2
H. M. Faidallah et al.
J Enzyme Inhib Med Chem, Early Online: 1–7
exposure to UV lamp at ꢀ 254. Biological testing was performed 4-[3-Aryl-5–(4-fluorophenyl)pyrazole-1-yl]benzenesulfonamide
in the Faculty of Medicine University of Alexandria, Egypt. (4 and 5)
Reagents were of analytical grade and were used without further
To a stirring suspension of the appropriate pyrazoline derivative
purification.
(0.01 mol) in water (10 mL), 15 mL of 5% bromine water was
gradually added over a period of 30 min at room temperature.
After stirring for another 3 h, the pyrazole derivatives thus formed
General procedure for the preparation of 1-fluorophenyl-
were collected by filtration, thoroughly washed with water and
3-substituted propen-1-one (Chalcones) (1a–d)
dried. They were recrystallized from ethanol.
A solution of 4-fluorobenzaldehyde (1.24 g, 10 mmol) in ethanol
(20 mL) was added to a stirred solution of appropriate ketone N1-Substituted-N3-{4-[(3-aryl-5–(4-fluorophenyl)-4,5-dihydro-
(1.12 g, 10 mmol) in ethanolic potassium hydroxide (20 mL, 20%) pyrazol-1-yl]benzenesulfonyl}urea derivatives (6–17)
and stirring was maintained for 6–8 h at room temperature. The
A mixture of the appropriate pyrazoline (10 mmol) and anhydrous
reaction mixture was then poured onto cold water (200 mL) and
K2CO3 (1.4 g, 10 mmol) in dry acetone (25 mL) was heated under
left overnight. The precipitated solid was collected, washed with
reflux with the corresponding isocyanate (10 mmol) for 18 h. The
water, dried and recrystallized from ethanol.
solvent was removed in vacuo and the remaining solid residue was
dissolved in water (30 mL). After neutralization of the resulting
3-(4-Bromophenyl)-1-(4-fluorophenyl)propen-1-one (1a)
solution with 2N HCl, the precipitated crude product was filtered,
Recrystallized from ethanol as needles; (2.9 g, 96%), m.p. 140– washed with water, dried and recrystallized from a proper solvent
142 ꢁC; ꢁmax (cmꢂ 1, KBr): 1644 (C¼O). 1H NMR (ꢂ/ppm, (Table S1).
DMSO-d6): ꢂ 7.20 (d, J¼ 24 Hz, 1H, H-a)7.78 (d, J ¼ 24 Hz, 1H,
H-b), 7.05–7.89 (m, 8H, Ar-H). 13C NMR (ꢂ/ppm, DMSO-d6): N1-Substituted-N3-{4-[(3-aryl-5–(4-fluorophenyl)-4,5-dihydro-
129.15 (C-a), 142.99 (C-b), 116.20, 121.14, 128.44, 130.23, pyrazol-1-yl]benzenesulfonyl}thiourea derivatives (18–32)
131.08, 131.63, 134.97, 163.82 (Ar-C), 187.92 (C¼O). Anal. %
A solution of the appropriate isothiocyanate (10 mmol) in dry
Calcd for C15H10BrFO: C, 59.04; H, 3.30. Found: C, 58.92;
acetone (5 mL) was added to a mixture of the pyrazoline
H, 3.41.
(10 mmol) and anhydrous K2CO3 (1.4 g, 10 mmol) in dry acetone
(25 mL). The resulting reaction mixture was heated under reflux
1-(4-Fluorophenyl)-3-(4-tolyl)propen-1-one (1b)
for 10 h. The reaction mixture was worked up as mentioned
Recrystallized from ethanol as needles; (2.3 g, 94%), m.p.134– previously for compounds 6–17. The crude products were
136 ꢁC; ꢁmax (cmꢂ 1, KBr): 1648 (C¼O). 1H NMR (ꢂ/ppm, recrystallized from the proper solvent (Table S1).
