Original antileishmanial hits: Variations around amidoximes

Article abstract of DOI:10.1016/j.ejmech.2018.02.029

In continuation to our previous findings on amidoximes' antiparasitic activities, a new series of 23 original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal alkenes and β-ketosulfones using manganese(III) acetate reactivity. Twenty-three amidoximes were tested for their in vitro activity against Leishmania amazonensis promastigotes and their toxicity on murine macrophages. Seven of the tested compounds exhibited an antileishmanial activity at lower than 10 μM with moderate to low toxicity. Six of these molecules showed activity at lower than 10 μM against promastigotes and toxicity at higher than 50 μM were selected and evaluated for their activity against intracellular Leishmania amazonensis amastigotes. Modulating chemical substituents in position 2 of dihydrofuran highly influenced their antileishmanial activities. The introduction of a methyl or trifluoromethyl group on the benzene ring of the benzyl group had a positive influence on activity without significantly increasing toxicity (52, 59, 60).

Full text of DOI:10.1016/j.ejmech.2018.02.029

Accepted Manuscript
Original antileishmanial hits: Variations around amidoximes
Clémence Tabélé, Viviane dos S. Faiões, Fabien Grimaud, Eduardo Caio Torres-
Santos, Omar Khoumeri, Christophe Curti, Patrice Vanelle
PII:
S0223-5234(18)30159-4
10.1016/j.ejmech.2018.02.029
EJMECH 10206
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 23 January 2018
Revised Date: 8 February 2018
Accepted Date: 9 February 2018
Please cite this article as: Clé. Tabélé, V.d.S. Faiões, F. Grimaud, E.C. Torres-Santos, O. Khoumeri,
C. Curti, P. Vanelle, Original antileishmanial hits: Variations around amidoximes, European Journal of
Medicinal Chemistry (2018), doi: 10.1016/j.ejmech.2018.02.029.
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ACCEPTED MANUSCRIPT
Graphical abstract
Original antileishmanial hits: variations around amidoximes.
Clémence Tabélé, Viviane dos S. Faiões, Fabien Grimaud, Eduardo Caio Torres-Santos, Omar Khoumeri,
Christophe Curti, Patrice Vanelle.

ACCEPTED MANUSCRIPT
Original antileishmanial hits: variations around amidoximes.
Clémence Tabélé,a Viviane dos S. Faiões,b Fabien Grimaud,a Eduardo Caio Torres-Santos,b Omar
Khoumeri,a Christophe Curti,a,* Patrice Vanelle.a,*
a
Aix Marseille Université, CNRS, ICR UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire,
Faculté de Pharmacie, 27 Boulevard Jean Moulin – CS30064, 13385 Marseille cedex 05, France
b
Laboratório de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, FIOCRUZ, Rio de
Janeiro, Brazil
A B S T R A C T
In continuation to our previous findings on amidoximes’ antiparasitic activities, a new series of 23
original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes
were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal
alkenes and β-ketosulfones using manganese(III) acetate reactivity. Twenty-three amidoximes were
tested for their in vitro activity against Leishmania amazonensis promastigotes and their toxicity on
murine macrophages. Seven of the tested compounds exhibited an antileishmanial activity at lower
than 10 µM with moderate to low toxicity. Six of these molecules showed activity at lower than 10
µM against promastigotes and toxicity at higher than 50 µM were selected and evaluated for their
activity against intracellular Leishmania amazonensis amastigotes. Modulating chemical substituents
in position 2 of dihydrofuran highly influenced their antileishmanial activities. The introduction of a
methyl or trifluoromethyl group on the benzene ring of the benzyl group had a positive influence on
activity without significantly increasing toxicity (52, 59, 60).
Highlights:
•
•
•
•
•
Synthesis of amidoxime derivatives with valuable antileishmanial activities
Radical synthesis of monoamidoxime derivatives mediated by manganese(III) acetate
Cytotoxicity evaluated on murine macrophages
Activity tested on Leishmania amazonensis promastigotes (strain MHOM/BR/77/LTB0016)
Activity tested on Leishmania amazonensis amastigotes
Keywords:
Amidoximes
Dihydrofuran
Manganese(III) acetate
Pharmacomodulation
Cytotoxicity in vitro
Antiprotozoan activity in vitro
1

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1. Introduction
Despite the existence of several active therapeutics,1-2 leishmaniasis remains a neglected disease
and a major public health problem3 worldwide, with 98 countries reporting endemic leishmaniasis
transmission.4 Discovery of effective antileishmanial treatments is therefore a challenge in the fight
against this neglected parasitosis.
As part of our focus on the synthesis of molecules with potential antiinfectious properties,5-8 our
laboratory extensively studied the radical synthesis of amidoxime derivatives mediated by
manganese(III) acetate. Mn(OAc)3 is able to realize a radical oxidative cyclization on various
substrates, such as β-diketones,9 β-ketoesters,10 β-ketoamides11 or β-ketophosphonates.12
The reaction between β-ketosulfones and terminal alkenes allowed us to synthesize more than 50
mono- and diamidoximes, some of them showed valuable antiparasitic activities.13-15
2,3-Dihydrofuran derivatives substituted both with a phenylamidoxime in position 5 and a 4-
fluorophenylsulfonyl in position 4 displayed the best activities coupled with moderate to low toxicity.
Moreover, the substitution by a methylene in position 2 was shown to have an influence on the
antileishmanial activity.15 Accordingly, we decided to explore the influence of substituents in position
2 on antileishmanial activity. The retrosynthetic approach yielding such derivatives is depicted in
Figure 1.
HO
N
NC
O
H2N
R1
O
R1
NC
R2
R2
O
R1
O
O
S
S
S
O
O
O
R2
O
F
F
F
Figure 1: Retrosynthetic pathway to antileishmanial amidoximes
The antileishmanial activities of the monoamidoxime derivatives (45-67) were thereby
evaluated against Leishmania amazonensis promastigotes, as well as their cytotoxicity against
peritoneal murine macrophages. The most promising compounds were selected and evaluated
for their activities against Leishmania amazonensis amastigotes.
2. Results and discussion
2.1 Chemistry
Monoamidoxime derivatives (48-66) were obtained by a convergent synthesis as illustrated in Figure 2.
2

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Reagents and conditions: (i) NaHCO3, Na2SO3, H2O, MW, 100 °C, 200 W, 1 h. (ii) Cs2CO3 (2 equiv.), Pd(OAc)2
(0.5 mol%), Xantphos (2 mol%), MW, 120-140 °C, 200 W, 1.5-2 h, air (iii) Mn(OAc)3 (2.1 equiv.), Cu(OAc)2 (1
equiv.), AcOH, MW, 80 °C, 200 W, 80 min. (iv) tBuOK (10 equiv.), NH2OH.HCl (10 equiv.), 0 °C RT, DMSO,
18 h, Ar.
Figure 2: Synthetic pathway of monoamidoximes 48-66.
Previously reported methods were used to synthesize the starting material. Thus, β-ketosulfones
(1-2) were obtained through a nucleophilic substitution of the bromine atom of the corresponding
bromoacetophenone by a 4-fluorophenylsulfonyl group of an extemporaneously synthesized sodium 4-
fluorophenylsulfonate under microwave irradiation.16 Terminal alkenes (3-21), as they were not
commercially available, were obtained by a pallado-catalyzed reaction between a boronic acid and
methylallyl alcohol.17-18
β-Ketosulfones and terminal alkenes thus obtained were reacted under microwave irradiation
through an oxidative free-radical cyclization mediated by manganese(III) acetate, yielding the
dihydrofuran moiety. This reaction has been extensively studied by our team,19-20 and largely depends
on the degree of substitution of the alkene used. In the present study, all alkenes are disubstituted and
as expected, the desired 2,3-dihydrofuran derivatives (22-44) were obtained in moderate to good yields
(Figure 3, Table 1). 2,3-Dihydrofuran derivatives (22-24, 44) were directly obtained from commercial
alkenes.
3

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Figure 3: Nitrile derivatives.
Table 1: Mn(OAc)3 assisted oxidative cyclizations
Compound Nitrile
R1
-Bz
R2
-CH3
-C2H5
Yield (%)a
61
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
-C2H5
64
69
52
17
65
50
62
32
46
36
26
34
58
17
55
45
-C5H10-
-p-CN-Bz
-m-CN-Bz
-p-CF3-Bz
-m-CF3-Bz
-o-CF3-Bz
-3,5-CF3-Bz
-p-NO2-Bz
-m-NO2-Bz
-p-OCH3-Bz
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-3,4,5-OCH3-Bz
-p-CH3-Bz
-m-CH3-Bz
-o-CH3-Bz
-p-CH2OH-Bz
-m-CH2OH-Bz
(1,1'-biphenyl-4-yl)methyl
48
52
37
26
29
29
para (2-fluoro-1,1'-biphenyl-4-yl)methyl -CH3
para
para
meta
3-(4-(trifluoromethyl)phenyl)allyl -CH3
-o-Br-Bz
-CH3
-CH3
-Bz
a Yield of isolated product based on the corresponding β-ketosulfone.
Cyano derivatives synthesized by manganese(III) acetate-mediated reactions (22-44) reacted
with hydroxylamine hydrochloride and potassium tert-butoxide in DMSO,21 providing amidoximes
45-67 (Figure 4) in moderate to excellent yields (20-95%) as shown in Table 2.
Figure 4: Monoamidoxime derivatives.
4

