Antimalarial Cryptolepine Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2707
then heated with H2SO4, heating to temperatures no higher
than 70 °C. When this method was originally developed, H2-
SO4 then available was probably less concentrated that the
98% used now; the use of concentrated H2SO4 often leads to
the formation of byproducts including a black resin that is
difficult to filter. The most satisfactory results were obtained
with acid corresponding to the monohydrate; at lower concen-
trations ring closure to form isatins was poor. When the
reaction proceeded so as to give a good yield, the solution
usually became violet. The reaction mixture was quenched by
pouring onto ice when the crude isatin usually precipitated.
The isatin was purified by dissolving in aqueous NaOH and
adjusting the pH to neutrality when dark, resinous byproducts
usually separated. On acidification, the released substituted
isatinic acid eliminated a molecule of water on ring closure to
form the isatin, sometimes slowly.
Ortho-, meta-, and para-substituted anilines formed 7-, a
mixture of 4- and 6-, and 5-substituted isatins, respectively.
Mixtures of 4- and 6-substituted derivatives were separated18
by acidification of the sodium isatinate solution with acetic
acid, when the 4-substituted isatin was released (usually as
red needles). The mother liquors were acidified with HCl, when
the 6-substituted isatin was released, usually as yellow plates.
The reaction between some isatin precursors and H2SO4
resulted in a red solution instead of violet, and no isatin was
deposited on quenching with ice. Ether extraction of the
quenched reaction mixture extracted a small amount of
material, and by repeated extraction with ether and back-
extraction into a small volume of aqueous NaOH, a small
amount of the expected isatin was obtained on acidification.
The red ether-insoluble byproduct may have been an isatin
sulfonic acid.
General Method for Preparation of Halogenated Cryp-
tolepine Derivatives (11a-o). O,N-Acetylindoxyl (6a) (5 g,
23 mmol) for 11a-e and 11g-j, 5-bromo-O,N-acetylindoxyl
(6b) (6.84 g, 23 mmol) for 11k-n, or 6-chloro-O,N-acetylin-
doxyl (6c) (6.11 g, 23 mmol) for 11f and 11o and water (50
mL) were stirred under nitrogen at room temperature. A
solution of isatin (7a) or a derivative 7b-j (23 mmol) and KOH
(26 g, 0.46 M) in water (50 mL) was slowly added. The reaction
mixture was refluxed for 4 h and then cooled to 70 °C; air was
then bubbled through the liquid for 20 min. The mixture was
filtered, and the filtrate was acidified to pH 1 with concen-
trated HCl. The precipitate of quindoline-11-carboxylic acid
derivative 8a-o was collected, washed with water, dried, and
used for the next step without further purification. Decar-
boxylation was carried out by refluxing the latter product with
diphenyl ether (50 mL) for 6 h. After the mixture was cooled,
it was poured into petroleum ether (200 mL) and allowed to
stand overnight at 4 °C. The precipitate was collected, washed
with petroleum ether, and dried. The product, a quindoline
derivative 9a-o, was then dissolved in the minimum amount
of tetramethylenesulfone (5-10 mL), and an excess of io-
domethane (2-3 mL) was added. The reaction vessel was
sealed and heated with stirring at 60 °C overnight. When cool,
the reaction mixture was poured into ether (200 mL), and the
reaction vessel was washed with a little methanol; this was
then added to the ether that was allowed to stand overnight
at 4 °C. The precipitate of the cryptolepine derivative as the
hydroiodide salt 10a-o was collected and washed with ether
and then dissolved in a mixture of chloroform:methanol:NH4-
OH (35%), 90:10:1. The solution was filtered, washed with
water, dried over anhydrous Na2SO4, filtered again, and
evaporated to dryness under reduced pressure (40 °C). Puri-
fication was carried out by column-chromatographing the
product over silica gel G (60 µM, TLC grade), under positive
pressure eluting with chloroform containing increasing amounts
of methanol. Cryptolepine derivatives 10a-o were converted
to their hydrochloride salts 11a-o by adding HCl in methanol
(5%) and then crystallizing from chloroform/methanol or
chloroform/methanol/ethyl acetate.
