Antimalarial cyclic peroxy ketals

Article abstract of DOI:10.1021/jm980088f

Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with readily available aryl methyl ketones. Structure- activity correlations using in vitro anti-malarial data as a guide for optimization of potency have led to the de

Full text of DOI:10.1021/jm980088f

2164
J . Med. Chem. 1998, 41, 2164-2167
An tim a la r ia l Cyclic P er oxy Keta ls
Gary H. Posner,*,† Hardwin O’Dowd,† Poonsakdi Ploypradith,† J ared N. Cumming,† Suji Xie,‡ and
Theresa A. Shapiro‡
Department of Chemistry, The J ohns Hopkins University, Baltimore, Maryland 21218, and Department of Medicine, School of
Medicine, The J ohns Hopkins University, Baltimore, Maryland 21205
Received February 9, 1998
Over 20 new, cyclic, peroxy ketals have been prepared via a two-step protocol starting with
readily available aryl methyl ketones. Structure-activity correlations using in vitro anti-
malarial data as a guide for optimization of potency have led to the design and synthesis of
seven new peroxides that have IC50 values of 31-85 nM (artemisinin IC50 ) 8.4 nM). Some
SAR generalizations are discussed.
Sch em e 1
Because of the rapidly increasing threat worldwide
of malaria epidemics resistant to alkaloid drugs such
as chloroquine, there is an urgent global need to isolate
from natural sources and/or to synthesize new classes
of antimalarial compounds.1-15 One natural and several
synthetic endoperoxides have recently shown excellent
efficacy as nonalkaloidal, fast-acting drugs effective for
chemotherapy of malaria.1-5 We recently reported the
first example of antimalarial activity in a cyclic peroxy
ketal (1) as well as a proposal for its mechanism of
action.16 Now we report in detail (1) preparation of over
20 such cyclic peroxy ketals, (2) structure-activity
relationship (SAR) generalizations within this class of
peroxides, and (3) identification of seven of these cyclic
inactive based on its inability (i.e. no olefinic bond) to
form a critical vicinal diepoxide as required by the
proposed mechanism of action for unsaturated peroxy
ketal 1a .16 Subsequent in vitro antimalarial testing
showed this saturated compound indeed to be inactive.
Therefore, we studied the antimalarial potencies of only
the unsaturated cyclic peroxy ketals shown in Scheme
1. When the Snider protocol was performed in the
absence of methanol as solvent, cyclic peroxy hemiketal
5 was formed (eq 1) and was found to be antimalarially
inactive. Other methods for synthesis of cyclic peroxy
hemiketals are known.20-23 When methoxy ketal 1j was
dissolved in isopropyl alcohol, acid catalyzed ketal
exchange cleanly produced propoxy ketal 6 (eq 2) that
was found to have little antimalarial activity, substan-
tially lower than that of its precursor methoxy ketal 1j
(IC50 ) 58 nM).
1
1
peroxy ketals that are between /4 and /10 as active in
vitro against Plasmodium falciparum malaria parasites
as the clinically used natural antimalarial cyclic peroxy
ketal drug artemisinin (qinghaosu, 2).
Ch em istr y
As shown in Scheme 1, enolization of a wide variety
of readily available aryl methyl ketones 3 allowed aldol
condensation with various R,R-disubstituted aldehydes
to produce, after dehydration, the conjugated enones 4.
Then, Snider photoenolization and oxygenation17,18 al-
lowed direct preparation of unsaturated cyclic peroxy
ketals 1. The overall yields for this two-step procedure
ranged from 16 to 61% (Table 2). Although the product
peroxy ketals are stable compounds that appeared by
TLC and NMR not to decompose when stored neat for
several months at -20 °C, in vitro antimalarial testing
of these samples did show diminished potency as a
function of time. Slow diimide reduction19 of unsatur-
ated peroxide 1a gave in low yield the corresponding
saturated cyclic peroxy ketal that was expected to be
Biology
Following our previously described protocol for de-
termining a new compound’s in vitro antimalarial
activity against P. falciparum malaria parasites,24 we
† Department of Chemistry.