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Table 2: Synthesis and structure of amidoxime derivatives
Compound amidoxime
R1
-Bz
R2
-CH3
-C2H5
Yield (%)a
85
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
meta
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
-C2H5
63
48
64
87
56
48
40
78
72
61
41
50
76
69
50
53
-C5H10-
-p-CNOHNH2-Bz
-m-CNOHNH2-Bz
-p-CF3-Bz
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-m-CF3-Bz
-o-CF3-Bz
-3,5-CF3-Bz
-p-NO2-Bz
-m-NO2-Bz
-p-OCH3-Bz
-3,4,5-OCH3-Bz
-p-CH3-Bz
-m-CH3-Bz
-o-CH3-Bz
-p-CH2OH-Bz
-m-CH2OH-Bz
(1,1'-biphenyl-4-yl)methyl
57
74
95
85
20
83
(2-fluoro-1,1'-biphenyl-4-yl)methyl -CH3
3-(4-(trifluoromethyl)phenyl)allyl -CH3
-o-Br-Bz
-CH3
-CH3
-Bz
a Yield of isolated product based on the corresponding nitrile derivative.
2.2 Biology
All amidoxime synthesized (45-67) were evaluated for both their antileishmanial activity against
Leishmania amazonensis promastigotes and their cytotoxicity against murine macrophages.
Amidoxime 45 was previously tested and showed good activity against Leishmania donovani
promastigotes.14 This molecule, which bears no substituent on its benzyl moiety, was used as a
reference to evaluate the effect of substitution, on the phenyl ring of the benzyl group by a variety of
substituents, on the antileishmanial activity. Inhibitory concentrations 50% (IC50) and cytotoxic
concentrations 50 (CC50) were determined, as well as their selectivity indexes (SI). For each assay,
three independent experiments in triplicate were performed. Results are summarized in Table 3.
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Table 3: Biological evaluation of amidoxime 45-67 against Leishmania amazonensis
promastigotes
Activity
L. amazonensis
promastigotes IC50
(µM)a
Cytotoxicity
murine
Selectivity
Indexb
Amido-
-xime
Compound
R1
R2
macrophages
CC50 (µM)a
102 ± 2.8
91.4 ± 0.8
92.9 ± 3.4
42.2 ± 1.4
50.2 ± 1.7
103.2 ± 13.6
49.8 ± 0.7
104.9 ± 3.9
43.1 ± 0.8
97.4 ± 1.2
86.6 ± 2.3
˃ 100c
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
5.4 ± 1.0
30.2 ± 2.3
49.5 ± 1.2
˃ 100c
18.9
3.0
1.9
NDe
NDe
12.6
7.4
21.9
8.0
5.8
7.5
˃ 4.2
2.0
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
para
meta
-Bz
-C2H5
-CH3
-C2H5
-C5H10-
-p-CNOHNH2-Bz
-m-CNOHNH2-Bz
-p-CF3-Bz
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
-CH3
˃ 100 c
8.2 ± 0.6
6.7 ± 0.2
4.8 ± 0.2
5.4 ± 0.9
16.7 ± 1.2
11.6 ± 1.3
24.0 ± 0.3
45.6 ± 2.2
23.2 ± 1.1
5.6 ± 0.9
2.1 ± 0.4
˃ 100c
-m-CF3-Bz
-o-CF3-Bz
-3,5-CF3-Bz
-p-NO2-Bz
-m-NO2-Bz
-p-OCH3-Bz
-3,4,5-OCH3-Bz
-p-CH3-Bz
-m-CH3-Bz
92.3 ± 2.4
54.4 ± 2.4
111.5 ± 7.3
77.6 ± 6.2
˃ 100c
2.3
19.9
37.0
NDe
NDe
2.3
2.0
2.6
12.0
˃ 2.7
1.5
-o-CH3-Bz
-p-CH2OH-Bz
-m-CH2OH-Bz
(1,1'-biphenyl-4-yl)methyl
(2-fluoro-1,1'-biphenyl-4-yl)methyl
3-(4-(trifluoromethyl)phenyl)allyl
-o-Br-Bz
˃ 100c
˃ 100c
14.8 ± 0.3
12.2 ± 1.1
17.2 ± 0.5
9.1 ± 1.4
74.7 ± 3.6
5.7 ± 0.12
33.9 ± 0.9
24.5 ± 0.6
43.9 ± 0.6
109.1 ± 1.6
˃ 200c
-Bz
Pentamidined
8.5 ± 1.25
a The values are means ± SD of three independent experiments.
b Selectivity Index was calculated according to the formula : SI = (Murine macrophages CC50) / (L. amazonensis IC50).
c Determination of the IC50 or CC50 value was limited by lack of solubility in the culture medium.
d Pentamidine was used as antileishmanial drug compound of reference.
e ND = not determinable.
Antileishmanial evaluation against promastigotes revealed that five amidoximes (45, 52, 53, 59, 60)
showed higher activity than that of the reference drug pentamidine. The good activity of amidoxime
45 against Leishmania amazonensis was also found against Leishmania donovani, suggests that
monoamidoximes’ antileishmanial activities are not limited to one Leishmania species alone.
Cytotoxicity of all tested derivatives against murine macrophages remained low in comparison with
that of pentamidine itself. The selectivity indexes of 21 of the tested amidoximes are higher than
pentamidine selectivity indexes. Moderate to low cytotoxicities were also previously described13-15
with other monoamidoxime derivatives against HepG2, J774A.1 and THP1 cells, making these
molecules strong candidates for further biological evaluations.
On the other hand, the influence of the substitution of the benzyl group was clearly demonstrated. A
dramatic decrease in the antileishmanial activity was observed upon replacement of the benzyl group
6

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by an aliphatic (46) or alicyclic (47) residue. It was noticed also that the introduction of a nitro (54,
55), a bromo (66) or one or more methoxyl groups (56, 57) in the benzene ring of the benzyl group
results in lowering the activity against Leishmania amazonensis promastigotes. Moreover, the
presence of a second amidoxime (48, 49) or of a hydroxymethyl substituent in the molecule (61, 62)
led to a decrease of its antileishmanial activity. Increasing the length of the substituent in position 2
with a biphenyl (63, 64) or an allyl (65) decreased antileishmanial activities and increased
cytotoxicities.
Derivatives in which the benzyl group bears a methyl (58-60) or a trifluoromethyl (50-53) substituent
showed the best antileishmanial activities. Ortho-substituted derivatives (52, 60) showed better
activities than pentamidine and reference monoamidoxime 45, clearly indicating the importance of
this position. Antileishmanial activities decreased with meta-substituted derivatives (51, 59) and even
further with para-substituted derivatives (50, 58).
The 6 molecules displaying an activity against Leishmania amazonensis promastigotes at lower than
10 µM and toxicity on murine macrophage at higher than 50 µM were selected as good candidates for
evaluation against intracellular Leishmania amazonensis amastigotes. These molecules are depicted in
Figure 5 and results are summarized in Table 4.
F3C
HO
HO
N
HO
N
N
H2N
CF3
H2N
H2N
O
O
O
O
CH3
O
CH3
O
CH3
S
S
S
O
O
O
F
F
F
45
50
52
CH3
HO
HO
HO
N
N
N
CH3
Br
H2N
H2N
H2N
O
O
O
O
CH3
O
CH3
O
CH3
S
S
S
O
O
O
F
F
F
59
60
66
Figure 5: Hit amidoximes
7

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Table 4: Biological evaluation of selected amidoxime derivatives against Leishmania
amazonensis amastigotes
Activity
Activity
L. amazonensis
promastigotes IC50
(µM)a
Cytotoxicity
murine
macrophages
CC50 (µM)a
L.
Selectivity
Indexb
Compound
amazonensis
amastigotes
IC50 (µM)a
7.9 ± 1.1
˃ 20
10.2 ± 1.1
6.7 ± 1.2
7.2 ± 1.2
9.3 ± 1.2
1.9 ± 0.12
5.4 ± 1.0
8.2 ± 0.6
4.8 ± 0.2
5.6 ± 0.9
2.1 ± 0.4
9.1 ± 1.4
5.7 ± 0.12
102 ± 2.8
103.2 ± 13.6
104.9 ± 3.9
111.5 ± 7.3
77.6 ± 6.2
12.9
NDd
10.3
16.6
10.8
11.7
4.5
45
50
52
59
60
66
109.1 ± 1.6
8.5 ± 1.25
Pentamidinec
a The values are means ± SD of three independent experiments.
b Selectivity Index was calculated according to the formula : SI = (Murine macrophages CC50) / (L. amazonensis amastigotes IC50).
c Pentamidine was used as antileishmanial drug compound of reference.
d ND = not determinable.
Antileishmanial activities for five of the six tested molecules were confirmed against Leishmania
amazonensis amastigotes. All Selectivity Indexes were higher than 10. Amidoxime 59 exhibited the
best activity (6.7 µM) and the lowest toxicity (111.5 µM). Moreover, it had a selectivity index as high
as 16.6, almost fourfold better than that of pentamidine itself. Therefore, we selected this molecule as
an excellent drug candidate for further biological evaluation.
3. Conclusion
Twenty-three amidoximes were synthesized and evaluated for their antileishmanial activities. Our
findings confirm the antiprotozoan potential of these derivatives, as previously described against
Leishmania donovani, Plasmodium falciparum, and as described here against Leishmania
amazonensis. Valuable activities were often coupled with moderate to low toxicities, and 5 hits were
identified for their activities against Leishmania amazonensis amastigotes. Several structural
constraints were found, rationalizing subsequent syntheses. While dihydrofurane monoamidoximes
can be considered as new original structures with antiprotozoan properties, the pharmacological
mechanism remains unknown. Accordingly, in vivo evaluation and a mechanistic study are currently
in progress on the five hit amidoximes described in the present study.
4. Experimental
4.1 Chemistry
4.1.1 General
TLC were performed on 5 cm × 10 cm aluminium plates coated with silica gel (layer 0.2 mm) 60F254
(Merck) in an appropriate solvent. The following adsorbent was used for flash column
chromatography: silica gel 60 (Merck, particle size 0.063-0.200 nm, 70-230 mesh ASTM). Melting
8

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points were determined through capillary tubes, with a B-540 Büchi melting point apparatus. 1H-NMR
and 13C-NMR spectra were recorded in CDCl3 or DMSO, with tetramethylsilane (Me4Si) as an internal
1
reference using a Bruker ARX 200 spectrometer operating at 250 MHz for H-NMR and 63 MHz for
13C-NMR; spectra were carried out at the NMR InterUniversity Unit of Pharmacy College, Aix-
1
Marseille University. The H chemical shifts are quoted in parts per million as δ downfield from
tetramethylsilane (δ 0.00) as an internal standard and the 13C chemical shifts were referenced to the
solvent peaks: CDCl3 (76.9 ppm) or DMSO-d6 (39.6 ppm). Coupling constants (J values) are given in
hertz. NMR multiplicities are abbreviated as follows: s (singlet), bs (broad singlet), d (doublet), t
(triplet), q (quartet) and m (a more complex multiplet or overlapping multiplets). Microwave-assisted
reactions were performed in a multimode microwave oven (ETHOS Synth Lab Station, Ethos start,
Milestone Inc., Rockford, IL, USA). Elemental analysis and mass spectra, run on an API-QqToF mass
spectrometer, were carried out at the Spectropole Unit of Saint Jerome Sciences College, Aix-
Marseille University. All commercial reagents were used without purification.
4.1.2 General procedure for preparation of β-Ketosulfones (1-2)
Sodium sulfite (1.26 g, 10 mmol) and sodium bicarbonate (0.84 g, 10 mmol) were added to a solution
of p-fluorobenzenesulfonyl chloride (1.17 g, 6.00 mmol) in water (15 mL). The reaction mixture was
heated under reflux in a microwave oven under irradiation (500 W, 100 °C) for 15 min. Then, an
ethanolic solution of 4-(2-bromoacetyl)benzonitrile or 3-(2-bromoacetyl)benzonitrile (6 mmol) was
added. Heating of the reaction mixture was continued for 45 min under the same conditions. After
cooling, the reaction mixture was filtered and the precipitate thus formed was crystallized from
isopropanol.
4.1.2.1. 4-(2-(4-fluorophenylsulfonyl)acetyl)benzonitrile (1)14 White powder, yield 82 %, m.p. 162
1
oC isopropyl alcohol). δ H NMR (200 MHz, CDCl3) δ: 4.74 (s, 2H, CH2), 7.21-7.30 (m, 2H, 2CH),
7.82 (d, J = 8.4 Hz, 2H, 2CH), 7.88-7.94 (m, 2H, 2CH), 8.08 (d, J = 8.4 Hz, 2H, 2CH). 13C NMR
(CDCl3), d: 63.7 (CH2), 116.8 (d, J = 22.7 Hz, 2CH), 117.5 (C), 117.7 (C), 129.7 (2CH), 131.6 (d, J =
9.9 Hz, 2CH), 132.7 (2CH), 134.2 (d, J = 3.3 Hz, C), 138.3 (C), 166.3 (d, J = 258.3 Hz, C), 187.0 (C).
4.1.2.2. 3-(2-((4-Fluorophenyl)sulfonyl)acetyl)benzonitrile (2) Yellow solid, yield 74%, m.p. 136
°C (isopropyl alcohol). δ 1H NMR (250 MHz, CDCl3) δ 8.20 (d, J = 8.9 Hz, 2H), 7.96 – 7.82 (m, 3H),
7.65 (t, J = 7.7 Hz, H), 7.24 (dd, J = 9.4, 7.6 Hz, 2H), 4.74 (s, 2H). 13C NMR (63 MHz, CDCl3) δ
186.5 (C), 166.4 (d, J = 258.7 Hz, C), 137.2 (CH), 136.4 (C), 134.4 (d, J = 3.2 Hz, C), 133.1 (d, J =
23.3 Hz, 2CH), 131.8 (CH), 131.6 (CH), 130.1 (CH), 117.5 (C), 116.9 (d, J = 22.8 Hz, 2CH), 113.8
(C), 63.6 (CH2). HRMS (ESI +) m/z calcd for C15H10FNO3S [M+NH4]+: 321.0704 Found: 321.0705.
4.1.3 General procedure for Mn(OAc)3-mediated reaction of β-Ketosulfones with alkenes
A solution of manganese(III) acetate dihydrate (6.87 mmol, 1.84 g, 2.1 equiv.) and copper(II) acetate
(3.27 mmol, 0.59 g, 1 equiv) in 15 mL of glacial acetic acid was heated at 80 °C under microwave
irradiation for 15 min. Then the reaction mixture was cooled and a solution of β-ketosulfone (3.27
mmol, 1 equiv.) and alkene (6.54 mmol, 2 equiv.) in acetic acid was added. The reaction mixture was
heated for 45 min under the same conditions, poured into 200 mL of cold water and extracted with
dichloromethane (3 × 40 mL). The organic extracts were collected and washed with saturated aqueous
NaHCO3 (3 × 40 mL) and dried (MgSO4). Solvent was evaporated under reduced pressure and crude
product was purified by column chromatography with an appropriate solvent; the product obtained
was recrystallized from the appropriate solvent.
9