NMR of free base (CDCl3, δ): 4.70 (3H, s, NCH3), 7.02 (1H, t,
J ) 7.4 Hz, 7 or 8-H), 7.54 (1H, t, J ) 6.7 Hz, 7 or 8-H), 7.78
(1H, d, J ) 8.4 Hz, 6-H), 8.10 (1H, d, J ) 8.4 H, 9-H), 8.21
(2H, m, 3-H, 4-H), 8.61 (1H, s, 11-H). MS (EI, m/z, relative
intensity, %) 301 (25) [M+], 286 (71), 266 (52), 252 (100), 217
(25), 190 (12), 142 (52). Anal. (C16H10N2Cl2‚1.5HCl) C, H, N.
2,3-Dichlorocryptolepine Hydrochloride (11c). The
title compound was prepared as above from 6a (23 mmol, 5.0
1
g) and 7c (23 mmol, 4.95 g). Yellow crystals, yield 1.1%. H
NMR of free base (CDCl3, δ): 4.80 (3H, s, NCH3), 7.05 (1H, t,
J ) 7.4 Hz, 7 or 8-H), 7.55 (1H, t, J ) 7.2 Hz, 7 or 8-H), 7.56-
8.11 (3H, m, 3Ar-H), 8.63 (1H, s, 1 or 4-H), 9.14 (1H, s, 11-H).
MS (EI, m/z, relative intensity, %) 301 (18) [M+], 288 (66), 286
(100), 252 (58), 216 (16), 188 (7), 142 (28). Anal. (C16H10N2-
Cl2‚HCl) C, H, N.
3-Chlorocryptolepine Hydrochloride (11d). The title
compound was prepared as above from 6a (23 mmol, 5.0 g)
and 7d (23 mmol, 4.18 g). Yellow crystals, yield 8.51%. 1H
NMR of free base (CDCl3, δ): 4.70 (3H, s, NCH3), 6.97 (1H, t,
J ) 7.4 Hz, 7 or 8-H), 7.51 (1H, t, J ) 6.9 Hz, 7 or 8-H), 7.54
(1H, d, J ) 8.7 Hz, 6-H), 7.80 (1H, d, J ) 8.7 Hz, 9-H), 8.03
(1H, s, 4-H), 8.07 (1H, d, J ) 2.97 Hz, 1-H), 8.10 (1H, d, J )
3.5 Hz, 2-H), 8.70 (1H, s, 11-H). MS (EI, m/z, relative intensity,
%) 267 (100) [M+], 251 (35), 231 (8), 222 (8), 216 (12), 190 (4).
Anal. (C16H11N2Cl‚HCl) C, H, N.
4-Chlorocryptolepine Hydrochloride (11e). The title
compound was prepared as above from 6a (23 mmol, 5.0 g)
and 7f (23 mmol, 4.18 g). Yellow crystals, yield 4.1%. 1H NMR
of free base (CDCl3, δ): 4.80 (3H, s, NCH3), 7.05 (1H, t, J )
7.4 Hz, 7 or 8-H), 7.45 (1H, dd, 1-H), 7.55 (1H, t, J ) 6.9 Hz,
7 or 8-H), 7.85 (2H, m, 6-H, 9-H), 8.15 (2H, m, 2-H, 3-H), 8.80
(1H, s, 11-H). MS (EI, m/z, relative intensity, %) 266 (84) [M+],
252 (100), 232 (15), 216 (13), 190 (6), 126 (12), 108 (5). Anal.
(C16H11N2Cl‚1.5HCl‚2H2O) C, H, N.
