bond
[9,13,17,18].
Fig. 1. General structures of amidoximes and Sulfonyl-Amidoximes.
like N-substituted asymmetric ureas [11] and cyanamides [11e13],
azirines [14,15], amidines [16] and 5-amino-1,2,4-thiadiazoles [17].
Nevertheless, besides aromatic amidoximes which are referred as
unstable [11,18], benzylic and aliphatic ones seem to be isolable
[9,11,13,17], however, in most of the cases they were prepared and
used in situ.
While exploring in our laboratories possible transformations
of sulfonyl-amidoximes, we have discovered that p-nitro-phenyl
and o-, m-, p-pyridine amidoxime sulfonyl derivatives were
tolerant to treatment with base, chromatographic separation and
long lasting storage. Interestingly, to the best of our knowledge,
none of the parent amidoximes have ever been sulfonylated
before. Our interest in the chemistry and biology of amidoximes
and their derivatives [6,19e24] and in antioxidanteantiin-
flammatory phenomena [19,24e34] has prompted us to investi-
gate the antioxidant activity of these new and stable sulfonyl-
amidoximes.
3. Biological assays
In this investigation, we synthesized a number of unknown,
stable aromatic and hetero-aromatic sulfonyl-amidoxime de-
rivatives which we envision to exhibit protection against radical
attack. In general, the implication of free radicals in the pathways of
the inflammatory process is particularly important. Antioxidants
are defined as substances that, even at low concentrations, signif-
icantly delay or prevent oxidation of easily oxidizable substrates.
Many non-steroidal anti-inflammatory drugs have been reported to
act either as inhibitors of free radical production or as radical
scavengers [37]. Consequently, compounds with antioxidant
properties could be expected to offer protection in rheumatoid
arthritis and inflammation and to lead to potentially effective drugs
[38]. For the estimation of the antioxidative potential of chemical
components, different experimental approaches were used [39].
Most of them require a spectrophotometric measurement and a
certain reaction time in order to obtain reproducible results [40].
The radical scavenging ability of compounds 11e34 as well as of
the parent amidoximes 1e4 was tested against the 1,1-diphenyl-2-
picryl-hydrazyl (DPPH) stable free radical as well as against the
hydroxyl radical (HOꢀ) generated by the Fe3þ/ascorbic acid system.
Finally, the ability of the synthesized sulfonyl-amidoximes to
inhibit lipid peroxidation induced by the thermal free radical pro-
ducer 2,20-azobis(2-amidinopropane) dihydrochloride (AAPH) was
evaluated.
In order to have a diverse pool of compounds to examine, we
have synthesized derivatives with electron donating and electron
withdrawing substituent aromatic sulfonyl groups, as well as
aliphatic ones bearing short to long linear chains. This allowed us to
examine the influence of both electronic effects and lipophilicity in
an effort to establish a Structure Activity Relationship (SAR). The
biological experiments described herein examine the capability of
the title compounds, as well as their parent amidoximes, to interact
with the stable radical 1,1-diphenyl-2-picryl-hydrazyl (DPPH), to
compete with DMSO for HOꢀ and to inhibit lipid peroxidation. The
results are discussed in terms of SAR and an attempt is made to
define the necessary structural features for active compounds.
2. Chemistry
Each one of amidoximes 1 [11], 2 [35], 3 [35] and 4 [36] reacted
with sulfonyl chlorides 5e10 in chloroform, or a mixture of chlo-
roform and dimethylformamide (DMF) or tetrahydrofuran (THF), in
the presence of triethylamine, to give the corresponding sulfonyl-
amidoximes in low to excellent yields, Scheme 1.
After aqueous work-up the crude material was recrystallized, or
in certain few cases purified with column chromatography. Yields
of aliphatic sulfonyl-amidoximes were generally low, due to the
sensitivity of the reagents and their low solubility in the reaction
solvents. An exception was observed in the case of aliphatic-
sulfonyl o-pyridine amidoximes (32e34), probably because, in
contrary to the other three, their parent amidoxime (4) was highly
soluble in chloroform. These products needed chromatographic
purification in order to remove the remained residues of the re-
agents used and their by-products. On the other hand, the aromatic
sulfonyl-chlorides (5e7) gave the corresponding sulfonyl-
amidoximes in good to excellent yields and purity, and in none of
these cases a column chromatography purification was necessary.
Additionally, the reaction of m-pyridine amidoxime with p-nitro-
phenyl-sulfonyl chloride occurred in a much better yield when THF
was used as a solvent. To our delight a simple aqueous work-up was
sufficient to remove the unreacted starting material (if any) when
p- and m-pyridine amidoximes were used. All compounds were
found to be quite stable after long storage, except of compound 25
3.1. Interaction with the DPPH stable free radical
We have performed a radical scavenging measuring method
using the stable radical DPPH [41] according to the methods of
Hadjipavlou et al. [42]. The compounds were tested at a final con-
centration of 100 mM after 20 and 60 min (Table 1). This interaction
indicates the reducing ability (RA) of the tested compounds in an
iron-free system. The DPPH test is very useful in the micromolar
range, demanding a very short period of time for the outcome of
the results, for both hydrophilic and lipophilic samples. Due to its
odd number of electrons DPPH gives a strong absorption band at
517 nm.
Perusal of the % RA values, showed that 9 out of 28 compounds
exhibited limited reducing ability less than 10% at 60 min, whereas
3 out of 28 more than 30% in both 20 and 60 min. Nordihy-
droguaiaretic Acid (NDGA) has been used as a reference compound.

I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
147
No
Amidoximes
No
Sulfonyl chlorides
R-
Sulfonyl-
Yields
%
Ar-
amidoximes
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
3
3
3
4
4
4
4
4
4
4-nitro-phenyl-
5
6
phenyl-
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
82
“
4-tolyl-
78
“
7
4-nitro-phenyl-
propyl-
96
“
8
58
“
9
decyl-
37 (65)
27 (56)
55
“
10
5
hexadecyl-
phenyl-
4-pyridyl-
“
6
4-tolyl-
81
“
7
4-nitro-phenyl-
propyl-
63
“
8
20
“
9
decyl-
15
“
10
5
hexadecyl-
phenyl-
27
3-pyridyl-
96
“
6
4-tolyl-
98
“
7
4-nitro-phenyl-
propyl-
77
“
8
93
“
9
decyl-
25
“
10
5
hexadecyl-
phenyl-
39
2-pyridyl-
99
“
“
“
“
“
6
4-tolyl-
95
7
4-nitro-phenyl-
propyl-
81
8
80
9
decyl-
86
10
hexadecyl-
80
Yields refer to purified products.
Yields in parenthesis are based on recovered starting material.
Scheme 1. Reaction of Amidoximes with the corresponding Sulfonyl Chlorides.
Slight differences were observed over time. The best activity was
observed by compounds 13, 24 and 31 (w30e40% over time),
whereas compounds 16, 23, 26 and 27 showed reducing activity of
w20% at 20 min. The same activity was observed for compounds 19,
21 and 22, however after relatively prolonged periods (60 min). The
latter compounds, which seem to respond in longer interaction
time, all possess the isonicotine-carbamidoxime (p-pyridine)
structure, followed by p-nitro-phenyl (13, 14 and 16). Interestingly,
almost all nicotine-carbamidoxime sulfonyl derivatives (m-pyri-
dine) exhibited reducing activity in the range of 20e40%, the best
among all derivatives.