ACCEPTED MANUSCRIPT
4.1.3.1.
4-(5,5-Diethyl-3-((4-fluorophenyl)sulfonyl)-4,5-dihydrofuran-2-yl)benzonitrile
(23)
1
Yellow oil, yield 64%. H NMR (250 MHz, CDCl3) δ 7.82 – 7.64 (m, 6H), 7.15 (d, J = 8.6 Hz, 2H),
2.82 (s, 2H), 1.68 (q, J = 7.4 Hz, 2H), 1.66 (q, J = 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 6H). 13C NMR (63
MHz, CDCl3) δ 165.3 (d, J = 255.8 Hz, C), 161.1 (C), 137.5 (d, J = 3.2 Hz, C), 133.2 (C), 131.6
(2CH), 130.3 (2CH), 129.7 (d, J = 9.4 Hz, 2CH), 118.2 (C), 116.4 (d, J = 22.6 Hz, 2CH), 114.4 (C),
111.4 (C), 92.3 (C), 39.7 (CH2), 31.7 (2CH2), 7.5 (2CH3). Anal. calcd for C21H20FNO3S (385.1148): C,
65.44; H, 5.23; N, 3.63; S, 8.32. Found: C, 65.32; H, 5.11; N, 3.26; S, 7.98.
4.1.3.2. 4-(3-((4-Fluorophenyl)sulfonyl)-1-oxaspiro[4.5]dec-2-en-2-yl)benzonitrile (24) Colorless
1
oil, yield 69%. H NMR (250 MHz, CDCl3) δ 7.74 (m, 6H), 7.15 (d, J = 8.3 Hz, 2H), 2.82 (s, 2H),
2.03 – 1.07 (m, 10H). 13C NMR (63 MHz, CDCl3) δ 165.3 (d, J = 255.8 Hz, C), 160.5 (C), 137.5 (d, J
= 3.1 Hz, C), 133.3 (C), 131.5 (2CH), 130.3 (2CH), 129.6 (d, J = 9.4 Hz, 2CH), 118.2 (C), 116.5 (d, J
= 22.6 Hz, 2CH), 114.3 (C), 111.3 (C), 89.3 (C), 42.9 (CH2), 36.7 (2CH2), 24.6 (CH2), 22.5 (2CH2).
Anal. calcd for C22H20FNO3S (397.1148): C, 66.48; H, 5.07; N, 3.52; S, 8.07. Found: C, 66.26; H,
4.78; N, 3.24; S, 7.86.
4.1.3.3.
4-(5-(4-Cyanobenzyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-
yl)benzonitrile (25) Colorless oil, yield 52%. 1H NMR (250 MHz, CDCl3) δ 7.71 (d, J = 8.6 Hz, 2H),
7.67 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H),
7.14 (d, J = 8.5 Hz, 2H), 3.04 (d, J = 13.9 Hz, H), 2.98 (d, J = 14.9 Hz, H), 2.96 (d, J = 13.9 Hz, H),
2.87 (d, J = 14.9 Hz, H), 1.46 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.4 (d, J = 256.6 Hz, C), 160.0
(C), 140.8 (C), 137.1 (d, J = 3.1 Hz, C), 132.5 (C), 131.9 (2CH), 131.6 (2CH), 131.0 (2CH), 130.0
(2CH), 129.6 (d, J = 9.5 Hz, 2CH), 118.4 (C), 118.0 (C), 116.4 (d, J = 22.6 Hz, 2CH), 114.6 (C),
111.9 (C), 111.2 (C), 88.2 (C), 46.4 (CH2), 42.2 (CH2), 27.0 (CH3). Anal. calcd for C26H19FN2O3S
(458.1100): C, 68.11; H, 4.18; N, 6.11; S, 6.99. Found: C, 68.10; H, 4.03; N, 6.22; S, 7.18.
4.1.3.4.
3-((5-(4-Cyanophenyl)-4-((4-fluorophenyl)sulfonyl)-2-methyl-2,3-dihydrofuran-2-
yl)methyl)benzonitrile (26) Colorless oil, yield 17%. 1H NMR (250 MHz, CDCl3) δ 7.72 (d, J = 8.5
Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.55 – 7.47 (m, H), 7.38 (s, H), 7.37 – 7.32
(m, 2H), 7.13 (d, J = 8.5 Hz, 2H), 3.02 (d, J = 14.1 Hz, H), 2.95 (d, J = 14.9 Hz, H), 2.93 (d, J = 14.1
Hz, H), 2.87 (d, J = 14.9 Hz, H), 1.47 (s, 3H).13C NMR (63 MHz, CDCl3) δ 165.3 (d, J = 256.4 Hz,
C), 160.1 (C), 137.1 (d, J = 3.2 Hz, C), 136.9 (C), 134.6 (CH), 133.6 (CH), 132.5 (C), 131.7 (2CH),
130.8 (CH), 130.0 (2CH), 129.6 (d, J = 9.5 Hz, 2CH), 129.1 (CH), 118.3 (C), 118.0 (C), 116.5 (d, J =
22.6 Hz, 2CH), 114.6 (C), 112.5 (C), 111.9 (C), 88.2 (C), 45.9 (CH2), 42.0 (CH2), 27.2 (CH3). Anal.
calcd for C26H19FN2O3S (458.1100): C, 68.11; H, 4.18; N, 6.11; S, 6.99. Found: C, 68.10; H, 4.03; N,
6.22; S, 7.18.
4.1.3.5.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(4-(trifluoromethyl)benzyl)-4,5-
dihydrofuran-2-yl)benzonitrile (27) Colorless oil, yield 40%. 1H NMR (250 MHz, CDCl3) δ 7.97 –
7.83 (m, 4H), 7.80 – 7.71 (m, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 8.7
Hz, 2H), 3.39 – 3.00 (m, 4H), 1.72 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.3 (d, J = 256.4 Hz, C),
160.2 (C), 139.5 (C), 137.0 (d, J = 3.2 Hz, C), 132.7 (C), 131.6 (2CH), 130.6 (2CH), 130.0 (2CH),
129.6 (d, J = 9.5 Hz, 2CH), 129.4 (q, J = 36.1 Hz, C), 125.1 (q, J = 3.7 Hz, 2CH), 123.9 (q, J = 229.8
Hz, C), 118.1 (C), 116.5 (d, J = 22.7 Hz, 2CH), 114.5 (C), 111.7 (C), 88.4 (C), 46.2 (CH2), 41.9 (CH2),
27.2 (CH3). HRMS (ESI +) m/z calcd for C26H19F4NO3S [M+H]+: 502.1095. Found: 502.1096.
4.1.3.6.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-(trifluoromethyl)benzyl)-4,5-
dihydrofuran-2-yl)benzonitrile (28) Yellow oil, yield 50%. 1H NMR (250 MHz, CDCl3) δ 7.68 (bs,
4H), 7.47 – 7.51 (m, 3H), 7.37 (s, H), 7.34 – 7.24 (m, 2H), 7.05 (d, J = 8.5 Hz, 2H), 3.08 (d, J = 14.1
10

