Synthesis and evaluation of original amidoximes as antileishmanial agents

Article abstract of DOI:10.1016/j.bmc.2010.06.099

An original series of amidoxime derivatives was synthesized using manganese(III) acetate, Buchwald-Hartwig and Heck reactions. Two amidoximes (39 and 52) showed interesting in vitro activities toward Leishmania donovani promastigotes, exhibiting 8.3 and 8.8 μM IC₅₀ values. Moreover, the cytotoxicity of these compounds was evaluated on human THP1 cells, giving access to the corresponding selectivity index. Among the 25 tested compounds, amidoximes 38 and 39 and diamidoximes 50 and 52 exhibited a better selectivity index than pentamidine used as a drug compound reference.

Full text of DOI:10.1016/j.bmc.2010.06.099

Bioorganic & Medicinal Chemistry 18 (2010) 7310–7320
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Bioorganic & Medicinal Chemistry
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Synthesis and evaluation of original amidoximes as antileishmanial agents
Ahlem Bouhlel a, Christophe Curti a, Aurélien Dumètre b, Michèle Laget b, Maxime D. Crozet a,
Nadine Azas b, Patrice Vanelle a,
*
a Laboratoire de Pharmaco-Chimie Radicalaire (LPCR), Faculté de Pharmacie, Universités d’Aix-Marseille I, II, et III—CNRS, UMR 6264: Laboratoire Chimie Provence,
27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France
b UMR-MD3-Relation Hôte-Parasites, Pharmacologie et Thérapeutique, Faculté de Pharmacie, Université d’Aix-Marseille II, 27 Boulevard Jean Moulin, 13385 Marseille cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An original series of amidoxime derivatives was synthesized using manganese(III) acetate, Buchwald–
Received 16 March 2010
Revised 25 June 2010
Accepted 29 June 2010
Available online 11 July 2010
Hartwig and Heck reactions. Two amidoximes (39 and 52) showed interesting in vitro activities toward
Leishmania donovani promastigotes, exhibiting 8.3 and 8.8 lM IC50 values. Moreover, the cytotoxicity of
these compounds was evaluated on human THP1 cells, giving access to the corresponding selectivity
index. Among the 25 tested compounds, amidoximes 38 and 39 and diamidoximes 50 and 52 exhibited
a better selectivity index than pentamidine used as a drug compound reference.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Amidoximes
Antileishmanial
Dihydrofuran
1. Introduction
Plasmodium and Pneumocystis jirovecii, and its prodrug, pafurami-
dine (DB289, Fig. 1), possesses a good oral bioavaibility.11
Leishmaniasis is one of the most important parasitic diseases
worldwide. It is transmitted by the bite of a sand-fly contaminated
by a flagellate protozoan belonging to the genus Leishmania. Three
different forms of the disease are encountered: visceral (VL), cuta-
neous (CL) and muco-cutaneous leishmaniasis (MCL). The disease
is endemic in 88 countries, leading to 500,000 new cases and
50,000 death due to its visceral form caused by Leishmania dono-
vani, each year.1
In view of our general interest in the preparation of antiparasitic
compounds,12 we report herein the synthesis of mono- and diary-
lamidoxime derivatives, presenting a 2,3-dihydrofuran heterocy-
clic scaffold in place of the furan scaffold of pafuramidine. Using
three different strategies, manganese(III) acetate radicalar oxida-
tive cyclization, Buchwald–Hartwig and Heck coupling reactions,
we decided to vary the angles and distances between the amidox-
imes groups.
There are very few antileishmanial therapeutics, among which
pentavalent antimonials are used as first-line drugs. However, they
are not well tolerated and antimonial-resistant parasites have
emerged in several endemic areas.2 1,5-Bis(4-amidinophen-
oxy)pentane (pentamidine, Fig. 1) is a well known antiprotozoan
aromatic diamidine.3 It is commonly used as antileishmanial drug,
in case of antimonial failure.4,5 Used in other various infections such
trypanosomiasis4,6 and HIV related Pneumocystis jirovecii opportu-
nistic pneumonia,7 pentamidine is not a well tolerated drug.3,8
Furthermore, at physiological pH, amidine groups are salified,
decreasing membrane permeability and thus imposing a paren-
teral administration.9
2. Results and discussion
2.1. Chemistry
Several b-ketosulfones (1–5) were synthesized using a previ-
ously reported microwave irradiated method.13
Thus, an aqueous solution of sodium sulfite, sodium bicarbon-
ate and sulfonyl chlorides was irradiated at 500 W for 20 min in
a microwave oven, giving the corresponding sodium sulfinates.
O
O
Arylamidines similar to pentamidine are known to bind to the
minor groove of AT DNA sequences.10 Among the series of syn-
thetic arylamidines, furamidine (DB75, Fig. 1) has shown interest-
ing therapeutic activities against Leishmania, Trypanosoma,
H2N
NH2
NH
Pentamidine
NH
H
N
H
N
H3C
CH3
H2N
HN
O
Furamidine
NH2
NH
O
O
O
HN
NH
* Corresponding author. Tel.: +33 4 91 83 55 80; fax: +33 4 91 79 46 77.
Pafuramidine
E-mail addresses:
patrice.vanelle@univmed.fr,
patrice.vanelle@pharmacie.
univ-mrs.fr (P. Vanelle).
Figure 1.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.06.099

A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
7311
Table 3
An ethanolic solution of the corresponding acetophenone was then
Buchwald–Hartwig pallado-catalyzed coupling reactions
added and the reaction mixture was irradiated for 10 min to give
sulfones (1–5) (Scheme 1).
Compound
R1
R2
R3/R4
Yielda (%)
The b-ketosulfone derivatives thus obtained are presented in
Table 1. All these products (1–5) bear an active methylene group
next to the carbonyl one, and constitute promising candidates to
effect a manganese(III) acetate oxidative cyclization.14
Following a previously described procedure,15 manganese(III)
acetate was dissolved in glacial acetic acid at 80 °C under nitrogen
atmosphere. To this solution, b-ketosulfones 1–5 and correspond-
ing alkene were added and the mixture was irradiated (200 W)
for 60 min.
The desired 2,3-dihydrofuran derivatives (6–15), were obtained
(Scheme 2, Table 2) in moderate to good yields.
Next, in order to develop a pharmacomodulation study, we
investigated palladium-catalyzed coupling reactions of molecules
9, 10, 14, 15, bearing a bromine atom. Thus, we examined the
Buchwald–Hartwig cross-coupling reaction.
The method employed to carry out palladium-catalyzed C–N
bond forming reaction (Scheme 3), used 4 mol % of palladium ace-
tate, 4 mol % of BINAP, 1.2 equiv of arylamine and 1.4 equiv of
Cs2CO3.16
Using o-, m- and p-aminobenzonitrile, a series of 12 substituted
2,3-dihydrofuran derivatives (16–27) was obtained (Table 3).
Yields observed were better for Buchwald–Hartwig amination
made on the sulfone moiety (51–87%). This difference could be
attributed to the electron-attracting effect of sulfonyl group. In-
deed, in the oxidative addition step, Pd(0) acts as a nucleophile
and will preferentially attack the most electron-deficient
position.17
NC
NH
NH
16
17
18
19
–CN
NC
–Ph/–Ph
–Ph/–Ph
–CH3/–Bn
–CH3/–Bn
51
26
57
26
NH
NH
–CN
NC
–CN
NC
–CN
NH
20
21
22
23
24
25
26
27
–CN
–Ph–Ph
63
47
78
28
85
32
87
32
NC
NH
–CN
–Ph/–Ph
–CH3/–Bn
–CH3/–Bn
–Ph/–Ph
–Ph/–Ph
–CH3/–Bn
–CH3/–Bn
NC
NH
–CN
NC
NH
–CN
NC
NH
–CN
CN
NH
–CN
NH
CN
–CN
NH
CN
–CN
CN
a
Yield of isolated product based on the corresponding dihydrofurans.
R2
Table 4
Heck pallado-catalyzed coupling reactions
1) Na2SO3, NaHCO3,
water, 100 oC
Yielda (%)
O
Compound
R1
R2
R3/R4
S
O
500 W, 20 min.
O
S
O
Br
R1
Cl
R2
R1
NC
28
29
30
31
–CN
NC
–Ph/–Ph
–Ph/–Ph
–CH3/–Bn
–CH3/–Bn
56
30
47
15
O
2) water, 100 oC
500 W, 10 min.
O
–CN
NC
1-5
–CN
NC
Scheme 1.
–CN
a
Yield of isolated product based on the corresponding dihydrofurans
Table 1
Microwave-assisted synthesis of b-ketosulfones
R2
R1
O
Compound
R1
R2
Yielda (%)
R3
R4
Mn(OAc)3, Cu(OAc)2
1
2
3
4
5
–CN
–H
–CN
–CN
–Br
–H
61
68
64
68
72
O
O
S
S
R3 R4
AcOH, 80 o
200 W, 60 min.
C
O
–CN
–CN
–Br
–CN
O
R1
O
R2
6-15
1-5
a
Yield of isolated product based on the corresponding acetophenone.
Scheme 2.
NC
R3
O
R4
Table 2
O
S
Mn(OAc)3 assisted oxidative cyclizations
Pd(OAc)2 (4 mol%)
BINAP (4 mol%)
Cs2CO3 (1.4 eq.)
O
R1
R3
CN
O
Compound
R1
R2
R3
R4
Yielda (%)
R4
NH2
Br
O
S
Tol.,N2, 80 o
18 h.
C
6
7
8
–CN
–H
–H
–Ph
–Ph
–Ph
–Ph
–Ph
–Bn
–Bn
–Bn
–Bn
–Bn
–Ph
–Ph
–Ph
–Ph
65
56
57
54
30
53
60
52
47
10
9, 14
O
–CN
–CN
–Br
–CN
–H
–CN
–CN
–Br
–CN
1.2 eq.
–CN
–CN
–Br
–CN
–H
–CN
–CN
–Br
Br
R3
O
R2
9
R4
10
11
12
13
14
15
–Ph
O
S
–CH3
–CH3
–CH3
–CH3
–CH3
O
NC
10,15
16-27
a
Yield of isolated product based on the corresponding b-ketosulfone.
Scheme 3.

7312
A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
Another palladium mediated coupling reaction investigated
Among the tested compounds, b-ketosulfone derivatives 32–34
are amidoximes which do not present a 2,3-dihydrofuran scaffold.
These compounds do not display activity toward Leishmania, which
indicates that the amidoxime group is not sufficient for the mole-
cules to present antileishmanial activity.
was the Heck coupling (Scheme 4). The method which was tested
to carry out the Heck palladium-catalyzed C–C coupling reaction
used 5 mol % of palladium acetate, 20 mol % of triphenylphosphine,
1 equiv of vinylic compound and 2 equiv of triethylamine.18
As observed for Buchwald–Hartwig amination, and most prob-
ably for same reasons, the yields observed were better for the viny-
lation reaction on the sulfone moiety (Table 4).
HO
HO
N
N
H2N
H
N
R3
R3
R3
O
H2N
O
O
Finally, treatment of all the previously synthesized nitrile deriva-
tives ( 1–3, 6–8, 11–13, 16–31) with hydroxylamine hydrochloride
and potassiumtert-butoxidein DMSO19 allowed conversion of the cy-
ano group into amidoximes (32–56) in moderate to excellent yields
(45–98%, mean yield = 62%) as shown in Scheme 5 and Table 5.
R4
R4
R4
O
O
O
S
S
S
O
O
O
35, 38
50, 52
36, 39
H2N
H2N
N
N
HO
HO
Among all other 2,3-dihydrofuran derivatives tested, 14 exhibited
an antileishmanial activity which suggests that 2,3-dihydrofuran
scaffold can be a valuable linker for amidoxime-containing antileish-
manial compounds. Moreover, monoamidoxime compound 39
2.2. Biology
Synthesized amidoximes 32–56 were evaluated in vitro for
their activity against promastigotes Leishmania donovani (GFP-
transfected strain HOM/IN/01/2001) and for their cytotoxicity to-
ward human monocytes THP1 (ATCC, Manassas VA, USA). THP1
cells commonly serve as in vitro model for screening antileishma-
nial drugs, because they can be used as host cells for the develop-
ment of the intracellular stage amastigote of the parasites
Leishmania.20 The results of the evaluation are summarized in Ta-
ble 6.