Regarding the substitution pattern of sulfonyl group, the best
activity was observed for compounds bearing aromatic groups (13,
p-nitro-phenyl and 24, p-tolyl). Additionally, a number of aliphatic
sulfonyl derivatives of the p-nitro, p-pyridyl and m-pyridyl ami-
doxime series showed reduced activities >20% (26, C3, 21, C10, 27,
The absence of hydrogen atoms (phenolic hydroxyl groups) which
could be donated to stabilize the DPPH radical has a direct impact
on our results. The low interaction values of amidoximes and of
sulfonyl-amidoximes compared to NDGA, should be mainly
attributed to the absence of easily oxidized functionalities like the
ones present in NDGA (two catechol subunits).
3.2. Free hydroxyl radical (HOꢀ) scavenging ability
During the inflammatory process, phagocytes generate the su-
peroxide anion radical at the inflamed site. At sites of inflammation
superoxide anion reacts with superoxide dismutase and forms
H2O2, which is dangerous in the cell because it can easily be
transformed into the highly reactive hydroxyl radical, one of the
most destructive free radicals [45].
Hydroxyl radicals formed in the body, can lead to the generation
of carbon-centered and peroxyl radicals, which are considered to be
responsible for several pathological conditions. It has been claimed
that hydroxyl radical scavengers could offer against pathological
disorders. The competition of sulfonyl-amidoximes with DMSO for
HOꢀ generated by the Fe3þ/ascorbic acid system, expressed as
percent inhibition of formaldehyde production, was used for the
evaluation of their hydroxyl radical scavenging activity [46].
All parent amidoximes 1, 2, 4 exhibited very good scavenging
activities (>80%) almost equal to the activity of the standard
compound Trolox (88%), with the exception of 3 which showed
C
10, 16, C16, 22, C16). According to these results for the aliphatic
series, increased lipophilicity does not seem to play a role, since
chain length of 3, 10 or 16 carbon atoms does not influence
dramatically the outcome of the experiments. This finding is in
accordance with the results obtained for several amphiphilic ben-
zamidoxime derivatives where expansion of the aliphatic chain
from 5 to 13 carbon atoms did not dramatically influence the
interaction with DPPH [43].
Lipophilicity, as clog P theoretically calculated values does not
seem to influence the interaction of the studied compounds [44].

148
I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
Table 1
3.3. Inhibition of lipid peroxidation
Interaction % with DPPH (RA%); Competition with DMSO for HOꢀ; Inhibition of lipid
peroxidation (LP); clog P.
AAPH induced linoleic acid oxidation has been developed as a
quick and reliable method for measuring the antioxidant activity
and provides a measure of how efficiently antioxidants protect
against lipid oxidation in vitro. The use of AAPH is recommended as
more appropriate for measuring radical-scavenging activity in vitro,
because the activity of the peroxyl radicals produced by the action
of AAPH shows a greater similarity to cellular activities such as lipid
peroxidation. Oxidation of exogenous linoleic acid by a thermal free
radical producer (AAPH) is followed by UV spectrophotometry in a
highly diluted sample [51].
With the exception of compounds 13, 25, 28, 30 and 31 for
which IC50 values were able to be determined, all the others did not
show significant anti-lipid peroxidation effect. Among these five
amidoximes three presented a 4-nitro-phenyl substitution at R
position underlying the positive influence of the electron with-
drawing effect of NO2 group. In compound 13 especially the com-
bination of two 4-nitro-phenyl groups is correlated with the
highest anti-lipid peroxidation response. The simultaneous pres-
ence of a pyridyl group enhances activity, independently of the
attachment position (2- or 3-). Four out of the rest 23 derivatives
inhibited lipid peroxidation in the range of w40e50% (1, 19, 24 and
33).
Considering the influence of the electronic phenomena of the
aromatic sulfonyl substituents we may conclude that the electron
withdrawing effect of NO2 group positively contributed to the
outcome of the antioxidant activity (19: 48.7, 13: 66.5-IC50, 25: 85-
IC50, 31: 72-IC50) comparing to reference compound Trolox. Lip-
ophilicity does not play an important role, since the most potent
derivative 13 presents low clog P value (1.66). The electron-
donating effect influenced only the o-pyridine amidoxime deriva-
tive (30: 80-IC50), whereas the long aliphatic chain seemed to
interfer in the m-pyridine derivative (28: 70-IC50). Finally, in gen-
eral sulfonyl substitution of parent amidoximes and specifically the
p-nitro-phenyl moiety enhanced lipid peroxidation activity.
Sulfonyl-
RA (%) 20
RA (%) 60
HOꢀ (%) % Inhibition of clog P [43]
amidoximes min 100
mM
min 100
m
M
100
mM
LP induced by
AAPH
100 mM (IC50)
1
3
4
7
85
87
60
81
34
78
no
75
48
100
44
32
0
66
70
no
28
95
18
63
72
69
32
72
98
83
79
no
41
no
no
no
5
25
66.5 (IC50
22
no
3
22
no
49
no
28
12
21
43
85 (IC50
16
33
70 (IC50
30
80 (IC50
72 (IC50
no
0.77
1.68
ꢁ0.47
ꢁ0.47
1.92
2.42
1.66
1.48
5.18
8.35
0.68
1.18
0.42
0.24
3.94
7.11
0.68
1.18
0.42
0.24
3.94
7.11
0.68
1.18
0.42
0.24
3.94
7.11
2
3
3
4
12
11
4
15
14
8.4
11
38
19
12
24
11
no
20
4
21
21
25
41
11
27
24
16
no
4
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
NDGA
Trolox
10
34
10
3
21
2
no
13
no
14
14
24
34
8
23
20
7
4
5
32
6
11
4
)
)
)
)
)
32
1
10
1
46
21
77.
81
88
55 (IC50
)
In the in vitro assays each experiment was performed at least in triplicate, and the
standard deviation of absorbance was less than 10% of the mean.
no ¼ no activity under the experimental conditions.
The bold numbers in the results presented, indicate a significant antioxidant
activity.
moderate activity (60%). Their low lipophilicity as clog P values
seems to be correlated with their high scavenging activity. Three
out of the six p-nitro-phenyl-amidoxime sulfonyl derivatives had
activity equal or over 75%, with the compound 16 to exhibit a
complete scavenging effect (100%). Two derivatives of the
isonicotinyl-series gave good results (20: 66% and 21: 70%),
whereas two others had moderate activity (17 and 18, w30e45%).
Four out of the six nicotinyl-derivatives exhibited scavenging ac-
tivity in the range of 63e95% (compound 24 was the most potent,
95%). The same high activity was evidenced for o-pyridyl de-
rivatives which exhibited activity in the range of 72e98% (31: 98%).
The results given in several publications indicate the importance of
pyridyl and/or sulphoxide groups for antioxidant activity [47]. It is
referred that the aggressive hydroxyl radicals are successfully
trapped by pyridyl substituted compounds, which exhibit potent
antioxidative profile and protective effect against oxidative stress
[48e50].
