Design, synthesis of new chiral fluorine-containing β-hydroxysulfonamides from natural amino acids and study of their anti-inflammatory and analgesic activities

Article abstract of DOI:10.1007/s00044-016-1590-2

A series of new chiral fluorine-containing β-hydroxysulfonamides were conveniently synthesized in three steps, starting from natural L-amino acids, and evaluated for their anti-inflammatory and analgesic activities. The structures of these compounds were supported by FT-IR, ¹H, ¹³C and ¹⁹F NMR, elemental analysis and HRMS. Among the tested compounds, 4c, 4g and 4h exhibited promising anti-inflammatory activity. Moreover, compound 4h showed a significant analgesic activity. The structure–activity relationships of selected compounds were discussed.

Full text of DOI:10.1007/s00044-016-1590-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1590-2
ORIGINAL RESEARCH
Design, synthesis of new chiral fluorine-containing
b-hydroxysulfonamides from natural amino acids and study
of their anti-inflammatory and analgesic activities
Monia Gloulou1 Jamil Kra¨ıem1 Fayc¸al Jennene1 Donia Ghedira1 Haifa Bel Haj Amor1 Sirine Lajili1
•
•
•
•
•
•
Emna Jalleli1 Maha Ferjani1 Abderrahman Bouraoui1 Mohamed Kallel1
•
•
•
Received: 20 January 2016 / Accepted: 23 April 2016
Ó Springer Science+Business Media New York 2016
Abstract A series of new chiral fluorine-containing b-
hydroxysulfonamides were conveniently synthesized in
three steps, starting from natural L-amino acids, and
evaluated for their anti-inflammatory and analgesic activ-
ities. The structures of these compounds were supported by
FT-IR, 1H, 13C and 19F NMR, elemental analysis and
HRMS. Among the tested compounds, 4c, 4g and 4h
exhibited promising anti-inflammatory activity. Moreover,
compound 4h showed a significant analgesic activity. The
structure–activity relationships of selected compounds
were discussed.
among others (Supuran et al., 2002). Their use as anti-
inflammatory and analgesic agents is also reported in the
literature (Tozkoparan et al., 2007). The pharmaceutical
industry continues to explore new scaffolds that incorpo-
rate the sulfonamide moiety.
Interest in new sulfonamide scaffolds has also extended
to compounds such as chiral b-hydroxysulfonamides.
Access to these chiral structures was established by addi-
tion of Grignard reagents to chiral amino acid esters (Kreft
et al., 2003; Yi-Feng et al., 2009). Some of these com-
pounds are reported as inhibitors of b-amyloid production
(Kreft et al., 2003).
Keywords (L)-amino acids Á b-Hydroxysulfonamides Á
Arylmagnesium bromide Á Anti-inflammatory Á Analgesic
Preparing of new fluorinated b-hydroxysulfonamides is
presumed to be an attractive approach since it could
improve and enlarge these structures application field. In
fact, the strategic placement of fluorine in a molecule has
become a rational and popular approach during design of
medicinal leads. The potential of fluorine-containing bio-
logically relevant molecules was recognized by research-
ers, and thus the new wave of fluorine chemistry has been
rapidly expanding its biomedical frontiers. This small size
atom improves metabolic stability, modulate physico-
chemical properties, such as lipophilicity or basicity, and
enhance the binding affinity to the target protein (Biffinger
Introduction
The sulfonamides constitute an important class of drugs,
with several types of pharmacological agents possessing
antibacterial (Drews, 2000), antitumor (Supuran, 2002),
anti-carbonic anhydrase (Supuran et al., 2003) diuretic
(Supuran et al., 1996), hypoglycemic (Boyd, 1988),
antithyroid (Thornber, 1979) or protease inhibitory activity
¨
et al., 2004; Bohm et al., 2004).
In this paper, we report a simple and efficient method for
the synthesis of new chiral fluorinated b-hydroxysulfon-
amides in a three steps reaction, using commercially
available (L)-amino acids as starting material. Their phar-
macological potential was then investigated, specifically
their anti-inflammatory and analgesic activities. The
rational for the design of these compounds was based on
the fact that such a scaffold was reported in previous series
as a part of anti-inflammatory compounds and structure–
activity relationship (SAR) studies demonstrated its crucial
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-016-1590-2) contains supplementary
material, which is available to authorized users.
¨
& Jamil Kraıem
jamilkraiem@gmail.com
1
´
Laboratoire de Developpement Chimique, Galenique et
Pharmacologique des Medicaments, Faculte de Pharmacie de
´
´
´
´
Monastir, Universite de Monastir, Rue Avicenne, 5000
Monastir, Tunisia
123

Med Chem Res
role (Tsai et al., 2006; Carter et al., 1999; Zarghi et al.,
MgSO4 and filtered. The solvent was evaporated under
reduced pressure, and the residue was purified by column
chromatography (cyclohexane- ethyl acetate: 80/20).
2006).
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxypropan-2-yl)ben-
zenesulfonamide (4a) White solid; mp 125–126 °C;
Materials and methods
Chemistry
[a]2D2 = ?3.5 (c 0.7, CH3OH); IR (KBr, cm-1
)
HN–H = 3245; HO–H = 3515; 1H NMR (CDCl3,
300 MHz): d = 1.01 (d, 3H, J = 6.6 Hz, CH3), 2.85 (brs,
1H, OH), 4.36 (m, 1 H, CH–NH), 4.98 (d, 1 H, J = 8.7 Hz,
–NH), 6.76–6.82 (m, 2H, Ar), 6.96–7.01 (m, 2H, Ar),
7.24–7.45 (m, 6H, Ar), 7.53–7.64 (m, 3H, Ar); 13C NMR
(CDCl3, 75 MHz): d = 17.3 (CH3), 55.9 (CH–NH), 79.9
(C–OH), 115.0 (d, 2C, JC–F = 21 Hz Ar, CH–C–F), 115.2
(d, 2C, JC–F = 21 Hz, Ar, CH–C–F), 126.7 (2C, Ph, CH),
127.4 (d, 2C, JC–F = 8 Hz Ar, CH–CH–C–F), 127.5 (d,
2C, JC–F = 8 Hz, Ar, CH–CH–C–F), 128.9 (2C, Ph, CH),
132.4 (1C, Ph, CH), 139.7 (m, 2C, Ar, C–CH–CH–C–F),
140.8 (1C, Ph), 161.6 (d, 1C, JC–F = 245 Hz, Ar, C–F),
161.8 (d, 1C, JC–F = 245 Hz, Ar, C–F); 19F NMR
(282,4 MHz, CDCl3): d = -115.3 (m, 1 F); -114.9 (m,
1F). HRMS [M ? Na]? Calcd for C21H19F2NO3S:
426.0951; Found: 426.0956; Elemental analysis for C21
H19F2NO3S. Calcd: C 62.52 %, H 4.75 %, N 3.47 %;
Found: C 62.59 %, H 4.70 %, N 3.53 %.
Chemicals were purchased from Sigma-Aldrich Chemical
Company. Melting points of all the synthesized compounds
were determined in open capillary tubes and are uncor-
rected. The IR spectra (In KBr pellets) were recorded on
1
Perkin-Elmer FT-IR spectrometer. H NMR spectra were
recorded on a Bruker DRX-300 MHz NMR spectrometer,
and 13C NMR spectra were recorded on a Bruker DRX-
75 MHz NMR in CDCl3 using tetramethylsilane (TMS) as
an internal standard and chemical shifts are in d (ppm).
