Brief Article
Journal of Medicinal Chemistry, 2011, Vol. 54, No. 1 395
of ethyl 3-bromo-5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxy-
late, 3 (0.50 mmol), in anhydrous THF (2.5 mL) under N2, was add-
ed n-BuLi (2.5 M in hexanes, 0.24 mL, 0.60 mmol) dropwise. After
5 min at -90 °C, methyl phenylchlorophosphonate (0.60 mmol) in
THF (0.5 mL) was added dropwise at the same temperature. The
reaction was allowed to warm up to room temperature over 3 h (TLC
monitoring, eluant dichloromethane/EtOAc 9/1). Water was then
added (5 mL). Extraction with EtOAc (3 ꢀ 20 mL) drying and eva-
poration led to a crude oil that was purified by chromatography on
silica gel to afford compound (()-8; colorless oil. 1H NMR (CDCl3,
300 MHz) δ 1.45 (t, J = 7.2 Hz, 3H), 3.80 (d, J = 11.4 Hz,3H), 4.54
(q, J = 7.2 Hz, 2H), 7.36 (dd, J = 2.1 and 9.0 Hz, 1H), 7.47-7.67
(m, 6H), 7.84-7.96 (m, 4H), 8.09-8.12 (m, 2H). 31P NMR (CDCl3,
101 MHz) δ 26.7. MS (ESI) m/z = 518 (M þ H)þ.
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Methyl 2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl-(phenyl)-
phosphinate, (()-14. This is also the typical procedure for the
synthesis of 10-15. Compound (()-8 (258 mg, 0.50 mmol) was
dissolved in a saturated solution of ammonia in methanol (5 mL)
in a pressure tube. The tube was heated under microwave irradi-
ation under pressure at 50 °C (maximum power input 100W, CEM
discover apparatus) for 2 h. After evaporation of solvents, purifica-
tion by chromatography on silica gel (eluant: dichloromethane/
MeOH 95/5 to 9/1) afforded desired carboxamide indole (()-14 in
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C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.; Goldman, M. E.;
Greenlee, W. J. 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: a
novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J. Med.
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1
58% yield; pale-yellow powder. H NMR (CDCl3, 300 MHz) δ
3.85 (d, J = 11.4 Hz, 3H), 6.08 (broad s, 1H), 7.30 (dd, J = 2.0 and
9.0 Hz, 1H), 7.36-7.56 (m, 4H), 7.68 (d, J = 1.8 Hz, 1H), 7.73-
7.81 (m, 2H), 10.78 (broad s, 1H), 10.03 (broad s, 1H). 31P NMR
(CDCl3, 101 MHz) δ 33.3. MS (ESI) m/z = 349 (M þ H)þ.
HPLC Chiral Separation. Enantiomers of (()-14 were sepa-
rated by supercritical fluid chromatography preparative method
at Chiral Technologies. Preparative column: Chiralpak AD-H
(250 mm ꢀ 20 mm) with CO2/MeOH þ 1% diethylamine 80/20
as the mobile phase, flow rate 60 mL/min. Analytical column:
Chiralcel OD-H (250 mm ꢀ 4.6 mm) with n-heptane/ethanol/
diethylamine 70/30/0.1 as the mobile phase, flow rate 1.0 mL/min.
First eluting enantiomer 18, tR = 8.89 min, second eluting enan-
tiomer 19, tR = 7.96 min, orders of elution refers to those observed
on the preparative column. Compounds 18 and 19 were repurified
by column chromatography on silica gel (eluant: dichloromethane/
MeOH 95/5 to 9/1) before biological testing.
Methods for Molecular Docking. Docking was done with
CDOCKER (CHARMm based molecular dynamic scheme to
dock ligands into a receptor binding site) from the Discovery
Studio 2.1 suite to obtain 10 poses per compound. Docked
poses were then minimized with the GBSW implicit solvent
model. The binding energy was calculated also with the GBSW
model.
(9) Storer, R.; Dousson, C.; Alexandre, F.-R.; Roland, A. Phospho-
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(c) Kondo, Y.; Yoshida, A.; Sato, S.; Sakamoto, T. Halogen-
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HIV-1 Infected Cells Inhibition Experiments. The antiviral
activity of compounds was measured by the inhibition of virus-
induced cytopathogenicity in MT-4 cells using the HIV strain
BH10 wild-type or the resistant viruses Y181C, K103N, and
Y181C/K103N as described in ref 14.
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Supporting Information Available: Synthetic procedures and
characterization data of all compounds. This material is avail-
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