Table 5
Synthesis of amidoximes from nitriles
Nitrile
substrate
Amidoxime
product
Yielda
(%)
Nitrile
substrate
Amidoxime
product
Yielda
(%)
1
2
3
6
7
32
33
34
35
36
37
38
39
40
41
42
43
44
87
83
71
94
93
98
97
95
93
72
72
80
89
20
21
22
23
24
25
26
27
28
29
30
31
45
46
47
48
49
50
51
52
53
54
55
56
83
52
83
89
61
52
57
45
73
70
77
51
2.2.1. Antiparasitic activity
HO
8
HO
N
N
11
12
13
16
17
18
19
H2N
H2N
O
O
O
S
S
S
O
O
O
HO N
H2N
HO N
H2N
O
O
O
a
Yield of isolated product based on the corresponding dihydrofurans.
33
32
34
Table 6
NC
R3
O
In vitro activity/cytotoxicity of compounds 32–56
R4
O
Compound
Leishmania donovani,
Cytotoxicity, THP1
Selectivity
M) index (SI)
S
O
promastigotes IC50
(l
M) monocytes IC50
(l
Pd(OAc)2 (5 mol%)
PPh3 (20 mol%)
NEt3 (2 eq.)
R1
R3
O
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
>125
>125
>125
20.6
17.6
74.3
30.3
8.3
99.5
39.1
>50
>50
30.1
>50
>50
>50
>50
39.1
13.3
48.3
8.8
>125
>125
>125
30.6
37.9
119.2
94.6
54.7
99.5
>50
nd
nd
nd
1.5
2.1
1.6
3.1
6.6
Br
R4
O
S
DMF, N2, 80 o
12 h.
C
9, 14
O
NC
1 eq.
Br
R3
O
R2
R4
O
S
O
1.0
NC
>1.3
<1.0
<1.0
0.3
28-31
10, 15
48.9
47.6
9.8
Scheme 4.
>50
nd
48.1
46.6
44.0
>50
47.8
48.4
48.1
>10
41.3
>50
23.4
31.2
0.008
<1.0
<1.0
<0.9
>1.3
3.6
1.0
5.5
>0.2
<0.9
nd
NH2OH, HCl (10 eq.)
tBuOK (10 eq.)
DMSO, N2
5 oC to R.T.
R2'
R2
R1'
R1
50
>50
>50
17.1
N OH
'
R1 , R2' = -H,
R1, R2 = -H,
CN
C
NH2
1.4
2.8
32-56
1-3, 6-8, 11-13, 16-31
Pentamidine 11.2
Doxorubicin
Scheme 5.

A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
7313
showed better antileishmanial activity than the one of pentamidine
(IC50 = 8.3 M, SI = 6.6). For this compound, a single amidoxime
IC50 (8.8 lM). In order to identify the biological target of mono-
amidoxime derivatives, mechanistic studies are in progress.
l
group appears to be sufficient for antileishmanial activity.
In diamidoximes series, compounds 50 and 52 exert a good
activity (13.3 and 8.8 lM, respectively). These compounds bear
4. Experimental
4.1. Chemistry
an amidoxime group in para-position on the sulfone moiety, and
on the other moiety a second amidoxime group in ortho-position.
This configuration including two amidoxime groups appears to
be the better combination for a good activity against Leishmania.
Moreover, structural differences between molecules 50 and 52
are on the R3/R4 moiety. The higher activity is obtained for 52,
which bears a methyl group as R3 and a benzyl group as R4. Struc-
tural modulations of these substituents may improve antileishma-
nial activities of diamidoximes compounds.
4.1.1. Instruments and analyses
Microwave assisted reactions were done in a multimode micro-
wave oven ETHOS Synth Lab Station (Ethos start, Milestone Inc.).
Melting points were determined with a B-540 Büchi melting point
apparatus. 1H NMR (200 MHz) and 13C NMR (50 MHz) spectra were
recorded on a Bruker ARX 200 spectrometer in CDCl3 at the Service
interuniversitaire de RMN de la Faculté de Pharmacie de Marseille.
1H and 13C NMR chemical shifts (d) are reported in parts per mil-
lion with respect to CDCl3 7.26 ppm (1H) and 77 ppm (13C). Ele-
mental analysis was carried out at the Spectropole de la Faculté
des Sciences et Techniques de Saint-Jérôme. The following adsor-
bent was used for flash column chromatography: Silica Gel 60
(Merck, particle size 0.063–0.200 nm, 70–230 mesh ASTM). TLC
was performed on 5 ꢀ 10 cm aluminium plates coated with Silica
Gel 60F254 (Merck) in appropriate solvent. Mass spectra were run
on an API-QqToF mass spectrometer.
2.2.2. Cytotoxicity
HO
N
H2N
HO
N
H2N
HN
O
O
CH3
CH3
O
O
S
S
O
O
4.1.2. b-Ketosulfones synthesis
56
44
H2N
H2N
To a solution of sulfonyl chloride (6.00 mmol) in water (15 mL),
sodium sulfite (1.26 g, 10 mmol) and sodium bicarbonate (0.84 g,
10 mmol) were added. The reaction mixture was heated under re-
flux in a microwave oven under irradiation (500 W, 100 °C) during
20 min. Then, an ethanolic solution of the corresponding acetophe-
none (2.05 mmol) was added. Heating of the reaction mixture was
continued for 10 min under the same conditions. After cooling, the
reaction mixture was neutralized with diluted hydrochloric acid.
The resulting solution was filtered and the precipitate thus formed
was crystallized from the appropriate solvent.
N
N
HO
HO
Except from molecules 44 (IC50 THP1 = 9.8
THP1 = 23.4
ing from low to moderate (30.6–119.2
Moreover, for the two most active compounds 39 and 52, cyto-
toxicity was moderate (39, IC50 THP1 = 54.7 M, and 52, IC50
M), which suggests that antileishmanial activity could
l
M) and 56 (IC50
l
M), cytotoxicity of mono- and diamidoximes was rang-
l
M).
l
THP1 = 48.1
be selective.
l
To sum up, comparison of antileishmanial activity and cytotox-
icity has allowed to determine a selectivity index (SI). This SI is bet-
ter than the one of pentamidine (2.8) in four of our molecules (38,
4.1.2.1. 4-[2-(Phenylsulfonyl)acetyl]benzonitrile (1). White so-
lid, mp 150–151 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 4.74
(s, 2H, CH2), 7.53–7.72 (m, 3H, 3CH), 7.79 (d, J = 8.3, 2H, 2CH),
7.85–7.89 (m, 2H, 2CH), 8.07 (d, J = 8.3, 2H, 2CH). 13C NMR (CDCl3),
d: 63.7 (CH2), 117.5 (2C), 128.5 (2CH), 129.4 (2CH), 129.7 (2CH),
132.6 (2CH), 134.6 (CH), 138.4 (C), 138.5 (C), 197.0 (C). Anal. Calcd
for C15H11NO3S (285.32): C, 63.14; H, 3.89; N, 4.91. Found: C,
63.32; H, 3.86; N, 4.80.
39, 50 and 52).
HO
N
H2N
H
N
O
O
CH3
CH3
O
O
S
S
O
O
52
39
H2N
H2N
N
4.1.2.2. 4-(2-Oxo-2-phenylethylsulfonyl)benzonitrile (2). White
solid, mp 148–149 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 4.79
(s, 2H, CH2), 7.47–7.55 (m, 2H, 2CH), 7.63–7.70 (m, 1H, CH),
7.83–7.94 (m, 4H, 4CH), 8.04 (d, J = 8.3, 2H, 2CH). 13C NMR (CDCl3),
d: 63.0 (CH2), 117.1 (C), 118.0 (C), 129.1 (2CH), 129.2 (2CH), 129.6
(2CH), 132.9 (2CH), 134.8 (CH), 135.4 (C), 142.6 (C), 187.7 (C). Anal.
Calcd for C15H11NO3S (285.32): C, 63.14; H, 3.89; N, 4.91. Found: C,
63.09; H, 3.88; N, 4.83.
N
HO
HO
Therefore, from our study, two different models of 2,3-dihydrofu-
rans bearing antileishmanial activity can be noted: 2,3-dihydrofu-
rans containing two amidoximes groups, for which spatial
configuration appears to present a great influence on the activity
and, surprisingly, 2,3-dihydrofurans substituted with only one ami-
doxime group.
4.1.2.3. 4-[2-(4-Cyanophenyl)-2-oxoethylsulfonyl]benzonitrile
(3). White solid, mp 174–176 °C (isopropyl alcohol) 1H NMR
(CDCl3), d: 4.78 (s, 2H, CH2), 7.84 (d, J = 8.6, 2H, 2CH), 7.89 (d,
J = 8.6, 2H, 2CH), 8.04 (d, J = 8.6, 2H, 2CH), 8.08 (d, J = 8.6, 2H, 2CH).
13C NMR (CDCl3), d: 63.2 (CH2), 116.9 (C), 117.4 (C), 118.0 (C),
118.4 (C), 129.5 (2CH), 129.7 (2CH), 132.8 (2CH), 133.1 (2CH),
138.2 (C), 142.2 (C), 186.7 (C). Anal. Calcd for C16H10N2O3S
(310.33): C, 61.93; H, 3.25; N, 9.03. Found: C, 61.70; H, 3.21; N, 8.83.
3. Conclusion
In conclusion, pallado-coupling and manganese(III) assisted
reactions have allowed the synthesis of a large series of original
molecules. Among 25 tested products, 12 exhibited antileishma-
nial activity and moderate cytotoxicity. In comparison with pent-
amidine, used as a reference, four molecules displayed a better
selectivity index.
Molecule 39, a monoamidoxime derivative, has the lowest IC50
4.1.2.4. 4-[2-(4-Bromophenylsulfonyl)acetyl]benzonitrile
against Leishmania donovani promastigote (8.3 vs 11.2
lM for pent-
(4). White solid, mp 163–164 °C (isopropyl alcohol) 1H NMR
amidine), and molecule 52, a diamidoxime derivative, also has a low

7314
A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
(CDCl3), d: 4.75 (s, 2H, CH2), 7.68–7.75 (m, 4H, 4CH), 7.80 (d,
J = 8.5, 2H, 2CH), 8.06 (d, J = 8.5, 2H, 2CH). 13C NMR (CDCl3),
d: 63.4 (CH2), 117.5 (C), 117.6 (C), 129.6 (2CH), 130.0 (2CH),
130.1 (C), 132.7 (4CH), 137.2 (C), 138.3 (C), 186.9 (C). Anal.
Calcd for C15H10BrNO3S (364.21): C, 49.47; H, 2.77; N, 3.85.
Found: C, 49.54; H, 2.74; N, 3.84.