High-resolution mass spectra (HRMS) were recorded on a
MicroTOF spectrometer. Elemental analysis was carried
out with a Perkin-Elmer apparatus. All dry reactions were
carried out under nitrogen in oven-dried glassware. All
reagents and solvents were dried prior to use according to
standard methods. Dichloromethane was dried over cal-
cium hydride and distillated before use. Tetrahydrofuran
was dried by heating over sodium-benzophenone and dis-
tilled before use. N-sulfonylated amino esters 3a–j were
prepared according to the literature (Anadi et al., 2014) and
were characterized by comparing their NMR spectra with
the literature data (see supplementary information).
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxy-3-phenylpropan-
2-yl)benzenesulfonamide
(4b) White
solid;
mp
159–162 °C; [a]2D2 = ? 17.5 (c 0.7, CH3OH); IR (KBr,
cm-1) HN–H = 3281; HO–H = 3484; 1H NMR (CDCl3,
300 MHz): d (ppm) = 2.53 (brs, 1H, OH), 2.87 (m, 1H,
CH2–Ph), 3.25 (m, 1 H, CH2–Ph), 4.66 (m, 1 H, CH–NH)
4.84 (m, 1H, NH), 6.73–7.48 (m, 18H, Ar); 13C NMR
(CDCl3, 75 MHz): d = 37.9 (CH2–Ph), 61.5 (CH–NH),
80.4 (C–OH), 115.0 (d, 2C, JC–F = 21 Hz, CH–C–F, Ar),
115.4 (d, 2C, JC–F = 21 Hz, Ar, CH–C–F), 126.4 (2C, Ph,
CH), 127.1 (d, 2C, JC–F = 7.8 Hz, Ar, –CH–CH–C–F),
127.1 (1C, Ph, CH), 127.7 (d, 2C, JC–F = 7.9 Hz, Ar, CH–
CH–C–F), 128.7 (2C, Ph, CH), 128.8 (2C, Ph, CH), 129.6
(2C, Ph, CH), 132.0 (1C, Ph, CH), 136.8 (1C, Ph, C), 139.5
(d, 1C, JC–F = 2.5 Hz, Ar, C–CH–CH–C–F), 139.6 (d, 1C,
Ar, JC–F = 2.5 Hz, C–CH–CH–C–F), 140.5 (1C, Ph, C),
161.6 (d, 1C, JC–F = 245 Hz, Ar, C–F), 161.9 (d, 1C,
JC–F = 245 Hz, Ar, C–F); 19F NMR (282,4 MHz, CDCl3):
d = -115.5, -114.5; Elemental analysis for C27H23F2
NO3S. Calcd: C 67.63 %, H 4.83 %, N 2.92 %; Found: C
67.70 %, H 4.82 %, N 2.97 %.
General procedure for the synthesis of N-[(1S)-1,1-diaryl-
1-hydroxyalkan-2-yl]sulphonamides 4a–l
In a dry three-necked flask fitted with a dropping funnel
and equipped with a magnetic stirrer, 29.38 mmol of
Magnesium turnings, 14.69 mmol of LiCl and 0.03 mmol
of LiAlH4 were introduced under nitrogen atmosphere.
Then, 6 ml of dry THF were added. After 5 min of stirring,
11.8 mmol of p-fluorobromobenzene dissolved in 30 ml of
dry THF were added dropwise. The reaction mixture was
stirred at room temperature for 1 h. After that, 3 mmol of
N-sulfonyl ester 3, dissolved in 10 mL of dry THF, were
added dropwise with stirring at 0 °C. The ice bath was
maintained 15 min after the addition. The reaction mixture
was then stirred at room temperature for 24 h and is con-
trolled with thin layer chromatography. A solution of
H2SO4 (10 %) is then added dropwise at 0 °C until total
disappearance of the Mg. The reaction mixture was stirred
for 1 h. After that, the mixture was diluted with ethyl
acetate (20 mL), washed with saturated aqueous NaHCO3
solution and extracted with 3 9 20 mL of ethyl acetate.
The organic layers were collected, dried over anhydrous
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxypropan-2-yl)methane-
sulfonamide (4c) Yellow viscous oil; [a]2D2 = ? 30.8 (c
0.7, CH3OH); IR (KBr, cm-1
)
HN–H = 3280;
1
HO–H = 3484; H NMR (CDCl3, 300 MHz): d = 1.26 (d,
3H, J = 6.6 Hz, CH3), 2.48 (s, 3H, CH3–SO2), 4.50 (m, 1
H, CH–NH), 4.77 (d, 1 H, J = 9 Hz, NH), 7.03 (dd, 4H,
123

Med Chem Res
JH–H = 8.7 Hz, JH–F = 15.9 Hz, Ar), 7.43 (dd, 2H,
J = 5.1, 8.8 Hz, Ar), 7.49 (dd, 2H, J = 5.1, 8.8 Hz, Ar);
13C NMR (CDCl3, 75 MHz): d = 18.3 (CH3), 41.7 (CH3–
SO2), 56.5 (CH–NH), 79.9 (C–OH), 115.2 (d, 2C,
JC–F = 21 Hz, Ar, CH–C–F), 115.4 (d, 2C, JC–F = 21 Hz,
Ar, CH–C–F), 127.6 (d, 2C, JC–F = 8.1 Hz, Ar, CH–CH–
C–F), 127.9 (d, 2C, JC–F = 8.1 Hz, Ar, CH–CH–C–F),
139.5 (d, 1C, JC–F = 3.3 Hz, Ar, C–CH–CH–C–F), 140.5
(d, 1C, JC–F = 3.3 Hz, Ar, C–CH–CH–C–F), 161.8 (d, 1C,
JC–F = 245 Hz, C–F), 161.9 (d, 1C, JC–F = 245 Hz, C–F);
19F NMR (282,4 MHz, CDCl3): d = -114.8, -114.6;
HRMS [M ? Na]? Calcd for C16H17F2NO3S: 364.0795;
Found: 364.0791; Elemental analysis for C16H17F2NO3S.
Calcd: C 56.29 %, H 5.02 %, N 4.10 %; Found: C
56.32 %, H 4.96 %, N 4.14 %.
C–F), 127.7 (d, 2C, JC–F = 7.9 Hz, Ar, CH–CH–C–F),
140.1 (d, 1C, JC–F = 3.4 Hz, Ar, C–CH–CH–C–F), 141.6
(d, 1C, JC–F = 2.9 Hz, Ar, C–CH–CH–C–F), 161.8 (d, 1C,
JC–F = 246 Hz, Ar, C–F), 161.8 (d, 1C, JC–F = 246 Hz,
Ar, C–F); 19F NMR (282,4 MHz, CDCl3): d = -114.8,
-114.6; HRMS [M ? Na]? Calcd for C18H21F2NO3S:
392.1108; Found: 392.1102; Elemental analysis for C18
H21F2NO3S. Calcd: C 58.52 %, H 5.73 %, N 3.79 %;
Found: C 58.60 %, H 5.69 %, N 3.80 %.