ACCEPTED MANUSCRIPT
13
Hz, H), 2.94 (d, J = 14.9 Hz, H), 2.91 (d, J = 14.1 Hz, H), 2.89 (d, J = 14.9 Hz, H), 1.51 (s, 3H). C
NMR (63 MHz, CDCl3) δ 165.2 (d, J = 256.0 Hz, C), 160.2 (C), 137.1 (d, J = 3.2 Hz, C), 136.3 (C),
133.5 (CH), 132.6 (C), 131.5 (2CH), 130.5 (q, J = 32.2 Hz, C), 130.0 (2CH), 129.4 (d, J = 9.5 Hz,
2CH), 128.8 (CH), 127.0 (q, J = 3.7 Hz, CH), 123.9 (q, J = 3.7 Hz, CH), 123.9 (q, J = 272.4 Hz, C),
118.1 (C), 116.3 (d, J = 22.7 Hz, 2CH), 114.5 (C), 111.8 (C), 88.3 (C), 46.0 (CH2), 41.7 (CH2), 27.4
(CH3). Anal. calcd for C26H19F4NO3S (501.1022): C, 62.27; H, 3.82; N, 2.79; S, 6.39. Found: C, 62.36;
H, 3.61; N, 2.66; S, 6.17.
4.1.3.7.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(2-(trifluoromethyl)benzyl)-4,5-
dihydrofuran-2-yl)benzonitrile (29) Yellow oil, yield 62%. 1H NMR (250 MHz, CDCl3) δ 7.77 (d, J
= 8.7 Hz, 2H), 7.72 (d, J = 8.7, 2H), 7.60 – 7.54 (m, 3H), 7.40 - 7.38 (m, 2H), 7.13 – 7.06 (m, 3H),
3.28 – 3.15 (m, 2H), 2.90 (d, J = 15.0 Hz, H), 2.81 (d, J = 15.0 Hz, H),1.45 (s, 3H). 13C NMR (63
MHz, CDCl3) δ 165.2 (d, J = 256.0 Hz, C), 159.7 (C), 137.0 (d, J = 3.2 Hz, C), 134.4 (d, J = 1.8 Hz,
C), 132.8 (C), 132.2 (CH), 131.6 (2CH), 131.5 (CH), 130.1 (2CH), 129.6 (C), 129.5 (d, J = 9.2 Hz,
2CH), 127.2 (CH), 126.1 (q, J = 5.5 Hz, CH), 124.2 (q, J = 274.4 Hz, C), 118.1 (C), 116.3 (d, J = 23.0
Hz, 2CH), 114.5 (C), 112.0 (C), 89.0 (C), 42.3 (CH2), 41.5 (CH2), 27.2 (CH3). HRMS (ESI +) m/z
calcd for C26H19F4NO3S [M+H]+: 502.1095. Found: 502.1092.
4.1.3.8.
4-(5-(3,5-Bis(trifluoromethyl)benzyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl)benzonitrile (30) Colorless oil, yield 32%.1H NMR (250 MHz, CDCl3) δ 7.74 (s,
H), 7.71 (bs, 4H), 7.58 (s, 2H), 7.53 (d, J = 8.9 Hz, H), 7.52 (d, J = 8.8 Hz, H), 7.06 (d, J = 8.5 Hz,
2H), 3.15 (d, J = 14.2 Hz, H), 3.02 (d, J = 14.2 Hz, H), 2.94 (d, J = 15.0 Hz, H), 2.86 (d, J = 15.0 Hz,
H), 1.52 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.3 (d, J = 256.6 Hz, C), 159.9 (C), 138.0 (C), 136.9
(d, J = 3.2 Hz, C), 132.3 (C), 131.6 (2CH), 131.6 (q, J = 33.3 Hz, 2C), 130.3 (q, J = 2.6 Hz, 2CH),
130.0 (2CH), 129.4 (d, J = 9.5 Hz, 2CH), 123.0 (q, J = 272.8 Hz, 2C), 121.1 (q, J = 3.7 Hz, CH),
118.0 (C), 116.4 (d, J = 22.7 Hz, 2CH), 114.7 (C), 112.1 (C), 87.7 (C), 45.7 (CH2), 42.0 (CH2), 27.2
(CH3).
4.1.3.9.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(4-nitrobenzyl)-4,5-dihydrofuran-2-
yl)benzonitrile (31) Orange oil, yield 46%. 1H NMR (250 MHz, CDCl3) δ 8.05 (d, J = 8.7 Hz, 2H),
7.71 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.8 Hz, H), 7.57 (d, J = 8.8 Hz, H), 7.26
(d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 3.09 (d, J = 13.9 Hz, H), 3.02 (d, J = 13.9 Hz, H), 3.00
(d, J = 14.9 Hz, H), 2.90 (d, J = 14.9 Hz, H), 1.48 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.4 (d, J =
256.7 Hz, C), 160.0 (C), 147.1 (C), 143.0 (C), 137.0 (d, J = 3.2 Hz, C), 132.5 (C), 131.7 (2CH), 131.1
(2CH), 130.0 (2CH), 129.7 (d, J = 9.5 Hz, 2CH), 123.4 (2CH), 118.0 (C), 116.5 (d, J = 22.6 Hz, 2CH),
114.7 (C), 112.0 (C), 88.2 (C), 46.2 (CH2), 42.2 (CH2), 27.1 (CH3). Anal. calcd for C25H19FN2O5S
(478.0999): C, 62.75; H, 4.00; N, 5.85; S, 6.70. Found: C, 62.49; H, 3.78; N, 5.79; S, 6.52.
4.1.3.10.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-nitrobenzyl)-4,5-dihydrofuran-2-
yl)benzonitrile (32) Orange oil, yield 36%. 1H NMR (250 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, H),
7.98 (s, H), 7.69 (bs, 4H), 7.53 (d, J = 8.9 Hz, H), 7.51 (d, J = 8.9 Hz, H), 7.43 (d, J = 7.6 Hz, H), 7.37
(d, J = 7.7 Hz, H), 7.06 (d, J = 8.5 Hz, 2H), 3.11 (d, J = 14.1 Hz, H), 2.99 (d, J = 14.1 Hz, H), 2.92 (s,
2H), 1.51 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.3 (d, J = 256.3 Hz, C), 160.1 (C), 148.2 (C),
137.4 (C), 137.0 (d, J = 3.1 Hz, C), 136.4 (CH), 132.5 (C), 131.6 (2CH), 130.1 (2CH), 129.55 (d, J =
9.5 Hz, 2CH), 129.3 (CH), 124.9 (CH), 122.1 (CH), 118.0 (C), 116.4 (d, J = 22.6 Hz, 2CH), 114.5 (C),
111.5 (C), 88.2 (C), 45.8 (CH2), 41.9 (CH2), 27.2 (CH3). Anal. calcd for C25H19FN2O5S (478.0999): C,
62.75; H, 4.00; N, 5.85; S, 6.70. Found: C, 62.86; H, 3.78; N, 5.63; S, 6.26.
11

ACCEPTED MANUSCRIPT
4.1.3.11.
4-(3-((4-Fluorophenyl)sulfonyl)-5-(4-methoxybenzyl)-5-methyl-4,5-dihydrofuran-2-
yl)benzonitrile (33) Green oil, yield 26%. 1H NMR (250 MHz, CDCl3) δ 7.69 (m, 4H), 7.47 (d, J =
8.8 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H),
2.92 (d, J = 14.8 Hz, H), 2.97 (d, J = 14.1 Hz, H), 2.85 (d, J = 14.8 Hz, H), 2.76 (d, J = 14.1 Hz, H),
1.50 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.1 (d, J = 255.4 Hz, C), 160.4 (C), 158.7 (C), 137.3 (d,
J = 3.1 Hz, C), 133.0 (C), 131.5 (2CH), 131.2 (2CH), 130.8 (2CH), 129.4 (d, J = 9.5 Hz, 2CH), 127.3
(C), 118.1 (C), 116.2 (d, J = 22.7 Hz, 2CH), 114.4 (C), 113.6 (2CH), 111.5 (C), 89.2 (C), 55.1 (CH3),
45.5 (CH2), 41.4 (CH2), 27.4 (CH3). Anal. calcd for C26H22FNO4S (463.1254): C, 67.37; H, 4.78; N,
3.02. Found: C, 67.49; H, 4.57; N, 2.73.
4.1.3.12. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3,4,5-trimethoxybenzyl)-4,5-dihydrofuran-
2-yl)benzonitrile (34) Orange oil, yield 34%. 1H NMR (250 MHz, CDCl3) δ 7.72 – 7.64 (m, 4H), 7.50
(d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.29 (s, 2H), 3.83 (s, 3H), 3.65 (s, 6H), 3.03 (d, J = 14.8
Hz, H), 2.98 (d, J = 14.1 Hz, H), 2.84 (d, J = 14.8 Hz, H), 2.75 (d, J = 14.1 Hz, H), 1.52 (s, 3H).13C
NMR (63 MHz, CDCl3) δ 165.2 (d, J = 256.0 Hz, C), 160.1 (C), 152.9 (2C), 137.2 (C), 137.1 (d, J =
3.2 Hz, C), 132.9 (C), 131.5 (2CH), 130.5 (C), 130.0 (2CH), 129.3 (d, J = 9.5 Hz, 2CH), 118.0 (C),
116.4 (d, J = 22.7 Hz, 2CH), 114.4 (C), 111.6 (C), 107.3 (2CH), 88.9 (C), 60.8 (CH3), 55.9 (2CH3),
46.8 (CH2), 41.7 (CH2), 27.5 (CH3). Anal. calcd for C28H26FNO6S (523.1465): C, 64.23; H, 5.01; N,
2.68; S, 6.12. Found: C, 63.91; H, 4.70; N, 2.60; S, 5.87.
4.1.3.13.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(4-methylbenzyl)-4,5-dihydrofuran-2-
yl)benzonitrile (35) Colorless oil, yield 58%. 1H NMR (250 MHz, CDCl3) δ 8.07 (d, J = 7.6 Hz, 2H),
7.90 (d, J = 9.0 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.11 – 7.01 (m, 4H), 3.01
(d, J = 14.8 Hz, H), 2.98 (d, J = 14.0 Hz, H), 2.83 (d, J = 14.8 Hz, H), 2.79 (d, J = 14.0 Hz, H), 2.32 (s,
13
3H), 1.50 (s, 3H). C NMR (63 MHz, CDCl3) δ 165.2 (d, J = 255.4 Hz, C), 160.4 (C), 137.3 (d, J =
3.2 Hz, C), 136.6 (C), 133.0 (C), 132.2 (C), 131.5 (2CH), 130.1 (2CH), 130.1 (2CH), 129.5 (d, J = 9.4
Hz, 2CH), 128.9 (2CH), 118.1 (C), 116.2 (d, J = 22.6 Hz, 2CH), 114.3 (C), 111.5 (C), 89.1 (C), 46.0
(CH2), 41.5 (CH2), 27.4 (CH3), 21.0 (CH3). Anal. calcd for C26H22FNO3S (447.1304): C, 69.78; H,
4.96; N, 3.13; S, 7.17. Found: C, 69.99; H, 4.98; N, 3.02; S, 7.12.
4.1.3.14.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-methylbenzyl)-4,5-dihydrofuran-2-
yl)benzonitrile (36) Yellow oil, yield 17%. 1H NMR (250 MHz, CDCl3) δ 7.90 – 7.75 (m, 4H), 7.69
(d, J = 9.0 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.25 – 7.01 (m, 3H), 6.88 (s, H), 3.01 (d, J = 14.8 Hz, H),
2.98 (d, J = 14.0 Hz, H), 2.83 (d, J = 14.8 Hz, H), 2.79 (d, J = 14.0 Hz, H), 2.25 (s, 3H), 1.51 (s, 3H).
13C NMR (63 MHz, CDCl3) δ 165.2 (d, J = 255.4 Hz, C), 160.4 (C), 137.3 (d, J = 3.2 Hz, C), 136.8
(C), 133.7 (C), 132.2 (C), 131.5 (2CH), 130.1 (2CH), 129.7 (CH), 129.5 (d, J = 9.4 Hz, 2CH), 128.2
(CH), 126.8 (CH), 126.0 (CH), 118.1 (C), 116.2 (d, J = 22.6 Hz, 2CH), 114.3 (C), 111.8 (C), 89.1 (C),
46.0 (CH2), 41.5 (CH2), 22.1 (CH3), 21.4 (CH3). Anal. calcd for C26H22FNO3S (447.1304): C, 69.78;
H, 4.96; N, 3.13; S, 7.17. Found: C, 69.99; H, 4.98; N, 3.02; S, 7.12.
4.1.3.15.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(2-methylbenzyl)-4,5-dihydrofuran-2-
yl)benzonitrile (37) Yellow oil, yield 55%. 1H NMR (250 MHz, CDCl3) δ 7.72 – 7.59 (m, 4H), 7.55 –
7.37 (m, 2H), 7.12 – 6.97 (m, 6H), 3.25 – 2.58 (m, 4H), 2.19 (s, 3H), 1.50 (s, 3H). 13C NMR (63 MHz,
CDCl3) δ 165.2 (d, J = 255.4 Hz, C), 160.4 (C), 137.3 (d, J = 3.2 Hz, C), 137.0 (C), 133.9 (C), 133.1
(C), 131.5 (2CH), 131.0 (CH), 130.8 (CH), 130.1 (2CH), 129.5 (d, J = 9.4 Hz, 2CH), 127.2 (CH),
125.8 (CH), 118.1 (C), 116.2 (d, J = 22.6 Hz, 2CH), 114.3 (C), 111.5 (C), 89.1 (C), 46.0 (CH2), 41.8
(CH2), 22.7 (CH3), 19.4 (CH3). Anal. calcd for C26H22FNO3S (447.1304): C, 69.78; H, 4.96; N, 3.13;
S, 7.17. Found: C, 69.99; H, 4.98; N, 3.02; S, 7.12.
12