4.1.3.4. 4-[3-(4-Bromophenylsulfonyl)-5,5-diphenyl-4,5-dihy-
drofuran-2-yl]benzonitrile (9). White solid, mp 183–184 °C (iso-
propyl alcohol) 1H NMR (CDCl3), d: 3.77 (s, 2H, CH2), 7.23–7.34 (m,
10H, 10CH), 7.50 (d, J = 9.0, 2H, 2CH), 7.56 (d, J = 9.0, 2H, 2CH), 7.74
(d, J = 8.5, 2H, 2CH), 7.89 (d, J = 8.5, 2H, 2CH). 13C NMR (CDCl3), d:
45.2 (CH2), 92.7 (C), 112.2 (C), 114.8 (C), 118.1 (C), 125.4 (4CH),
128.2 (2CH), 128.4 (2CH), 128.5 (C), 128.6 (4CH), 130.5 (2CH),
131.7 (2CH), 132.3 (C), 132.4 (2CH), 140.1 (C), 143.1 (2C), 160.2
(C). Anal. Calcd for C29H20BrNO3S (542.44): C, 64.21; H, 3.72; N,
2.58. Found: C, 64.25; H, 3.80; N, 2.50.
4.1.2.5. 4-[2-(4-Bromophenyl)-2-oxoethylsulfonyl]benzonitrile
(5). White solid, mp 229 °C (dichloromethane) 1H NMR (DMSO-
d6), d: 5.56 (s, 2H, CH2), 7.78 (d, J = 7.9, 2H, 2CH), 7.87 (d, J = 7.9,
2H, 2CH), 8.13 (m, 4H, 4CH). 13C NMR (DMSO-d6), d: 61.7 (CH2),
116.3 (C), 117.5 (C), 128.8 (C), 128.9 (2CH), 130.9 (2CH), 131.9
(2CH), 133.3 (2CH), 134.5 (C), 143.4 (C), 188.4 (C). Anal. Calcd for
4.1.3.5. 4-[2-(4-Bromophenyl)-5,5-diphenyl-4,5-dihydrofuran-
3-ylsulfonyl]benzonitrile (10). White solid, mp 200 °C (isopropyl
alcohol) 1H NMR (CDCl3), d: 3.78 (s, 2H, CH2), 7.26–7.34 (m, 10H,
10CH), 7.57–7.73 (m, 8H, 8CH). 13C NMR (CDCl3), d: 45.5 (CH2),
92.6 (C), 109.6 (C), 116.7 (C), 117.2 (C), 125.5 (4CH), 126.5 (C),
126.6 (C), 127.5 (2CH), 128.2 (2CH), 128.8 (4CH), 131.5 (2CH),
131.6 (2CH), 132.9 (2CH), 143.3 (2C), 145.7 (C), 163.0 (C). Anal.
Calcd for C29H20BrNO3S (542.44): C, 64.21; H, 3.72; N, 2.58. Found:
C, 64.15; H, 3.77; N, 2.54.
C15H10BrNO3S (364.21): C, 49.47; H, 2.77; N, 3.85. Found: C,
49.11; H, 2.75; N, 3.78.
4.1.3. General procedure for Mn(OAc)3-mediated reaction of b-
ketosulfones with alkenes
A solution of manganese(III) acetate dihydrate (6.87 mmol,
1.84 g) and copper(II) acetate (3.27 mmol, 0.59 g) in 30 mL of gla-
cial acetic acid was heated under microwave irradiation (200 W,
80 °C) for 15 min, until dissolution. Then, the reaction mixture
was cooled down to 50 °C, and a solution of 1–5 (3.27 mmol) and
1,1-diphenylethene (9.81 mmol) in 5 mL acetic acid was added.
The mixture was heated under microwave irradiation (200 W,
80 °C) for 45 min. The reaction mixture was poured into 200 mL
of cold water, and extracted with chloroform (3 ꢀ 40 mL). The or-
ganic extracts were collected and washed with saturated aqueous
NaHCO3 (3 ꢀ 40 mL) and dried (MgSO4). Solvent evaporation was
followed by column chromatography (gradient, from chloroform/
petroleum ether (1:1) to chloroform/petroleum ether/diethyl ether
(5:3:2)), and the product obtained was recrystallized from the
appropriate solvent.
4.1.3.6. 4-[5-Benzyl-5-methyl-3-(phenylsulfonyl)-4,5-dihydro-
furan-2-yl]benzonitrile (11). White solid, mp 143–144 °C (iso-
propyl alcohol) 1H NMR (CDCl3), d: 1.49 (s, 3H, CH3), 2.82–3.10
(m, 4H, 2CH2), 7.03–7.08 (m, 2H, 2CH), 7.17–7.23 (m, 3H, 3CH),
7.38–7.55 (m, 5H, 5CH), 7.63–7.68 (m, 4H, 4CH). 13C NMR (CDCl3),
d: 27.1 (CH3), 41.8 (CH2), 46.4 (CH2), 88.9 (C), 111.7 (C), 114.2 (C),
118.2 (C), 126.7 (2CH), 127.0 (CH), 128.3 (2CH), 129.0 (2CH), 130.1
(2CH), 130.2 (2CH), 131.4 (2CH), 132.9 (CH), 133.1 (C), 135.3 (C),
141.1 (C), 160.1 (C). Anal. Calcd for C25H21NO3S (415.50): C,
72.27; H, 5.09; N, 3.37. Found: C, 72.07; H, 5.27; N, 3.34.
4.1.3.7. 4-(5-Benzyl-5-methyl-2-phenyl-4,5-dihydrofuran-3-yl-
sulfonyl)benzonitrile (12). Yellow oil, 1H NMR (CDCl3), d: 1.53
(s, 3H, CH3), 2.80–3.11 (m, 4H, 2CH2), 7.13–7.27 (m, 5H, 5CH),
7.33–7.59 (m, 9H, 9CH). 13C NMR (CDCl3), d: 27.6 (CH3), 41.2
(CH2), 46.3 (CH2), 88.5 (C), 108.3 (C), 115.8 (C), 117.3 (C), 126.9
(CH), 127.0 (2CH), 127.8 (2CH), 128.1 (2CH), 128.2 (C), 129.1
(2CH), 130.3 (2CH), 131.0 (CH), 132.4 (2CH), 135.4 (C), 145.9 (C),
164.7 (C). HMRS (EI): m/z calcd for C25H21NO3S M+H+: 416.1315.
Found: 416.1314.
4.1.3.1. 4-[5,5-Diphenyl-3-(phenylsulfonyl)-4,5-dihydrofuran-2-
yl]benzonitrile (6). White solid, mp 208–209 °C (isopropyl alco-
hol) 1H NMR (CDCl3), d: 3.80 (s, 2H, CH2), 7.24–7.35 (m, 10H,
10CH), 7.40–7.61 (m, 3H, 3CH), 7.67–7.74 (m, 4H, 4CH), 7.88 (d,
J = 8.6, 2H, 2CH). 13C NMR (CDCl3), d: 45.4 (CH2), 92.5 (C), 112.7
(C), 114.6 (C), 118.2 (C), 125.5 (4CH), 127.0 (2CH), 128.2 (2CH),
128.6 (4CH), 129.2 (2CH), 130.5 (2CH), 131.6 (2CH), 132.6 (C),
133.3 (CH), 141.1 (C), 143.3 (2C), 159.7 (C). Anal. Calcd for
4.1.3.8. 4-[5-Benzyl-2-(4-cyanophenyl)-5-methyl-4,5-dihydro-
furan-3-ylsulfonyl]benzonitrile (13). Yellow solid, mp 139–
141 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 1.54 (s, 3H, CH3),
2.78–3.10 (m, 4H, 2CH2), 7.06–7.09 (m, 2H, 2CH), 7.16–7.23 (m,
3H, 3CH), 7.51 (d, J = 8.4, 2H, 2CH), 7.65–7.73 (m, 6H, 6CH). 13C
NMR (CDCl3), d: 27.7 (CH3), 41.2 (CH2), 46.4 (CH2), 89.5 (C), 110.2
(C), 114.7 (C), 116.5 (C), 117.1 (C), 117.9 (C), 127.1 (3CH), 128.3
(2CH), 130.0 (2CH), 130.3 (2CH), 131.6 (2CH), 132.6 (C), 132.8
(2CH), 135.1 (C), 145.3 (C), 162.1 (C). Anal. Calcd for C26H20N2O3S
(440.51): C, 70.89; H, 4.58; N, 6.36. Found: C, 70.95; H, 4.71; N,
6.31.
C29H21NO3S (463.55): C, 75.14; H, 4.57; N, 3.02. Found: C, 75.04;
H, 4.63; N, 3.00.
4.1.3.2. 4-(2,5,5-Triphenyl-4,5-dihydrofuran-3-ylsulfonyl)ben-
zonitrile (7). White solid, mp 153 °C (isopropyl alcohol) 1H
NMR (CDCl3), d: 3.83 (s, 2H, CH2), 7.26–7.35 (m, 10H, 10CH),
7.40–7.54 (m, 3H, 3CH), 7.59 (d, J = 8.6, 2H, 2CH), 7.67 (d, J = 8.6,
2H, 2CH), 7.73–7.78 (m, 2H, 2CH). 13C NMR (CDCl3), d: 45.3
(CH2), 92.3 (C), 109.2 (C), 116.3 (C), 117.3 (C), 125.4 (4CH), 127.3
(2CH), 127.8 (C), 128.1 (4CH), 128.6 (4CH), 129.7 (2CH), 131.7
(CH), 132.6 (2CH), 143.4 (2C), 145.8 (C), 164.4 (C). Anal. Calcd for
C
29H21NO3S (463.55): C, 75.14; H, 4.57; N, 3.02. Found: C, 74.67;
4.1.3.9. 4-[5-Benzyl-3-(4-bromophenylsulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl]benzonitrile (14). White solid, mp 181–
182 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 1.52 (s, 3H, CH3),
2.82 (d, J = 13.9, 1H, CH), 2.85 (d, J = 14.8, 1H, CH), 3.00 (d,
J = 14.8, 1H, CH), 3.02 (d, J = 13.9, 1H, CH), 7.03–7.08 (m, 2H,
2CH), 7.15–7.23 (m, 3H, 3CH), 7.32 (d, J = 8.6, 2H, 2CH), 7.54 (d,
J = 8.6, 2H, 2CH), 7.64–7.73 (m, 4H, 4CH). 13C NMR (CDCl3), d:
27.5 (CH3), 41.4 (CH2), 46.4 (CH2), 89.1 (C), 111.2 (C), 114.4 (C),
118.1 (C), 127.1 (CH), 128.0 (C), 128.2 (2CH), 128.3 (2CH), 130.1
(2CH), 130.2 (2CH), 131.5 (2CH), 132.3 (2CH), 132.9 (C), 135.2
(C), 140.2 (C), 160.7 (C). Anal. Calcd for C25H20BrNO3S (494.40):
C, 60.73; H, 4.08; N, 2.83. Found: C, 60.69; H, 4.16; N, 2.76.
H, 4.62; N, 2.96.
4.1.3.3. 4-[2-(4-Cyanophenyl)-5,5-diphenyl-4,5-dihydrofuran-3-
ylsulfonyl]benzonitrile (8). White solid, mp 197–198 °C (isopro-
pyl alcohol) 1H NMR (CDCl3), d: 3.78 (s, 2H, CH2), 7.26–7.39 (m,
10H, 10CH), 7.70–7.78 (m, 6H, 6CH), 7.90 (d, J = 8.4, 2H, 2CH). 13C
NMR (CDCl3), d: 45.1 (CH2), 93.1 (C), 111.2 (C), 115.1 (C), 116.8 (C),
117.0 (C), 117.9 (C), 125.3 (4CH), 127.4 (2CH), 128.3 (2CH), 128.7
(4CH), 130.5 (2CH), 131.7 (2CH), 132.0 (C), 132.9 (2CH), 142.8 (2C),
145.1 (C), 161.6 (C). Anal. Calcd for C30H20N2O3S (488.56): C,
73.75; H, 4.13; N, 5.73. Found: C, 73.45; H, 4.21; N, 5.52.

A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
7315
4.1.3.10. 4-[5-Benzyl-2-(4-bromophenyl)-5-methyl-4,5-dihydro-
furan-3-ylsulfonyl]benzonitrile (15). White solid, mp 98 °C (iso-
propyl alcohol) 1H NMR (CDCl3), d: 1.52 (s, 3H, CH3), 2.81 (d,
J = 14.0, 1H, CH), 2.87 (d, J = 14.6, 1H, CH), 3.03 (d, J = 14.6, 1H,
CH), 3.05 (d, J = 14.0, 1H, CH), 7.11–7.26 (m, 5H, 5CH), 7.41–7.65
(m, 8H, 8CH). 13C NMR (CDCl3), d: 27.6 (CH3), 41.3 (CH2), 46.4
(CH2), 88.8 (2C), 108.7 (C), 116.2 (C), 117.3 (C), 125.9 (C), 127.1
(3CH), 128.3 (2CH), 130.3 (2CH), 130.8 (2CH), 131.2 (2CH), 132.7
(2CH), 135.4 (C), 145.8 (C), 163.4 (C). Anal. Calcd for C25H20BrNO3S
(494.40): C, 60.73; H, 4.08; N, 2.83. Found: C, 60.86; H, 4.12; N,
2.99.