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxy-4-methylpentan-
2-yl)methanesulfonamide
(4f) White
solid;
mp
176–178 °C; [a]2D2 = ? 38.5 (c 0.7, CH3OH); IR (KBr,
cm-1) HN–H = 3250; HO–H = 3505; 1H NMR (CDCl3,
300 MHz): d (ppm) = 0.91 (d, 3H, J = 6.6 Hz, CH3–i–
Bu), 1.08 (d, 3H, J = 6.6 Hz, CH3–i–Bu), 1.31 (m, 2H,
CH2–i–Bu), 1.94 (m, 1H, CH–i–Bu), 2.31 (s, 3H, CH3–
SO2), 2.54 (s, 1H, OH), 4.20 (d, 1H, J = 9 Hz, NH), 4.55
(m, 1H, CH–NH), 7.06 (m, 4H–Ar), 7.47 (m, 4H–Ar); 13C
NMR (CDCl3, 75 MHz) d = 21.0 (1C, CH3–i–Bu), 24.0
(1C, CH–i–Bu), 24.2 (1C, CH3–i–Bu), 41.4 (1C, CH2–
iBu), 41.8 (1C, CH3–SO2), 59.9 (1C, CH–NH), 80.4(1C,
C–OH), 115.3 (d, 2C, JC–F = 21 Hz, Ar, CH–C–F), 115.4
(d, 2C, JC–F = 21 Hz, Ar, CH–C–F), 127.8 (d, 2C,
JC–F = 7.8 Hz, Ar, CH–CH–C–F), 128.0 (d, 2C,
JC–F = 8.1 Hz, Ar, CH–CH–C–F), 139.5 (d, 1C,
JC–F = 3.4 Hz, Ar C–CH–CH–C–F), 140.9 (d, 1C,
JC–F = 3.3 Hz, Ar, C–CH–CH–C–F), 161.9 (d, 1C,
JC–F = 254 Hz, Ar, C–F), 162.0 (d, 1C, JC–F = 261 Hz,
Ar, C–F); 19F NMR (282,4 MHz, CDCl3): d = -114.6,
-114.4; HRMS [M ? Na]? Calcd for C19H23F2NO3S:
406.1264; Found: 406.1263; Elemental analysis for C19
H23F2NO3S. Calcd: C 59.51 %, H 6.05 %, N 3.65 %;
Found: C 59.55 %, H 6.04 %, N 3.60 %.
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxy-3-phenylpropan-
2-yl)methanesulfonamide
(4d) White
solid;
mp
185–187 °C; [a]2D2 = ? 33.6 (c 0.7, CH3OH); IR (KBr,
cm-1) HN–H = 3322; HO–H = 3498; 1H NMR (CDCl3,
300 MHz): d = 1.99 (s, 3H, CH3–SO2), 2.66 (dd, 1H,
J = 9, 14.1 Hz, CH2–Ph), 3.06 (dd, 1H, J = 2.7, 9 Hz,
CH2–Ph), 4.68 (m, 2H, CH–NH), 7.04–7.33 (m, 9H–Ar),
7.51–7.58 (m, 4H, Ar); 13C NMR (CDCl3, 75 MHz):
d = 38.3 (1C, CH2–Ph), 41.3 (1C, CH3–SO2), 63.1 (1C,
CH–NH), 80.3 (1C, C–OH), 115.3 (t (2d), 4C,
JC–F = 21 Hz, Ar, CH–C–F), 127.2 (1C, Ph, CH), 128.1
(d, 2C, JC–F = 8 Hz, Ar, CH–CH–C–F), 128.5 (d, 2C,
JC–F = 8 Hz, Ar, CH–CH–C–F), 128.9 (2C, Ph, CH),
129.7 (2C, Ph, CH), 137.6 (1C, Ph, CH), 139.2 (d, 1C,
JC–F = 3.3 Hz, Ar, C–CH–CH–C–F), 140.1 (d, 1C,
JC–F = 2.9 Hz, Ar, C–CH–CH–C–F), 161.9 (d, 1C,
JC–F = 246 Hz, Ar, C–F), 162.0 (d, 1C, JC–F = 246 Hz,
Ar, C–F); 19F NMR (282,4 MHz, CDCl3): d = -114.6,
-114.4; HRMS [M ? Na]? Calcd for C22H21F2NO3S:
440.1108; Found: 440.1101; Elemental analysis for C22
H21F2NO3S. Calcd: C 63.29 %, H 5.07 %, N 3.36 %;
Found: C 63.30 %, H 5.12 %, N 3.29 %.
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxypropan-2-yl)-2,4,6-
trimethylbenzenesulfonamide (4g) White solid; mp
77–81 °C; [a]2D2 = ? 4.2 (c 0.7, CH3OH); IR (KBr, cm-1
)
HN–H = 3396; HO–H = 3484; 1H NMR (CDCl3,
300 MHz): d = 1.15 (d, 3H, J = 6.6 Hz, CH3–CH), 2.31
(s, 3H, CH3-mesityl), 2.48 (s, 6H, 2CH3-mesityl), 4.36 (m,
1H, CH-NH), 4.98 (brs, 1H, NH), 6.72 (td, 2H, J = 2.1,
8.7 Hz, Ar), 6.86 (s, 2H–Ar), 6.97 (td, 2H J = 2.1, 8.7 Hz,
Ar), 7.23 (m, 2H–Ar), 7.33 (m, 2H–Ar); 13C NMR (CDCl3,
75 MHz): d = 17.3 (1C, CH3–CH), 20.8 (1C, CH3-me-
sityl), 22.9 (2C, CH3-mesityl), 55.9 (1C, CH–NH), 79.8
(1C, C–OH), 114.7 (d, 2C, JC–F = 21 Hz, Ar, CH–C–F),
115.3 (d, 2C, JC–F = 21 Hz, Ar, CH–C–F), 127.0 (d, 2C,
JC–F = 7.9 Hz, Ar, CH–CH–C–F), 127.3 (d, 2C,
JC–F = 8 Hz, Ar, CH–CH–C–F), 131.9 (2C, mesityl, CH),
134.7 (1C, mesityl, C), 138.4 (2C, mesityl, C), 139.8 (1C,
Ar, C–CH–CH–C–F), 140.0 (1C, Ar, C–CH–CH–C–F),
142.0 (1C, mesityl, C), 161.5 (d, 1C, JC–F = 244 Hz, Ar,
C–F), 161.7 (d, 1C, JC–F = 244 Hz, Ar, C–F); 19F NMR
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxy-3-methylbutan-2-
yl)methanesulfonamide
(4e) White
solid;
mp
161–163 °C; [a]2D2 = ? 25.9 (c 0.7, CH3OH); IR (KBr,
cm-1) HN–H = 3352; HO–H = 3494; 1H NMR (CDCl3,
300 MHz): d = 0.90 (d, 3H, J = 6.6 Hz, CH3–i–Pr), 1.10
(d, 3H, J = 6.6 Hz, CH3–i–Pr), 2.04 (hd, 1H, J = 1.5,
6.6 Hz, CH–i–Pr), 2.26 (s, 3H, CH3–SO2), 2.56 (s, 1H,
OH), 4.41 (dd, 1H, J = 1.5, 9.4 Hz, CH–NH), 4.58 (d, 1H,
J = 9.4 Hz, NH), 7.05 (dd, 4H, JH–H = 8.7 Hz,
JH–F = 17.5 Hz, Ar), 7.47 (dd, 2H, J = 5.1, 8.7 Hz, Ar),
7.53 (dd, 2H, J = 5.1, 8.7 Hz, Ar); 13C NMR (CDCl3,
75 MHz): d = 17.3 (1C, CH3–iPr), 22.5 (1C, CH3–iPr),
28.6 (1C, CH–i–Pr), 41.9 (1C, CH3–SO2), 64.8 (1C, CH–
NH), 81.6 (1C, C–OH), 115.4 (t (2d), 4C, JC–F = 21 Hz,
Ar, CH–C–F), 127.1 (d, 2C, JC–F = 7.1 Hz, Ar, CH–CH–
123

Med Chem Res
(282,4 MHz, CDCl3): d = -115.5, -115.0; HRMS
[M ? Na]? Calcd for C24H25F2NO3S: 468.1421; Found:
468.1421; Elemental analysis for C24H25F2NO3S. Calcd: C
64.70 %, H 5.66 %, N 3.14 %; Found: C 64.68 %, H
5.69 %, N 3.17 %.