‡ Department of Medicine.
S0022-2623(98)00088-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/05/1998

Antimalarial Cyclic Peroxy Ketals
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12 2165
Ta ble 2. Summary of Experimental Results (Scheme 1)
a
Ta ble 1. In Vitro Antimalarial Activities
Scheme 1
overall
yield, %
HPLC tR, min
(solvent, %
EtOAc/hexane)
peroxy
ketal
4, mg
(% yield)
1, mg
(% yield)
physical state
(mp, °C)
Ar
R, R
IC50, nM
1a
Ph
Ph
Ph
Ph
4-MeOPh
4-MeOPh
4-MeOPh
3,4,5-(MeO)3Ph cycloheptyl
4-CF3OPh
4-ClPh
Me, Me
1100
190
280
220
160
180
210
120
61
58
85
78
31
19
24b
20
14
6
61
29
13
26
23
31
10
100c
23
34
93c
4d
4a , 700 (50)
1a , 119 (38)
solid (35-38)
oil
solid (33-35)
oil
oil
oil
oil
solid (98-100)
solid (76-78)
solid (71-73)
solid (48-49)
solid (68-70)
9.9 (10)
8.8 (10)
8.3 (10)
8.0 (10)
9.1 (20)
12.3 (10)
8.0 (20)
15.7 (20)
8.1 (10)
8.1 (10)
8.5 (10)
10.3 (10)
9.2 (50)
7.3 (10)
10.7 (10)
9.5 (50)
8.6 (20)
8.5 (10)
8.7 (10)
9.3 (10)
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
cyclopentyl
cyclohexyl
cycloheptyl
cyclobutyl
cyclohexyl
cycloheptyl
4b, 287 (47)a 1b, 144 (51)
4c, 640 (39)
4d , 114 (26)
4e, 640 (40)
1c, 150 (52)
1d , 49 (53)
1e, 20 (16)
4f, 980 (100) 1f, 227 (61)
4g, 220 (48)
4h , 285 (50)
4i, 340 (61)
4j, 192 (41)
4k , 210 (47)
4l, 137 (23)
1g, 76 (60)
1h , 41 (25)
1i, 51 (43)
1j, 83 (55)
2k , 88 (66)
1l, 59 (43)
cycloheptyl
cycloheptyl
cycloheptyl
cycloheptyl
cycloheptyl
cycloheptyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
4-FPh
4-MeSPh
4-MeS(O2)Ph
4-EtPh
4-MeSPh
4-MeS(O2)Ph
4-O2NPh
4-ClPh
1m , 39 (100)b oil
1n , 62 (47)
180
160
56
4n , 220 (48)
4o, 940 (100) 1o, 110 (34)
oil
oil
oil
1p , 31 (93)b
46
4q, 106 (13)
4r , 390 (44)
4s, 430 (38)
4t, 234 (46)
1q, 42 (33)c
1r , 71 (53)
1s, 186 (64)
1t, 46 (35)
solid (77-79)
solid (83-85)
solid (55-57)
solid (60-62)
100
200
140
23
24
16
1s
1t
4-FPh
4-F3CPh
artemisinin (2)
8.4 ( 1.2
a
Prepared in two steps from 3-cyclopentylpropionyl chloride,
a
Antimalarial activity was determined as reported previously.24
The standard deviation for each set of quadruplicates was an
average of 9% (e38%) of the mean. R2 values for the fitted curves
were g0.979. Artemisinin activity is mean ( standard deviation
b
overall yield. Prepared by m-CPBA oxidation of the correspond-
c
ing sulfide. Photoenolization-oxygenation step yielded the
hemiketal, which was subsequently converted into the methoxy
ketal by acid-catalyzed exchange, overall yield.