4.1.4.4. 2-{4-[5-Benzyl-3-(4-cyanophenylsulfonyl)-5-methyl-
4,5-dihydrofuran-2-yl]phenylamino}benzonitrile (19). solid,
mp 120 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 1.52 (s, 3H,
CH3), 2.84 (d, J = 14.0, 1H, CH), 2.88 (d, J = 14.5, 1H, CH), 3.04 (d,
J = 14.5, 1H, CH), 3.06 (d, J = 14.0, 1H, CH), 7.10–7.25 (m, 10H,
10CH), 7.50–7.65 (m, 7H, 7CH). 10 (NH) not observed in these con-
ditions.13C NMR (CDCl3), d: 27.6 (CH3), 41.6 (CH2), 46.2 (CH2), 88.3
(C), 105.3 (C), 111.0 (C), 115.6 (C), 116.8 (2CH), 117.7 (2CH), 118.3
(C), 119.2 (C), 124.0 (C), 127.1 (2CH), 128.3 (2CH), 129.7 (CH),
130.4 (2CH), 131.1 (2CH), 132.7 (2CH), 133.9 (2CH), 135.6 (C),
143.3 (C), 143.5 (C), 147.7 (C), 161.0 (C). HMRS (EI): m/z calcd for
C
32H25N3O3S M+H+: 532.1689. Found: 532.1697.
4.1.4. General procedure for Buchwald coupling reactions
A
solution of palladium acetate (0.024 mmol, 0.005 g,
4.1.4.5. 3-{4-[2-(4-Cyanophenyl)-5,5-diphenyl-4,5-dihydrofu-
ran-3-ylsulfonyl]phenylamino}benzonitrile (20). Yellow solid,
mp 209–210 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.81 (s,
2H, CH2), 6.98 (d, J = 8.8, 2H, 2CH), 7.37–7.44 (m, 14H, 14CH),
7.57 (d, J = 8.8, 2H, 2CH), 7.72 (d, J = 8.5, 2H, 2CH), 7.91 (d, J = 8.5,
2H, 2CH). 10 (NH) not observed in these conditions. 13C NMR
(CDCl3), d: 45.4 (CH2), 92.3 (C), 113.3 (C), 113.7 (C), 114.4 (C),
115.9 (2CH), 118.2 (C), 118.3 (C), 122.4 (CH), 124.0 (CH), 125.5
(4CH), 126.6 (CH), 128.1 (2CH), 128.6 (4CH), 129.2 (2CH), 130.4
(2CH), 130.6 (CH), 131.6 (2CH), 132.4 (C), 133.0 (C), 141.4 (C),
143.5 (2C), 146.7 (C), 158.8 (C). HMRS (EI): m/z calcd for
0.04 equiv) and BINAP (0.024 mmol, 0.005 g, 0.04 equiv) in 20 mL
of dry and degazed toluene was stirred under inert atmosphere.
Then, dihydrofuran derivative (0.59 mmol, 1 equiv), corresponding
aminobenzonitrile (0.71 mmol, 0.084 g, 1.2 equiv) and cesium car-
bonate (0.83 mmol, 0.16 g, 1.4 equiv) were added. The reaction
mixture was stirred at 80 °C from 18 h, and monitored by TLC. Sol-
vent evaporation gave a crude mixture, solubilized in dichloro-
methane and filtered in order to remove inorganic salts. The
mixture was purified by column chromatography (CH2Cl2), and
the product obtained was recrystallized from the appropriate
solvent.
C
36H25N3O3S M+NH4+: 597.1955. Found: 597.1953.
4.1.4.1.
4-{4-[2-(4-Cyanophenyl)-5,5-diphenyl-4,5-dihydrofu-
4.1.4.6. 3-{4-[3-(4-Cyanophenylsulfonyl)-5,5-diphenyl-4,5-dihy-
drofuran-2-yl]phenylamino}benzonitrile (21). Yellow solid, mp
112 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.77 (s, 2H, CH2),
6.24 (br s, 1H), 7.08 (d, J = 8.8, 2H, 2CH), 7.27–7.33 (m, 10H,
10CH), 7.37–7.41 (m, 4H, 4CH), 7.60 (d, J = 8.5, 2H, 2CH), 7.71 (d,
J = 8.5, 2H, 2CH), 7.85 (d, J = 8.8, 2H, 2CH). 13C NMR (CDCl3), d:
45.4 (CH2), 91.8 (C), 106.6 (C), 113.5 (C), 115.9 (2CH), 116.2 (C),
117.3 (C), 118.6 (C), 120.4 (C), 121.5 (CH), 123.0 (CH), 125.4
(4CH), 125.6 (CH), 127.2 (2CH), 128.1 (2CH), 128.5 (4CH), 130.4
(CH), 131.9 (2CH), 132.6 (2CH), 142.4 (C), 143.3 (2C), 145.2 (C),
146.0 (C), 163.8 (C). HMRS (EI): m/z calcd for C36H25N3O3S M+H+:
580.1689. Found: 580.1681.
ran-3-ylsulfonyl]phenylamino}benzonitrile (16). Yellow solid,
mp 222–223 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.82 (s,
2H, CH2), 6.61 (br s, 1H), 7.08 (d, J = 8.7, 2H, 2CH), 7.13 (d, J = 8.7,
2H, 2CH), 7.29–7.35 (m, 10H, 10CH), 7.57 (d, J = 8.7, 2H, 2CH),
7.59 (d, J = 8.7, 2H, 2CH), 7.71 (d, J = 8.6, 2H, 2CH), 7.89 (d, J = 8.6,
2H, 2CH). 13C NMR (CDCl3), d: 45.4 (CH2), 92.3 (C), 104.6 (C),
113.1 (C), 114.4 (C), 117.3 (2CH), 117.7 (2CH), 118.1 (C), 119.1
(C), 125.5 (4CH), 128.1 (2CH), 128.6 (4CH), 129.0 (2CH), 130.4
(2CH), 131.6 (2CH), 132.7 (C), 133.3 (C), 133.8 (2CH), 143.4 (2C),
145.0 (C), 145.6 (C), 159.0 (C). HMRS (EI): m/z calcd for
C
36H25N3O3S M+H+: 580.1689. Found: 580.1689.
4.1.4.2. 4-{2-[4-(4-Cyanophenylamino)phenyl]-5,5-diphenyl-
4,5-dihydrofuran-3-ylsulfonyl}benzonitrile (17). Yellow solid,
mp 127 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.77 (s, 2H,
CH2), 7.15 (d, J = 8.7, 2H, 2CH), 7.18 (d, J = 8.7, 2H, 2CH), 7.28–
7.33 (m, 10H, 10CH), 7.55 (d, J = 8.7, 2H, 2CH), 7.61 (d, J = 8.2, 2H,
2CH), 7.71 (d, J = 8.2, 2H, 2CH), 7.86 (d, J = 8.7, 2H, 2CH). 10 (NH)
not observed in these conditions. 13C NMR (CDCl3), d: 45.5 (CH2),
91.9 (C), 103.9 (C), 107.2 (C), 116.3 (C), 117.0 (2CH), 117.5 (2CH),
121.5 (CH), 124.9 (C), 125.5 (4CH), 127.3 (2CH), 128.1 (2CH),
128.6 (4CH), 131.8 (2CH), 132.6 (2CH), 133.9 (2CH), 143.3 (2C),
143.9 (C), 145.2 (C), 145.7 (C), 145.9 (C), 163.6 (C). HMRS (EI): m/
z calcd for C36H25N3O3S M+H+: 580.1689. Found: 580.1676.
4.1.4.7. 3-{4-[5-Benzyl-2-(4-cyanophenyl)-5-methyl-4,5-dihy-
drofuran-3-ylsulfonyl]phenylamino}benzonitrile (22). Yellow
oil, 1H NMR (CDCl3), d: 1.49 (s, 3H, CH3), 2.85 (d, J = 14.8, 1H,
CH), 2.90 (d, J = 13.8, 1H, CH), 3.01 (d, J = 13.8, 1H, CH), 3.08 (d,
J = 14.8, 1H, CH), 6.58 (br s, 1H), 6.96 (d, J = 8.8, 2H, 2CH), 7.08–
7.12 (m, 2H, 2CH), 7.21–7.24 (m, 3H, 3CH), 7.33–7.43 (m, 6H,
6CH), 7.64 (d, J = 8.5, 2H, 2CH), 7.72 (d, J = 8.5, 2H, 2CH). 13C NMR
(CDCl3), d: 27.0 (CH3), 41.9 (CH2), 46.4 (CH2), 88.8 (C), 112.2 (C),
113.4 (C), 113.9 (C), 115.7 (2CH), 118.2 (C), 118.4 (C), 122.2 (CH),
123.6 (CH), 126.1 (CH), 126.9 (CH), 128.2 (2CH), 128.8 (2CH),
130.1 (2CH), 130.3 (2CH), 130.5 (CH), 131.4 (2CH), 132.2 (C),
133.2 (C), 135.4 (C), 141.6 (C), 146.6 (C), 159.3 (C). HMRS (EI): m/
z calcd for C32H25N3O3S M+H+: 532.1689. Found: 532.1686.
4.1.4.3. 4-{4-[5-Benzyl-2-(4-cyanophenyl)-5-methyl-4,5-dihy-
drofuran-3-ylsulfonyl]phenylamino}benzonitrile (18). Yellow
oil, 1H NMR (CDCl3), d: 1.49 (s, 3H, CH3), 2.84 (d, J = 14.8, 1H,
CH), 2.88 (d, J = 13.9, 1H, CH), 3.00 (d, J = 13.9, 1H, CH), 3.06 (d,
J = 14.8, 1H, CH), 6.90 (br s, 1H), 7.06–7.14 (m, 5H, 5CH), 7.18–
7.23 (m, 4H, 4CH), 7.41 (d, J = 8.7, 2H, 2CH), 7.55 (d, J = 8.7, 2H,
2CH), 7.65 (d, J = 8.7, 2H, 2CH), 7.71 (d, J = 8.7, 2H, 2CH). 13C NMR
(CDCl3), d: 27.0 (CH3), 41.9 (CH2), 46.4 (CH2), 88.8 (C), 104.1 (C),
112.2 (C), 114.0 (C), 117.2 (2CH), 117.5 (2CH), 118.2 (C), 119.2
(C), 126.9 (CH), 128.2 (2CH), 128.7 (2CH), 130.1 (2CH), 130.3
(2CH), 131.4 (2CH), 132.2 (C), 133.7 (2CH+1C), 135.4 (C), 145.3
(C), 145.5 (C), 159.5 (C). HMRS (EI): m/z calcd for C32H25N3O3S
M+H+: 532.1689. Found: 532.1693.
4.1.4.8. 3-{4-[5-Benzyl-3-(4-cyanophenylsulfonyl)-5-methyl-
4,5-dihydrofuran-2-yl]phenylamino}benzonitrile (23). Yellow
solid, mp 102 °C 1H NMR (CDCl3), d: 1.51 (s, 3H, CH3), 2.83 (d,
J = 14.0, 1H, CH), 2.88 (d, J = 14.4, 1H, CH), 3.04 (d, J = 14.4, 1H,
CH), 3.06 (d, J = 14.0, 1H, CH), 5.30 (br s, 1H), 7.00–7.65 (m, 17H,
17CH). 13C NMR (CDCl3), d: 27.5 (CH3), 41.6 (CH2), 46.4 (CH2),
88.1 (C), 106.2 (C), 113.5 (C), 116.0 (C), 116.1 (2CH), 117.4 (C),
118.6 (C), 121.1 (C), 121.2 (CH), 122.8 (CH), 125.4 (CH), 127.0
(CH), 127.1 (2CH), 128.3 (2CH), 130.4 (3CH), 131.2 (2CH), 132.6
(2CH), 135.6 (C), 142.4 (C), 144.6 (C), 146.2 (C), 164.2 (C). HMRS
(EI): m/z calcd for C32H25N3O3S M+H+: 532.1689. Found: 532.1696.