4. Conclusion
Novel stable aromatic and heteroaromatic sulfonyl-amidoximes
were synthesized in low to excellent yields. A preliminary biolog-
ical evaluation concerning their antioxidant activity was attempted
for the first time and was combined with a SAR study. The inter-
action of these compounds with the stable free radical DPPH was
low, however, more than half of the 28 compounds, parent ami-
doximes included, highly compete DMSO (60e100%) for HOꢀ.
Compounds 1, 2, 4 and 32 exhibited activity close to the reference
drug Trolox (>80%, compared to 88.2%) whereas compounds 16 and
24 showed 100% and 95% scavenging activity, respectively. Inhibi-
tion of lipid peroxidation was interesting for five compounds (13,
25, 28, 30 and 31).
In our opinion, the herein presented results designate sulfonyl
amidoximes as a new class of antioxidant compounds. Nicotine and
picoline amidoximes were generally overall the most potent ones.
Finally, combining reducing and anti-lipid peroxidation activity,
compounds 13 and 31 could be used as lead molecules.
Considering the sulfonyl residue, we may assume that among
the aromatic substituents, the presence of the electron-donating p-
tolyl group led to a relatively positive effect in almost all cases (12:
78%, 18: 32%, 24: 95%, 30: 72%), whereas most of the aliphatic ones
showed considerably good scavenging activity [(14: C3, 75%), (16:
5. Experimental
C
16, 100%), (20, C3, 65%), (21: C10, 70%), (26, C3, 63%), (27, C10, 72%),
5.1. Chemistry
(28, C16, 69%), (32, C3, 83%), (33, C10, 79%)]. Comparing the activity of
parent compounds m- and o-pyridine-amidoxime with their
substituted ones, the sulfonyl substitution seems to enhance
scavenging activity. No role was found for the chain length size (3,
10 or 16 carbon atoms) as well as for the lipophilicity.
Mps were measured on a Kofler hot-stage apparatus and are
uncorrected. FT-IR spectra were obtained in a PerkineElmer 1310
spectrometer using potassium bromide pellets. NMR spectra were
recorded on a Bruker AM 300 (300 MHz and 75 MHz for 1H and 13
C

I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
149
respectively) or Agilent 500/54 (500 MHz and 125 MHz for 1H and
13C respectively) spectrometer using CDCl3, and/or DMSO-d6 as
solvent. J values are reported in Hz. Quint and sext are the abbre-
viations for quintet and sextet multiple NMR peaks. High resolution
mass spectra (HRMS) were recorded on micrOTOF GCeMS QP 5050
Shimadzu single-quadrupole mass spectrometer. Mass spectra
were determined on a Shimadzu LCMS-2010 EV system under
Electrospray Ionization (ESI) conditions. Micro-analyses were per-
formed on a PerkineElmer 2400-II Element analyzer. Analyses
indicated by the symbols of the elements or functions were within
0.4% of the theoretical values. All reactions were monitored on
commercial available pre-coated TLC plates (layer thickness
negative ¼ 202 (100%) [(O2NeC6H4eSO3)]ꢁ; Elem. Anal.: calcd for
C
13H10N4O7S: C, 42.63; H, 2.75; N, 15.30; Found: C, 42.75; H, 2.74; N,
15.34.
5.1.1.4. 4-Nitro-N’-(propylsulfonyloxy)benzimidamide
(14).
Solvent: Chloroform/DMF (8/1); Reaction time: 20 h; Purification
method: recrystallization; Pale yellow crystals, yield 58%, mp 110e
112 ꢂC (hexanes/ethyl acetate); IR (KBr): 3474, 3368, 2972, 2933,
2874, 1640, 1347 & 1172 (S]O) cmꢁ1 1H NMR (300 MHz, CDCl3)
;
d
1.10 (t, J ¼ 7.6 Hz, 3H), 1.93 (sext, J ¼ 7.6 Hz, 2H), 3.38 (t, J ¼ 7.6 Hz,
2H), 5.40 (br s, 2H), 7.86 (d, J ¼ 8.9 Hz, 2H), 8.27 (d, J ¼ 8.9 Hz, 2H);
13C NMR (75 MHz, CDCl3)
d 12.8, 17.1, 50.6, 124.0, 127.9, 136.0, 149.7,
0.25 mm) of Kieselgel 60 F254. Silica gel Merck 60 (40e60
mM) has
155.7; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 288 [MþH]þ, 243
[Mþ2HeNO2]þ, 166 (100%) [Mþ2HeC3H7SO3]þ; negative ¼ 123
(100%) [C3H7SO3]ꢁ; Elem. Anal.: calcd for C10H13N3O5S: C, 41.81; H,
4.56; N, 14.63; Found: C, 41.92; H, 4.57; N, 14.67.
been used for column chromatography. Yields were calculated after
recrystallization or column chromatography.
5.1.1. General procedure
Parent amidoxime (2 mmol) was dissolved in the indicated
solvent (0.15 M) and cooled to 0 ꢂC under an argon atmosphere.
Triethylamine (0.28 mL, 2 mmol) was added, followed by the
required sulfonyl chloride (2 mmol) and the mixture was stirred for
the indicated period allowing the temperature to slowly rise to
25 ꢂC. Then, water (70 mL) was added and the mixture was
extracted with dichloromethane (2 ꢃ 70 mL). The combined
organic extracts were dried (Na2SO4) and concentrated under
vacuum (rotary evaporator) to give a residue which was either
recrystallized or purified using column chromatography.
5.1.1.5. N’-(decylsulfonyloxy)-4-nitrobenzimidamide
(15).
Solvent: Chloroform/DMF (8/1); Reaction time: 20 h; Purification
method: column chromatography; Baize crystals, yield 37% or 65%
(based on recovered SM), mp 90e92 ꢂC (hexanes/ethyl acetate); IR
(KBr): 3482, 3353, 2954, 2921, 2851,1639,1360 & 1166 (S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
0.87 (t, J ¼ 6.8 Hz, 3H), 1.25 (br s, 12H),
1.46 (quint, J ¼ 7.5 Hz, 2H), 1.89 (quint, J ¼ 7.3 Hz, 2H), 3.39 (t,
J ¼ 7.7 Hz, 2H), 5.39 (br s, 2H), 7.86 (d, J ¼ 8.9 Hz, 2H), 8.28 (d,
J ¼ 8.9 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d 14.0, 22.6, 23.3, 28.1,
28.9, 29.2, 29.2, 29.4, 31.8, 48.9, 124.0, 127.9, 136.0, 149.7, 155.7; MS
(LCeMS) (ESI, 1.65 eV): m/z positive ¼ 386 [MþH]þ, 341 [Mþ2He
NO2]þ, 166 (100%) [Mþ2HeC10H21SO3]þ; negative ¼ 221 (100%)
[C10H21SO3]ꢁ; Elem. Anal.: calcd for C17H27N3O5S: C, 41.81; H, 4.56;
N, 14.63; Found: C, 41.92; H, 4.55; N, 14.67.
5.1.1.1. 4-Nitro-N’-(phenylsulfonyloxy)benzimidamide
(11).