Ar, C–F), 163.4 (1C, Ar, C–F); 19F NMR (282,4 MHz,
CDCl3): d = -115.5, -114.9; Elemental analysis for
C26H29F2NO3S. Calcd: C 65.94 %, H 6.17 %, N 2.96 %;
Found: C 65.89 %, H 6.09 %, N 3.02 %.
(S)-N-(1-hydroxy-1,1-bis(4-(trifluoromethyl)phenyl)propan-
2-yl)methanesulfonamide (4j) Yellow viscous oil;
[a]2D2 = ? 16.8 (c 0.7, CH3OH); IR (KBr, cm-1
)
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxy-3-phenylpropan-
2-yl)-2,4,6-trimethylbenzenesulfonamide
(4h) White
solid; mp 91–93 °C; [a]2D2 = ? 7.0 (c 0.7, CH3OH); IR
(KBr, cm-1) HN–H = 3400; HO–H = 3471; 1H NMR
(CDCl3, 300 MHz): d = 2.28 (s, 3H, CH3-mesityl), 2.40
(s, 6H, 2 CH3–mesityl), 2.57 (s, 1H, OH), 2.91 (dd, 1H,
J = 5.7, 14.1 Hz, H–CH–Ph), 3.28 (dd, 1H, J = 4.2, 14.1,
H–CH–Ph), 4.68 (m, 1H, CH–NH), 5.00 (d, 1H,
J = 8.7 Hz, NH), 6.65 (t, 2H, J = 8.7 Hz, Ar), 6.74 (s,
2H–Ar), 6.98 (m, 2H–Ar), 7.07 (t, 2H, J = 8.7 Hz, Ar),
7.20 (m, 5H, Ar), 7.45 (dd, 2H, J = 5.1, 9 Hz, Ar); 13C
NMR (CDCl3, 75 MHz): d = 20.7 (1C, CH3–mesityl),
23.0 (2C, CH3-mesityl), 38.0 (1C, CH2–Ph), 61.1 (1C, CH–
NH), 80.5 (1C, C–OH), 114.7 (d, 2C, JC–F = 21 Hz, Ar,
CH–C–F), 115.5 (d, 2C, JC–F = 21 Hz, Ar, CH–C–F),
126.3 (d, 2C, JC–F = 8.1 Hz, Ar, CH–CH–C–F), 127.0
(1C, Ph, CH), 127.5 (d, 2C, JC–F = 7.8 Hz, Ar, CH–CH–
C–F), 128.8 (2C, Ar, CH), 129.5 (2C, Ar, CH), 131.8 (2C,
Ar, CH), 134.8 (1C, mesityl, C), 136.7 (1C, Ar, C), 137.9
(2C, mesityl, C), 139.7 (d, 1C, JC–F = 3.1 Hz, Ar, C–CH–
CH–C–F), 139.9 (d, 1C, JC–F = 3.1 Hz, Ar, C–CH–CH–
C–F), 141.7 (1C, Ar, C), 161.5 (d, 1C, JC–F = 244 Hz, Ar,
C–F), 161.9 (d, 1C, JC–F = 245 Hz, Ar, C–F); 19F NMR
(282,4 MHz, CDCl3): d = -115.6, -114.6; Elemental
analysis for C30H29F2NO3S. Calcd: C 69.08 %, H 5.60 %,
N 2.69 %; Found: C 69.13 %, H 5.58 %, N 2.65 %.
HN–H = 3322; HO–H = 3464; 1H NMR (CDCl3,
300 MHz): d = 1.27 (d, 3H, J = 6.6 Hz, CH3–CH), 2.50
(s, 3H, CH3–SO2), 4.66 (m, 1H, CH–NH), 4.85 (d, 1H,
J = 9 Hz, NH), 7.61 (m, 6H–Ar), 7.70 (d, 2H, J = 8.4 Hz,
Ar); 13C NMR (CDCl3, 75 MHz): d = 17.9 (1C, CH3–
CH), 41.8 (1C, CH3–SO2), 56.0 (1C, CH–NH), 80.3 (1C,
C–OH), 123.7 (q, 2C, JC–F = 270 Hz, CF3), 125.4 (q, 2C,
JC-F = 3.8 Hz, Ar, CH–C–CF3), 125.7 (q, 2C,
JC–F = 3.8 Hz, Ar, CH–C–CF3), 126.1 (2C, Ar, CH–CH–
C–CF3), 126.4 (2C, Ar, CH–CH–C–CF3), 129.9 (q, 1C,
JC–F = 33 Hz, C–CF3), 130.0 (q, 1C, JC–F = 33 Hz, C–
CF3), 147.1 (1C, Ar, C–CH–CH–C–CF3), 148.06 (1C, Ar,
C–CH–CH–C–CF3); 19F NMR (282,4 MHz, CDCl3):
d = -62.74, -62.71; Elemental analysis for C18H17F6
NO3S. Calcd: C 48.98 %, H 3.88 %, N 3.17 %; Found: C
49.04 %, H 3.89 %, N 3.12 %.