7316
A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
4.1.4.9. 2-{4-[2-(4-Cyanophenyl)-5,5-diphenyl-4,5-dihydrofu-
ran-3-ylsulfonyl]phenylamino}benzonitrile (24). White solid,
mp 98–99 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.82 (s, 2H,
CH2), 6.62 (br s, 1H), 7.05–7.12 (m, 3H, 3CH), 7.26–7.35 (m, 10H,
10CH), 7.37 (d, J = 8.4, 1H, CH), 7.48–7.52 (m, 1H, CH), 7.56–7.63
(m, 3H, 3CH), 7.72 (d, J = 8.3, 2H, 2CH), 7.91 (d, J = 8.3, 2H, 2CH).
13C NMR (CDCl3), d: 45.4 (CH2), 92.3 (C), 102.6 (C), 113.2 (C),
114.4 (C), 116.8 (C), 117.5 (2CH), 118.0 (CH), 118.2 (C), 122.5
(CH), 125.5 (4CH), 128.1 (2CH), 128.6 (4CH), 129.0 (2CH), 130.4
(2CH), 131.6 (2CH), 132.7 (C), 133.5 (CH), 133.6 (C), 134.0 (CH),
143.4 (2C), 144.0 (C), 145.7 (C), 159.0 (C). HMRS (EI): m/z calcd
for C36H25N3O3S M+H+: 580.1689. Found: 580.1697.
leum ether (9:1)), and the product obtained was recrystallized
from the appropriate solvent.
4.1.5.1. 4-{4-[2-(4-Cyanophenyl)-5,5-diphenyl-4,5-dihydro-
furan-3-ylsulfonyl]styryl}benzonitrile (28). White solid, mp
123 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.82 (s, 2H, CH2),
7.19 (s, 2H, 2CH), 7.26–7.32 (m, 10H, 10CH), 7.55 (d, J = 8.4, 2H,
2CH), 7.61 (d, J = 8.8, 2H, 2CH), 7.66–7.70 (m, 4H, 4CH), 7.73 (d,
J = 8.8, 2H, 2CH), 7.90 (d, J = 8.4, 2H, 2CH). 13C NMR (CDCl3), d:
45.3 (CH2), 92.5 (C), 111.6 (C), 112.6 (C), 114.6 (C), 118.1 (C),
118.7 (C), 125.5 (4CH), 127.2 (3CH), 127.3 (2CH), 127.5 (2CH),
128.1 (2CH), 128.6 (4CH), 130.0 (CH), 130.4 (2CH), 131.6 (2CH),
132.5 (C), 132.6 (2CH), 140.3 (C), 140.6 (C), 141.2 (C), 143.2 (2C),
159.8 (C). HMRS (EI): m/z calcd for C38H26N2O3S M+H+: 591.1737.
Found: 591.1724.
4.1.4.10. 2-{4-[3-(4-Cyanophenylsulfonyl)-5,5-diphenyl-4,5-
dihydrofuran-2-yl]phenylamino}benzonitrile (25). Yellow so-
lid, mp 194 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 3.79 (s, 2H,
CH2), 6.51 (br s, 1H), 6.98–7.06 (m, 1H, CH), 7.19 (d, J = 8.6, 2H,
2CH), 7.28–7.37 (m, 10H, 10CH), 7.42–7.50 (m, 3H, 3CH), 7.61 (d,
J = 8.5, 2H, 2CH), 7.71 (d, J = 8.5, 2H, 2CH), 7.87 (d, J = 8.6, 2H,
2CH). 13C NMR (CDCl3), d: 45.6 (CH2), 92.0 (C), 101.5 (C), 107.5
(C), 116.4 (C), 117.0 (CH), 117.2 (C), 117.4 (C), 117.9 (2CH), 121.7
(CH), 121.8 (C), 125.6 (4CH), 127.4 (2CH), 128.2 (2CH), 128.7
(4CH), 131.9 (2CH), 132.8 (2CH), 133.6 (CH), 134.1 (CH), 143.5
(2C), 144.2 (C), 145.0 (C), 146.1 (C), 164.8 (C). HMRS (EI): m/z calcd
for C36H25N3O3S M+H+: 580.1689. Found: 580.1681.
4.1.5.2. 4-{4-[3-(4-Cyanophenylsulfonyl)-5,5-diphenyl-4,5-dihy-
drofuran-2-yl]styryl}benzonitrile (29). Yellow solid, mp 234 °C
(isopropyl alcohol) 1H NMR (CDCl3), d: 3.81 (s, 2H, CH2), 7.22 (s,
2H, 2CH), 7.28–7.35 (m, 10H, 10CH), 7.58–7.87 (m, 8H, 8CH),
7.71 (d, J = 8.4, 2H, 2CH), 7.85 (d, J = 8.8, 2H, 2CH). 13C NMR (CDCl3),
d: 45.6 (CH2), 92.3 (C), 109.2 (C), 111.3 (C), 116.4 (C), 117.3 (C),
118.9 (C), 125.5 (4CH), 126.4 (2CH), 127.2 (2CH), 127.4 (2CH),
127.6 (C), 128.2 (2CH), 128.6 (4CH), 129.1 (CH), 130.5 (2CH),
131.1 (CH), 132.6 (2CH), 132.7 (2CH), 139.7 (C), 141.2 (C), 143.3
(2C), 145.8 (C), 163.6 (C). HMRS (EI): m/z calcd for C38H26N2O3S
M+H+: 591.1737. Found: 591.1739.
4.1.4.11. 2-{4-[5-Benzyl-2-(4-cyanophenyl)-5-methyl-4,5-dihy-
drofuran-3-ylsulfonyl]phenylamino}benzonitrile (26). Yellow
oil, 1H NMR (CDCl3), d: 1.48 (s, 3H, CH3), 2.85 (d, J = 14.8, 1H,
CH), 2.87 (d, J = 13.8, 1H, CH), 3.00 (d, J = 13.8, 1H, CH), 3.07 (d,
J = 14.8, 1H, CH), 6.74 (br s, 1H), 7.04–7.11 (m, 5H, 5CH), 7.21–
7.26 (m, 3H, 3CH), 7.35–7.39 (m, 1H, CH), 7.42 (d, J = 8.8, 2H,
2CH), 7.48–7.52 (m, 1H, CH), 7.56–7.62 (m, 1H, CH), 7.65 (d,
J = 8.9, 2H, 2CH), 7.71 (d, J = 8.9, 2H, 2CH). 13C NMR (CDCl3), d:
27.0 (CH3), 41.9 (CH2), 46.4 (CH2), 88.7 (C), 102.6 (C), 112.3 (C),
114.0 (C), 116.8 (C), 117.3 (2CH), 118.0 (CH), 118.2 (C), 122.5
(CH), 126.9 (CH), 128.2 (2CH), 128.7 (2CH), 130.1 (2CH), 130.3
(2CH), 131.4 (2CH), 133.2 (C), 133.5 (CH), 133.7 (C), 134.0 (CH),
135.4 (C), 144.1 (C), 145.5 (C), 159.4 (C). HMRS (EI): m/z calcd for
4.1.5.3. 4-{4-[5-Benzyl-2-(4-cyanophenyl)-5-methyl-4,5-dihy-
drofuran-3-ylsulfonyl]styryl}benzonitrile (30). Brown oil, 1H
NMR (CDCl3), d: 1.50 (s, 3H, CH3), 2.84–3.12 (m, 4H, 2CH2), 7.05–
7.09 (m, 2H, 2CH), 7.17–7.22 (m, 5H, 5CH), 7.50 (d, J = 8.6, 2H,
2CH), 7.55 (d, J = 8.6, 2H, 2CH), 7.60–7.73 (m, 8H, 8CH). 13C NMR
(CDCl3), d: 27.1 (CH3), 41.7 (CH2), 46.4 (CH2), 89.0 (C), 111.6 (C),
111.7 (C), 114.2 (C), 118.1 (C), 118.7 (C), 127.0 (CH), 127.2 (4CH),
127.3 (2CH), 128.2 (2CH), 130.0 (2CH), 130.1 (CH), 130.2 (CH),
130.3 (2CH), 131.5 (2CH), 132.6 (2CH), 133.0 (C), 135.3 (C), 140.5
(C), 140.7 (C), 140.8 (C), 160.3 (C). HMRS (EI): m/z calcd for
C
34H26N2O3S M+H+: 543.1737. Found: 543.1730.
C
32H25N3O3S M+H+: 532.1689. Found: 532.1696.
4.1.5.4. 4-{5-Benzyl-2-[4-(4-cyanostyryl)phenyl]-5-methyl-4,5-
dihydrofuran-3-ylsulfonyl}benzonitrile (31). Yellow solid, mp
88 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 1.54 (s, 3H, CH3),
2.84 (d, J = 14.0, 1H, CH), 2.90 (d, J = 14.5, 1H, CH), 3.07 (d,
J = 14.5, 1H, CH), 3.09 (d, J = 14.0, 1H, CH), 7.14–7.26 (m, 9H,
9CH), 7.47–7.70 (m, 10H, 10CH). 13C NMR (CDCl3), d: 27.6 (CH3),
41.5 (CH2), 46.4 (CH2), 88.6 (C), 108.5 (C), 111.2 (C), 116.1 (C),
117.3 (C), 118.8 (C), 126.3 (2CH), 127.0 (2CH), 127.1 (2CH), 128.3
(2CH), 128.4 (CH), 128.8 (CH), 129.9 (2CH), 130.4 (2CH), 131.1
(CH), 132.5 (2CH), 132.6 (2CH), 135.5 (C), 136.4 (C), 139.0 (C),
141.2 (C), 146.0 (C), 164.0 (C). HMRS (EI): m/z calcd for
4.1.4.12. 4-{5-Benzyl-2-[4-(4-cyanophenylamino)phenyl]-5-
methyl-4,5-dihydrofuran-3-ylsulfonyl}benzonitrile (27). Yel-
low solid, mp 113 °C (isopropyl alcohol) 1H NMR (CDCl3), d: 1.52
(s, 3H, CH3), 2.84 (d, J = 13.9, 1H, CH), 2.89 (d, J = 14.5, 1H, CH),
3.00 (d, J = 14.5, 1H, CH), 3.06 (d, J = 13.9, 1H, CH), 6.45 (br s, 1H),
7.11–7.66 (m, 17H, 17CH. 13C NMR (CDCl3), d: 27.1 (CH3), 41.6
(CH2), 47.1 (CH2), 88.2 (C), 107.0 (C), 109.3 (C), 115.2 (C), 118.0
(2CH), 118.7 (2CH), 120.1 (C), 121.3 (C), 122.4 (C), 127.1 (2CH),
128.4 (2CH), 130.2 (2CH), 130.6 (2CH), 131.1 (CH), 132.3 (CH),
132.4 (CH), 133.2 (CH), 136.5 (C), 141.3 (C), 141.6 (C), 143.4 (C),
146.2 (C), 163.5 (C). HMRS (EI): m/z calcd for C32H25N3O3S M+H+:
532.1689. Found: 532.1686.
C
34H26N2O3S M+H+: 543.1737. Found: 543.1715.