Solvent: Chloroform; Reaction time: 6 h; Purification method:
recrystallization; Pale yellow crystals, yield 82%, mp 133e135 ꢂC
(hexanes/ethyl acetate); IR (KBr): 3472, 3379, 1657, 1615, 1356 &
1188 (S]O) cmꢁ1; 1H NMR (500 MHz, CDCl3 þ DMSO-d6)
d
6.62 (br
5.1.1.6. N’-(hexadecylsulfonyloxy)-4-nitrobenzimidamide
(16).
s, 2H), 7.50 (t, J ¼ 7.8 Hz, 2H), 7.59 (t, J ¼ 7.5 Hz, 1H), 7.72 (d,
Solvent: Chloroform/DMF (8/1); Reaction time: 20 h; Purification
method: column chromatography; Pale yellow crystals, yield 27% or
56% (based on recovered SM), mp 95e96 ꢂC (ethyl acetate); IR
(KBr): 3483, 3354, 2952, 2919, 2849, 1638, 1360 & 1167 (S]O)
J ¼ 8.8 Hz, 2H), 7.93 (d, J ¼ 8.3 Hz, 2H), 8.11 (d, J ¼ 8.5 Hz, 2H); 13
C
NMR (125 MHz, CDCl3 þ DMSO-d6)
d 122.6,127.4, 127.8, 128.1, 133.0,
134.9, 135.8, 148.3, 155.4; MS (LCeMS) (ESI, 1.65 eV): m/z
positive ¼ 322 [MþH]þ, 277 [Mþ2HeNO2]þ, 166 (100%) [Mþ2He
C6H5SO3]þ; negative ¼ 157 (100%) [C6H5SO3]ꢁ; Elem. Anal.: calcd
for C13H11N3O5S: C, 48.59; H, 3.45; N, 13.08; Found: C, 48.68; H,
3.46; N, 13.09.
cmꢁ1
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d
0.80 (t, J ¼ 6.2 Hz,
3H), 1.17 (br s, 24H), 1.38 (quint, J ¼ 6.8 Hz, 2H), 1.80 (quint,
J ¼ 7.6 Hz, 2H), 3.31 (t, J ¼ 7.7 Hz, 2H), 6.34 (br s, 2H), 7.88 (d,
J ¼ 8.9 Hz, 2H), 8.18 (d, J ¼ 8.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3 þ DMSO-d6)
d 13.7, 22.2, 22.9, 27.7, 28.5, 28.8, 28.9, 29.0, 29.1,
5.1.1.2. 4-Nitro-N’-(tosyloxy)benzimidamide (12). Solvent: Chloro-
form; Reaction time: 6 h; Purification method: recrystallization;
Pale yellow crystals, yield 78%, mp 148e150 ꢂC (hexanes/ethyl ac-
29.16, 29.19, 31.4, 48.3, 123.2, 127.9, 136.2, 149.0, 155.8; MS (LCeMS)
(ESI, 1.65 eV): m/z positive ¼ 524 [MþNaþMeOH]þ, 425 [Mþ2He
NO2]þ, 166 (100%) [Mþ2HeC16H33SO3]þ; negative ¼ 305 (100%)
[C16H33SO3]ꢁ; Elem. Anal.: calcd for C23H39N3O5S: C, 58.82; H, 8.37;
N, 8.95; Found: C, 58.99; H, 8.39; N, 8.98.
etate); IR (KBr): 3498, 3391, 1637, 1598, 1359 & 1191 (S]O) cmꢁ1
;
1H NMR (500 MHz, CDCl3 þ DMSO-d6)
d 2.36 (s, 3H), 6.60 (br s, 2H),
7.28 (d, J ¼ 8.2 Hz, 2H), 7.74 (d, J ¼ 8.9 Hz, 2H), 7.80 (d, J ¼ 8.3 Hz,
2H), 8.11 (d, J ¼ 8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3 þ DMSO-d6)
5.1.1.7. N’-((phenylsulfonyl)oxy)isonicotinimidamide
(17).
d
20.8, 122.5, 127.3, 127.7, 128.6, 131.9, 135.8, 143.9, 148.2, 155.2; MS
Solvent: Chloroform/DMF (8/1); Reaction time: 4 h; Purification
method: recrystallization; White crystals, yield 55%, mp 130e
132 ꢂC (ethyl acetate); IR (KBr): 3409, 3361, 3103,1654,1602,1364 &
(LCeMS) (ESI, 1.65 eV): m/z positive ¼ 390 [MþNaþMeOH]þ, 336
[MþH]þ, 166 [Mþ2HeC7H7SO3]þ; negative
¼
171 (100%)
[C7H7SO3]ꢁ; Elem. Anal.: calcd for C14H13N3O5S: C, 50.14; H, 3.91; N,
12.53; Found: C, 50.33; H, 3.92; N, 12.58.
1189 (S]O) cmꢁ1; 1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d 6.60 (br
s, 2H), 7.46e7.53 (m, 4H), 7.59 (t, J ¼ 7.7 Hz, 1H), 7.93 (d, J ¼ 7.8 Hz,
2H) 8.55 (d, J ¼ 5.6 Hz, 2H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6)
5.1.1.3. 4-Nitro-N’-(4-nitrophenylsulfonyloxy)benzimidamide
(13).
d 120.3, 127.7, 128.0, 132.9, 135.0, 137.8, 148.8, 155.0; MS (LCeMS)
Solvent: Chloroform/DMF (8/1); Reaction time: 5 h; Purification
method: recrystallization; Baize crystals, yield 96%, mp 142e144 ꢂC
(hexanes/ethyl acetate); IR (KBr): 3484, 3359, 1651, w1350 & 1188
(ESI, 1.65 eV): m/z positive ¼ 278 (100%) [MþH]þ, 122 [Mþ2He
C6H5SO3]þ; negative ¼ 157 (100%) [C6H5SO3]ꢁ; Elem. Anal.: calcd
for C12H11N3O3S: C, 51.98; H, 4.00; N,15.15; Found: C, 52.13; H, 4.01;
N, 15.19.
(S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d 6.73 (br s,
2H), 7.73 (d, J ¼ 8.9 Hz, 2H), 8.12 (d, J ¼ 8.9 Hz, 2H), 8.16 (d,
J ¼ 8.9 Hz, 2H), 8.32 (d, J ¼ 8.9 Hz, 2H); 13C NMR (75 MHz,
5.1.1.8. N’-(tosyloxy)isonicotinimidamide (18). Solvent: Chloroform/
DMF (8/1); Reaction time: 4 h; Purification method: recrystalliza-
tion; White crystals, yield 81%, mp 174e176 ꢂC (ethyl acetate); IR
CDCl3 þ DMSO-d6)
d 122.7, 123.3, 127.6, 129.4, 135.5, 140.9, 148.6,
150.0, 156.1; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 322
[Mþ2HeNO2]þ,
166
(100%)
[Mþ2He(O2NeC6H4eSO3)]þ;
(KBr): 3436, 3338, 3129, 2963, 1657, 1346 & 1188 (S]O) cmꢁ1 1H
;

150
I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
NMR (500 MHz, DMSO-d6)
d
2.39 (s, 3H), 7.36 (br s, 2H), 7.44 (d,
calcd for C22H39N3O3S C, 62.08; H, 9.24; N, 9.87; Found: C, 62.14; H,
9.26; N, 9.88.