ACCEPTED MANUSCRIPT
4.1.3.16.
4-(3-((4-Fluorophenyl)sulfonyl)-5-(4-(hydroxymethyl)benzyl)-5-methyl-4,5-
dihydrofuran-2-yl)benzonitrile (38) Yellow oil, yield 45%. 1H NMR (250 MHz, CDCl3) δ 7.92 (d, J
= 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.15 (d, J =
7.9 Hz, 2H), 7.06 (d, J = 7.9 Hz, 2H), 5.19 (bs, H), 4.47 (s, 2H), 2.97 (d, J = 13.8 Hz, H), 2.96 (d, J =
14.9 Hz, H), 2.89 (d, J = 13.8 Hz, H), 2.81 (d, J = 14.9 Hz, H), 1.45 (s, 3H). 13C NMR (63 MHz,
CDCl3) δ 164.5 (d, J = 252.2 Hz, C), 160.1 (C), 140.8 (C), 137.0 (d, J = 2.9 Hz, C), 133.9 (C), 132.9
(C), 131.8 (2CH), 129.9 (2CH), 129.8 (2CH), 129.5 (d, J = 9.8 Hz, 2CH), 126.1 (2CH), 118.1 (C),
116.5 (d, J = 22.8 Hz, 2CH), 113.1 (C), 111.0 (C), 89.3 (C), 62.6 (CH2), 44.9 (CH2), 40.8 (CH2), 26.7
(CH3). Anal. calcd for C26H22FNO4S (463.1254): C, 67.37; H, 4.78; N, 3.02; S, 6.92. Found: C, 67.27;
H, 4.68; N, 2.92; S, 6.90.
4.1.3.17.
4-(3-((4-Fluorophenyl)sulfonyl)-5-(3-(hydroxymethyl)benzyl)-5-methyl-4,5-
dihydrofuran-2-yl)benzonitrile (39) Yellow oil, yield 48%. 1H NMR (250 MHz, CDCl3) δ 7.91 (d, J
= 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.56 – 7.47 (m, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 7.6
Hz, H), 7.15 – 7.10 (m, 2H), 6.98 (d, J = 7.1 Hz, H), 5.18 (bs, H), 4.42 (s, 2H), 2.99 (d, J = 13.8 Hz,
H), 2.95 (d, J = 14.9 Hz, H), 2.90 (d, J = 13.8 Hz, H), 2.81 (d, J = 14.9 Hz, H), 1.47 (s, 3H). 13C NMR
(63 MHz, CDCl3) δ 164.5 (d, J = 252.3 Hz, C), 160.2 (C), 142.1 (C), 137.1 (d, J = 2.9 Hz, C), 135.3
(C), 132.9 (C), 131.7 (2CH), 129.9 (2CH), 129.4 (d, J = 9.8 Hz, 2CH), 128.4 (CH), 128.3 (CH), 127.7
(CH), 124.8 (CH), 118.1 (C), 116.5 (d, J = 22.8 Hz, 2CH), 113.1 (C), 111.1 (C), 89.3 (C), 62.7 (CH2),
45.2 (CH2), 40.8 (CH2), 26.8 (CH3). Anal. calcd for C26H22FNO4S (463.1254): C, 67.37; H, 4.78; N,
3.02; S, 6.92. Found: C, 67.52; H, 4.67; N, 2.83; S, 6.92.
4.1.3.18.
4-(5-([1,1'-Biphenyl]-4-ylmethyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl)benzonitrile (40) Yellow oil, yield 52%. 1H NMR (250 MHz, CDCl3) δ 7.69 (m,
4H), 7.56 (d, J = 7.5 Hz, 2H), 7.53 – 7.31 (m, 7H), 7.14 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H),
3.06 (d, J = 14.8 Hz, H), 3.05 (d, J = 13.9 Hz, H), 2.89 (d, J = 14.8 Hz, H), 2.88 (d, J = 13.9 Hz, H),
1.53 (s, 3H).13C NMR (63 MHz, CDCl3) δ 165.1 (d, J = 255.7 Hz, C), 160.3 (C), 140.2 (C), 139.8 (C),
137.2 (d, J = 3.2 Hz, C), 134.4 (C), 133.0 (C), 131.5 (2CH), 130.7 (2CH), 130.1 (2CH), 129.5 (d, J =
9.5 Hz, 2CH), 128.9 (2CH), 127.5 (CH), 126.8 (2CH), 126.8 (2CH), 118.1 (C), 116.2 (d, J = 22.6 Hz,
2CH), 114.3 (C), 111.7 (C), 89.0 (C), 46.1 (CH2), 41.7 (CH2), 30.9 (CH3). Anal. calcd for
C31H24FNO3S (509.1461): C, 73.06; H, 4.75; N, 2.75. Found: C, 72.99; H, 4.46; N, 2.55.
4.1.3.19. 4-(5-((2-Fluoro-[1,1'-biphenyl]-4-yl)methyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl)benzonitrile (41) Yellow oil, yield 37%. 1H NMR (250 MHz, CDCl3) δ 7.71 (s,
4H), 7.65 – 7.22 (m, 8H), 7.13 – 6.75 (m, 4H), 3.05 (d, J = 14.9 Hz, H), 3.04 (d, J = 14.0 Hz, H), 2.90
(d, J = 14.9 Hz, H), 2.89 (d, J = 14.0 Hz, H), 1.53 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 165.3 (d, J =
255.9 Hz, C), 161.8 (C), 160.3 (C), 137.22 (d, J = 3.3 Hz, C), 136.8 (C), 136.6 (C), 135.1 (C), 132.8
(C), 131.6 (C), 131.6 (2CH), 130.4 (d, J = 4.0 Hz, CH), 130.1 (2CH), 129.5 (d, J = 9.5 Hz, 2CH),
128.8 (2CH), 128.6 (2CH), 127.9 (CH), 126.3 (d, J = 3.4 Hz, CH), 117.9 (d, J = 22.9 Hz, CH), 116.4
(d, J = 22.6 Hz, 2CH), 114.5 (C), 111.9 (C), 88.7 (C), 45.8 (CH2), 41.9 (CH2), 27.2 (CH3). Anal. calcd
for C31H23F2NO3S (527.1367): C, 70.57; H, 4.39; N, 2.65; S, 6.08. Found: C, 70.42; H, 4.65; N, 2.44;
S, 6.12.
4.1.3.20. (E)-4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-(4-(trifluoromethyl)phenyl)allyl)-4,5-
dihydrofuran-2-yl)benzonitrile (42) Yellow oil, yield 26%. 1H NMR (250 MHz, CDCl3) δ 7.76 (d, J
= 8.2 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.73 – 7.63 (m, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.1
Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 6.42 (d, J = 15.8 Hz, H), 6.19 – 6.05 (m, H), 3.01 (d, J = 14.8 Hz,
H), 2.90 (d, J = 14.8 Hz, H), 2.62 (dd, J = 14.3, 7.3 Hz, H), 2.53 (dd, J = 14.3, 7.3 Hz, H), 1.50 (s,
3H). 13C NMR (63 MHz, CDCl3) δ 165.2 (d, J = 256.1 Hz, C), 160.4 (C), 140.0 (C), 137.31 (d, J = 3.2
13