8-Chlorocryptolepine Hydrochloride (11f). The title
compound was prepared as above from 6c (23 mmol, 6.11 g)
and 7a (23 mmol, 3.38 g). Yellow crystals, yield 15%. 1H NMR
of free base (CDCl3, δ): 4.80 (3H, s, NCH3), 7.01 (1H, dd, J )
2.0, 9.2, Hz, 1-H or 4-H), 7.60 (1H, t, J ) 7.9, 2-H or 3-H), 7.8
(1H, d, J ) 1.7 Hz, 9-H), 7.9 (1H dt, J ) 1.6, 6.7 Hz, 2-H or
3-H), 8.11 (1H, d, J ) 8.9, 1-H or 4-H), 8.13 (1H, d, J ) 8.7,
6-H), 8.19 (1H, dd J ) 1.7, 8.4, 7-H), 8.83 (1H, s, 11-H). MS
(EI, m/z, relative intensity, %) 267 (33) [M+], 266 (100) [M+],
251 (22), 250 (26), 216 (6), 133, (5). Anal. (C16H11N2Cl‚1.5HCl)
C, H, N.
7-Bromo-2-chlorocryptolepine Hydrochloride (11k).
The title compound was prepared as above from 6b (23 mmol,
6.84 g) and 7b (23 mmol, 4.18 g). Yellow crystals, yield 13.0%.
1H NMR of free base (CDCl3, δ): 4.70 (3H, s, NCH3), 7.45 (1H,
d, J ) 9.2 Hz, 9-H), 7.54 (1H, d, J ) 8.9 Hz, 8-H), 7.72 (1H, d,
J ) 9.4, 4-H), 8.00 (1H, d, J ) 9.4 Hz, 3-H), 8.04 (1H, s, 1-H
or 6-H), 8.09 (1H, s, 1-H or 6-H), 8.50 (1H, s, 11-H). MS (EI,
m/z, relative intensity, %) 346 (100) [M+], 344 (64) [M+], 332
(80), 330 (62), 251 (18), 215 (15), 142 (15), 108 (10). Anal.
(C16H10N2BrCl‚HCl‚CHCl3) C, H, N.
7-Bromo-2-fluorocryptolepine Hydrochloride (11l). The
title compound was prepared as above from 6b (23 mmol, 6.84
1
g) and 7g (23 mmol, 3.80 g). Yellow crystals, yield 13.0%. H
NMR of free base (CDCl3, δ): 4.70 (3H, s, NCH3), 7.62 (2H,
m, 3-H, 4-H), 7.74 (1H, d, J ) 10, 9-H), 7.85 (1H, dd, J ) 2.8,
8.5 Hz, 1-H), 8.16 (1H, dd, J ) 4.3, 9.5, 8-H), 8.35 (1H, s, 6-H),
8.79 (1H, s, 11-H). MS (EI, m/z, relative intensity, %) 330 (37)
[M+], 328 (33) [M+], 316 (98), 314 (100), 235 (48), 208 (23),
158 (18), 118 (20). Anal. (C16H10N2BrF‚HCl‚2.5H2O) C, H, N.
7-Bromo-3-chlorocryptolepine Hydrochloride (11m).
The title compound was prepared as above from 6b (23 mmol,
6.84 g) and 7d (23 mmol, 4.18 g). Yellow crystals, yield 13.0%.
1H NMR of free base (CDCl3, δ): 4.71 (3H, s, NCH3), 7.55 (2H,
d, 8-H, 9-H), 7.70 (1H, d, J ) 8.9 Hz, 1-H), 8.10 (2H, m, 2-H,
4-H or 6-H), 8.30 (1H, s, 4-H or 6-H), 8.80 (1H, s, 11-H). MS
(EI, m/z, relative intensity, %) 346 (100) [M+], 344 (30) [M+],
332 (100), 330 (79), 251 (25), 216 (15), 142 (37), 108 (11). Anal.
(C16H10N2BrCl‚HCl‚0.3C2H5COOCH3) C, H, N.
1,2-Dichlorocryptolepine Hydrochloride (11a). The
title compound was prepared as above from 6a (23 mmol, 5.0
1
g) and 7b (23 mmol, 3.38 g). Yellow crystals, yield 10.9%. H