J ¼ 8.3 Hz, 2H), 7.50 (d, J ¼ 7.3 Hz, 2H), 7.86 (d, J ¼ 8.3 Hz, 2H), 8.64
(d, J ¼ 7.3 Hz, 2H); 13C NMR (125 MHz, DMSO-d6)
d 21.1, 121.0, 128.3,
129.7,132.6,138.0,144.7,150.2,155.9; MS (LCeMS) (ESI,1.65 eV): m/
z positive ¼ 346 [MþNaþMeOH]þ, 314 [MþNa]þ, 292 (100%)
[MþH]þ; negative ¼ 290 [MꢁH]ꢁ, 171 (100%) [C7H7SO3]ꢁ; Elem.
Anal.: calcd for C13H13N3O3S: C, 53.60; H, 4.50; N, 14.42; Found: C,
53.75; H, 4.51; N, 14.46.
5.1.1.13. N0-((phenylsulfonyl)oxy)nicotinimidamide
(23).
Solvent: Chloroform/DMF (8/1); Reaction time: 3 h; Purification
method: recrystallization; Pale yellow crystals, yield 96%, mp 125e
127 ꢂC (ethyl acetate/ethanol); IR (KBr): 3418, 3325, 3150, 1657,
1350 & 1182 (S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d
6.63 (br s, 2H), 7.26 (dd, J ¼ 7.9, 4.8 Hz, 1H), 7.50 (t, J ¼ 7.5 Hz, 2H),
7.60 (t, J ¼ 7.9 Hz, 1H), 7.83 (d, J ¼ 7.9 Hz, 1H), 7.94 (d, J ¼ 7.6 Hz, 2H),
5.1.1.9. N’-(4-nitrophenylsulfonyloxy)isonicotinimidamide
(19).
8.59 (d, J ¼ 3.6 Hz, 1H), 8.69 (d, J ¼ 1.4 Hz, 1H); 13C NMR (75 MHz,
Solvent: Chloroform/DMF (8/1); Reaction time: 5 h; Purification
method: recrystallization; Extraction with an additional amount of
ethyl acetate; Pale yellow crystals, yield 63%, mp 169e171 ꢂC
(ethanol); IR (KBr): 3457, 3308, 3104, 1657, 1376 & 1189 (S]O)
CDCl3 þ DMSO-d6)
d 122.2, 125.7, 127.5, 127.8, 132.7, 133.7, 135.0,
146.9, 150.5, 155.2; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 278
[MþH]þ, 122 [Mþ2HeC6H5SO3]þ; negative
¼
157 (100%)
[C6H5SO3]ꢁ; Elem. Anal.: calcd for C12H11N3O3S: C, 51.98; H, 4.00; N,
15.15; Found: C, 52.08; H, 4.01; N, 15.19.
cmꢁ1
;
1H NMR (300 MHz, CDCl3þDMSO-d6)
d 6.98 (br s, 2H), 7.44
(d, J ¼ 5.9 Hz, 2H), 8.18 (d, J ¼ 8.9 Hz, 2H), 8.34 (d, J ¼ 8.7 Hz, 2H),
8.54 (d, J ¼ 5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3þDMSO-d6)
d 119.9,
5.1.1.14. N’-(tosyloxy)nicotinimidamide (24). Solvent: Chloroform/
DMF (8/1); Reaction time: 4 h; Purification method: recrystalliza-
tion; Pale yellow crystals, yield 98%, mp 140e142 ꢂC (ethyl acetate);
IR (KBr): 3408, 3310, 3114, 1654, 1343 & 1189 (S]O) cmꢁ1; 1H NMR
122.8, 128.9, 136.7, 140.3, 148.8, 149.4, 155.5; MS (LCeMS) (ESI,
1.65 eV): m/z positive ¼ 323 [MþH]þ, 122 (100%) [Mþ2He(O2Ne
C6H4eSO3)]þ; negative ¼ 202 (100%) [(O2NeC6H4eSO3)]ꢁ; Elem.
Anal.: calcd for C12H10N4O5S: C, 44.72; H, 3.13; N, 17.38; Found: C,
44.76; H, 3.14; N, 17.43.
(300 MHz, CDCl3 þ DMSO-d6)
d 2.37 (s, 3H), 6.47 (br s, 2H), 7.25 (dd,
J ¼ 8.1, 4.9 Hz, 1H), 7.27 (d, J ¼ 7.8 Hz, 2H), 7.82 (d, J ¼ 8.1 Hz, 2H),
7.83 (dt, J ¼ 7.2, 1.8 Hz, 1H), 8.56 (dd, J ¼ 4.8, 1.5 Hz, 1H), 8.70 (d,
5.1.1.10. N’-(propylsulfonyloxy)isonicotinimidamide
(20).
J ¼ 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6)
d 21.4, 123.0,
Solvent: Chloroform/DMF (8/1); Reaction time: 20 h; Purification
method: column chromatography; White crystals, yield 20%, mp
134e136 ꢂC (hexanes/ethyl acetate); IR (KBr): 3437, 3330, 3173,
126.6, 128.5, 129.3, 132.8, 134.5, 144.5, 147.9, 151.4, 155.9; MS (LCe
MS) (ESI, 1.65 eV): m/z positive ¼ 292 (100%) [MþH]þ, 122 [Mþ2He
C7H7SO3]þ; negative ¼ 171 (100%) [C7H7SO3]ꢁ; Elem. Anal.: calcd
for C13H13N3O3S: C, 53.60; H, 4.50; N, 14.42. Found: C, 53.69; H,
4.49; N, 14.45.
2967, 1665, 1352 & 1172 (S]O) cmꢁ1
;
1H NMR (300 MHz,
CDCl3 þ DMSO-d6)
d
1.02 (t, J ¼ 7.4 Hz, 3H), 1.85 (sext, J ¼ 7.6 Hz,
2H), 3.30 (t, J ¼ 7.6 Hz, 2H), 6.33 (br s, 2H), 7.56 (d, J ¼ 4.5 Hz, 2H),
8.61 (d, J ¼ 4.5 Hz, 2H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6)
d 12.4,
5.1.1.15. N0-((4-nitrophenyl)sulfonyloxy)nicotinimidamide
(25).
