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has been proposed that quinolone 3-esters 1 (Scheme 1) target the
Qo site of the enzyme in the bc1 complex, leading to a drop of
mitochondrial function (relevant to provide intermediates for py-
rimidine and ATP synthesis),18,19 collapse of the trans-membrane
electrochemical potential and parasite death.20 However, com-
pounds 1 present some liabilities, such as poor solubility (poor
pharmacokinetic profile).
ethoxymethylenemalonate (9.4 mL; 45.7 mmol) were stirred at
110 ꢀC, overnight. The reaction mixture was cooled, hexane was
added, and the precipitate was collected by filtration to give diethyl
2-((3-iodo-phenylamino)methylene)malonate
(97%). Melting range 86.4e87.9 ꢀC. 1H NMR (400 MHz, CDCl3)
10.97 (d, J¼13.5 Hz, 1H), 8.47e8.42 (m, 1H), 7.51e7.46 (m, 2H),
7.11e7.08 (m, 2H), 4.28 (dq, J¼19.1, 7.1 Hz, 4H), 1.36 (dt, J¼16.8,
4 as white solid
d
7.1 Hz, 6H). 13C NMR (100 MHz, CDCl3)
d 168.9, 151.3, 140.4, 133.8,
131.2, 126.0, 116.4, 95.0, 94.6, 60.6, 60.3, 14.4, 14.2. MS (ESþ) m/z 412
(MþNa)þ Acc. mass found: 412.0020, calculated 412.0022 for
C14H16INO4 Na.
2.1.3. Preparation of ethyl 4-oxo-7-iodo-quinoline-3-carboxylate
(OIQC, 1). Diethyl 2-((3-iodo-phenylamino)methylene)malonate 4
(10.14 g; 26.1 mmol) was suspended in Dowtherm A (80 mL), under
a nitrogen atmosphere, and the mixture was heated at 250 ꢀC for
3 h. The reaction mixture was cooled to room temperature. The
solid precipitate was filtered, washed with hexane and diethyl
ether, and dried to afford ethyl 4-oxo-7-iodo-quinoline-3-
carboxylate OIQC, 1 (R¼I) as white solid (44%). Melting range
Scheme 1. General structure for target 7-substituted quinolones 3-esters (1) and for
7-substituted 4-chloroquinolines 3-esters (2).
It is proposed that structure-based optimization of 1 may be
achieved by altering the nature of the substituent in position 7. As
such, a representative library of compounds 1 for SAR studies is
required, and these studies should provide compounds with im-
proved pharmacological profile that have the potential to be taken
forward as drug leads. Ethyl 4-chloro-7-iodoquinoline-3-
carboxylate (2, CIQCeScheme 2), proved to be instrumental as in-
termediate for easy access to a range of new quinolone 3-esters 1.
306e308 ꢀC. 1H NMR (400 MHz, (CD3)2SO)
d 8.56 (s, 1H), 8.15 (s,
1H), 8.02 (s, 1H), 7.88 (d, J¼8.5 Hz, 1H), 7.73 (d, J¼8.4 Hz, 1H),
4.25e4.16 (q, J¼7.1 Hz, 2H), 1.27 (t, J¼7.1 Hz, 3H). MS (ESþ) m/z 366
(MþNa)þ Acc. mass found: 365.9591; calculated for C12H10INO3Na:
Scheme 2. Synthetic approach to ethyl 4-oxo-7-iodoquinoline-3-carboxylate, OIQC (1, R¼I) and to ethyl 4-chloro-7-iodoquinoline-3-carboxylate, CIQC (2, R¼I). Conditions:
(a) 110 ꢀC, o.n.; (b) Dowtherm A, 250 ꢀC, 3 h; (c) POCl3, 97 ꢀC, o.n.
We report the synthesis and detailed structure of CIQC. The
monomeric structure of CIQC was studied using the matrix iso-
lation technique coupled to infrared spectroscopy and contempo-
rary molecular orbital calculations. The structure of crystalline CIQC
was studied by X-ray crystallography and vibrational spectroscopy.