b
of concurrent control (n ) 20). Prepared in three steps from
3-cyclopentylpropionyl chloride. c Prepared by m-CPBA oxidation
IC50 of 85 nM. Theinductively electron-withdrawing
p-su lfon e substituent imparted higher antimalarial
potency than did the corresponding p-su lfid e substitu-
ent (in Table 1, compare peroxides 1m vs 1l and 1p vs
1o). Other recent examples show also that sulfones are
more potent antimalarials than the corresponding sul-
fides.25,26 Finally, peroxide 1q, carrying also a strongly
electron-withdrawing p-nitro group on the aromatic
ring, was very potent.
d
of the corresponding sulfide. Photoenolization-oxygenation step
yielded the hemiketal, which was subsequently converted into the
methoxy ketal by acid-catalyzed exchange.
evaluated the 20 peroxy ketals 1a -t (Table 1). This in
vitro assay actually was crucial in providing structure-
activity relationship (SAR) correlations after only a few
of these peroxy ketals were made so that design of the
next members of the series could be modified to optimize
antimalarial activity; this iterative process of synthesis
and then biological testing provided critical SAR feed-
back that greatly facilitated progress toward prepara-
tion of potent peroxy ketals.
Despite the earlier conclusion that carbocyclic ring
size did not appreciably alter potency in phenyl perox-
ides 1b-d and in p-methoxyphenyl peroxides 1e-g,
p-chlorophenyl cycloh exyl peroxide 1r (IC50 ) 100 nM)
was found to be considerably less potent than p-
chlorophenyl cycloh ep tyl peroxide 1j (IC50 ) 58 nM).
Likewise, p-fluorophenyl cycloh exyl peroxide 1s (IC50
) 200 nM) was found to be considerably less potent than
p-fluorophenyl cycloh ep tyl peroxide 1k (IC50 ) 85 nM).
Also in the sulfide/sulfone set of four compounds, the
cycloh exyl carbocycles 1o and 1p were found to be
much less potent than the corresponding cycloh ep tyl
carbocycles 1l and 1m . We do not yet have a good
rationale for this SAR trend.
The first structural parameter in peroxy ketal 1 that
was explored in depth involved the R groups. Whereas
dimethyl peroxide 1a had an IC50 of 1100 nM, the
corresponding carbocyclic peroxides 1b-d had IC50
values below 300 nM. No large difference in potency
was evident as the carbocyclic ring was increased in size
from 5 (1b) to 6 (1c) to 7 (1d ). Likewise, in p-
methoxyphenyl carbocyclic peroxides 1e-g, anti-
malarial activity did not change appreciably in going
from carbocyclic ring size 4 (1e) to 6 (1f) to 7 (1g). The
second structural parameter investigated in depth
involved changing the substituents on the aryl group
of peroxy ketal 1. In comparison to p-methoxyphenyl
cycloheptyl peroxide 1g (IC50 ) 210 nM), trimethoxy-
phenyl cycloheptyl peroxide 1h was more potent (IC50
) 120 nM). Even more so, p-trifluoromethoxy cyclo-
In conclusion, regular feedback from in vitro antima-
larial testing has allowed iterative design and synthesis
of several potent cyclic peroxy ketals. Of the 20 such
easily synthesized peroxides reported in Table 1, seven
(1i-m , 1p , and 1q) have antimalarial potencies between
1
1/4 to /10 that of the clinically used natural trioxane
1
heptyl peroxide 1i (IC50 ) 61 nM) was about /7 as potent
antimalarial artemisinin (2). Thus, further biological
evaluation of these seven new, readily prepared perox-
ides will establish ultimately whether they will become
promising drug candidates in the international effort
using chemotherapy to combat malaria.
as artemisinin (2). Halogen substitutents on the aro-
matic ring also were advantageous. Thus, p-chlorophen-
yl cycloheptyl peroxide 1j had an IC50 of 58 nM, and
the corresponding p-fluorophenyl peroxide 1k had an

2166 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 12
Posner et al.