16.7, 49.9, 120.6, 137.8, 149.8, 155.5; MS (LCeMS) (ESI, 1.65 eV): m/z
Solvent: Tetrahydrofuran; Reaction time: 1 h; Purification method:
recrystallization; Extraction with ethyl acetate instead of
dichloromethane; Baize crystals, yield 77%, mp 110e111 ꢂC (ethyl
positive
negative
¼
244 (100) [MþH]þ, 122 [Mþ2HeC3H7SO3]þ;
¼
123 (100%) [C3H7SO3]ꢁ; Elem. Anal.: calcd for
C9H13N3O3S: C, 44.43; H, 5.39; N, 17.27; Found: C, 44.56; H, 5.40; N,
17.32.
acetate), IR (KBr): 3425, 3323, 3106, 1659, 1367 & 1185 (S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d 6.82 (br s, 2H), 7.27 (dd,
J ¼ 7.8, 4.8 Hz, 1H), 7.83 (dt, J ¼ 8.1, 1.7 Hz, 1H), 8.17 (d, J ¼ 8.9 Hz,
2H), 8.33 (d, J ¼ 8.9 Hz, 2H), 8.57 (dd, J ¼ 4.8, 1.5 Hz, 1H), 8.70 (d,
5.1.1.11. N’-(decylsulfonyloxy)isonicotinimidamide
(21). Solvent:
J ¼ 1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3 þ DMSO-d6)
d 122.3, 123.0,
Chloroform/DMF (8/1); Reaction time: 20 h; Purification method:
column chromatography; White crystals, yield 15%, mp 86e88 ꢂC
(hexanes/ethyl acetate); IR (KBr): 3472, 3368, 2954, 2921, 2853,
1637, 1360 & 1174 (S]O) cmꢁ1; 1H NMR (300 MHz, CDCl3þDMSO-
125.5, 129.1, 133.8, 140.7, 146.9, 149.6, 150.7, 155.8; HRMS (ESI) Calc
C
12H11N4O5S [MþH]þ, 323.0445; found 323.0443.
d6)
d
0.79 (t, J ¼ 6.1 Hz, 3H), 1.17 (br s, 12H), 1.38 (quint, J ¼ 6.9 Hz,
5.1.1.16. N’-(propylsulfonyloxy)nicotinimidamide
(26). Solvent:
2H), 1.76 (quint, J ¼ 7.8 Hz, 2H), 3.30 (t, J ¼ 7.8 Hz, 2H), 6.56 (br s,
Chloroform; Reaction time: 20 h; Purification method: recrystalli-
zation; Pale yellow crystals, yield 93%, mp 105e106 ꢂC (hexanes/
ethyl acetate); IR (KBr): 3415, 3332, 3087, 2966, 1655, 1347 & 1197
2H), 7.58 (d, J ¼ 6.1 Hz, 2H), 8.59 (d, J ¼ 6.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3þDMSO-d6)
d 13.3, 21.8, 22.5, 27.2, 28.1, 28.3, 28.4,
(S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d 1.03 (t,
28.6, 31.0, 47.8, 120.4, 137.5, 149.4, 155.3; MS (LCeMS) (ESI, 1.65 eV):
m/z positive ¼ 342 (100%) [MþH]þ, 122 [Mþ2HeC10H21SO3]þ;
J ¼ 7.6 Hz, 3H), 1.85 (sext, J ¼ 7.6 Hz, 2H), 3.30 (t, J ¼ 7.6 Hz, 2H), 6.46
(br s, 2H), 7.31 (dd, J ¼ 7.9, 4.8 Hz, 1H), 7.98 (dt, J ¼ 7.9, 1.8 Hz, 1H),
8.62 (dd, J ¼ 4.8, 1.5 Hz, 1H), 8.88 (d, J ¼ 1.7 Hz, 1H); 13C NMR
negative
¼
221 (100%) [C10H21SO3]ꢁ; Elem. Anal.: calcd for
C
16H27N3O3S: C, 56.28; H, 7.97; N, 12.31; Found: C, 56.39; H, 7.99; N,
12.32.
(75 MHz, CDCl3 þ DMSO-d6)
d 12.2, 16.5, 49.7, 122.7, 126.1, 134.1,
147.5, 151.2, 155.6; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 244
5.1.1.12. N’-(hexadecylsulfonyloxy)isonicotinimidamide
(22).
[MþH]þ, 122 [Mþ2HeC3H7SO3]þ; negative
¼
123 (100%)
Solvent: Chloroform/DMF (8/1); Reaction time: 20 h; Purification
method: recrystallization; White crystals, yield 27%, mp 78e80 ꢂC
(hexanes/ethyl acetate); IR (KBr): 3469, 3365, 2953, 2921, 2847,
1637, 1359 & 1174 (S]O) cmꢁ1; 1H NMR (300 MHz, CDCl3þDMSO-
[C3H7SO3]ꢁ; Elem. Anal.: calcd for C9H13N3O3S: C, 44.43; H, 5.39; N,
17.27; Found: C, 44.51; H, 5.38; N, 17.22.
5.1.1.17. N’-(decylsulfonyloxy)nicotinimidamide (27). Solvent: Chlo-
roform; Reaction time: 20 h; Purification method: recrystallization;
Pale yellow crystals, yield 25%, mp 85e87 ꢂC (hexanes/ethyl ace-
tate); IR (KBr): 3411, 3325, 3125, 2925, 2848, 1653, 1347 & 1192 (S]
d6)
d
0.80 (t, J ¼ 6.9 Hz, 3H), 1.17 (br s, 24H), 1.38 (quint, J ¼ 7.1 Hz,
2H), 1.80 (quint, J ¼ 7.8 Hz, 2H), 3.30 (t, J ¼ 7.8 Hz, 2H), 6.35 (br s,
2H), 7.56 (d, J ¼ 5.8 Hz, 2H), 8.60 (d, J ¼ 5.9 Hz, 2H); 13C NMR
(75 MHz, CDCl3þDMSO-d6)
d
13.3, 21.8, 22.5, 27.3, 28.1, 28.39,
O) cmꢁ1
;
1H NMR (500 MHz, DMSO-d6)
d
0.83 (t, J ¼ 6.4 Hz, 3H),
28.44, 28.6, 28.7, 28.75, 28.78, 31.0, 47.9, 120.4, 137.5, 149.4, 155.3;
MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 448.5 [MþNa]þ, 426
(100%) [MþH]þ; negative ¼ 305 (100%) [C16H33SO3]ꢁ; Elem. Anal.:
1.20 (br s, 12H), 1.39 (quint, J ¼ 7.2 Hz, 2H), 1.71 (quint, J ¼ 7.6 Hz,
2H), 3.43 (t, J ¼ 7.9 Hz, 2H), 7.33 (br s, 2H), 7.50 (dd, J ¼ 7.9, 4.8 Hz,
1H), 8.06 (dt, J ¼ 7.9,1.8 Hz,1H), 8.70 (dd, J ¼ 4.8,1.5 Hz,1H), 8.86 (d,

I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
151
J ¼ 1.8 Hz, 1H); 13C NMR (125 MHz, DMSO-d6)
d
14.0, 22.1, 23.0, 27.2,
5.1.1.22. N’-(propylsulfonyloxy)picolinimidamide
(32). Solvent:
28.4, 28.68, 28.71, 28.9, 31.3, 47.6, 123.6, 126.7, 134.7, 147.7, 151.7,
Chloroform; Reaction time: 20 h; Purification method: recrystalli-
zation; White crystals, yield 80%, mp 65e66 ꢂC (hexanes/ethyl ac-
etate); IR (KBr): 3456, 3345, 2974, 2944, 2927, 1647, 1359 & 1169
155.8; MS (LCeMS) (ESI, 1.65 eV): m/z positive
¼
396
[MþNaþMeOH]þ, 364 [MþNa]þ, 342 (100%) [MþH]þ, 122 [Mþ2He
C
C
10H21SO3]þ; negative ¼ 221 [C10H21SO3]ꢁ; Elem. Anal.: calcd for
(S]O) cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
1.10 (t, J ¼ 7.4 Hz, 3H),1.96
16H27N3O3S: C, 56.28; H, 7.97; N, 12.31; Found C, 55.95; H, 8.00; N,
(sext, J ¼ 7.6 Hz, 2H), 3.40 (t, J ¼ 7.1 Hz, 2H), 6.11 (br s, 2H), 7.41 (dd,
12.33.