365.9603. CHNS for C12H10INO3 requires C 42.01%, H 2.94%, N 4.08%,
found C 42.17%, H 2.84%, N 3.95%.
2.1.4. Preparation of ethyl 4-chloro-7-iodo-quinoline-3-carboxylate
(CIQC, 2). Ethyl 4-oxo-7-iodo-quinoline-3-carboxylate OIQC
(0.7 g; 2.04 mmol) was suspended in phosphoryl chloride (5 mL),
under a nitrogen atmosphere, and the resulting mixture was
refluxed at 97 ꢀC overnight. The mixture was cooled to room
temperature, poured into a beaker of ice, stirred for 1 h and then
extracted with chloroform. Organic layers were collected, dried
under MgSO4 and the solvent was removed to afford ethyl 4-
chloro-7-iodo-quinoline-3-carboxylate CIQC, 2 (R¼I) as yellow
solid (95%). Melting range 269e271 ꢀC. 1H NMR (400 MHz, CDCl3)
2. Experimental and computational methods
2.1. Synthesis
2.1.1. General methods. All reagents and solvents were purchased
from commercial sources and used as received. When necessary,
solvents were freshly distilled from appropriate drying agents be-
fore use. The reactions were monitored by TLC, using silica gel F254
plates. Whenever required, inorganic solids were removed by fil-
tration through a layer of CeliteÒ 512 medium. NMR spectra for
compounds, in appropriate solvents (D6-DMSO or D1-chloroform),
d
9.19 (s, 1H), 8.60 (s, 1H), 8.12 (d, J¼8.9 Hz, 1H), 7.99 (d, J¼1.6 Hz,
1H), 4.50 (q, J¼7.1 Hz, 2H), 1.47 (t, J¼7.1 Hz, 3H. 13C NMR (100 MHz,
CDCl3)
d 164.18, 150.95, 149.75, 138.69, 137.29, 126.59, 125.52,
123.33, 99.18, 62.28, 14.25. MS (ESþ) m/z 361.9/363.9 [MþH]þ.
CHNS for C12H9ClINO2 requires C 39.86%, H 2.51%, N 3.87%; found C
39.28%, H 2.73%, N 3.56%.
were measured using TMS as internal reference (
d
¼0.0 ppm).
Chemical shifts ( ) are described in parts per million (ppm). Split-
d
ting patterns are designated as s (singlet), d (doublet), t (triplet), q
(quartet) and m (multiplet). NMR spectra for target compounds,
operated at 400 and 100 MHz, for 1H and 13C, respectively, are
provided as Supplementary Data (Figs. S1eS5). Melting points were
recorded on a Stuart Scientific SMP3 melting point apparatus and
are uncorrected. Mass spectra were recorded using Micromass LCT,
via electrospray (ES), and are provided as Supplementary Data
(Figs. S6eS8). Elemental analyses (CHNS) were performed at the
University of Liverpool, Department of Chemistry.
2.2. X-ray diffraction studies
A single crystal X-ray Diffraction (XRD) study of the title com-
pound (CIQC) was performed at room temperature on a Bruker
APEXII diffractometer using graphite monochromatized Mo Ka ra-
ꢀ
diation (
l
¼0.71073 A). The unit cell derived from the first 36 CCD
frames was found to be hexagonal with cell parameters,
a¼b¼17.7928(2) A, c¼6.98300(10) A,
a
¼b
¼90ꢀ,
g
¼120ꢀ. Systematic
ꢀ
ꢀ
absences pointed to the structure belonging to either P63 or P63/m
space groups, the latter being confirmed during structure solution
and refinement. The refined structural model gave a final R1 factor
2.1.2. Preparation of diethyl 2-((3-iodo-phenylamino)methylene)
malonate (4). 3-Iodo-aniline 3 (5 mL; 41.6 mmol) and diethyl