(S)-N-(1-hydroxy-3-phenyl-1,1-bis(4-(trifluoromethyl)phenyl)
propan-2-yl)-2,4,6-trimethylbenzenesulfonamide (4k) White
solid; mp 168–170 °C; [a]2D2 = ? 21.7 (c 0.7, CH3OH); IR
(KBr, cm-1) HN–H = 3322; HO–H = 3464; 1H NMR
(CDCl3, 300 MHz): d = 2.27 (s, 3H, CH3-mesityl), 2.39
(s, 6H, 2 CH3-mesityl), 2.81 (s, 1H, OH), 3.02 (dd, 1H,
J = 4.8, 14.4 Hz, H–CH–Ph), 3.36 (dd, 1H, J = 4.8,
14.4 Hz, H–CH–Ph), 4.81 (m, 1H, CH–NH), 5.14 (d, 1H,
J = 9 Hz, NH), 6.75 (s, 2H–Ar), 6.94–7.03 (m, 2H–Ar),
7.20 (d, 2H, J = 8.4 Hz, Ar), 7.22-7.25 (m, 3H–Ar), 7.36
(d, 2H, J = 8.1 Hz, Ar), 7.61 (s, 4H, Ar); 13C NMR
(CDCl3, 75 MHz): d = 20.6 (1C, CH3–mesityl), 22.8 (2C,
CH3-mesityl), 37.7 (1C, CH2–Ph), 60.4 (1C, CH–NH), 81.0
(1C, C–OH), 124.8 (2C, Ar, CH), 125.0 (q, 2C,
JC–F = 3.8 Hz, Ar, CH–C–CF3), 125.7 (q, 2C,
JC–F = 3.8 Hz, Ar, CH–C–CF3), 125.8 (2C, Ar, CH), 127.2
(1C, Ph, CH), 128.7 (2C, Ar, CH), 129.0 (q, 2C,
JC–F = 32 Hz, Ar, C–CF3), 129.0 (2C, Ar, CH), 131.8 (2C,
Ar, CH), (1C, Ph, C), 136.5 (1C, mesityl, C), 138.0 (2C,
mesityl, C), 142.0 (1C, mesityl, C), 147.4 (1C, Ar, C–CH–
CH–C–CF3), 147.6 (1C, Ar, C–CH–CH–C–CF3); 19F
NMR (282,4 MHz, CDCl3): d = -62.6, -62.6; HRMS
[M ? Na]? Calcd for C32H29F6NO3S: 644.1670; Found:
644.1681; Elemental analysis for C32H29F6NO3S. Calcd: C
61.83 %, H 4.70 %, N 2.25 %; Found: C 61.87 %, H
4.63 %, N 2.32 %.
(S)-N-(1,1-bis(4-fluorophenyl)-1-hydroxy-3-methylbutan-2-
yl)-2,4,6-trimethylbenzenesulfonamide (4i) White solid;
mp 135–137 °C; [a]2D2 = ? 28.7 (c 0.7, CH3OH); IR (KBr,
cm-1) HN–H = 3335; HO–H = 3481; 1H NMR (CDCl3,
300 MHz): d = 0.84 (d, 3H, J = 6.9 Hz, CH3–i–Pr),
0.0.97 (d, 3H, J = 6.9 Hz, CH3–i–Pr), 1.98 (m, 1H, CH–i–
Pr), 2.28 (s, 3H, CH3-mesityl), 2.51 (s, 6H, 2 CH3-mesityl),
2.51 (brs, 1H, OH), 4.36 (dd, 1H, J = 1.5, 9.6 Hz, CH–
NH), 4.87 (d, 1H, J = 9.6 Hz, NH), 6.66 (t, 2H,
J = 8.7 Hz, Ar), 6.80 (s, 2H, Ar), 7.02 (t, 2H, J = 8.7 Hz,
Ar), 7.24 (dd, 2H, J = 5.2, 8.8 Hz, Ar), 7.39 (dd, 2H,
J = 5.1, 9 Hz, Ar); 13C NMR (CDCl3, 75 MHz): d = 17.7
(1C, CH3–i–Pr), 20.7 (1C, CH3–i–Pr), 22.6 (1C, CH3-me-
sityl), 22.9 (2C, CH3-mesityl), 28.9 (1C, CH–i–Pr), 64.7
(1C, CH–NH), 81.7 (1C, C–OH), 114.6 (d, 2C,
JC–F = 21 Hz, Ar, CH–C–F), 115.4 (d, 2C, JC–F = 21 Hz,
Ar, CH–C–F), 126.6 (d, 2C, JC–F = 8.1 Hz, Ar, CH–CH–
C–F), 127.2 (d, 2C, JC–F = 7.8 Hz, Ar, CH–CH–C–F),
131.7 (2C, mesityl, CH), 136.3 (1C, mesityl, C), 137.3 (2C,
mesityl, C), 140.4 (1C, Ar, C–CH–CH–C–F), 140.5 (1C,
Ar, C–CH–CH–C–F), 141.4 (1C, mesityl, C), 163.0 (1C,
(S)-N-(1-hydroxy-1,1-diphenylpropan-2-yl)benzenesulfon-
amide (4l) White solid; mp 113–115 °C; [a]2D2 = ? 11.5
123

Med Chem Res
(c 0.7, CH3OH); IR (KBr, cm-1
) HN–H = 3348;
Swiss mice (20–30 g) were selected one day prior to each
test and were divided into three groups (n = 6). The con-
trol group was pretreated with saline at 10 ml/kg by sub-
cutaneous (s.c) administration. The second group was
pretreated with the reference drug, Acetylsalicylate of
lysine (ASL) at the dose of 200 mg/kg (s.c). The test
groups received an injection of 50 mg/kg of compounds
4a–i by the same route (s.c). Thirty minutes later, animals
of all groups received, by the intraperitoneally (i.p.) route,
10 ml/kg of 1 % acetic acid. The number of writhing was
recorded during 30 min after the acetic acid injection. A
writhe is indicated by abdominal constriction and stretch-
ing of at least one hind limb. Analgesic activity was
expressed as inhibition percent of the usual number of
writhes observed in control animals. The percentages of
inhibition were calculated according to the following
formula:
HO–H = 3496; 1H NMR (CDCl3, 300 MHz): d = 1.14
(3H, Me), 2.85 (brs, 1H, OH), 4.47 (m, 1H, CH–NH), 4.96
(brs, 1H, NH), 7.12–7.28 (m, 4H–Ar), 7.28–7.46 (m, 8H–
Ar), 7.48–7.58 (m, 1H–Ar), 7.62–7.70 (m, 2H–Ar); 13C
NMR (CDCl3, 75 MHz): d = 17.3 (1C, CH3–CH), 55.8
(1C, CH–NH), 80.4 (1C, C–OH), 125.6 (2C, Ph, CH),
125.7 (2C, Ph, CH), 126.8 (2C, Ph, CH), 127.0 (1C, Ph,
CH), 127.2 (1C, Ph, CH), 128.3 (2C, Ph, CH), 128.4 (2C,
Ph, CH), 128.9 (2C, Ph, CH), 132.2 (1C, Ph, CH), 140.9
(1C, Ph, C), 143.9 (1C, Ph, C), 144.0 (1C, Ph, C); Ele-
mental analysis for C21H21NO3S. Calcd: C 68.64 %, H
5.76 %, N 3.81 %; Found: C 68.72 %, H 5.70 %, N
3.84 %.
Pharmacology
Animals
% inhibition ¼ ðNumber of writhesÞcontrol
À ðNumber of writhesÞtreated group
Þ
Wistar rats weighing 150–170 g and swiss albinos
(20–30 g) were obtained from Pasteur Institute (Tunis,
Tunisia). Housing conditions and in vivo experiments were
approved, according to the guidelines established by the
European Union on Animal Care (CCE Council 86/609).