4.1.6. General procedure for amidoximes synthesis from nitriles
suspension of hydroxylamine hydrochloride (1.7 mmol,
4.1.5. General procedure for Heck coupling reactions
A
A solution of dihydrofuran derivative (0.46 mmol, 1 equiv) and
4-vinylbenzonitrile (0.46 mmol, 0.059 g, 1 equiv) in 10 mL of dry
and degazed DMF was stirred under inert atmosphere. Then, palla-
dium acetate (0.023 mmol, 0.005 g, 0.05 equiv), triphenylphos-
phine (0.092 mmol, 0.024 g, 0.2 equiv) and triethylamine
(0.92 mmol, 0.11 g, 2 equiv) were added. The reaction mixture
was stirred at 80 °C from 12 h, and monitored by TLC. The reaction
mixture was poured into 100 mL of cold water, and extracted with
chloroform (3 ꢀ 40 mL). The organic extracts were collected and
washed with brine (3 ꢀ 40 mL) and dried (MgSO4). Solvent evapo-
ration was followed by column chromatography (CH2Cl2/petro-
0.12 g, 10 equiv) in 8 mL of DMSO was stirred under inert atmo-
sphere and cooled down to 5 °C. Then, potassium tertiobutylate
(1.7 mmol, 0.19 g, 10 equiv) was slowly added. The reaction mix-
ture was stirred at room temperature from 30 min, and the corre-
sponding nitrile (0.17 mmol, 1 equiv) was added. The reaction
mixture was stirred from 12 h and poured into 100 mL of cold
water. The precipitate thus formed was crystallized from the
appropriate solvent.
4.1.6.1. N0-Hydroxy-4-(2-oxo-2-phenylethylsulfonyl) benzimi-
damide (32). White solid, mp 192–194 °C (ethyl alcohol/diethyl

A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
7317
ether, (3:1)) 1H NMR (DMSO-d6), d: 5.31 (s, 2H, CH2), 5.95 (br s,
2H), 7.58–7.70 (m, 3H, 3CH), 7.79 (d, J = 8.4, 2H, 2CH), 7.86–7.94
(m, 4H, 4CH), 10.00 (br s, 1H). 13C NMR (DMSO-d6), d: 62.4 (CH2),
125.6 (2CH), 128.2 (2CH), 129.2 (2CH), 129.4 (2CH), 134.2 (CH),
135.9 (C), 138.6 (C), 139.7 (C), 150.1 (C), 188.7 (C). HMRS (EI): m/
z calcd for C15H14N2O4S M+H+: 319.0747. Found: 319.0740.
(CH), 127.4 (C), 128.2 (2CH), 129.0 (2CH), 129.5 (2CH), 130.5
(2CH), 133.2 (CH), 135.4 (C), 136.0 (C), 141.5 (C), 150.5 (C), 161.8
(C). HMRS (EI): m/z calcd for C25H24N2O4S M+H+: 449.1530. Found:
449.1528.
4.1.6.8. 4-(5-Benzyl-5-methyl-2-phenyl-4,5-dihydrofuran-3-yl-
sulfonyl)-N0-hydroxybenzimidamide (39). White solid, mp 76–
80 °C (ethyl alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.43 (s,
3H, CH3), 2.77–3.04 (m, 4H, 2CH2), 5.98 (br s, 2H), 7.14–7.19 (m,
5H, 5CH), 7.38–7.52 (m, 7H, 7CH), 7.79 (d, J = 8.4, 2H, 2CH), 9.99
(br s, 1H). 13C NMR (DMSO-d6), d: 26.9 (CH3), 41.4 (CH2), 45.5
(CH2), 88.5 (C), 109.2 (C), 126.2 (2CH), 126.3 (2CH), 126.8 (CH),
128.0 (2CH), 128.2 (2CH), 128.7 (C), 129.2 (2CH), 130.5 (2CH),
131.0 (C), 136.0 (C), 137.7 (C), 141.5 (C), 149.8 (C), 162.4 (C). HMRS
(EI): m/z calcd for C25H24N2O4S M+H+: 449.1530. Found: 449.1530.
4.1.6.2. N0-Hydroxy-4-[2-(phenylsulfonyl)acetyl]benzimidamide
(33). White solid, mp 148–150 °C (ethyl alcohol/diethyl ether,
(3:2)) 1H NMR (DMSO-d6), d: 5.42 (s, 2H, CH2), 5.99 (br s, 2H),
7.47–7.66 (m, 3H, 3CH), 7.88–7.97 (m, 6H, 6CH), 10.00 (br s, 1H).
13C NMR (DMSO-d6), d: 62.3 (CH2), 126.0 (2CH), 128.1 (2CH),
128.9 (2CH), 129.2 (2CH), 134.4 (CH), 135.9 (C), 138.6 (C), 139.6
(C), 149.8 (C), 189.3 (C). HMRS (EI): m/z calcd for C15H14N2O4S
M+H+: 319.0747. Found: 319.0740.
4.1.6.3. N0-Hydroxy-4-{2-[4-(N0-hydroxycarbamimidoyl)phenyl]
-2-oxoethylsulfonyl}benzimidamide (34). White solid, mp 211–
212 °C (ethyl alcohol/diethyl ether, (3:1)) 1H NMR (DMSO-d6), d:
5.39 (s, 2H, CH2), 6.02–6.04 (br s, 4H), 7.81 (d, J = 8.2, 2H, 2CH),
7.88–7.92 (m, 4H, 4CH), 7.97 (d, J = 8.2, 2H, 2CH), 10.01 (br s,
1H), 10.03 (br s, 1H). 13C NMR (DMSO-d6), d: 62.3 (CH2), 125.6
(2CH), 126.1 (2CH), 128.1 (2CH), 129.2 (2CH), 135.9 (C), 138.6
(2C), 139.6 (C), 149.9 (C), 150.2 (C), 188.7 (C). HMRS (EI): m/z calcd
for C16H16N4O5S M+H+: 377.0914. Found: 377.0908.
4.1.6.9. 4-{5-Benzyl-2-[4-(N0-hydroxycarbamimidoyl)phenyl]-5-
methyl-4,5-dihydrofuran-3-ylsulfonyl}-N0-hydroxybenzimid-
amide (40). White solid, mp 114–117 °C (ethyl alcohol/water,
(1:1)) 1H NMR (DMSO-d6), d: 1.43 (s, 3H, CH3), 2.73–3.03 (m, 4H,
2CH2), 6.23 (br s, 2H), 7.10 (br s, 2H), 7.13–7.20 (m, 5H, 5CH),
7.49–7.56 (m, 4H, 4CH), 7.72–7.84 (m, 4H, 4CH), 10.10 (br s, 1H),
10.28 (br s, 1H). 13C NMR (DMSO-d6), d: 26.8 (CH3), 41.4 (CH2),
45.5 (CH2), 88.8 (C), 109.7 (C), 125.7 (2CH), 126.3 (2CH), 126.5
(2CH), 126.8 (CH), 128.2 (2CH), 129.2 (2CH), 130.1 (C), 130.4
(2CH), 133.4 (C), 135.9 (C), 137.2 (C), 141.6 (C), 150.4 (C), 152.7
(C), 161.6 (C). HMRS (EI): m/z calcd for C26H26N4O5S M+H+:
507.1697. Found: 507.1718.
4.1.6.4. 4-[5,5-Diphenyl-3-(phenylsulfonyl)-4,5-dihydrofuran-2-
yl]-N0-hydroxybenzimidamide (35). White solid, mp 163–164 °C
(ethyl alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.82 (s, 2H,
CH2), 5.95 (br s, 2H), 7.28–7.49 (m, 10H, 10CH), 7.53–7.83 (m,
9H, 9CH), 9.89 (br s, 1H). 13C NMR (DMSO-d6), d: 45.2 (CH2), 91.7
(C), 110.6 (C), 125.2 (2CH), 125.3 (4CH), 126.6 (2CH), 128.0
(2CH), 128.2 (C), 128.8 (4CH), 129.4 (2CH), 129.6 (2CH), 133.6
(CH), 136.2 (C), 141.3 (C), 144.0 (2C), 150.3 (C), 161.1 (C). HMRS
(EI): m/z calcd for C29H24N2O4S M+H+: 496.1430. Found: 496.1545.
4.1.6.10. N0-Hydroxy-4-[4-{2-[4-(N0-hydroxycarbamimidoyl)-
phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-ylsulfonyl}phenyl-
amino]benzimidamide (41). White solid, mp 146–147 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.79 (s, 2H, CH2),
5.74 (br s, 2H), 5.94 (br s, 2H), 7.04–7.95 (m, 22H, 22CH), 9.00
(br s, 1H), 9.52 (br s, 1H), 9.88 (br s, 1H). 13C NMR (DMSO-d6), d:
45.3 (CH2), 91.3 (C), 112.1 (C), 114.8 (2CH), 118.8 (2CH), 125.2
(2CH), 125.3 (4CH), 126.7 (2CH), 127.4 (2CH), 128.0 (2CH), 128.8
(4CH), 129.5 (2CH), 136.0 (C), 136.6 (C), 141.8 (C), 144.2 (C),
144.3 (2C), 148.2 (C), 150.5 (C), 150.8 (C), 159.4 (C), 167.5 (C).
HMRS (EI): m/z calcd for C36H31N5O5S M+H+: 646.2119. Found:
646.2099.
4.1.6.5.
N0-Hydroxy-4-(2,5,5-triphenyl-4,5-dihydrofuran-3-yl-
sulfonyl)benzimidamide (36). White solid, mp 157–158 °C
(ethyl alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.83 (s, 2H,
CH2), 5.96 (br s, 2H), 7.28–7.47 (m, 10H, 10CH), 7.51–7.58 (m,
3H, 3CH), 7.66–7.83 (m, 6H, 6CH), 9.99 (br s, 1H). 13C NMR
(DMSO-d6), d: 45.0 (CH2), 91.7 (C), 110.4 (C), 125.3 (4CH), 126.3
(2CH), 126.5 (2CH), 128.0 (2CH), 128.3 (2CH), 128.7 (4CH), 129.5
(2CH), 131.6 (CH), 138.0 (C), 141.2 (C), 144.0 (2C), 149.7 (C),
161.7 (C), 10 (C) not observed in these conditions. HMRS (EI): m/z
calcd for C29H24N2O4S M+H+: 497.1530. Found: 497.1521.
4.1.6.11. N0-Hydroxy-4-[2-{4-[4-(N0-hydroxycarbamimidoyl)-
phenylamino]phenyl}-5,5-diphenyl-4,5-dihydrofuran-3-yl-
sulfonyl]benzimidamide (42). Yellow solid, mp 132 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.83 (s, 2H, CH2),
5.95 (br s, 4H), 7.23–7.85 (m, 22H, 22CH), 8.89 (br s, 1H), 9.34
(br s, 1H), 9.97 (br s, 1H). 13C NMR (DMSO-d6), d: 45.3 (CH2), 91.0
(C), 101.2 (C), 108.3 (C), 116.6 (2CH), 117.2 (2CH), 119.9 (C),
120.2 (C), 125.3 (4CH), 126.3 (2CH), 126.4 (2CH), 128.0 (2CH),
128.7 (4CH), 131.3 (2CH), 134.0 (2CH), 138.0 (C), 141.6 (C), 144.1
(2C), 144.4 (C), 146.8 (C), 149.8 (C), 161.3 (C). HMRS (EI): m/z calcd
for C36H31N5O5S M+H+: 646.2119. Found: 646.2098.
4.1.6.6. N0-Hydroxy-4-{2-[4-(N0-hydroxycarbamimidoyl)phenyl]-
5,5-diphenyl-4,5-dihydrofuran-3-ylsulfonyl}benzimidamide
(37). White solid, mp 155–156 °C (ethyl alcohol/water, (1:1)) 1H
NMR (DMSO-d6), d: 3.83 (s, 2H, CH2), 6.34 (br s, 2H), 7.06 (br s,
2H), 7.29–7.46 (m, 10H, 10CH), 7.74 (d, J = 8.5, 2H, 2CH), 7.80–
7.91 (m, 6H, 6CH), 10.19 (br s, 1H), 10.52 (br s, 1H). 13C NMR
(DMSO-d6), d: 45.0 (CH2), 92.1 (C), 111.1 (C), 125.2 (4CH), 126.4
(2CH), 126.6 (2CH), 126.8 (2CH), 128.1 (2CH), 128.8 (4CH), 129.7
(2CH), 129.8 (C), 130.4 (C), 130.5 (C), 137.2 (C), 141.4 (C), 143.9
(2C), 150.7 (C), 160.9 (C). HMRS (EI): m/z calcd for C30H26N4O5S
M+H+: 555.1697. Found: 555.1695.