DMSO-d6): ꢂ 2.39 (s, 3H, CH3), ꢂ 7.47 (d, J ¼ 24 Hz, 1H, H-a),
7.77 (d, J ¼ 24 Hz, 1H, H-b), 7.09–7.94 (m, 8H, Ar-H). 13C NMR 3-Substituted-2-[4–(5-fluorophenyl-3-substituted-4,5-dihydropyr-
(ꢂ/ppm, DMSO-d6): 21.71 (CH3), 129.38 (C-a), 143.76 (C-b), azol-1-yl)benzenesulfonylimino]-4-oxothiazolidines (33–37)
116.19, 121.81, 128.65, 130.34, 131.29, 135.56, 143.09, 164.85
To a solution of the appropriate thiourea derivative (0.01 mol) in
(Ar-C), 189.80 (C¼O). Anal. % Calcd for C16H13FO: C, 79.98; H,
absolute ethanol (20 mL) was added ethyl bromoacetate (1.84 g,
5.45. Found: C, 80.10; H, 5.41.
0.011 mol) and anhydrous sodium acetate (1.64 g, 0.02 mol). The
reaction mixture was heated under reflux for 2 h. After cooling,
1-(4-Fluorophenyl)-3-(2-furyll)propen-1-one (1c)
the reaction mixture was poured into ice-cold water (30 mL). The
Recrystallized from ethanol as needles; (1.9 g, 88%), m.p. 110– solid product thus formed was filtered, washed with water, dried
112 ꢁC; ꢁmax (cmꢂ 1, KBr): 1650 (C¼O). 1H NMR (ꢂ/ppm, and recrystallized from the proper solvent (Table S1).
DMSO-d6): ꢂ 7.25 (d, J ¼ 24 Hz, 1H, H-a), 7.80 (d, J ¼ 24 Hz,
1H, H-b), 6.81–7.88 (m, 8H, Ar-H). 13C NMR (ꢂ/ppm, DMSO- 3-Substituted-2-[4–(5-fluorophenyl-3-substituted-4,5-pyrazol-1-
d6): 129.55 (C-a), 143.08 (C-b), 111.89, 112.45, 116.72, 131.43, yl)benzenesulfonylimino]-thiazolines (38 and 39)
132.83, 145.32, 155.65, 166.02 (Ar-C), 188.92 (C¼O). Anal. %
A solution of the appropriate thiourea derivative (0.01 mol) in
Calcd for C13H9FO2: C, 72.22; H, 4.20. Found: C, 72.34; H, 4.40.
absolute ethanol (20 mL) was refluxed with phenacyl bromide
(2.2 g, 0.011 mol) and anhydrous sodium acetate (1.64 g,
1-(4-Fluorophenyl)-3-(2-pyidyl)propen-1-one (1d)
0.02 mol) for 3 h. During reflux, the solid product was partially
Recrystallized from ethanol as needles; (2.0 g, 89%), m.p. 98– separated in the reaction mixture. The mixture was allowed to
100 ꢁC; ꢁmax (cmꢂ 1, KBr): 1646 (C¼O). 1H NMR (ꢂ/ppm, attain room temperature and the solid product was filtered,
DMSO-d6): ꢂ 7.23 (d, J ¼ 24 Hz, 1H, H-a), 7.86 (d, J ¼ 24 Hz, washed with cold ethanol, dried and recrystallized from ethanol.
1H, H-b), 7.10–7.87 (m, 8H, Ar-H). 13C NMR (ꢂ/ppm, DMSO-
d6): 129.02 (C-a), 146.36 (C-b), 121.76, 122.26, 116.75, 131.73,
Biological evaluation
132.32, 136.87, 149.08, 155.73, 167.03 (Ar-C), 187.2 (C¼O).
Anal. % Calcd for C14H10FNO: C, 74.00; H, 4.44; N, 6.16. Found: Procedure for antidiabetic activity
C, 74.21; H, 4.52; N, 6.23.
Compounds 2–7, 10, 11, 14, 15, 18, 21, 22, 25, 27, 30, 31 and
33–39 were tested for hypoglycemic activity using alloxan-treated
4-[3-Aryl-5-(4-fluorophenyl)-4,5-dihydropyrazole-1-yl]benzene-
female albino mice weighing 20 g. Alloxan 100 mg/kg was
sulfonamide (2 and 3)
injected into the tail vein in a 10 mg/mL saline solution
A solution of the appropriate chalcone (0.02 mol) in ethanol (Supplementary material). Three days later, the mice were given
(25 mL) was refluxed with p-sulfonylphenylhyrazine hydrochlor- the test compounds orally in suspension in 1% carboxymethyl-
ide (4.9 g, 0.022 mol) for 3 h. The reaction mixture was cellulose solution at the rate of 0.2 mmol/kg of the body weight.
concentrated, and the separated product was filtered, washed Each day, a group of four mice was used as a control group and
with cold ethanol/water (20:80) mixture and recrystallized from one group of five mice was given the standard 100 mg of
ethanol (Table S1).
phenformin/kg. Up to six groups of four mice received the test