=ðNumber of writhesÞcontrol  100
Statistics
Data are expressed as the mean standard error of the
mean (SEM) of six animals per group. Statistical analysis
was performed using paired-sample T Test (IBM SPSS
Statistics Version 20 software). The significance of dif-
ference was considered to include values of *p \ 0.05;
**p \ 0.01; ***p \ 0.001.
Anti-inflammatory activity
The anti-inflammatory activity of compounds 4a–l on
carrageenan-induced rat paw edema was evaluated by the
method of Winter et al. (1962). Three groups of Wistar rats
(n = 6) were considered. The control group received
2.5 mL/kg of vehicle solution (tween 80/absolute ethanol/
saline solution (0.9 %) in the ratio 1:1:18) by the
intraperitoneally (i.p.) route. The reference group received
DiclofenacÒ which is a non-steroidal anti-inflammatory
drug (10 mg/kg, i.p.) and the test groups received com-
pounds 4c at increasing doses (10, 25 and 50 mg/kg, i.p)
and 4a, b, d–l (50 mg/kg, i.p.). After 30 min, 0.05 ml of a
1 % carrageenan suspension was injected into the left hind
paw. The paw volume up to the tibiotarsal articulation was
measured using a plethysmometer (model 7150, UgoBa-
sile, Italy) at 0 h (V0) (before carrageenan injection) and 1,
2, 3, 4 and 5 h later (VT) (after carrageenan injection). Paw
swelling was determined for each rat and the difference
between VT and V0 was taken as the edema value. The
percent inhibition was calculated by the formula given
below: % Inhibition: [(VT - V0) control–(VT - V0)
treated] 9 100/(VT - V0) control.
Results and discussion
Chemistry
Our synthetic route to target compounds 4a–l are outlined
in scheme 1. The commercially available (L)- amino acids
1, were converted quantitatively to amino acid esters 2 by
use of the SiMe3Cl/MeOH system as described previously
(Jiabo and Yaowu 2008). The N-sulfonylation of amino
acid esters 2 with CH3–SO2–Cl or Ar–SO2–Cl in CH2Cl2
and in the presence of Et3N, afforded the N-sulfonylated
amino acid esters 3a–j in good yields (Anadi et al., 2014).
Compounds 3a–j were subjected to react with Ar–Mg–Br,
in the presence of LiCl, to afford products 4a–l in good to
excellent yields (Table 1). This approach, developed and
used by Knochel and co-workers (Piller et al., 2008) for the
preparation of diaryl compounds from aryl iodide and aryl
magnesium halides, was applied in this work to convert the
ester group of compounds 3a–j to the corresponding fluo-
rine-containing diaryl alcohols 4a–l. This method appears
to be more efficient than the classic use of aryl Grignard
Analgesic activity
The analgesic activity of the compounds of the series was
performed according to the method of Koster et al. (1959).
123

Med Chem Res
Scheme 1 Synthesis of
compounds 4a–l from natural
amino acids. Reagents and
reaction conditions:
(i) SiMe3Cl, MeOH, rt, 12 h;
(ii) R’SO2Cl, Et3N, CH2Cl2,
0 °C-rt, 24 h; (iii) Mg, LiCl,
LiAlH4 (1 %), THF, rt, 1–2 h;
(iv) 3, 24 h, rt; (v) H2SO4
(10 %), 0 °C, 1 h
reagents (without LiCl), especially, when the aryl is sub-
stituted with electron-withdrawing groups such as fluorine
and trifluoromethyl groups. As shown in Table 1, com-
pounds 4a and 4j were obtained in good isolated yields in
the presence of LiCl (4a: 95 % and 4j: 81 %), whereas,
without use of LiCl, lower yields were obtained for these
compounds (4a: 57 % and 4j: 16 %). On the other hand,
we have found that the use of LiAlH4 (1 %) is convenient
and sufficient for activation of magnesium and then avoid
heating for the in situ preparation of the Grignard reagent.
Compounds 4a–l were characterized by physical, chemical
and spectral studies. For example, the IR of 4a showed two
absorption peaks at 3245 and 3515 cm-1 which correspond
to the N–H and the O–H groups, respectively. The 1H
NMR spectrum of 4a displays a broad signal at 2.85 ppm
attributable to the proton of the OH group, and a doublet at
4.98 ppm attributable to the proton of the N–H group (CH–
NH). The signal of the C–OH carbon is observed at
79.9 ppm. These results are in agreement with spectral data
of structural analogues of 4a such as compound 5 (Fig. 1)
(Zhang et al., 2014). The 13C NMR spectrum of 4a dis-
plays two different characteristic signals which correspond
to the diastereotopic C-F groups at 161.6 ppm (d,
JC–F = 245 Hz) and at 161.8 ppm (d, JC–F = 245 Hz).
This non-equivalence was also observed in the 19F NMR
spectrum of 4a which displays two signals of the diaster-
eotopic fluorine atoms at -115.3 and -144.9 ppm (Fig. 1).
method of Winter et al. is shown in Table 2. These results
indicate that the compound 4c tested at 10, 25, and 50 mg/
kg i.p. exhibited potency comparable to DiclofenacÒ since
a significant reduction of the edema was noted even at the
lower dose (Fig. 2). The anti-inflammatory activity of 4c,
at 50 mg/kg appears to be similar to the reference drug
after 2 and 4 h and slightly inferior after 5 h (Table 3;
Fig. 3). Also, the inhibition of edema along the whole
observation period was noted for the rest of the com-
pounds. At 50 mg/kg, the highest reduction of the edema
was observed 5 h after carrageen injection for three com-
pounds of the series: 43.73 % of inhibition for compound
4a, 50 % for compound 4g and 50.19 % for compound 4h,
whereas the reference drug (DiclofenacÒ, 10 mg/kg,) pro-
duced a reduction of 60 % in paw volume. For compounds
4d, 4e and 4f, the greatest reduction of edema was
observed 3 h after carrageen injection with an inhibition
percentage equal to 42.28, 41.97 and 40.32 %, respec-
tively. The rest of the compounds of the series showed a
moderate activity (Table 2).
The SAR study allows us to conclude that the nature of
substituents R and R’ play a major role in the anti-in-
flammatory activity of the structures of the series. In fact,
replacement of the phenyl ring group on R’ by CH3 or a
mesityl group (2,4,6-trimethylphenyl) is accompanied by
an increase in the anti-inflammatory activity. This fact
correlated with literature since the methanesulfonyl moiety
was reported to be present in common anti-inflammatory
structures belonging to the coxibs class (Zarghi and Arfaei
2011). On the other hand, we have found that introducing a
fluorine atom in the para-positions of the two phenyl rings
enhances obviously the anti-inflammatory activity. Indeed,
Pharmacology
The anti-inflammatory potential of compounds 4a–l on
carrageenan-induced rat paw edema determined by the
123

Med Chem Res
Table 1 Synthesis of products 4a–l by reaction of Ar–Mg–Br
Compounds
R
R’
Ar
Yields
(%)
4a
4b
4c
4d
4e
4f
–CH3
–ph
4-F–Ph
4-F–Ph
4-F–Ph
4-F–Ph
4-F–Ph
4-F–Ph
4-F–Ph
4-F–Ph
4-F–Ph
4-CF3–Ph
4-CF3–Ph
Ph
95a (57)b
89a
94a
85a
92a
93a
90a
87a
90a
–Ph–CH2
–CH3
–Ph
–CH3
–PhCH2
–CH(CH3)2
–CH2CH(CH)2
–CH3
–CH3
–CH3
–CH3
4g
4h
4i
2, 4,6-trimethylphenyl
2, 4,6-trimethylphenyl
2, 4,6-trimethylphenyl
–CH3
–Ph–CH2
–CH(CH3)2
–CH3
4j
81c (16)b
78c
92a (75)b
4k
4l
–PhCH2
–CH3
2, 4,6-trimethylphenyl
Ph
LiCl complexes with sulfonyl esters 3a–j
a
4-F–Ph–MgBr. LiCl was prepared in 1 h before the addition of 3
Isolated yield without LiCl
b
c
CF3–Ph–MgBr. LiCl was prepared in 2 h before the addition of 3
Fig. 1 Characteristic NMR chemical shifts of compounds 4a and 5
compound 4a produced 43.73 % of edema inhibition better
than its structural analogue without fluorine 4l (16.55 %).
