Journal of Medicinal Chemistry
Article
were calculated by using MarvinSketch and a calculator plug-in by
ChemAxon Kft.
48.8, 40.0, 36.6, 36.3, 36.1, 34.4, 30.2, 26.1, 24.9, 24.7, 20.2, 16.1, 13.0.
[α]D24 +29 (c 0.12, CHCl3); [α]D24 +44 (c 0.12, CHCl3). HRMS m/z
calculated for C25H36SNO6 (M + H)+ 478.2263, found 478.2266.
Analytical Data of 3-(R)-Sulfoxide 12h. Amorphous, white
Synthesis of 3-ArteSanilide 12d. To an oven-dried 10 mL
round-bottom flask were added carboxylic acid monomer 11 (15 mg,
0.044 mmol), EDC (9.3 mg, 0.048 mmol), HOBt (6.5 mg, 0.048
mmol), and CH2Cl2 (1 mL). The mixture was stirred for 1 h before
commercially available 3-aminothioanisole (6.5 μL, 0.053 mmol) was
added dropwise and stirred for an additional 18 h at room temperature
until TLC analysis indicated consumption of starting material. The
reaction was quenched with brine (3 mL) and the appropriate layer
extracted with CH2Cl2 (3 × 3 mL). The resulting organic extracts were
dried over MgSO4 and concentrated in vacuo. The crude product was
purified by preparative thin layer chromatography (silica gel, 40% ethyl
acetate/hexanes) to afford 12d as a colorless, amorphous solid (88%
yield, 18.0 mg, 0.039 mmol). FT-IR (thin film, cm−1) 3331, 2941,
1670, 1550, 1466, 1384, 1301, 1299, 1106, 1053. 1H NMR (400 MHz,
CDCl3) δ 7.78 (bs, 1H), 7.57 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.19
(t, J = 8.0 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 5.35 (s, 1H), 4.17 (m,
1H), 2.77−2.59 (m, 2H), 2.48 (m, 1H), 2.47 (s, 3H), 2.33 (m, 1H)
2.05−1.76 (m, 5H), 1.62 (m, 2H), 1.49−1.22 (m, 5H), 1.39 (s, 3H),
0.95 (d, J = 5.6 Hz, 3H), 0.89 (d, J = 7.6 Hz, 3H). 13C NMR
(100 MHz, CDCl3) 171.4, 139.3, 138.7, 129.0, 122.0, 117.3, 116.3,
103.4, 88.9, 81.1, 76.0, 52.3, 44.4, 37.4, 36.5, 36.0, 34.4, 30.2, 26.1,
26.1, 24.9, 24.6, 20.2, 15.6, 13.1. [α]D26 +51.3 (c 0.72, CHCl3). HRMS
m/z for C25H36NO6 (M + H)+ calculated 463.2392, found 463.2390.
Synthesis of 3,5-ArteSanilide 12f. To an oven-dried 10 mL
round-bottom flask was added carboxylic acid monomer 11 (15 mg,
0.044 mmol), EDC (9.3 mg, 0.048 mmol), HOBt (6.5 mg, 0.048
mmol), and 3,5-bis(methylsulfanyl)aniline (9.8 mg, 0.053 mmol). The
contents were dissolved in CH2Cl2 (1 mL) and stirred for 18 h at
room temperature until TLC analysis indicated consumption of
starting material. The reaction was quenched with brine (3 mL), and
the appropriate layer was extracted with CH2Cl2 (3 × 3 mL). The
resulting organic extracts were dried over MgSO4 and concentrated in
vacuo. The crude product was purified by preparative thin layer
chromatography (silica gel, 40% ethyl acetate/hexanes) to afford 12d
as a colorless, amorphous solid (61% yield, 13.6 mg, 0.027 mmol). FT-
IR (thin film, cm−1) 3333, 2989, 1661, 1541, 1451, 1368, 1289, 1204,
1045, 1008. 1H NMR (400 MHz, CDCl3) δ 7.71 (bs, 1H), 7.60
(s, 2H), 7.43 (s, 1H), 5.32 (s, 1H), 4.20 (m, 1H), 2.79−2.49 (m, 2H),
2.44 (m, 1H), 2.40 (s, 6H), 2.32 (m, 1H) 2.21−1.70 (m, 4H), 1.59 (m,
3H), 1.42−1.22 (m, 5H), 1.42 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.90
(d, J = 7.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) 171.0, 138.8, 138.3,
128.0, 121.0, 116.4, 116.1, 100.8, 87.5, 80.2, 75.5, 52.1, 50.4, 47.2, 38.1,
36.6, 365.7, 34.2, 30.7, 26.2, 25.8, 23.1, 22.2, 20.1, 16.0, 12.9. [α]D23 +43
(c 0.40, CHCl3). HRMS m/z calculated for C28H36S2NO5 (M + H)+
508.7136, found 508.7139.
1
solid. H NMR (300 MHz, CDCl3) δ 8.28 (bs, 1H), 7.88 (m, 1H),
7.75 (d, J = 6.9 Hz, 1H) 7.47 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz,
1H), 5.35 (s, 1H), 4.22 (m, 1H), 2.79−2.46 (m, 5H), 2.74 (s, 3H),
2.34 (td, J = 14.4, 3.9 Hz, 1H), 2.09−1.79 (m, 5H), 1.69−1.55 (m,
2H), 1.50−1.20 (m, 3H), 1.38 (s, 3H), 0.96 (d, J = 5.7 Hz, 3H), 0.91
(d, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.0, 137.4,
134.9, 129.9, 125.6, 123.3, 122.9, 103.9, 89.3, 87.0, 75.4, 57.2, 48.6,
39.8, 36.8, 36.3, 36.0, 34.5, 30.1, 26.3, 24.8, 24.3, 20.2, 16.1, 13.0. [α]D24
+61 (c 0.12, CHCl3). HRMS m/z calculated for C25H36SNO6
(M + H)+ 478.2263, found 478.2265.