4.1.6.12. 4-[4-{5-Benzyl-2-[4-(N0-hydroxycarbamimidoyl)phenyl]-
5-methyl-4,5-dihydrofuran-3-ylsulfonyl}phenylamino]-N0-
hydroxybenzimidamide (43). White solid, mp 75–76 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.41 (s, 3H, CH3),
2.79–3.04 (m, 4H, 2CH2), 5.74 (br s, 2H), 5.90 (br s, 2H), 7.05–
7.24 (m, 10H, 10CH), 7.36 (d, J = 8.4, 2H, 2CH), 7.48–7.66 (m, 3H,
3CH), 7.72 (d, J = 8.4, 2H, 2CH), 8.98 (br s, 1H), 9.51 (br s, 1H),
9.82 (br s, 1H). 13C NMR (DMSO-d6), d: 26.7 (CH3), 41.8 (CH2),
45.5 (CH2), 88.0 (C), 110.8 (C), 114.8 (2CH), 117.2 (2CH), 118.6
(2CH), 124.8 (2CH), 126.7 (2CH), 126.8 (CH), 128.3 (2CH), 129.1
(2CH), 129.3 (C), 130.3 (C), 130.5 (2CH), 132.7 (C), 135.4 (C),
4.1.6.7. 4-[5-Benzyl-5-methyl-3-(phenylsulfonyl)-4,5-dihydro-
furan-2-yl]-N0-hydroxybenzimidamide (38). White solid, mp
58–61 °C (ethyl alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.42
(s, 3H, CH3), 2.75–3.03 (m, 4H, 2CH2), 5.90 (br s, 2H), 7.11–7.23
(m, 5H, 5CH), 7.47–7.65 (m, 7H, 7CH), 7.71 (d, J = 8.4, 2H, 2CH),
9.83 (br s, 1H). 13C NMR (DMSO-d6), d: 26.8 (CH3), 41.6 (CH2),
45.4 (CH2), 88.5 (C), 109.4 (C), 124.9 (2CH), 126.3 (2CH), 126.9

7318
A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
136.2 (C), 141.9 (C), 146.3 (C), 147.9 (C), 150.4 (C), 160.1 (C). HMRS
119.5 (CH), 126.2 (4CH), 126.8 (CH), 128.2 (2CH), 129.2 (CH),
130.5 (2CH), 130.9 (2CH), 134.7 (C), 136.2 (C), 137.5 (C), 141.7
(C), 142.1 (C), 146.4 (C), 149.9 (C), 151.2 (C), 162.3 (C). HMRS
(EI): m/z calcd for C32H31N5O5S M+H+: 646.2119. Found: 646.2126.
(EI): m/z calcd for C32H31N5O5S M+H+: 598.2119. Found: 598.2125.
4.1.6.13. 4-[5-Benzyl-2-{4-[4-(N0-hydroxycarbamimidoyl)phe-
nylamino]phenyl}-5-methyl-4,5-dihydrofuran-3-ylsulfonyl]-N0-
hydroxybenzimidamide (44). Yellow solid, mp 126 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.40 (s, 3H, CH3),
2.71–3.09 (m, 4H, 2CH2), 5.71 (br s, 2H), 5.97 (br s, 2H), 7.20–
7.88 (m, 17H, 17CH), 8.76 (br s, 1H), 9.23 (br s, 1H), 9.97 (br s,
1H). 13C NMR (DMSO-d6), d: 26.7 (CH3), 41.8 (CH2), 45.4 (CH2),
87.7 (C), 100.9 (C), 107.5 (C), 116.3 (2CH), 117.2 (2CH), 119.9 (C),
121.2 (C), 126.1 (2CH), 126.2 (CH), 126.8 (2CH), 128.2 (2CH),
130.5 (2CH), 130.8 (2CH), 133.9 (2CH), 136.1 (C), 137.5 (C), 141.8
(C), 143.7 (C), 147.0 (C), 149.8 (C), 161.9 (C). HMRS (EI): m/z calcd
for C32H31N5O5S M+H+: 598.2119. Found: 598.2122.
4.1.6.18.
N0-Hydroxy-2-[4-{2-[4-(N0-hydroxycarbamimidoyl)-
phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-ylsulfonyl}phenyla-
mino]benzimidamide (49). White solid, mp 129–131 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.79 (s, 2H, CH2),
5.94 (br s, 2H), 6.01 (br s, 2H), 7.03 (d, J = 8.5, 2H, 2CH), 7.28–
7.95 (m, 20H, 20CH), 9.16 (br s, 1H), 9.87 (br s, 2H). 13C NMR
(DMSO-d6), d: 45.3 (CH2), 91.4 (C), 105.2 (C), 111.9 (C), 115.8
(2CH), 115.9 (2CH), 117.5 (C), 122.2 (C), 124.1 (CH), 126.2 (2CH),
125.3 (4CH), 127.4 (CH), 128.0 (2CH), 128.5 (CH), 128.8 (4CH),
129.5 (2CH), 131.3 (C), 134.4 (CH), 134.7 (C), 136.0 (C), 144.2
(2C), 148.1 (C), 150.5 (C), 159.7 (C). HMRS (EI): m/z calcd for
4.1.6.14. N0-Hydroxy-3-[4-{2-[4-(N0-hydroxycarbamimidoyl)-
phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-ylsulfonyl}phenyl-
amino]benzimidamide (45). White solid, mp 211–212 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.78 (s, 2H, CH2),
5.80 (br s, 2H), 5.94 (br s, 2H), 7.04 (d, J = 8.4, 2H, 2CH), 7.28–
7.55 (m, 16H, 16CH), 7.73–7.86 (m, 4H, 4CH), 8.94 (br s, 1H),
9.64 (br s, 1H), 9.88 (br s, 1H). 13C NMR (DMSO-d6), d: 45.4
(CH2), 91.2 (C), 112.0 (C), 114.4 (2CH), 117.0 (CH), 119.9 (CH),
120.5 (CH), 125.1 (2CH), 125.3 (4CH), 128.0 (2CH), 128.5 (C),
128.8 (4CH), 128.9 (2CH), 129.4 (2CH), 129.5 (C), 134.8 (C), 135.9
(C), 140.9 (C), 144.2 (2C), 148.7 (C), 150.4(C), 151.0 (C), 159.2 (C),
1 (CH) not observed in these conditions. HMRS (EI): m/z calcd for
C
36H31N5O5S M+H+: 646.2119. Found: 646.2119.
4.1.6.19.
N0-Hydroxy-2-[4-{3-[4-(N0-hydroxycarbamimidoyl)-
phenylsulfonyl]-5,5-diphenyl-4,5-dihydrofuran-2-yl}phenyla-
mino]benzimidamide (50). Yellow solid, mp 210 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.83 (s, 2H, CH2),
5.95–6.04 (br s, 4H), 7.13–7.78 (m, 22H, 22CH), 9.90–9.97 (br s,
3H). 13C NMR (DMSO-d6), d: 45.3 (CH2), 90.8 (C), 107.5 (C), 116.0
(2CH), 118.0 (CH), 118.8 (C), 120.8 (2CH), 125.3 (4CH), 126.2
(2CH), 126.3 (2CH), 127.9 (2CH), 128.7 (4CH), 129.4 (CH), 131.4
(2CH), 137.8 (C), 139.8 (C), 141.7 (C), 144.1 (2C), 145.9 (C), 149.8
(C), 152.2 (C), 161.5 (C). 10 (C) not observed in these conditions.
HMRS (EI): m/z calcd for C36H31N5O5S M+H+: 646.2119. Found:
646.2105.
C
36H31N5O5S M+H+: 646.2119. Found: 646.2104.
4.1.6.15. N0-Hydroxy-3-[4-{3-[4-(N0-hydroxycarbamimidoyl)-
phenylsulfonyl]-5,5-diphenyl-4,5-dihydrofuran-2-yl}phenylami-
no]benzimidamide (46). Yellow solid, mp 135 °C (ethyl alco-
hol/water, (1:1)) 1H NMR (DMSO-d6), d: 3.81 (s, 2H, CH2), 5.79
(br s, 2H), 5.93 (br s, 2H), 7.09–7.80 (m, 22H, 22CH), 8.81 (br s,
1H), 9.63 (br s, 1H), 9.96 (br s, 1H). 13C NMR (DMSO-d6), d: 45.3
(CH2), 90.6 (C), 106.8 (C), 114.3 (2CH), 115.5 (C), 115.8 (CH),
117.5 (CH), 119.0 (2CH), 119.7 (CH), 125.3 (4CH), 126.3 (2CH),
127.9 (2CH), 128.7 (4CH), 129.3 (CH), 131.4 (2CH), 134.7 (C),
137.7 (C), 141.5 (C), 141.8 (C), 144.2 (2C), 147.1 (C), 149.8 (C),
151.1 (C), 161.6 (C). HMRS (EI): m/z calcd for C36H31N5O5S
M+H+: 646.2119. Found: 646.2104.
4.1.6.20. 2-[4-{5-Benzyl-2-[4-(N0-hydroxycarbamimidoyl)-
phenyl]-5-methyl-4,5-dihydrofuran-3-ylsulfonyl}phenyl-
amino]-N0-hydroxybenzimidamide (51). White solid, mp
117–118 °C (ethyl alcohol/water, (1:1))1H NMR (DMSO-d6),
d: 1.41 (s, 3H, CH3), 2.72–2.94 (m, 4H, 2CH2), 5.90 (br s, 2H),
6.02 (br s, 2H), 7.01–7.28 (m, 9H, 9CH), 7.36 (d, J = 8.7, 2H,
2CH), 7.51 (d, J = 8.3, 2H, 2CH), 7.59–7.63 (m, 1H, CH), 7.72
(d, J = 8.3, 2H, 2CH), 7.78–7.82 (m, 1H, CH), 9.83 (br s, 2H),
9.92 (br s, 1H). 13C NMR (DMSO-d6), d: 26.8 (CH3), 41.8
(CH2), 45.5 (CH2), 88.1 (C), 110.8 (C), 116.0 (2CH), 118.8
(CH), 121.7 (CH), 124.9 (CH), 126.9 (CH), 128.2 (2CH), 128.6
(2CH), 128.9 (CH), 129.1 (2CH), 129.5 (CH), 130.5 (2CH),
131.3 (C), 134.4 (C), 134.7 (C), 135.4 (C), 136.1 (C), 139.3 (C),
147.3 (C), 150.5 (C), 152.1 (C), 160.3 (C). HMRS (EI): m/z calcd
for C32H31N5O5S M+H+: 598.2119. Found: 598.2126.
4.1.6.16. 3-[4-{5-Benzyl-2-[4-(N0-hydroxycarbamimidoyl)-
phenyl]-5-methyl-4,5-dihydrofuran-3-ylsulfonyl}phenylami-
no]-N0-hydroxybenzimidamide (47). White solid, mp 100–
101 °C (ethyl alcohol/water, (1:1)) 1H NMR (DMSO-d6), d:
1.41 (s, 3H, CH3), 2.72–3.01 (m, 4H, 2CH2), 5.81 (br s, 2H),
5.91 (br s, 2H), 7.03–7.38 (m, 12H, 12CH), 7.52–7.56 (m, 3H,
3CH), 7.73 (d, J = 8.4, 2H, 2CH), 8.93 (br s, 1H), 9.65 (br s,
1H), 9.83 (br s, 1H). 13C NMR (DMSO-d6), d: 26.7 (CH3), 41.8
(CH2), 45.5 (CH2), 87.9 (C), 110.8 (C), 114.4 (2CH), 116.7
(CH), 119.7 (CH), 120.3 (CH), 124.8 (2CH), 126.8 (CH), 128.2
(2CH), 128.6 (2CH), 129.1 (2CH), 129.3 (C), 129.4 (CH), 130.1
(C), 130.5 (2CH), 134.9 (C), 135.4 (C), 136.1 (C), 141.0 (C),
148.3 (C), 150.4 (C), 151.1 (C), 160.0 (C). HMRS (EI): m/z calcd
for C32H31N5O5S M+H+: 598.2119. Found: 598.2119.
