Journal of Medicinal Chemistry
ARTICLE
small molecule-based drugs may represent a better approach for
treating filarial diseases. In particular, since current drugs only
target O. volvulus microfilariae, the addition of an antilarval drug
opens up the possibility for a multidrug combination, which
could synergize the reduction of worm burden by effectively
targeting both the developing larvae and microfilariae, thereby
decreasing the chance of transmission. We hope that our
discovery of small molecule probes that target filarial species
based on new mechanisms of inhibition may spark additional
interest in this field.
Compound 3g. 42% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
12.99 (br s, 1H), 10.72 (br s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.17 (d, J =
2.0 Hz, 1H), 7.56ꢀ7.63 (m, 2H), 7.15ꢀ7.21 (m, 2H), 2.82ꢀ2.87 (m,
1H), 1.20ꢀ1.24 (m, 6H); HRMS (ESI-TOF) m/z calcd for
C16H15I2NO2 [M þ H]þ 506.9192, found 507.1047.
Compound 3h. 51% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
11.72 (br s, 1H), 10.77 (br s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.63ꢀ7.70
(m, 3H), 7.36ꢀ7.44 (m, 2H), 7.16ꢀ7.22 (m, 1H), 6.81 (d, J = 8.4 Hz,
1H); HRMS (ESI-TOF) m/z calcd for C13H10INO2 [M þ H]þ
338.9756, found 339.1285.
1
Compound 3i. 59% yield; H NMR (500 MHz, DMSO, 25 ꢀC) δ
11.70 (br s, 1H), 10.62 (br s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.62ꢀ7.75
(m, 3H), 7.32ꢀ7.38 (m, 2H), 6.83 (d, J = 8.4 Hz, 1H), 2.34 (s, 3H);
HRMS (ESI-TOF) m/z calcd for C14H12INO2 [M þ H]þ 352.9913,
found 353.1551.
’ EXPERIMENTAL SECTION
General Chemistry Methods. Reactions were carried out under a
nitrogen atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. Methylene chloride (CH2Cl2) was
distilled from calcium hydride. Yields refer to chromatographically and
spectroscopically homogeneous materials, unless otherwise stated.
Reactions were monitored by thin-layer chromatography (TLC) carried
out on 0.25 mm EMD silica gel plates (60F-254) using ninhydrin
staining or UV light (254 nm). Flash chromatography separations were
performed on Silicycle silica gel (40ꢀ63 mesh). All compounds were
confirmed to have g95% purity by HPLC (254 nm; see Supporting
Information for HPLC traces). NMR spectra were recorded on a Bruker
500 MHz spectrometer and calibrated using a solvent peak as an internal
reference. The following abbreviations are used to indicate the multi-
plicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad. Purity was assessed using HPLC (detection at 254 nm).
General Synthetic Procedure for Salicylanilides 3aꢀw.
A stirring solution of carboxylic acid (compounds 2aꢀw) (1.0 equiv)
in CH2Cl2 (0.25 M) was cooled to 0 ꢀC in an iceꢀwater bath and
subsequently treated with oxalyl chloride (2.4 equiv) and DMF (∼1
drop). After the mixture was stirred for 2 h at 0 ꢀCꢀ25 ꢀC, the solvent
was concentrated in vacuo. The resulting residue was then dissolved in
THF (0.25 M) and cooled to 0 ꢀC. A THF solution (0.25 M with respect
to carboxylic acid) of amine (R3NH2) (1.1 equiv) and triethylamine (3.0
equiv) was then added, and the solution was stirred overnight from 0 to
25 ꢀC. The solvent was then concentrated in vacuo, and the resulting
crude residue was extracted with ethyl acetate and washed with water
and brine. After the mixture was dried with Na2SO4 and concentrated in
vacuo, the residue was purified by flash column chromatography (EtOAc
in hexanes) to yield the chromatographically pure salicylanilide
(compounds 3aꢀw).
1
Compound 3j. 61% yield; H NMR (500 MHz, DMSO, 25 ꢀC) δ
11.70 (br s, 1H), 10.62 (br s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.60ꢀ7.70
(m, 3H), 7.30ꢀ7.39 (m, 2H), 6.80 (d, J = 8.4 Hz, 1H), 3.79 (s, 3H);
HRMS (ESI-TOF) m/z calcd for C14H12INO3 [M þ H]þ 368.9862,
found 369.1544.
Compound 3k43. 68% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
11.70 (br s, 1H), 10.62 (br s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 7.66ꢀ7.77
(m, 3H), 7.40ꢀ7.46 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H).
Compound 3l15,45. 66% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
13.24 (br s, 1H), 10.77 (br s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.51 (d, J =
1.9 Hz, 1H), 7.61ꢀ7.70 (m, 2H), 7.36ꢀ7.43 (m, 2H), 7.16ꢀ7.24 (m,
1H).