J ¼ 7.1, 4.9 Hz,1H), 7.76 (t, J ¼ 7.7 Hz,1H), 8.02 (d, J ¼ 7.9 Hz,1H), 8.59
(d, J ¼ 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 12.9, 17.2, 50.5, 121.2,
125.8, 136.9, 146.8, 148.6, 154.7; MS (LCeMS) (ESI, 1.65 eV): m/z
5.1.1.18. N’-((hexadecylsulfonyl)oxy)nicotinimidamide
(28).
positive
¼
266 [MþNa]þ, 244 [MþH]þ, 122 (100) [Mþ2He
Solvent: Chloroform; Reaction time: 20 h; Purification method:
recrystallization; Pale yellow crystals, yield 39%, mp 109e111 ꢂC
(hexanes/ethyl acetate); IR (KBr): 3416, 3332, 3121, 2918, 2849,
1655, 1351 & 1166 (S]O) cmꢁ1; 1H NMR (300 MHz, CDCl3 þ DMSO-
C3H7SO3]þ; negative ¼ 123 (100%) [C3H7SO3]ꢁ; Elem. Anal.: calcd
for C9H13N3O3S: C, 44.43; H, 5.39; N, 17.27; Found: C, 44.36; H, 5.40;
N, 17.30.
d6)
d
0.80 (t, J ¼ 6.7 Hz, 3H), 1.18 (br s, 24H), 1.39 (quint, J ¼ 7.0 Hz,
5.1.1.23. N’-((decylsulfonyl)oxy)picolinimidamide
(33). Solvent:
2H), 1.81 (quint, J ¼ 7.5 Hz, 2H), 3.31 (t, J ¼ 7.7 Hz, 2H), 6.28 (br s,
2H), 7.30 (dd, J ¼ 8.0, 4.8 Hz, 1H), 7.97 (dt, J ¼ 8.0, 2.0 Hz, 1H), 8.63
(dd, J ¼ 4.8, 1.5 Hz, 1H), 8.87 (d, J ¼ 1.5 Hz, 1H); 13C NMR (75 MHz,
Chloroform; Reaction time: 20 h; Purification method: recrystalli-
zation; White crystals, yield 86%, mp 66e67 ꢂC (hexanes/ethyl ac-
etate); IR (KBr): 3469, 3353, 2916, 2851, 1648, 1364 & 1178 (S]O)
CDCl3 þ DMSO-d6)
d 13.6, 22.1, 22.9, 27.7, 28.5, 28.7, 28.8, 29.0,
cmꢁ1; 1H NMR (300 MHz, CDCl3)
d
0.87 (t, J ¼ 6.9 Hz, 3H), 1.25 (br s,
29.06, 29.10, 29.12, 29.13, 31.4, 48.3, 122.8, 126.3, 134.2, 147.7, 151.5,
155.7; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 448 [MþNa]þ, 426
[MþH]þ; negative ¼ 305 (100%) [C16H33SO3]ꢁ; Elem. Anal.: calcd
for C22H39N3O3S C, 62.08; H, 9.24; N, 9.87; Found: C, 61.90; H, 9.21;
N, 9.88.
12H), 1.42e1.51 (m, 2H), 1.91 (quint, J ¼ 7.3 Hz, 2H), 3.41 (t,
J ¼ 7.7 Hz, 2H), 6.02 (br s, 2H), 7.40 (ddd, J ¼ 7.3, 4.9, 1.0 Hz, 1H), 7.75
(dt, J ¼ 7.7, 1.6 Hz, 1H), 8.02 (dd, J ¼ 7.9, 0.8 Hz, 1H), 8.59 (d,
J ¼ 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 14.0, 22.6, 23.3, 28.1,
28.9, 29.1, 29.2, 29.4, 31.8, 48.8, 121.1, 125.8, 136.8, 146.8, 148.6,
154.6; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 364 [MþNa]þ, 342
5.1.1.19. N’-((phenylsulfonyl)oxy)picolininidamide
(29). Solvent:
[MþH]þ, 122 (100%) [Mþ2HeC10H21SO3]þ; negative
¼
221
Chloroform; Reaction time: 5 h; Purification method: recrystalli-
[C10H21SO3]ꢁ; Elem. Anal.: calcd for C16H27N3O3S: C, 56.28; H, 7.97;
N, 12.31; Found: C, 56.33; H, 7.96; N, 12.28.
zation; White crystals, yield 99%, mp 118e120 ꢂC (hexanes/ethyl
acetate); IR (KBr): 3457, 3301, 3138, 1645, 1364 & 1188 (S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3)
d
6.02 (br s, 2H), 7.33 (dd, J ¼ 8.1, 5.4 Hz,
5.1.1.24. N0-((hexadecylsulfonyl)oxy)picolinimidamide
(34).
1H), 7.54 (t, J ¼ 7.5 Hz, 2H), 7.63 (t, J ¼ 6.9 Hz, 1H), 7.68 (dt, J ¼ 7.9,
1.3 Hz, 1H), 7.84 (d, J ¼ 8.1 Hz, 1H), 8.06 (d, J ¼ 7.6 Hz, 2H), 8.51 (d,
Solvent: Chloroform; Reaction time: 20 h; Purification method:
column chromatography; White crystals, yield 80%, mp 89e90 ꢂC
(hexanes/ethyl acetate); IR (KBr): 3470, 3353, 2916, 2850, 1650,
J ¼ 4.5 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 121.1, 125.7, 128.82,
128.79, 133.7, 136.0, 136.7, 146.8, 148.5, 154.5; MS (LCeMS) (ESI,
1.65 eV): m/z positive ¼ 300 [MþNa]þ, 278 [MþH]þ, 122 (100%)
[Mþ2HeC6H5SO3]þ; negative ¼ 157 (100%) [C6H5SO3]ꢁ; Elem.
Anal.: calcd for C12H11N3O3S: C, 51.98; H, 4.00; N, 15.15; Found: C,
51.88; H, 3.99; N, 15.12.