J ) 6.4), 2.6 (m, 1 H), 6.82 (dd, 1 H, J ) 1.6, 15.6), 7.04 (dd,
1 H, J ) 6.8, 15.6 Hz), 7.6-7.4 (m, 3 H), 7.95-7.90 (m, 2 H);
13C NMR (CDCl3) δ 21.4, 31.5, 123.0, 128.41, 128.44, 132.5,
138.0, 156.0, 191.3; FT-IR (neat, cm-1) 1672, 1619.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, reactions were run in
oven-dried glassware under an atmosphere of argon. Diethyl
ether (ether) and tetrahydrofuran (THF) were distilled from
sodium benzophenone ketyl prior to use. Methylene chloride
(CH2Cl2) was distilled from calcium hydride prior to use. All
other compounds were purchased from Aldrich Chemical Co.
and used without further purification. Analytical thin-layer
chromatography (TLC) was conducted with silica gel 60 F254
plates (250 mm thickness, Merck). Column chromatography
was performed using flash silica gel (partical size 400-230
mesh). Yields are not optimized. Purity of final products was
judged to be >95% based on their chromatographic homogene-
ity. High-performance liquid chromatography (HPLC) was
carried out with a Rainin HPLX system equipped with two 25
mL/min preparative pump heads using a Rainin Dynamax 10
mm × 250 mm (semipreparative) column packed with 60 Å
silica gel (8 µm pore size) as bare silica. Melting points were
measured using a Mel-Temp metal-block apparatus and are
uncorrected. Nuclear magnetic resonance (NMR) spectra were
obtained either on a Varian XL-400 spectrometer, operating
at 400 MHz for 1H and 100 MHz for 13C. Chemical shifts are
reported in parts per million (ppm, δ) downfield from tetra-
methylsilane. Splitting patterns are described as singlet (s),
doublet (d), triplet (t), quartet (q), multiplet (m), and broad
(br). Infrared (IR) spectra were obtained using a Perkin-Elmer
1600 FT-IR spectrometer. Resonances are reported in wave-
numbers (cm-1). Low- and high-resolution mass spectra
(LRMS and HRMS) were obtained with electronic or chemical
ioniztion (EI or CI) either (1) at J ohns Hopkins University on
a VG Instruments 70-S spectrometer run at 70 eV for EI and
run with ammonia (NH3), butane (C4H10), or methane (CH4)
as carrier gas for CI or (2) at the University of Illinois at
Champaign-Urbana on a Finnigan-MAT CH5, a Finnigan-
MAT 731, or a VG Instruments 70-VSE spectrometer run at
70 eV for EI and run with methane (CH4) for CI. Combustion
analyses were conducted by Atlantic Microlab (Norcross, GA).
Dim eth yl P h en yl P er oxy Keta l 1a . Phenyl enone 4a
(247 mg, 1.42 mmol) and copper(II) sulfate (20 mg) were
irradiated for 17 h according to general procedure 2. Flash
column chromatography of the crude product using 5% EtOAc/
hexanes on silica gel gave desired peroxide 1a (119 mg, 0.54
mmol, 38%) as a white solid: mp 35-38 °C; 1H NMR (CDCl3)
δ 1.33 (s, 3), 3.38 (s, 3), 5.78 (d, 1, J ) 10 Hz), 5.98 (d, 1, J )
10 Hz), 7.4-7.3 (m, 3), 7.5 (m, 2); 13C NMR (CDCl3) δ 24.53,
24.60, 51.4, 76.9, 99.6, 125.7, 126.4, 128.5, 128.6, 134.1, 138.0;
HRMS m/z (M + H+) calcd. 221.1178, found 221.1179. Ketal
1a was further purified using HPLC prior to antimalarial
testing (10% EtOAc/hexanes, 3.0 mL/min, 254 nm, tR ) 9.9
min).
Ack n ow led gm en t. We thank the NIH (AI-34885
and NCRR OPD-GCRC RR 00722) and the Burroughs
Wellcome Fund for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR,
IR, and mass spectral data for peroxy ketals 1b-t and for
hemiketal 5 and propoxy ketal 6 (8 pages). Ordering informa-
tion is given on any current masthead page.
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Antimalarial Cyclic Peroxy Ketals
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J M980088F