Compound 3m15,45. 80% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC)
δ 12.99 (br s, 1H), 10.72 (br s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.62 (d, J =
2.0 Hz, 1H), 7.56ꢀ7.61 (m, 2H), 7.21ꢀ7.43 (m, 2H), 2.31 (s, 3H).
Compound 3n15,45. 84% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC)
δ 13.08 (br s, 1H), 10.81 (br s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.60 (d, J =
2.0 Hz, 1H), 7.51ꢀ7.63 (m, 2H), 6.97ꢀ7.07 (m, 2H), 3.78 (s, 3H).
Compound 3o15,45. 73% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC)
δ 13.02 (br s, 1H), 10.89 (br s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.71 (d, J =
2.0 Hz, 1H), 7.68ꢀ7.73 (m, 2H), 7.43ꢀ7.49 (m, 2H).
Compound 3p45. 88% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
13.24 (br s, 1H), 10.77 (br s, 1H), 8.18 (d, J = 1.9 Hz, 1H), 8.01 (d, J =
1.9 Hz, 1H), 7.63ꢀ7.70 (m, 2H), 7.36ꢀ7.44 (m, 2H), 7.16ꢀ7.22
(m, 1H).
Compound 3q45. 63% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
12.99 (br s, 1H), 10.72 (br s, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.00 (d, J =
2.0 Hz, 1H), 7.56ꢀ7.63 (m, 2H), 7.15ꢀ7.21 (m, 2H), 2.32 (s, 3H).
Compound 3r45. 62% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
13.08 (br s, 1H), 10.81 (br s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.99 (d, J =
2.0 Hz, 1H), 7.51ꢀ7.63 (m, 2H), 6.97ꢀ7.07 (m, 2H), 3.80 (s, 3H).
Compound 3s45. 50% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
12.98 (br s, 1H), 10.73 (br s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 8.00 (d, J =
2.0 Hz, 1H), 7.63ꢀ7.68 (m, 2H), 7.56ꢀ7.62 (m, 2H).
Compound 3a43. 47% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
13.24 (br s, 1H), 10.77 (br s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.21 (d, J =
1.9 Hz, 1H), 7.63ꢀ7.70 (m, 2H), 7.36ꢀ7.44 (m, 2H), 7.16ꢀ7.22
(m, 1H).
Compound 3b44. 49% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
12.99 (br s, 1H), 10.72 (br s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.17 (d, J =
2.0 Hz, 1H), 7.56ꢀ7.63 (m, 2H), 7.15ꢀ7.21 (m, 2H), 2.34 (s, 3H).
Compound 3c44. 42% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
13.08 (br s, 1H), 10.81 (br s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.18 (d, J =
2.0 Hz, 1H), 7.51ꢀ7.63 (m, 2H), 6.97ꢀ7.07 (m, 2H), 3.83 (s, 3H).
Compound 3d43,44. 51% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC)
δ 13.12 (br s, 1H), 10.82 (br s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.19 (d, J =
2.0 Hz, 1H), 7.63ꢀ7.68 (m, 2H), 7.07ꢀ7.15 (m, 2H).
1
Compound 3t. 41% yield; H NMR (500 MHz, DMSO, 25 ꢀC) δ
10.81 (br s, 1H), 10.12 (br s, 1H), 7.55ꢀ7.61 (m, 2H), 7.46 (d, J = 1.9
Hz, 1H), 7.36ꢀ7.44 (m, 2H), 7.32 (d, J = 1.9 Hz, 1H), 7.25ꢀ7.31 (m,
2H), 7.16ꢀ7.22 (m, 1H), 2.95ꢀ3.02 (m, 1H), 2.85ꢀ2.90 (m, 1H),
1.11ꢀ1.20 (m, 12H); HRMS (ESI-TOF) m/z calcd for C19H23NO2 [M
þ H]þ 297.1729, found 297.3914.
Compound 3u. 39% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
10.81 (br s, 1H), 10.12 (br s, 1H), 7.55ꢀ7.61 (m, 2H), 7.47 (d, J = 1.9
Hz, 1H), 7.36ꢀ7.47 (m, 3H), 7.22ꢀ7.31 (m, 2H), 2.95ꢀ3.02 (m, 1H),
2.85ꢀ2.90 (m, 1H), 2.31 (s, 3H), 1.11ꢀ1.20 (m, 12H); HRMS (ESI-
TOF) m/z calcd for C20H25NO2 [M þ H]þ 311.1885, found 311.4180.
Compound 3v. 52% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC) δ
10.81 (br s, 1H), 10.12 (br s, 1H), 7.55ꢀ7.61 (m, 2H), 7.46 (d, J = 1.9
Hz, 1H), 7.32ꢀ7.41 (m, 2H), 7.25ꢀ7.31 (m, 2H), 3.81 (s, 3H),
2.95ꢀ3.02 (m, 1H), 2.85ꢀ2.90 (m, 1H), 1.11ꢀ1.20 (m, 12H); HRMS
Compound 3e43,44. 63% yield; 1H NMR (500 MHz, DMSO, 25 ꢀC)
δ 12.98 (br s, 1H), 10.73 (br s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.23 (d, J =
2.0 Hz, 1H), 7.63ꢀ7.68 (m, 2H), 7.56ꢀ7.62 (m, 2H).
1
Compound 3f. 53% yield; H NMR (500 MHz, DMSO, 25 ꢀC) δ
13.15 (br s, 1H), 10.85 (br s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.20 (d, J =
2.0 Hz), 7.90ꢀ7.97 (m, 2H), 7.57ꢀ7.64 (m, 2H). HRMS (ESI-TOF)
m/z calcd for C13H8I3NO2 [M þ H]þ 590.7689, found 590.9215.
3969
dx.doi.org/10.1021/jm200364n |J. Med. Chem. 2011, 54, 3963–3972