1364 & 1178 (S]O) cmꢁ1 1H NMR (300 MHz, CDCl3)
; d 0.88 (t,
J ¼ 6.9 Hz, 3H), 1.26 (br s, 24H), 1.47 (quint, J ¼ 7.4 Hz, 2H), 1.91
(quint, J ¼ 7.3 Hz, 2H), 3.41 (t, J ¼ 7.8 Hz, 2H), 6.07 (br s, 2H), 7.40
(dd, J ¼ 7.4, 4.9 Hz,1H), 7.76 (dt, J ¼ 7.7,1.5 Hz,1H), 8.02 (d, J ¼ 7.9 Hz
1H), 8.59 (d, J ¼ 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 14.1, 22.7,
23.4, 28.2, 29.0, 29.25, 29.33, 29.5, 29.58, 29.64, 31.9, 48.8, 121.2,
125.8, 136.9, 146.8, 148.6, 154.7; MS (LCeMS) (ESI, 1.65 eV): m/z
positive ¼ 448.5 [MþNa]þ, 426.5 [MþH]þ, 122 (100) [Mþ2He
5.1.1.20. N’-(tosyloxy)picolinimidamide (30). Solvent: Chloroform;
Reaction time: 6 h; Purification method: recrystallization; White
crystals, yield 95%, mp 144e146 ꢂC (hexanes/ethyl acetate); IR
C
C
16H33SO3]þ; negative ¼ 305 [C16H33SO3]ꢁ; Elem. Anal.: calcd for
(KBr): 3480, 3365, 1642, 1586, 1364 & 1181 (S]O) cmꢁ1 1H NMR
;
22H39N3O3S C, 62.08; H, 9.24; N, 9.87; Found: C, 61.95; H, 9.25; N,
(300 MHz, CDCl3)
d 2.41 (s, 3H), 5.97 (br s, 2H), 7.31e7.35 (m, 1H),
9.89.
7.32 (d, J ¼ 8.1 Hz, 2H), 7.67 (dt, J ¼ 7.9, 1.6 Hz,1H), 7.85 (d, J ¼ 7.9 Hz,
1H), 7.93 (d, J ¼ 8.2 Hz, 2H), 8.50 (d, J ¼ 4.9 Hz, 1H); 13C NMR
5.2. Biological evaluation
(75 MHz, CDCl3)
d 21.6, 121.1, 125.6, 128.8, 129.4, 132.9, 136.7, 144.7,
146.8, 148.4, 154.3; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 314
All the reagents used were commercially available by Merck, 1,1-
diphenyl-2-picrylhydrazyl (DPPH), nordihydroguaiaretic acid
(NDGA) were purchased from the Aldrich Chemical Co. Milwaukee,
WI, (USA). linoleic acid sodium salt, were obtained from Sigma
Chemical, Co. (St. Louis, MO, USA).
(100%) [MþNa]þ, 292 [MþH]þ, 122 [Mþ2HeC7H7SO3]þ;
negative
¼
171 (100%) [C7H7SO3]ꢁ; Elem. Anal.: calcd for
C
13H13N3O3S: C, 53.60; H, 4.50; N,14.42; Found: C, 53.76; H, 4.49; N,
14.46.
5.1.1.21. N’-(4-nitrophenylsulfonyloxy)picolinimidamide
(31).
5.2.1. Experiments in vitro
Solvent: Chloroform; Reaction time: 5 h; Purification method:
recrystallization; Yellow crystals, yield 81%, mp 125e127 ꢂC (hex-
anes/ethyl acetate); IR (KBr): 3494, 3384, 3108, 1652, 1377 & 1188
In the in vitro assays each experiment was performed at least in
triplicate, and the standard deviation of absorbance was less than
10% of the mean.
(S]O) cmꢁ1
;
1H NMR (300 MHz, CDCl3 þ DMSO-d6)
d 6.75 (br s,
2H), 7.32e7.37 (m, 1H), 7.64e7.71 (m, 2H), 8.20 (d, J ¼ 9.1 Hz, 2H),
5.2.1.1. Determination of the reducing activity of the stable radical
1,1-diphenyl-picrylhydrazyl (DPPH) [42]. To a solution of DPPH (final
concentration 50 mM) in absolute ethanol was added an equal
volume of the compounds dissolved in dimethylsulfoxide. As con-
8.33 (d, J ¼ 8.9 Hz, 2H), 8.48 (d, J ¼ 5.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3 þ DMSO-d6)
d
119.9, 122.9, 124.8, 129.1, 135.8, 140.5, 145.5,
147.6, 149.5, 154.3; MS (LCeMS) (ESI, 1.65 eV): m/z positive ¼ 393
(100%) [MþKþMeOH]þ; negative ¼ 321 (100%) [MꢁH]ꢁ; Elem.
Anal.: calcd for C12H10N4O5S: C, 44.72; H, 3.13; N, 17.38; Found C,
44.77; H, 3.12; N, 17.88.
trol solution ethanol was used. The final concentration of the tested
compounds was 100
mM. After 20 and 60 min at room temperature,
the absorbance was recorded at 517 nm (Table 1). All tests were

152
I. Doulou et al. / European Journal of Medicinal Chemistry 80 (2014) 145e153
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ascorbic acid system, were detected according to Nash, by the
determination of formaldehyde produced from the oxidation of
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tested compounds (concentration 0.1 mM) and ascorbic acid
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Production of conjugated diene hydroperoxide by oxidation of
linoleic acid in an aqueous dispersion is monitored at 234 nm. 2,20-
Azobis(2-amidinopropane) dihydrochloride (AAPH) is used as a
free radical initiator. Ten microliters of the 16 mM linoleic acid
dispersion was added to the UV cuvette containing 0.93 mL of
0.05 M phosphate buffer, pH 7.4 prethermostated at 37 ꢂC. The
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50
mL of 40 mM AAPH solution. Oxidation was carried out in the
presence of aliquots (10
m
L) of KukA and its analogues. In the assay
without antioxidant, lipid oxidation was measured in the presence
of the same level of DMSO. The rate of oxidation at 37 ꢂC was
monitored by recording the increase in absorption at 234 nm
caused by conjugated diene hydroperoxides.
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formation of arylamidoximes in the presence of phosphorus ylides. Unex-
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K.C. Fylaktakidou, An easy transformation of 2-amino-2-(hydroxyimino)ace-
tates to carbamoylformamidoximes, Synthesis (2005) 407e410.
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D.N. Nicolaides, Synthesis of oxadiazoloquinoxaline, oxathiadiazoloquinoxa-
line and oxadiazolo-benzothiazine derivatives, Journal of Heterocyclic
Chemistry 43 (2006) 579e583.
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amino-substituted 1,2,4-oxadiazole derivatives via reactions of amidoximes
with carbodiimides, Heterocycles 75 (2008) 1321e1328.
Acknowledgments
We would like to thank Dr A. Leo and Biobyte Corp. 201 West 4th
Str., Suite 204, Claremont CA California, 91711, USA for free access to
the C-QSAR program.
[24] M. Ispicoudi, M. Amvrazis, C. Kontogiorgis, A.E. Koumbis, K.E. Litinas,
D.J. Hadjipavlou-Litina, K.C. Fylaktakidou, Convenient synthesis and biological
profile of 5-amino-substituted 1,2,4-oxadiazole derivatives, European Journal
of Medicinal Chemistry 45 (2010) 5635e5645.
[25] D.N. Nicolaides, K.C. Fylaktakidou, K.E. Litinas, D. Hadjipavlou-Litina, Synthesis
and biological evaluation of some 4-(isoxazolinyl or 1,2,4-oxadiazolyl) cou-
marins, Journal of Heterocyclic Chemistry 33 (1996) 967e971.
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D. Hadjipavlou-Litina, 1,3-Cycloaddition reactions of 2-oxo-2H-[1]benzo-
pyran-4-carbonitrile N-oxide. Synthesis of several new 4-Substituted cou-
marins, Journal of Heterocyclic Chemistry 35 (1998) 619e625.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.04.040.
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