4.1.6.21. 2-[4-{5-Benzyl-3-[4-(N0-hydroxycarbamimidoyl)phen-
ylsulfonyl]-5-methyl-4,5-dihydrofuran-2-yl}phenylamino]-N0-
hydroxybenzimidamide (52). Yellow solid, mp 105 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.40 (s, 3H, CH3),
2.71–3.09 (m, 4H, 2CH2), 5.97 (br s, 4H), 7.04–7.78 (m, 17H,
17CH), 8.89 (br s, 1H), 9.86 (br s, 1H), 9.97 (br s, 1H). 13C NMR
(DMSO-d6), d: 26.4 (CH3), 41.6 (CH2), 45.2 (CH2), 87.3 (C), 103.3
(C), 106.9 (C), 115.8 (2CH), 117.4 (C), 120.0 (C), 120.3 (CH), 122.4
(CH), 125.9 (2CH), 126.5 (CH), 127.9 (2CH), 130.2 (2CH), 130.5
(2CH), 130.7 (CH), 134.0 (CH), 134.3 (2CH), 135.9 (C), 137.3 (C),
141.7 (C), 145.0 (C), 145.3 (C), 149.6 (C), 161.8 (C). HMRS (EI): m/
z calcd for C32H31N5O5S M+H+: 646.2119. Found: 646.2127.
4.1.6.17. 3-[4-{5-Benzyl-3-[4-(N0-hydroxycarbamimidoyl)phen-
ylsulfonyl]-5-methyl-4,5-dihydrofuran-2-yl}phenylamino]-N0-
hydroxybenzimidamide (48). Yellow solid, mp 114 °C (ethyl
alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.38 (s, 3H, CH3),
2.73–3.02 (m, 4H, 2CH2), 5.82 (br s, 2H), 5.97 (br s, 2H), 6.95–
7.80 (m, 17H, 17CH), 8.70 (br s, 1H), 9.64 (br s, 1H), 9.97 (br s,
1H). 13C NMR (DMSO-d6), d: 26.6 (CH3), 45.4 (CH2), 41.9 (CH2),
87.3 (C), 106.0 (C), 114.2 (2CH), 115.6 (CH), 118.4 (CH), 118.8 (C),
4.1.6.22. N0-Hydroxy-4-[4-{2-[4-(N0-hydroxycarbamimidoyl)-
phenyl]-5,5-diphenyl-4,5-dihydrofuran-3-ylsulfonyl}styryl]-
benzimidamide (53). White solid, mp 129 °C (ethyl alcohol/
water, (1:1)) 1H NMR (DMSO-d6), d: 3.83 (s, 2H, CH2), 5.85 (br
s, 2H), 5.95 (br s, 2H), 7.31–7.42 (m, 12H, 12CH), 7.70–7.80 (m,
12H, 12CH), 9.71 (br s, 1H), 9.89 (br s, 1H). 13C NMR (DMSO-

A. Bouhlel et al. / Bioorg. Med. Chem. 18 (2010) 7310–7320
7319
d6), d: 45.2 (CH2), 91.7 (C), 110.8 (C), 125.2 (2CH), 125.3 (4CH),
125.9 (2CH), 126.9 (2CH), 127.1 (2CH), 127.3 (2CH), 128.0
(CH), 128.2 (2CH), 128.3 (CH), 128.7 (4CH), 129.4 (2CH), 131.7
(C), 133.3 (C), 136.2 (C), 137.0 (C), 139.5 (C), 142.1 (C), 144.0
(2C), 150.3 (C), 150.6 (C), 160.9 (C). HMRS (EI): m/z calcd for
Late log-phase THP1 cells were incubated in RPMI 1640 (without
phenolred) supplemented with10% FSC, 2% -glutamineand 1% pen-
L
icillin–streptomycin mix (complete RPMI medium) and a range of
compound concentrations incorporated in duplicate (final DMSO
concentration less than 0.5% v/v). Appropriate controls treated with
or without solvent (DMSO), and various concentrations of doxorubi-
cin (positive control) and pentamidine were added to each set of
experiments. After 72 h incubation at 37 °C and 6% CO2, cell growth
C
38H32N4O5S M+H+: 657.2166. Found: 657.2184.
4.1.6.23. N0-Hydroxy-4-[4-{3-[4-(N 0-hydroxycarbamimidoyl)-
phenylsulfonyl]-5,5-diphenyl-4,5-dihydrofuran-2-yl}styryl]benz-
imidamide (54). Yellow solid, mp 133 °C (ethyl alcohol/water,
(1:1)) 1H NMR (DMSO-d6), d: 3.85 (s, 2H, CH2), 5.85 (br s, 2H),
5.96 (br s, 2H), 7.29–7.54 (m, 12H, 12CH), 7.63–7.95 (m, 12H,
12CH), 9.71 (br s, 1H), 9.99 (br s, 1H). 13C NMR (DMSO-d6), d:
45.2 (CH2), 91.6 (C), 110.2 (C), 125.3 (4CH), 125.8 (2CH), 126.3
(2CH), 126.4 (2CH), 126.5 (2CH), 126.7 (2CH), 128.0 (2CH), 128.7
(4CH), 130.0 (2CH), 130.4 (CH), 130.7 (CH), 132.9 (C), 133.0 (C),
137.3 (C), 137.8 (C), 140.2 (C), 141.3 (C), 144.0 (2C), 149.8 (C),
150.6 (C), 161.3 (C). HMRS (EI): m/z calcd for C38H32N4O5S M+H+:
657.2166. Found: 657.2178.
was measured by flow cytometry after staining monocytes with 5
of propidium iodide. Antiproliferative activity was evaluated by
counting the number of live cells in a 100 L sample. Inhibitory con-
lL
l
centration 50% (IC50 THP1) was defined as the concentration of drug
required to induce a 50% in the THP1 cell proliferation compared to
the control. IC50 was calculated by non-linear regression analysis
processed on dose–response curves, using GraphPad Prism (version
4.03) software. IC50 values represent the mean value calculated from
three independent experiments.
4.2.3. Antileishmanial activity
The effects of the tested compounds on the growth of Leish-
mania donovani promastigotes (GFP-transfected strain HOM/IN/
01/2001, kindly provided by Dr. N. Singh, Lucknow, India) were as-
sessed by flow cytometry as described previously by Singh and
Dube.22 Briefly, promastigotes in late log-phase in M199 medium
4.1.6.24. 4-[4-{5-Benzyl-2-(4-[N0-hydroxycarbamimidoyl)-
phenyl]-5-methyl-4,5-dihydrofuran-3-ylsulfonyl}styryl]-N0-
hydroxybenzimidamide (55). White solid, mp 145–147 °C
(ethyl alcohol/water, (1:1)) 1H NMR (DMSO-d6), d: 1.41 (s,
3H, CH3), 2.75–3.02 (s, 4H, 2CH2), 5.83 (br s, 2H), 5.89 (br s,
2H), 7.10–7.21 (m, 5H, 5CH), 7.40–7.52 (m, 6H, 6CH), 7.66–
7.74 (m, 8H, 8CH), 9.69 (br s, 1H), 9.81 (br s, 1H). 13C NMR
(DMSO-d6), d: 26.8 (CH3), 42.8 (CH2), 45.4 (CH2), 88.4 (C),
109.6 (C), 124.8 (2CH), 125.8 (2CH), 126.8 (3CH), 126.9
(2CH), 127.2 (CH), 127.3 (2CH), 128.2 (2CH), 129.0 (C), 129.1
(2CH), 130.4 (2CH), 131.5 (CH), 133.2 (C), 135.6 (C), 136.0
(C), 137.1 (C), 139.9 (C), 141.8 (C), 150.3 (C), 150.6 (C), 161.6
(C). HMRS (EI): m/z calcd for C34H32N4O5S M+H+: 609.2166.
Found: 609.2173.
supplemented with 10% FCS and 500 lg/mL of G418 were incu-
bated at an average density of 105 parasites/mL in 24-well plates
with various concentrations of compounds dissolved in DMSO (fi-
nal concentration less than 0.5% v/v) incorporated in duplicate.
Appropriate controls treated by DMSO or pentamidine (reference
drug) were added to each set of experiments. After a 72-h incuba-
tion period at 27 °C, parasite growth was determined using a FAC-
Sort flow cytometer. Settings were: Forward Scatter (FSC-H), size:
Voltage E-1, gain 1, mode Lin; Side Scatter (SSC-H), granulosity:
Voltage 489, gain 1, mode Lin; Fluorescence 1 (FL1), green fluores-
cence: Voltage 505, gain 1, mode Log. Pentamidine and amphoter-
icin B were used as the reference drug. Inhibitory concentration
50% (IC50 Ld) was defined as the concentration of drug required
to induce a 50% in the Leishmania proliferation compared to the
control. IC50 was calculated by non-linear regression analysis pro-
cessed on dose–response curves, using GraphPad Prism (version
4.03) software. IC50 values represent the mean value calculated
from three independent experiments.
4.1.6.25. 4-[5-Benzyl-2-{4-[4-(N0-hydroxycarbamimidoyl)styryl]-
phenyl}-5-methyl-4,5-dihydrofuran-3-ylsulfonyl]-N0-hydrox-
ybenzimidamide (56). Yellow solid, mp 110 °C (ethyl alcohol/
water, (1:1)) 1H NMR (DMSO-d6), d: 1.44 (s, 3H, CH3), 2.73–3.05
(m, 4H, 2CH2), 5.84 (br s, 2H), 5.99 (br s, 2H), 7.14–7.84 (m, 19H,
19CH), 9.70 (br s, 1H), 9.99 (br s, 1H). 13C NMR (DMSO-d6), d:
26.8 (CH3), 41.6 (CH2), 45.5 (CH2), 88.3 (C), 109.0 (C), 109.3 (C),
125.8 (2CH), 126.0 (2CH), 126.5 (CH), 126.6 (2CH), 126.7 (2CH),
126.8 (CH), 127.6 (2CH), 128.2 (2CH), 129.7 (2CH), 130.5 (CH),
132.9 (2CH), 136.0 (C), 137.7 (C), 139.0 (C), 141.5 (C), 141.6 (C),
141.7 (C), 149.8 (C), 150.7 (C), 161.9 (C). HMRS (EI): m/z calcd for
Acknowledgments
This work is supported by the CNRS and the Universities of Aix-
Marseille. The authors thank V. Remusat for the NMR spectra
recording and V. Monnier for the mass spectra recording.
C
34H32N4O5S M+H+: 609.2166. Found: 609.2177.
4.2. Biology
Supplementary data
4.2.1. General
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2010.06.099.
Cell culture media (RPMI 1640 and M199), foetal calf serum
(FCS), L-glutamine, non essential amino acids and others medium
additives were from Eurobio (Paris, France). All other chemicals
were of highest chemical purity and were purchased from Sigma
except contrary mention. Stock solutions of amidoxime derivatives
were prepared in DMSO. Stock solutions of reference drugs (doxo-
rubicin and pentamidine) were prepared in DMSO. Flow cytometry
was performed at the Faculté de Pharmacie de Marseille, using a
FACSort flow cytometer apparatus (Becton Dickinson, Paris,
France), equipped with an argon laser (power of 15 mW, and wave-
length of 488 nm).
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