ACCEPTED MANUSCRIPT
Hz, C), 133.4 (CH), 132.8 (C), 131.6 (2CH), 130.1 (2CH), 129.6 (d, J = 9.4 Hz, 2CH), 129.5 (q, J =
32.5 Hz, C), 126.2 (2CH), 125.6 (q, J = 3.8 Hz, 2CH), 125.5 (CH), 124.1 (q, J = 271.9 Hz, C), 118.0
(C), 116.3 (d, J = 22.6 Hz, 2CH), 114.5 (C), 111.7 (C), 88.6 (C), 44.4 (CH2), 42.2 (CH2), 26.8 (CH3).
Anal. calcd for C28H21F4NO3S (527.1178): C, 63.75; H, 4.01; N, 2.66; S, 6.08. Found: C, 63.97; H,
3.95; N, 2.44; S, 5.95.
4.1.3.21.
4-(5-(2-Bromobenzyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-
yl)benzonitrile (43) Yellow oil, yield 29%. 1H NMR (250 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, H),
7.74 (d, J = 8.3 Hz, H), 7.51 – 7.32 (m, 2H), 7.24 – 6.90 (m, 8H), 3.43 (d, J = 10.2 Hz, H), 3.34 (d, J =
10.2 Hz, H), 3.13 (d, J = 14.6 Hz, H), 2.82 (d, J = 14.6 Hz, H), 1.47 (s, 3H). 13C NMR (63 MHz,
CDCl3) δ 165.3 (d, J = 255.5 Hz, C), 160.1 (C), 137.2 (d, J = 3.2 Hz, C), 135.3 (C), 133.2 (CH), 133.0
(C), 132.8 (C), 132.4 (CH), 131.6 (2CH), 130.2 (2CH), 129.8 (C), 129.6 (d, J = 9.5 Hz, 2CH), 128.8
(CH), 127.3 (CH), 116.4 (d, J = 22.6 Hz, 2CH), 114.4 (C), 111.9 (C), 89.2 (C), 44.9 (CH2), 41.9
(CH2), 27.6 (CH3). Anal. calcd for C25H19BrFNO3S (511.0253): C, 58.60; H, 3.74; N, 2.73; S, 6.26.
Found: C, 58.62; H, 3.84; N, 2.78; S, 6.12.
4.1.3.22. 3-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)benzonitrile
1
(44) White oil, yield 29%. H NMR (250 MHz, CDCl3) δ 7.88 – 7.72 (m, 3H), 7.56 – 7.48 (m, 3H),
7.25 – 7.16 (m, 3H), 7.13 – 7.06 (m, 4H), 3.06 (d, J = 14.8 Hz, H), 3.04 (d, J = 13.8 Hz, H), 2.86 (d, J
= 14.8 Hz, H), 2.88 (d, J = 13.8, H), 1.53 (s, 3H). 13C NMR (63 MHz, CDCl3) δ 160.00 (C), 137.2 (d,
J = 3.7 Hz, C), 135.3 (C), 133.9 (d, J = 4.1 Hz, 2CH), 132.6 (CH), 130.3 (2CH), 130.0 (C), 129.6
(CH), 129.4 (CH), 128.7 (CH), 128.3 (2CH), 127.1 (CH), 118.0 (C), 116.3 (d, J = 22.5 Hz, 2CH),
112.3 (C), 111.2 (C), 88.9 (C), 45.5 (CH2), 41.5 (CH2), 27.4 (CH3). 1 C did not appear under these
conditions. HRMS (ESI +) m/z calcd for C25H20FNO3S [M+H]+: 434.1221 Found: 434.1222.
4.1.4 General procedure for amidoxime synthesis from nitriles
A suspension of hydroxylamine hydrochloride (1.7 mmol, 0.12 g, 10 equiv.) in 8 mL of DMSO was
stirred under inert atmosphere and cooled to 5 oC. Potassium terbutoxide (1.7 mmol, 0.19 g, 10 equiv.)
was added progressively and the reaction mixture was stirred for 30 min. Then the corresponding
nitrile was added (0.17 mmol, 1 equiv.) and the reaction mixture was stirred for 12 h. The mixture
obtained was poured into cold water and the precipitate thus formed was filtrated and crystallized from
the appropriate solvent.
4.1.4.1.
4-(5,5-Diethyl-3-((4-fluorophenyl)sulfonyl)-4,5-dihydrofuran-2-yl)-N'-
1
hydroxybenzimidamide (46) Brown solid, yield 63%, m.p. 123 °C (ethanol/water, 1:1). H NMR
(250 MHz, DMSO) δ 9.85 (s, H), 7.76 – 7.73 (m, 4H), 7.57 – 7.54 (m, 2H), 7.46 – 7.40 (m, 2H), 5.93
(bs, 2H), 2.81 (s, 2H), 1.65-1.62 (m, 4H), 0.79 (bs, 6H). 13C NMR (63 MHz, DMSO) δ 162.5 (C),
150.2 (C), 137.9 (d, J = 2.9 Hz, C), 135.5 (C), 129.6 (d, J = 9.7 Hz, 2CH), 128.9 (2CH), 128.8 (C),
124.8 (2CH), 116.7 (d, J = 22.8 Hz, 2CH), 109.2 (C), 91.3 (C), 38.5 (CH2), 31.2 (2CH2), 7.2 (2CH3). 1
C did not appear under these conditions. HRMS (ESI +) m/z calcd for C21H23FN2O4S [M+H]+:
419.1363. Found: 419.1433.
4.1.4.2. 4-(3-((4-Fluorophenyl)sulfonyl)-1-oxaspiro[4.5]dec-2-en-2-yl)-N'-hydroxybenzimidamide
(47) Beige solid, yield 48%, m.p. 94 °C (ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.85 (s,
H), 7.83 – 7.72 (m, 4H), 7.56 (d, J = 8.2 Hz, 2H), 7.45 – 7.38 (m, 2H), 5.93 (bs, 2H), 2.81 (s, 2H),
13
1.73 – 1.39 (m, 10H). C NMR (63 MHz, DMSO) δ 161.9 (C), 150.1 (C), 137.9 (d, J = 2.9 Hz, C),
135.5 (C), 129.5 (d, J = 9.8 Hz, 2CH), 129.1 (2CH), 128.8 (C), 124.7 (2CH), 116.6 (d, J = 22.8 Hz,
2CH), 109.1 (C), 88.5 (C), 42.2 (CH2), 35.9 (2CH2), 30.1 (CH2), 22.1 (2CH2). 1 C did not appear
14

ACCEPTED MANUSCRIPT
under these conditions. HRMS (ESI +) m/z calcd for C22H23FN2O4S [M+H]+: 431.1363. Found:
431.1436.
4.1.4.3. 4-((4-((4-Fluorophenyl)sulfonyl)-5-(4-(N'-hydroxycarbamimidoyl)phenyl)-2-methyl-2,3-
dihydrofuran-2-yl)methyl)-N'-hydroxybenzimidamide (48) White solid, yield 64%, m.p. 124 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.88 (s, H), 9.68 (s, H), 7.71 (d, J = 8.5 Hz, 2H),
7.56 – 7.43 (m, 6H), 7.32-7.25 (m, 2H), 7.15 (d, J = 8.2 Hz, 2H), 5.91 (bs, 2H), 5.82 (bs, 2H), 3.04 –
2.79 (m, 4H), 1.44 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.6 (d, J = 252.3 Hz, C), 162.0 (C), 150.9
(C), 150.4 (C), 137.7 (d, J = 3.2 Hz, C), 136.9 (C), 135.6 (C), 131.9 (C), 130.4 (2CH), 129.5 (d, J =
10.1 Hz, 2CH), 129.0 (2CH), 128.8 (C), 125.2 (2CH), 125.0 (2CH), 116.6 (d, J = 22.5 Hz, 2CH),
109.4 (C), 88.6 (C), 45.2 (CH2), 41.3 (CH2), 27.1 (CH3). HRMS (ESI +) m/z calcd for C26H25FN4O5S
[M+H]+: 525.1602. Found: 525.1602.
4.1.4.4. 3-((4-((4-Fluorophenyl)sulfonyl)-5-(4-(N'-hydroxycarbamimidoyl)phenyl)-2-methyl-2,3-
dihydrofuran-2-yl)methyl)-N'-hydroxybenzimidamide (49) White solid, yield 87%, m.p. 97 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.86 (s, H), 9.67 (s, H), 7.72 (d, J = 8.5 Hz, 2H),
7.60 – 7.46 (m, 6H), 7.33 – 7.12 (m, 4H), 5.91 (bs, 2H), 5.82 (bs, 2H), 3.05 – 2.80 (m, 4H), 1.45 (s,
3H). 13C NMR (63 MHz, DMSO) δ 164.5 (d, J = 252.3 Hz, C), 162.1 (C), 150.7 (C), 150.3 (C), 137.7
(d, J = 2.8 Hz, C), 135.7 (C), 135.5 (C), 133.1 (C), 130.9 (CH), 129.3 (d, J = 9.6 Hz, 2CH), 129.0
(2CH), 128.7 (C), 127.9 (CH), 127.6 (CH), 124.8 (2CH), 123.9 (CH), 116.5 (d, J = 23.0 Hz, 2CH),
109.3 (C), 88.4 (C), 45.4 (CH2), 41.3 (CH2), 27.0 (CH3). HRMS (ESI +) m/z calcd for C26H25FN4O5S
[M+H]+: 525.1602. Found: 525.1602.
4.1.4.5.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(4-(trifluoromethyl)benzyl)-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (50) White solid, yield 56%, m.p. 86 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.84 (s, H), 7.72 (d, J = 8.5 Hz, 2H), 7.61 – 7.29
(m, 10H), 5.92 (bs, 2H), 3.06 – 2.84 (m, 4H), 1.46 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J =
252.3 Hz, C), 161.8 (C), 150.1 (C), 140.8 (C), 137.7 (d, J = 2.7 Hz, C), 135.5 (C), 131.1 (2CH), 129.3
(d, J = 9.6 Hz, 2CH), 129.2 (q, J = 30.0 Hz, C), 128.8 (2CH),128.6 (C), 124.8 (4CH), 116.5 (d, J =
22.8 Hz, 2CH), 109.5 (C), 88.0 (C), 45.0 (CH2), 41.3 (CH2), 26.9 (CH3). 1 C did not appear under
these conditions. HRMS (ESI +) m/z calcd for C26H22F4N2O4S [M+H]+: 535.1309. Found: 535.1312.
4.1.4.6.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-(trifluoromethyl)benzyl)-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (51) White solid, yield 48%, m.p. 88 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.87 (s, H), 7.73 (d, J = 8.5 Hz, 2H), 7.58 – 7.27
(m, 10H), 5.94 (bs, 2H), 3.12 (d, J = 14.1 Hz, H), 3.05 (d, J = 14.1 Hz, H), 2.93 (d, J = 15.2 Hz, H),
2.86 (d, J = 15.2 Hz, H), 1.46 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.3 Hz, C), 161.6
(C), 150.1 (C), 137.5 (d, J = 2.7 Hz, C), 137.2 (C), 135.4 (C), 134.3 (CH), 129.3 (d, J = 9.6 Hz, 2CH),
128.9 (CH), 128.9 (q, J = 30.7 Hz, C), 128.7 (2CH),128.4 (C), 126.8 (q, J = 3.8 Hz, CH), 125.2 (q, J =
248.7 Hz, C), 124.6 (2CH), 123.4 (q, J = 3.7 Hz, CH), 116.4 (d, J = 22.8 Hz, 2CH), 109.3 (C), 87.9
(C), 44.6 (CH2), 41.1 (CH2), 27.0 (CH3). HRMS (ESI +) m/z calcd for C26H22F4N2O4S [M+H]+:
535.1309. Found: 535.1306.
4.1.4.7.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(2-(trifluoromethyl)benzyl)-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (52) White solid, yield 40%, m.p. 89-90 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.90 (s, H), 7.77 (d, J = 8.4 Hz, 2H), 7.65 – 7.31
(m, 10H), 5.96 (bs, 2H), 3.27 – 3.14 (m, 2H), 2.85 (bs, 2H), 1.41 (s, 3H). 13C NMR (63 MHz, DMSO)
δ 164.5 (d, J = 252.3 Hz, C), 161.5 (C), 150.2 (C), 137.5 (d, J = 2.8 Hz, C), 135.6 (C), 134.6 (d, J =
1.4 Hz, C), 132.6 (CH), 132.2 (CH), 129.5 (d, J = 9.5 Hz, 2CH), 128.9 (2CH), 128.5 (C), 128.1 (q, J =
15