Synthesis of 3-Sulfone 12j. 3-ArteSanilide 12d (16.1 mg, 0.035
mmol) was dissolved in CH2Cl2 (1.5 mL) to which mCPBA (≤77%,
17.1 mg, 0.077 mmol) was added and stirred for 2.5 h. The reaction
was quenched with NaHCO3 (aq, 2 mL) and the appropriate layer
extracted with CH2Cl2 (3 × 3 mL). The organic layers were washed
with saturated NaHCO3 and saturated NaHSO3, dried with MgSO4,
concentrated in vacuo, and purified by preparative thin layer
chromatography (silica gel, 60%, ethyl acetate/hexanes) to yield 12j
as a colorless, amorphous solid (94% yield, 16.2 mg, 0.033 mmol). FT-
IR (thin film, cm−1) 3298, 2921, 1666, 1570, 1531, 1444, 1372, 1296,
1124, 1092, 1058, 1008. 1H NMR (300 MHz, CDCl3) δ 8.32 (bs, 1H),
8.11 (s, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.9, 1H), 7.50 (t, J =
8.0 Hz, 1H), 5.36 (s, 1H), 4.19 (m, 1 H), 3.06 (s, 3H), 2.79−2.50 (m,
3H), 2.33 (m, 1H), 2.04−1.58 (m, 6H), 1.46−1.16 (m, 7H), 1.38 (s,
3H), 0.96 (d, J = 9.0 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 171.9, 138.6, 135.3, 129.9 128.8, 126.4, 123.7, 122.9,
103.3, 89.0, 87.1, 75.4, 57.8, 54.6, 43.8, 37.4, 36.5, 36.1, 34.4, 30.2,
26.1, 24.9, 24.4, 20.2, 12.9. [α]D22 +41 (c 0.19, CHCl3). HRMS m/z
calculated for C25H36NO7S (M + H)+ 494.2212, found 494.2216.
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional synthesis details and analytical data for compounds
12b, 12c, 12e, 12i, and 12k−q. This material is available free of
AUTHOR INFORMATION
Corresponding Author
*Phone: 410-516-4670. Fax: 410-516-8420. E-mail: ghp@
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ACKNOWLEDGMENTS
Synthesis of 3-Methyl Sulfoxides 12g and 12h. Carboxylic
acid 11 (15 mg, 0.044 mmol), EDC (9.3 mg, 0.048 mmol), and HOBt
(6.5 mg, 0.048 mmol) were dissolved in CH2Cl2 (2 mL) in a 10 mL
round-bottom flask. The solution was stirred for 1 h at room
temperature before ( )-15 (8.1 mg, 0.053 mmol) was added. The
mixture was allowed to stir for 48 h before it was quenched with brine
(3 mL) and extracted with CH2Cl2 (3 × 4 mL). The combined organic
layers were dried with MgSO4 and concentrated under reduced
pressure. The resulting crude oil was purified by preparative thin layer
chromatography (silica gel, 100% EtOAc) to afford a 1:1
diastereomeric mixture of 12g and 12h (51% yield, mg, 10.5 mg,
0.022 mmol). This mixture was separated by HPLC (Regis Whelk-01
(S,S); 10−50% IPA in hexanes; detection wavelength 254 nm; flow
rate of 2.5 mL/min); tr = 115.1 min (S)-sulfoxide 12g and 128.1 min
(R)-sulfoxide 12h. Spectral data are shown below.
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We thank the NIH (Grant AI 34885 to G.H.P. and Grant
RR025005 to T.A.S.), the Johns Hopkins Malaria Research
Institute, and the Bloomberg Family Foundation for financial
support (to G.H.P. and T.A.S.).
ABBREVIATIONS USED
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ACT, artemisinin combination therapy; EDC, N-(3-dimethyla-
minopropyl)-N′-ethylcarbodiimide hydrochloride; HOBT,
1-hydroxybenzotriazole; DMSO, dimethylsulfoxide; mCPBA,
m-chloroperbenzoic acid
REFERENCES
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(1) Olliaro, P. L.; Boland, P. B. Clinical Public Health Implications of
Antimalarial Drug Resistance. In Antimalarial Chemotherapy: Mecha-
nisms of Action, Resistance, and New Directions in Drug Discovery;
Rosenthal, P. J., Ed.; Humana Press: Totowa, NJ, 2001; pp 65−83.
(2) Guidelines for the Treatment of Malaria; World Health
Organization: Geneva, 2006.
Analytical Data of 3-(S)-Sulfoxide 12g. Amorphous, white
1
solid. H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 8.5 Hz, 1H), 7.82
(dd, J = 7.4, 1.2 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 7.2 Hz,
1H), 5.32 (s, 1H), 4.20 (dd, J = 9.1, 6.8 Hz, 1 H), 3.10 (m, 2H), 2.75
(s, 3H), 2.73 (m, 2H), 2.51 (m, 1H), 2.31 (td, J = 14.1, 3.6 1H), 2.04
(m, 2H), 1.71 (m, 4H), 1.70 (m, 4H), 1.36 (s, 3H), 0.94 (d, J = 6 Hz,
3H), 0.88 (d, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 172.2,
137.3, 134.9, 129.9, 125.8, 123.6, 123.0, 103.7, 89.0, 87.1, 75.4, 57.8,
(3) Ashley, E. A.; White, N. J. Artemisinin-based Combinations.
Curr.Opin. Infect. Dis. 2005, 18, 531−536.
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dx.doi.org/10.1021/jm201214d | J. Med. Chem. 2012, 55, 291−296