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DOI: 10.1055/s-0031-1290124
Sultam Thioureas: Synthesis and Antiviral Activity Against West Nile Virus
Publikationsverlauf
Publikationsdatum:
22. Dezember 2011 (online)
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Abstract
The syntheses of eleven sultam thioureas, including nine new compounds, are described. These compounds were synthesized from thioureas and include the first sultam thioureas in which the two thiourea nitrogen groups are not identical. In addition, the first X-ray crystal structures of sultam thioureas and the antiviral activity of these compounds against West Nile virus (WNV) are reported.
Key words
medicinal chemistry - antiviral agents - West Nile virus - heterocycles - sultam thioureas - thioureas
- Supporting Information for this article is available online:
- Supporting Information
- 1
Barklis E.Still A.Sabri MI.Hirsch AJ.Nikolich-Zugich J.Brien J.Dhenub TC.Scholz I.Alfadhli A. Antimicrob. Agents Chemother. 2007, 51: 2642 - 2
Linden H.Goerdeler J. Tetrahedron Lett. 1977, 20: 1729 - 3
Argyropoulos N. Science of Synthesis 2003, 13: 29 -
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Oliver JE. J. Org. Chem. 1971, 36: 3465 -
4b
Diveley WWR. inventors; Dithiazolium salts X; US 3,166,564. -
5a
Dixit SN.Verma VK. Indian Journal of Chemistry 1963, 1: 487 -
5b
Pandeya SN.Kumar A.Singh BN.Mishra DN. Pharmaceutical Research 1987, 4: 321 -
5c
Joshua C.Prasannan E.Thomas S. Australian Journal of Chemistry 1981, 34: 917 -
6a
Shibuya I,Tsucha T,Taguchi Y, andOoishi A. inventors; Preparation of dithiazolium compounds; JP 08027148. -
6b
Epstein MG.Valente EJ.Wood WJL.
J. Chem. Crystallogr. 2011, 41: 1060 - 12
Georgiev AG, andDaskalov HP. inventors; 5-Substituted derivatives of 5H-dibenz(b,f)azepine and method for obtaining the same; US 4,124,583. -
13a
Sheldrick GM. Acta Crystallogr., Sect. A 2008. 64: p.112 -
13b
Sheldrick GM. Program for crystal structure solution and refinement University of Göttingen; Germany: 1998. - 18
Structure
Correlation
Vol. 2:
Burgi H.-B.Dunitz JD. VCH Publishers; Weinheim: 1994.
References and Notes
Typical procedure
for the synthesis of sultam thioureas. To a flame-dried flask
under nitrogen, were added thiourea (1 equiv) and THF to make a
0.4 M solution. Next NaH (60% in paraffin, 1.5
equiv) was added in portions. Phenylisothiocyanate (1 equiv) was
added, the reaction mixture was heated in a 45 ˚C
oil bath, and the reaction was monitored by TLC. The reaction mixture
was cooled to room temperature and then cooled in an ice-water
bath. To this reaction mixture was added a 0.5 M solution
of HBr (5 equiv) in THF (made using 5.1 M HBr in acetic
acid), followed by the addition of hydrogen peroxide (3.5 equiv, 30% H2O2 solution).
The reaction was stirred overnight and filtered, after which, the
solid was dissolved in CH2Cl2 (10 mL) and
washed with sat. Na2CO3 (10 mL). The organic layer
was removed and the aqueous layer was washed with a second portion
of CH2Cl2 (10 mL). The combined CH2Cl2 solution
was dried with anhydrous MgSO4, filtered and concentrated
in vacuo. The solid was dissolved in CH2Cl2 to make
a 0.05 M solution, which was cooled in an ice bath under nitrogen.
To this solution was added triethylamine (7.2 equiv based on the
crude weight of the filtered solid), followed by dropwise addition
of a 0.75 M solution of methanesulfonyl chloride (1.5 equiv based
on the crude weight of the filtered solid) in CH2Cl2.
After stirring the reaction for 1 h, the reaction was diluted with
CH2Cl2 and washed twice with H2O.