ACCEPTED MANUSCRIPT
28.5 Hz, C), 127.5 (CH), 125.9 (q, J = 5.5 Hz, CH), 124.9 (2CH), 124.4 (q, J = 273.9 Hz, C), 116.6 (d,
J = 23.0 Hz, 2CH), 109.6 (C), 88.1 (C), 41.8 (CH2), 40.5 (CH2), 27.1 (CH3). HRMS (ESI +) m/z calcd
for C26H22F4N2O4S [M+H]+: 535.1309. Found: 535.1310.
4.1.4.8.
4-(5-(3,5-Bis(trifluoromethyl)benzyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (53) White solid, yield 78%, m.p. 85 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.86 (s, H), 7.95 – 7.91 (m, 3H), 7.76 – 7.71 (m,
2H), 7.54 – 7.49 (m, 4H), 7.32 - 7.25 (m, 2H), 5.94 (bs, 2H), 3.23 (bs, 2H), 2.88 (bs, 2H), 1.49 (s, 3H).
13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.9 Hz, C), 161.4 (C), 150.0 (C), 139.5 (C), 137.5 (d, J
= 2.6 Hz, C), 135.6 (C), 131.1 (bs, 2CH), 129.8 (q, J = 32.6 Hz, 2C), 129.2 (d, J = 9.6 Hz, 2CH),
128.7 (2CH), 128.2 (C), 124.6 (2CH), 123.3 (q, J = 273.0 Hz, 2C), 120.6 (bs, CH), 116.4 (d, J = 22.8
Hz, 2CH), 109.4 (C), 87.6 (C), 44.1 (CH2), 41.2 (CH2), 27.1 (CH3). HRMS (ESI +) m/z calcd for
C27H21F7N2O4S [M+H]+: 603.1110. Found: 603.1062.
4.1.4.9.
4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(4-nitrobenzyl)-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (54) Beige solid, yield 72%, m.p. 116 °C (ethanol/water, 1:1). 1H NMR (250
MHz, DMSO) δ 9.84 (s, H), 8.02 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.59 – 7.26 (m, 8H),
5.92 (bs, 2H), 3.15 (d, J = 13.5 Hz, H), 3.09 (d, J = 13.5 Hz, H), 2.98 (d, J = 15.0 Hz, H), 2.90 (d, J =
15.0 Hz, H), 1.49 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.5 Hz, C), 161.7 (C), 150.1
(C), 146.3 (C), 144.1 (C), 137.6 (d, J = 3.1 Hz, C), 135.5 (C), 131.5 (2CH), 129.5 (d, J = 9.7 Hz,
2CH), 128.8 (2CH), 128.5 (C), 124.8 (2CH), 122.9 (2CH), 116.4 (d, J = 22.8 Hz, 2CH), 109.5 (C),
87.9 (C), 44.9 (CH2), 41.2 (CH2), 27.1 (CH3). HRMS (ESI +) m/z calcd for C25H22FN3O6S [M+H]+:
512.1286. Found: 512.1290.
4.1.4.10. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-nitrobenzyl)-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (55) Beige solid, yield 61%, m.p. 87 °C (ethanol/water, 1:1). 1H NMR (250
MHz, DMSO) δ 9.85 (s, H), 8.08 - 7.26 (m, 12H), 5.93 (bs, 2H), 3.20 – 2.84 (m, 4H), 1.49 (s, 3H). 13C
NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.7 Hz, C), 161.7 (C), 150.1 (C), 147.3 (C), 138.2 (C),
137.4 (d, J = 2.8 Hz, C), 137.1 (CH), 135.5 (C), 129.4 (CH), 129.3 (d, J = 9.7 Hz, 2CH), 128.8 (2CH),
128.4 (C), 124.8 (CH), 124.7 (2CH), 121.8 (CH), 116.5 (d, J = 22.8 Hz, 2CH), 109.4 (C), 87.9 (C),
44.4 (CH2), 41.1 (CH2), 27.1 (CH3). HRMS (ESI +) m/z calcd for C25H22FN3O6S [M+H]+: 512.1286.
Found: 512.1289.
4.1.4.11. 4-(3-((4-Fluorophenyl)sulfonyl)-5-(4-methoxybenzyl)-5-methyl-4,5-dihydrofuran-2-yl)-
N'-hydroxybenzimidamide (56) White solid, yield 41%, m.p. 81 °C (ethanol/water, 1:1). 1H NMR
(250 MHz, DMSO) 9.84 (s, H), 7.73 (d, J = 8.5 Hz, 2H), 7.56 – 7.47 (m, 4H), 7.35 – 7.28 (m, 2H),
7.04 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 5.92 (bs, 2H), 3.72 (s, 3H), 2.98 – 2.78 (m, 4H),
1.43 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.0 Hz, C),161.9 (C), 158.0 (C), 150.2 (C),
137.7 (d, J = 3.0 Hz, C), 135.5 (C), 131.3 (2CH), 129.4 (d, J = 9.6 Hz, 2CH), 128.8 (2CH), 128.7 (C),
127.7 (C), 124.7 (2CH), 116.4 (d, J = 22.8 Hz, 2CH), 113.3 (2CH), 109.2 (C), 88.6 (C), 54.9 (CH3),
44.4 (CH2), 41.0 (CH2), 26.8 (CH3). HRMS (ESI +) m/z calcd for C26H25FN2O5S [M+H]+: 497.1468.
Found: 497.1463.
4.1.4.12. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3,4,5-trimethoxybenzyl)-4,5-dihydrofuran-
1
2-yl)-N'-hydroxybenzimidamide (57) Pink solid, yield 50%, m.p. 98 °C (ethanol/water, 1:1). H
NMR (250 MHz, DMSO) δ 9.89 (s, H), 7.74 (d, J = 7.8 Hz, 2H), 7.56 – 7.51 (m, 4H), 7.34 – 7.27 (m,
2H), 6.44 (s, 2H), 5.94 (bs, 2H), 3.63 – 3.57 (m, 9H), 3.04 (d, J = 14.5 Hz, H), 2.94 (d, J = 13.6 Hz,
H), 2.84 (d, J = 14.5 Hz, H), 2.82 (d, J = 13.6 Hz, H), 1.50 (s, 3H). 13C NMR (63 MHz, DMSO) δ
164.5 (d, J = 251.6 Hz, C), 161.7 (C), 152.4 (2C), 150.1 (C), 137.8 (d, J = 2.7 Hz, C), 136.3 (C), 135.6
16

