A. Mital et al. / European Journal of Medicinal Chemistry 103 (2015) 530e538
537
Table 3
In vivo antimalarial Activity against P. berghei (ANKA).
Dose (mg/kg/day ꢃ 4)
Route
% Reduction parasitaemia P. berghei ANKA GFP
Survival (days)
20
50
10
ipa
ip
12
99.97
6
20
7
Chloroquine
Control
a
ip: intraperitoneal route of administration.
Table 4
Physicochemical data of 20.
Compound
MW
H-bond
Don
0
PSA
63
FRB
4
LogDa pH 7.4
7.1
Solubility (
pH 2.0
mg/ml)
Acc
4
pH 6.5
20
473.6
<0.8
0.8e1.6
a
Value measured using the chromatographic gLogD technique.
Table 5
Metabolic stability of compound 20 based on NADPH-dependent degradation profiles in human/mouse liver microsomes.
Compound
Species
In vitro
CLint
Microsome predicted in vivo
CLint (mL/min/kg)
Microsome predicted hepatic
extraction ratio EH
Metabolites
detected
a
a
(ml/min/mg Protein)
20
Human
Mouse
0.36
0.055
42
216
0.67
0.71
None
None
a
Intrinsic clearance.
conducted with a Waters Xbridge C18 column, 50 mm ꢃ 2.1 mm,
3.5
m particle size; mobile phase, water/acetonitrile þ0.1%
7.3. General procedure for the microwave-accelerated synthesis of
2,5-dimethyl-1-aryl-1H-pyrroles (6aei): [7]
m
HCOOH, or water/acetonitrile þ 0.1% NH3; linear gradient from
80:20 to 5:95 over 3.5 min and then held for 1.5 min; flow rate of
0.5 mL minꢂ1. All assay compounds had a measured purity of ꢄ95%
(by total ion current (TIC) and UV) as determined using this
analytical LCꢂMS system. High resolution electrospray measure-
ments were performed on a Bruker DaltonicsMicrOTOF mass
spectrometer.
2,5-Hexandione (4) (1 mmol), the appropriate aniline (5a-i)
(1.2 equiv) and p-toluenesulfonic acid bound with silica gel
(0.4 equiv) were mixed in oven dried pressure vials with magnetic
stir bars. The vessel was placed in a microwave oven and heated
(180 ꢀC, 15e20 min) under microwave irradiation (0e400 W at
2.45 GHz), then stirred for 15 min at room temperature. The silica
residue was removed by filtration, washing with DCM (10 mL) The
solvent was removed under reduced pressure to give the 2,5-
dimethyl-1-aryl-1H-pyrroles (6a-i) (Purity >95% by HPLC, 80e90%
yield), which were used without further purification.
7.2. (Z)-3-Cyclohexyl-2-(phenylimino)thiazolidin-4-one (3)
7.4. General procedure for the synthesis of 2,5-dimethyl-1-aryl-3-
formylpyrroles (7aei): [7]
As we have previously described [7] phosphorous oxychloride
(6 mmol) was added dropwise to stirred ice-cooled DMF (12 mL)
under a N2 atmosphere. The mixture was kept at room temperature
for 15 min and then a solution of the appropriate 2,5-dimethyl-1-
aryl-1H-pyrrole (6aei) (1 mmol) in DMF (5 mL) was added and
the mixture then heated at 100 ꢀC for 3 h under a N2 atmosphere.
After cooling 30% NaOH was added dropwise to adjust to pH ~10.
The solid precipitate was filtered, washed with water and dried in
vacuo to afford the 2,5-dimethyl-1-aryl-3-formylpyrrole (7aei)
(80e95% yield), which was used without further purification.
A mixture of 3-cyclohexyl-1-phenyl-2-thiourea (5 g, 21 mmol),
monochloroacetic acid (2.02 g, 21 mmol), and anhydrous sodium
acetate (1.75 g, 21 mmol) in absolute ethanol (100 mL) was refluxed
for 8e10 h. The reaction mixture was filtered and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on a silica gel column (dichloromethane/
hexane) to give (1.44 g, 25%) of 3 as a yellowish solid, mp. 88-90 ꢀC.
7.5. General condensation procedure for cyclohexyl-2-
(phenylimino)thiazolidin-4-one; 3-methyl-2-(phenylimino)
thiazolidine-4-one; 3-methyl-2-(methylimino)thiazolidine-4-one;
thiazolidine-2,4-dione; 3-methyl thiazolidine-2,4-dione and
imidazolidine-2,4-dione derivatives (20e54)
1H NMR (500 MHz; CDCl3/Me4Si):
d 7.28 (m, 2H), 7.06 (m, 1H), 6.86
(m, 2H), 4.39 (m, 1H), 3.65 (s, 2H), 2.34 (m, 2H), 1.79 (d, 2H,
J ¼ 13.45 Hz), 1.64 (d, 2H, J ¼ 4.9 Hz), 1.59 (d, 1H, J ¼ 12.75 Hz), 1.30
(m, 2H), 1.17 (m,1H); 13C NMR (125 MHz, CDCl3/Me4Si):
d 172.1,
154.6, 148.5, 129.3 (2C), 124.5, 120.9 (2C), 56.1, 32.5 (2C), 28.1 (2C),
26.1, 25.1; HRMS (m/z): [MHþ] calcd for C15H18FN2OS, 275.0154;
found 275.2415.
To a solution of cyclohexyl-2-(phenylimino)-4-thiazolidineione,
3-methyl-2-(phenylimino) thiazolidine-4-one, thiazolidine-2,4-
dione, 3-methyl thiazolidine-2,4-dione or imidazolidine-2,4-