This fact is not surprising since fluorine is well known
nowadays in medicinal chemistry, and it has become a
common practice to examine the effects of substitution of
fluorine or a trifluoromethyl group on a lead compound
123

Med Chem Res
Table 2 Anti-inflammatory activity evaluation of compounds 4a–l on carrageenan-induced rat paw edema, in comparison to the reference drug,
Diclofenac
Sample
Dose (mg/kg)
Edema volume (10-2mL) (m SEM)
% of edema inhibition
1h
3h
5h
1h
3h
5h
Vehicle (2,5 mL/kg)
–
27.00 0.81
60.75 0.50
72.50 2.64
–
–
–
Diclofenac (reference)
10
50
50
10
25
50
50
50
50
50
50
50
50
50
50
50
16.00 3.65**
22.75 1.12
25.25 3.30***
39.75 3.10**
49.75 3.72
29.00 2.51***
44.10 1.18**
54.25 2.00
41.00
12.50
1.92
58.43
34.56
18.10
34.97
41.97
51.44
37.44
42.38
41.97
40.32
48.14
44.85
34.56
34.97
16.00
16.00
60.00
43.73
30.62
42.00
45.51
54.48
43.44
35.51
24.13
28.62
50.00
50.19
23.10
37.24
18.62
16.55
4a
4b
25.50 2.08
4c
18.75 1.70*
17.00 2.94**
15.00 0.81***
19.50 1.29*
20.00 3.26
39.50 1.29**
35.50 1.50**
29.50 4.20***
38.00 1.63**
35.00 4.08**
35.25 2.62**
36.25 2.75**
31.5 4.20***
33.5 2.64***
39.75 2.06*
39.5 2.38*
42.00 3.16**
39.50 3.00***
33.00 3.26***
41.00 3.16**
46.75 2.42*
55.00 3.74
30.75
40.70
44.00
27.77
25.92
58.33
39.81
37.00
36.11
44.44
38.88
12.00
8.33
4c
4c
4c (racemic)a
4d
4e
4f
11.25 2.50***
16.25 1.25**
17.00 0.81**
17.25 1.70**
15.00 4.61***
16.50 0.57**
23.75 2.62
51.75 0.95
4g
4h
4i
36.25 2.62***
36.00 1.25***
55.75 3.30
4j
45.5 1.29*
4k
4l
51.25 2.21*
51.00 2.70
59.00 2.94
24.75 2.21
60.5 1.00
The most active compound is given in bold. Reference drug is underlined
The values represent the mean difference of volume of paw SEM (n = 6)
* p \ 0.05; ** p \ 0.01; ***p \ 0.001 significantly different from control group
a
Prepared from (D, L)-alanine
inflammatory activity compared to the mono-fluorinated
parent 4c (37.24 vs. 54.48 %). This may be related to the
steric bulk of the trifluoromethyl group at this position,
constraining the phenyl ring to adopt a conformation which
disfavors binding to the appropriate site on the target.
Similarly, the racemic analogue of 4c prepared from
(D,L)-alanine displayed a reduced activity. Thus, 43.44 %
of edema inhibition was observed for 50 mg of the racemic
compound which is equivalent to 25 mg of the (S)-enan-
tiomer and 25 mg of the (R)-enantiomer. In the opposite,
54.48 and 45.51 % of o edema inhibition were described,
respectively, for 50 and 25 mg of the (S)-enantiomer
(Table 2). This let us conclude that the anti-inflammatory
activity of the compounds of our series is depending on the
absolute configuration of the stereogenic center, and it is
more pronounced when the asymmetric carbon has the
(S) configuration.
4.05
4
y = 0,0066x + 3,6649
R² = 0,9945
IC50 = 37,44 mg/Kg
3.95
3.9
3.85
3.8
3.75
3.7
0
10
20
30
40
50
60
Dose (mg/Kg)
Fig. 2 Dose–effect curve 5 h after intraperitoneal administration of
4c (50 mg/kg)
under development. There are patterns to explain how this
atom contributes to the efficiency of a drug: increasing bio-
absorption by lipophilic effects, polar hydrophobicity
enhances binding of fluorinated molecules to protein
recognition sites and selective interactions with amino acid
residues in a binding site (Hagmann, 2008; Kirk, 2006;
Purser et al., 2008).
The evaluation of analgesic potential of the compounds
of the series according to the method of Koster et al.
indicate that some compounds have a significant analgesic
activity; however, the compounds 4c, 4e, 4h and 4i provide
better protection (Table 4) and the compound 4h revealed
to be quite similar to the reference drug (60.43 vs.
60.92 %) (Figs. 4, 5).
Contrary to our expectation, the inclusion of a trifluo-
romethyl group in compound 4j decreased the anti-
123

Med Chem Res
Table 3 Comparison of the anti-inflammatory activities of compound 4c and the reference drug, Diclofenac
Diclofenac (Reference drug)
4c
Dose (m/kg)
Edema volume (10-2 mL) (m SEM)
10
50
1 h
16.00 3.65**
21.50 1.29***
25.25 3.30***
30.00 4.69***
29.00 2.51***
15.00 0.81***
21.00 2.16***
29.50 4.20***
31.00 4.16***
33.00 3.26***
2 h
3 h
4 h
5 h
% of edema inhibition
1 h
2 h
3 h
4 h
5 h
41.00
49.00
58.43
54.54
60.00
44.00
50.29
51.44
53.00
54.48
Reference drug is underlined
Data expressed as mean SEM (n = 6)
*p \ 0.05; **p \ 0.01; ***p \ 0.001 significantly different from the control group
Table 4 Analgesic effect of compounds 4a–i and of the reference
drug (acetylsalicylate of lysine: ASL) in the acetic acid 1 % writhing
test in mice
35
30
25
20
15
10
5
Sample
Dose
(mg/kg)
Number of
writhes SEM
Inhibition of
writhing (%)
4c (50 mg/Kg)
Vehicle (2.5 ml/kg)
68.25 3.61
Acetylsalicylate of
lysine (reference
drug)
200
26.66 3.30***
60.92
Reference (10 mg/Kg)
4a
4b
4c
4d
4e
4f
50
50
50
50
50
50
50
50
50
66.75 4.32
50.75 3.21
37.83 3.97*
62.20 3.56
35.20 4.43**
48.00 4.38
45.00 3.31
27.00 – 1.26***
36.80 3.27*
2.19
25.64
44.57
8.86
0
0
1
2
3
4
5
6
Time (h)
48.42
29.60
34.00
60.43
46.00
Fig. 3 Anti-inflammatory effect of the intraperitoneal administration
of 4c (50 mg/kg, i.p) and of the reference drug (Diclofenac, 10 mg/
kg, i.p) in carrageenan-induced rat paw edema
4g
4h
4i
Conclusion
The most active compounds are given in bold
We have prepared a series of new chiral fluorine-contain-
ing b-hydroxysulfonamides in three steps from natural (L)-
amino acids. The diarylation of amino acid esters with
fluorine-containing ArMgBr-LiCl complexes, in the pres-
ence of LiAlH4 (1 %), have led to the desired products in
good to excellent yields, and appears to be better than the
classic method of the Grignard reagents preparation. This
work showed significant anti-inflammatory and analgesic
activities for some compounds of our prepared series. A
structure–activity relationship study showed that the
(S) configuration on the asymmetric carbon and the pres-
ence of the para-fluorinated di-phenyl groups seem to be
Data expressed as mean SEM (n = 6)
*p \ 0.05; **p \ 0.01; ***p \ 0.001 significantly different from the
control group
necessary for the anti-inflammatory activity. The chiral
fluorine-containing b-hydroxysulfonamides, prepared in
this work, represent, in our acknowledgment, a new class
of anti-inflammatory and analgesic compounds. However,
further studies are needed to explore the molecular target
and the mechanism of action of this class of compounds.