ACCEPTED MANUSCRIPT
(C), 131.5 (C), 129.1 (d, J = 9.5 Hz, 2CH), 128.9 (2CH), 128.7 (C), 124.7 (2CH), 116.5 (d, J = 22.9
Hz, 2CH), 109.1 (C), 107.5 (2CH), 88.4 (C), 60.1 (CH3), 55.5 (2CH3), 45.8 (CH2), 41.1 (CH2), 27.4
(CH3). HRMS (ESI +) m/z calcd for C28H29FN2O7S [M+H]+: 557.1680. Found: 557.1678.
4.1.4.13. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(4-methylbenzyl)-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (58) Beige solid, yield 76%, m.p. 101 °C (ethanol/water, 1:1). 1H NMR (250
MHz, DMSO) δ 9.84 (s, H), 7.73 (d, J = 8.4 Hz, 2H), 7.58 – 7.31 (m, 6H), 7.00 – 6.95 (m, 4H), 5.92
(bs, 2H), 2.98 – 2.76 (m, 4H), 2.25 (s, 3H), 1.43 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.3 (d, J =
235.3 Hz, C), 161.8 (C), 150.2 (C), 137.7 (d, J = 2.9 Hz, C), 135.6 (C), 135.4 (C), 132.7 (C), 130.1
(2CH), 129.3 (d, J = 9.8 Hz, 2CH), 128.9 (2CH), 128.7 (C), 128.6 (2CH), 124.7 (2CH), 116.5 (d, J =
22.7 Hz, 2CH), 109.2 (C), 88.5 (C), 44.9 (CH2), 41.0 (CH2), 26.8 (CH3), 20.7 (CH3). HRMS (ESI +)
m/z calcd for C26H25FN2O4S [M+H]+: 481.1592. Found: 481.1591.
4.1.4.14. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(3-methylbenzyl)-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (59) Yellow solid, yield 69%, m.p. 95 °C (ethanol/water, 1:1). 1H NMR (250
MHz, DMSO) δ 9.86 (s, H), 7.73 (d, J = 8.3 Hz, 2H), 7.54 – 7.09 (m, 6H), 7.12 – 6.91 (m, 4H), 5.93
(bs, 2H), 2.97 – 2.77 (m, 4H), 2.19 (s, 3H), 1.45 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J =
251.9 Hz, C), 161.9 (C), 150.1 (C), 137.7 (d, J = 2.9 Hz, C), 136.9 (CH), 135.7 (CH), 135.5 (C), 131.1
(C), 129.3 (d, J = 9.8 Hz, 2CH), 128.9 (2CH), 128.7 (C), 127.9 (CH), 127.3 (CH+C), 124.7 (2CH),
116.5 (d, J = 23.0 Hz, 2CH), 109.2 (C), 88.4 (C), 45.3 (CH2), 41.0 (CH2), 27.0 (CH3), 21.0 (CH3).
HRMS (ESI +) m/z calcd for C26H25FN2O4S [M+H]+: 481.1592. Found: 481.1590.
4.1.4.15. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-(2-methylbenzyl)-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (60) White solid, yield 50%, m.p. 138 °C (ethanol/water, 1:1). 1H NMR (250
MHz, DMSO) δ 9.84 (s, H), 7.71 (d, J = 8.3 Hz, 2H), 7.65 – 7.24 (m, 6H), 7.09 – 6.91 (m, 4H), 5.91
(bs, 2H), 3.01 – 2.17 (m, 4H), 2.18 (s, 3H), 1.44 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J =
251.9 Hz, C), 161.8 (C), 150.2 (C), 137.7 (d, J = 2.9 Hz, C), 136.9 (C), 135.4 (C), 134.4 (C), 131.0
(CH), 130.2 (CH), 129.4 (d, J = 9.8 Hz, 2CH), 128.9 (C), 128.8 (2CH), 126.7 (CH), 125.5 (CH), 124.8
(2CH), 116.6 (d, J = 22.5 Hz, 2CH), 109.3 (C), 89.1 (C), 41.7 (CH2), 41.6 (CH2), 26.9 (CH3), 19.9
(CH3). HRMS (ESI +) m/z calcd for C26H25FN2O4S [M+H]+: 481.1592. Found: 481.1591.
4.1.4.16.
4-(3-((4-Fluorophenyl)sulfonyl)-5-(4-(hydroxymethyl)benzyl)-5-methyl-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (61) White solid, yield 53%, m.p. 116 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.86 (s, H), 7.72 (d, J = 8.5 Hz, 2H), 7.55 – 7.48
(m, 4H), 7.35 (t, J = 8.8 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.1 Hz, 2H), 5.92 (bs, 2H), 5.21
13
(t, J = 5.5 Hz, H), 4.47 (d, J = 5.5 Hz, 2H), 3.00 – 2.77 (m, 4H), 1.43 (s, 3H). C NMR (63 MHz,
DMSO) δ 164.4 (d, J = 252.1 Hz, C), 161.8 (C), 150.2 (C), 140.8 (C), 137.7 (d, J = 2.7 Hz, C), 135.5
(C), 134.1 (C), 130.1 (2CH), 129.3 (d, J = 9.7 Hz, 2CH), 128.9 (2CH), 128.7 (C), 126.2 (2CH), 124.8
(2CH), 116.5 (d, J = 22.8 Hz, 2CH), 109.2 (C), 88.5 (C), 62.7 (CH2), 45.0 (CH2), 41.1 (CH2), 26.8
(CH3). HRMS (ESI +) m/z calcd for C26H25FN2O5S [M+H]+: 497.1541. Found: 497.1540.
4.1.4.17.
4-(3-((4-Fluorophenyl)sulfonyl)-5-(3-(hydroxymethyl)benzyl)-5-methyl-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (62) White solid, yield 57%, m.p. 103 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.87 (s, H), 7.73 (d, J = 8.4 Hz, 2H), 7.55– 7.49
(m, 4H), 7.32 (t, J = 8.8 Hz, 2H), 7.18 – 6.98 (m, 4H), 5.94 (bs, 2H), 5.22 (t, J = 5.5 Hz, H), 4.44 (d, J
= 5.5 Hz, 2H), 2.99 (d, J = 13.8 Hz, H), 2.97 (d, J = 14.5 Hz, H), 2.91 (d, J = 13.8 Hz, H), 2.82 (d, J =
14.5 Hz, H), 1.44 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 251.7 Hz, C), 162.0 (C), 150.2
(C), 142.2 (C), 137.8 (d, J = 2.0 Hz, C), 135.6 (C), 135.5 (C), 129.3 (d, J = 9.6 Hz, 2CH), 129.0
(2CH), 128.7 (C), 128.6 (CH), 128.5 (CH), 127.8 (CH), 124.8 (CH), 124.7 (2CH), 116.5 (d, J = 22.7
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Hz, 2CH), 109.2 (C), 88.5 (C), 62.8 (CH2), 45.3 (CH2), 41.1 (CH2), 26.9 (CH3). HRMS (ESI +) m/z
calcd for C26H25FN2O5S [M+H]+: 497.1541. Found: 497.1541.
4.1.4.18.
4-(5-([1,1'-Biphenyl]-4-ylmethyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (63) White solid, yield 74%, m.p. 96 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.85 (s, H), 7.75 – 7.19 (m, 17H), 5.93 (bs, 2H),
3.06 – 2.82 (m, 4H),1.47 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.1 Hz, C), 161.9 (C),
150.2 (C), 139.7 (C), 138.4 (C), 137.7 (d, J = 2.9 Hz, C), 135.5 (C), 135.2 (C), 130.9 (2CH), 129.3 (d,
J = 9.7 Hz, 2CH), 129.0 (2CH), 128.9 (2CH), 128.7 (C), 127.4 (CH), 126.5 (2CH), 126.1 (2CH),
124.8 (2CH), 116.5 (d, J = 22.8 Hz, 2CH), 109.4 (C), 88.5 (C), 44.9 (CH2), 41.3 (CH2), 26.8 (CH3).
HRMS (ESI +) m/z calcd for C31H27FN2O4S [M+H]+: 543.1676. Found: 543.1666.
4.1.4.19. 4-(5-((2-Fluoro-[1,1'-biphenyl]-4-yl)methyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (64) White solid, yield 95%, m.p. 117 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.84 (s, H), 7.76 – 7.04 (m, 16H), 5.92 (bs, 2H),
3.06 – 2.84 (m, 4H), 1.48 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 251.9 Hz, C), 161.8 (C),
150.2 (C), 138.2 (d, J = 2.3 Hz, C), 138.0 (C), 137.8 (d, J = 7.8 Hz, CH), 137.7 (d, J = 2.8 Hz, CH),
135.5 (C), 134.9 (C), 129.4 (d, J = 9.6 Hz, 2CH), 128.8 (2CH), 128.7 (C), 128.6 (4CH), 127.8 (CH),
126.9 (C), 124.8 (2CH), 117.8 (d, J = 23.0 Hz, CH), 116.5 (d, J = 23.0 Hz, 2CH), 109.5 (C), 88.3 (C),
44.6 (CH2), 41.3 (CH2), 26.8 (CH3). 1 C did not appear under these conditions. HRMS (ESI +) m/z
calcd for C31H26F2N2O4S [M+H]+: 561.1581. Found: 561.1655.
4.1.4.20. 4-(3-((4-Fluorophenyl)sulfonyl)-5-methyl-5-((E)-3-(4-(trifluoromethyl)phenyl)allyl)-4,5-
dihydrofuran-2-yl)-N'-hydroxybenzimidamide (65) White solid, yield 85%, m.p. 91 °C
(ethanol/water, 1:1). 1H NMR (250 MHz, DMSO) δ 9.86 (s, H), 7.75 – 7.18 (m, 12H), 6.57 – 6.51 (m,
H), 6.36 – 6.27 (m, H), 5.92 (bs, 2H), 3.02 (d, J = 14.7 Hz, H), 2.89 (d, J = 14.7 Hz, H), 2.50 – 2.60
(m, 2H), 1.48 (s, 3H). 13C NMR (63 MHz, DMSO) δ 164.4 (d, J = 252.1 Hz, C), 162.0 (C), 150.2 (C),
140.7 (C), 137.8 (d, J = 3.0 Hz, C), 135.6 (C), 132.4 (C), 129.4 (d, J = 9.8 Hz, 2CH), 129.5 (q, J =
32.5 Hz, C), 129.0 (2CH), 128.7 (CH), 127.1 (CH), 126.6 (2CH), 125.4 (q, J = 3.7 Hz, 2CH), 124.8
(2CH), 124.1 (q, J = 271.9 Hz, C), 116.4 (d, J = 23.0 Hz, 2CH), 109.4 (C), 88.2 (C), 43.8 (CH2), 41.4
(CH2), 26.7 (CH3). HRMS (ESI +) m/z calcd for C28H24F4N2O4S [M+H]+: 561.1393. Found: 561.1390.
4.1.4.21. 4-(5-(2-Bromobenzyl)-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (66) Yellow solid, yield 20%, m.p. 92 °C (ethanol/water, 1:1). 1H NMR (250
MHz, DMSO) δ 9.85 (s, H), 7.74 – 7.01 (m, 12H), 5.92 (bs, 2H), 3.21 (d, J = 14.7 Hz, H), 3.16 (d, J =
14.7 Hz, H), 3.04 (d, J = 13.5 Hz, H), 2.87 (d, J = 13.5 Hz, H), 1.48 (s, 3H). 13C NMR (63 MHz,
DMSO) δ 164.5 (d, J = 251.9 Hz, C), 161.6 (C), 150.2 (C), 137.6 (d, J = 3.2 Hz, C), 135.5 (C), 135.3
(C), 132.7 (CH), 132.6 (C), 129.4 (d, J = 9.5 Hz, 2CH), 129.0 (CH), 128.9 (2CH), 128.5 (CH), 127.5
(CH), 125.1 (C), 124.7 (2CH), 116.4 (d, J = 23.0 Hz, 2CH), 109.4 (C), 88.3 (C), 44.1 (CH2), 41.5
(CH2), 27.1 (CH3). HRMS (ESI +) m/z calcd for C25H22BrFN2O4S [M+H]+: 545.0540. Found:
545.0546.
4.1.4.22.
3-(5-Benzyl-3-((4-fluorophenyl)sulfonyl)-5-methyl-4,5-dihydrofuran-2-yl)-N'-
hydroxybenzimidamide (67) White solid, yield 83%, m.p. 67-69 °C (ethanol/water, 1:1).1H NMR
(250 MHz, DMSO) δ 9.80 (s, H), 7.86 (s, H), 7.79 – 7.74 (m, H), 7.63 – 7.59 (m, 2H), 7.47 – 7.35 (m,
4H), 7.25 – 7.17 (m, 5H), 5.92 (bs, 2H), 3.05 – 2.80 (m, 4H), 1.46 (s, 3H). 13C NMR (63 MHz,
DMSO) δ 164.4 (d, J = 251.9 Hz, C), 161.9 (C), 150.2 (C), 137.6 (d, J = 3.2 Hz, C), 135.8 (C), 133.0
(C), 130.3 (2CH), 129.6 (CH), 129.4 (d, J = 9.2 Hz, 2CH), 128.3 (C), 128.0 (2CH), 127.7 (CH), 127.5
(CH), 126.7 (CH), 126.1 (CH), 116.5 (d, J = 23.0 Hz, 2CH), 109.4 (C), 88.5 (C), 45.3 (CH2), 41.1
(CH2), 26.7 (CH3). HRMS (ESI +) m/z calcd for C25H23FN2O4S [M+H]+: 467.1435. Found: 467.1432.
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4.2 Biology
4.2.1. Parasites
Leishmania amazonensis (MHOM/BR/77/LTB0016) was maintained as promastigotes at 26 °C in
Schneider's insect medium (Sigma-Aldrich, St Louis, MO, USA) with 10% and heat-inactivated fetal
calf serum (HIFCS), 100 µg/mL streptomycin and 100 U/mL penicillin. Parasites were maintained
until the 10th passage; subsequently, new cultures were obtained from infected animals.
4.2.2. Antipromastigote activity
L. amazonensis promastigotes were cultivated in Schneider's insect medium supplemented with 10%
HIFCS as above, in either absence or presence of different concentrations of prototypes. The culture
was initiated with 1.0ꢀ×ꢀ106 cells/mL and maintained at 26 °C for 72 h. The cell viability was estimated
by resazurin assay. The 50% inhibitory concentration (IC50) was determined by logarithmic regression
analysis using GraphPrism 5 software.
4.2.3. Antiamastigote activity
To evaluate the effect of the substances on intracellular amastigotes, resident peritoneal macrophages
of BALB/c mice were plated in RPMI (Sigma-Aldrich, St. Louis, USA) at 1x106/mL in Lab-Tek 8-
chamber slides (Nunc, Roskilde, Denmark) and incubated at 37 °C in 5% CO2 for 1 h. The resulting
monolayers were washed with pre-warmed phosphate-buffered saline to remove non-adherent cells.
Stationary-phase of L. amazonensis promastigotes were added at 3:1 parasite/macrophage ratio, and
the cultures were incubated for additional 4 hours. After incubation, the chambers were washed again
to remove free parasites, the substances were added and the chambers were incubated for 72h. Next,
the slides were stained using an Instant Prov hematological dye system (Newprov, Curitiba, Brazil)
and then examined under light microscopy. The number of infected cells and intracellular amastigotes
was determined by counting at least 100 macrophages per sample. Concentration effect curves were
fitted using nonlinear regression using Graph Pad Prism 5.0 and IC50 values determined.
4.2.4. Cytotoxicity assay
Peritoneal macrophages were harvested by peritoneal washing with 5 ml of RPMI 1640 medium
supplemented with 10% HIFCS, 2 mM L-glutamine, 1 mM pyruvate, 100 µg/mL streptomycin and
100 U/mL penicillin. The peritoneal cell suspension was adjusted to 1.0ꢀ×ꢀ106 cells/mL and then plated
in triplicate in 96-well plates (Falcon Co, Franklin Lakes, USA). Cultures were incubated for 1 h at
37°C in a 5% CO2 atmosphere. Afterwards, the cells were washed to remove nonadherent cells and
incubated in either absence or presence of different concentrations of prototypes for 72 h. The cell
viability was estimated by resazurin assay. The 50% inhibitory concentration (IC50) was determined by
logarithmic regression analysis using GraphPrism 5 software.
Acknowledgments
This work was supported by the CNRS and Aix- Marseille University. The authors thank V. Remusat
for the NMR spectra recording and V. Monnier for the mass spectra recording.
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Supplementary data
Supplementary data associated with this article can be found in the online version, at doi:
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