123

Med Chem Res
80
70
60
50
40
30
20
10
0
Bohm HJ, Banner D, Bendels S, Kansy M, Kuhn B, Muller K, Obst-
Sander U, Stahl M (2004) Fluorine in medicinal chemistry.
Chem Bio Chem 5:637–643
¨
¨
Boyd AE (1988) Sulfonylurea receptors, ion channels, and fruit flies.
Diabetes 37:847–850
Carter JS, Kramer S, Talley JJ, Penning T, Collins P, Graneto MJ, Seibert
K, Koboldt CM, Masferrer J, Zweifel B (1999) Synthesis and activity
of sulfonamide-substituted 4,5-diaryl thiazoles as selective cyclooxy-
genase-2 inhibitors. Bioorg Med Chem Lett 9:1171–1174
Drews J (2000) Drug discovery: a historical perspective. Science
287:1960–1964
Hagmann WK (2008) The many roles for fluorine in medicinal
chemistry. J Med Chem 51:4359–4369
Jiabo L, Yaowu S (2008) A convenient synthesis of amino acid
methyl esters. Molecules 13:1111–1119
*
*
**
***
***
Kirk KL (2006) Fluorine in medicinal chemistry: recent therapeutic
applications of fluorinated small molecules. J Fluor Chem
127:1013–1029
Koster R, Anderson M, De Beer EJ (1959) Acetic acid for analgesic
screening. Fed Proc 18:412–415
Sample
Kreft AF, Cole DC, Woller KR, Stock JR, Kutterer KM, Kubrak DM,
Mann CW, Moore JW, Case-Bier DS (2003) Substituted phenyl-
sulfonamide inhibitors beta amyloid production. US Patent
2003-18198, filled June 9, 2003, issued December 18, 2003
Piller FM, Appukkuttan P, Gavryushin A, Helm M, Knochel P (2008)
convenient preparation of polyfunctional aryl magnesium
reagents using a direct magnesium insertion in the presence of
LiCl. Angew Chem Int Ed 47:6802–6806
Fig. 4 Analgesic effect of compounds 4a–i and of the reference drug
(acetylsalicylate of lysine: ASL) in the acetic acid 1 % writhing test
in mice. The values represent number of writhes SEM.*p \ 0.05;
**p \ 0.01; ***p \ 0.001 significantly different from the control
group
70
60
50
40
30
20
10
0
Purser S, Moore PR, Swallow S, Gouverneur V (2008) Fluorine in
medicinal chemistry. Chem Soc Rev 37:320–330
Supuran CT (2002) Indisulam. Eisai. IDrugs 5:1075–1079
Supuran CT, Conroy CW, Maren TH (1996) Carbonic anhydrase
inhibitors: synthesis and inhibitory properties of 1,3,4-thiadia-
zole-2,5-bissulfonamide. Eur J Med Chem 31:843–846
Supuran CT, Scozzafava A, Clare BW (2002) Bacterial protease
inhibitors. Med Res Rev 22:329–372
Supuran CT, Scozzafava A, Casini A (2003) Carbonic anhydrase
inhibitors. Med Res Rev 23:146–189
Thornber CW (1979) Isosterism and molecular modification in drug
design. Chem Soc Rev 8:563–580
Tozkoparan B, Kupeli E, Yesilada E, Ertan M (2007) Preparation of
5-aryl-3-alkylthio-l,2,4-triazoles and corresponding sulfones
with antiinflammatory-analgesic activity. Bioorg Med Chem
15:1808–1814
Sample
Tsai W-J, Shiao Y-J, Lin S-J, Chiou W-F, Lin L-C, Yang T-H, Teng
C-M, Wu T-S, Yang L-M (2006) Selective COX-2 inhibitors.
Part 1: synthesis and biological evaluation of phenylazoben-
zenesulfonamides. Bioorg Med Chem Lett 16:4440–4443
Winter CA, Risley GA, Nuss GW (1962) Carrageenin-induced edema
in hind paw of the rat as an assay for antiinflammatory drugs.
Proc Soc Exp Biol Med 111:544–547
Fig. 5 Percentage inhibition of writhing for compounds 4a–i and the
reference drug (acetylsalicylate of lysine: ASL) in the acetic acid 1 %
writhing test in mice
´ ´
Acknowledgments We gratefully thank the ‘Direction generale de la
´
Recherche scientifique et de la Renovation technologique’ and the
`
´
‘Ministere de l’Enseignement superieur’ (Tunisia) for their generous
support of our program. We are thankful to Pr. Jean Daniel Brion
(University Paris Sud, Faculty of Pharmacy Chatenay-Malabry) for
help and for HRMS analysis.
Yi-Feng Z, Zhi-Jian Li Q, Jin-Yan L, Feng-Bo R, Rui W (2009)
Asymmetric addition of phenylacetylene to aromatic ketones
catalyzed by zinc or titanium complexes with chiral hydroxy-
sulfonamide. Chirality 21:473–479
Zarghi A, Arfaei S (2011) Selective COX-2 Inhibitors: a review of their
structure activity relationships. Iran J Pharm Res 10:655–683
Zarghi A, Zebardast T, Hakimion F, Shirazi FH, Rao PN, Knaus EE
(2006) Synthesis and biological evaluation of 1,3-diphenylprop-
2-en-1-ones possessing a methanesulfonamide or an azido
pharmacophore as cyclooxygenase-1/-2 inhibitors. Bioorg Med
Chem 14:7044–7050
Zhang X, Teo WT, Rao W, Ma D-L, Leung C-H, Chan PWH (2014)
Synthesis of highly substituted indene derivatives by Brønsted
acid catalyzed Friedel–Crafts reaction of homoallylic alcohols.
Tetrahedron Lett 55:3881–3884
References
Anadi S, Laxminarayan S, Babu V, Duraikkannu L (2014) Synthesis
of glycopeptoid sulfonamides diversifying N-glycopeptide link-
age region mimics. RSC Adv 4:18038–18043
Biffinger JC, Kim HW, DiMagno SG (2004) Fluorine in the life
sciences. Chem Bio Chem 5:622–627
123