The organic layer was dried with anhydrous MgSO4, filtered
and concentrated in vacuo.
The residue was purified by
silica chromatography (ethyl acetate-n-hexane,
95% or CH2Cl2-n-hexane, 95%). The purity of
the product was confirmed by HPLC analysis using two different conditions
with a C18, 5 µm (250 × 4.6 mm) column
at 40 ˚C, and monitored at 220 nm.
Compound 1: ¹H
NMR (400 MHz, CDCl3): δ = 4.38 (s, 2 H),
6.90-7.44 (m, 15 H). ¹³C
NMR (100 MHz, CDCl3):
δ = 46.46,
126.7, 126.8, 127.7, 127.9, 128.8, 128.9, 129.3, 129.4, 129.5, 131.9,
144.0, 144.8, 161.8, 188.4. HRMS (ESI+): m/z [M + H]+ calcd
for C21H18N3O2S3:
440.0556; found: 440.0545. HPLC conditions A: MeCN/H2O
with 0.1% AcOH and the following gradient: 5% MeCN
for 2 min, 5-95% MeCN over 16 min,
95% MeCN for 2 min at 0.5 mL/min.
HPLC conditions B: MeOH/H2O with 0.1% AcOH
and the following gradient: 5% MeOH for 2 min,
5-95% MeOH over 16 min, 95% MeOH
for 2 min at 1.0 mL/min. The retention
time of the product under conditions A was 16.9 min (>99% purity)
and under conditions B it was 17.9 min (>99% purity).
Compound 6a: ¹H NMR
(400 MHz, CDCl3): δ = 1.83 (d,
J = 6.8 Hz,
3 H), 4.51 (q, J = 6.8 Hz,
1 H), 6.85-7.50 (m, 15 H). ¹³C
NMR (100 MHz, CDCl3): δ = 14.7, 55.1,
126.7, 126.8, 127.6, 127.9, 128.6, 128.6, 129.2, 129.4, 129.4, 132.2,
144.1, 144.8, 160.7, 188.4. HRMS (ESI+): m/z [M + H]+ calcd
for C22H20N3O2S3:
454.0712; found: 454.0701. HPLC conditions A: MeCN/H2O
with 0.1% AcOH and the following gradient: 45% MeCN
for 3 min, 45-95% MeCN over 15 min,
95% MeCN for 2 min at 1.0 mL/min.
HPLC conditions B: MeOH/H2O with 0.1% AcOH
and the following gradient: 55% MeOH for 3 min,
55-95% MeOH over 15 min, 95% MeOH
for 2 min at 1.0 mL/min. The retention
time of the product under conditions A was 17.4 min (>99% purity)
and under conditions B was 18.0 min (>99% purity).
Compound 6b: ¹H
NMR (400 MHz, CDCl3): δ = 1.91 (s, 6 H),
6.90-7.02 (m, 4 H), 7.02-7.14 (m, 3 H),
7.14-7.22 (m, 2 H), 7.22-7.42 (m, 6 H). ¹³C
NMR (100 MHz, CDCl3): δ = 23.4, 63.7,
126.7, 126.8, 127.6, 127.9, 128.4, 128.7, 129.2, 129.3, 129.3, 132.5,
144.1, 144.9, 160.1, 188.5. HRMS (ESI+): m/z [M + H]+ calcd
for C23H22N3O2S3:
468.0869; found: 468.0860. HPLC conditions A: MeCN/H2O
with 0.1% AcOH and conditions B: MeOH/H2O
with 0.1% AcOH. The following gradient was used: 40% organic solvent
for 3 min, 40-95% organic solvent over
15 min, 95% organic solvent for 2 min
at 1.0 mL/min. The retention time of the product
under conditions A was 13.6 min (>99% purity)
and under conditions B it was 15.8 min (>99% purity).
For procedures see the Supporting Information.
10
Compound 6c: ¹H
NMR (400 MHz, CDCl3): δ = 2.27 (s, 3 H),
2.32 (s, 3 H), 6.77-7.32 (m, 13 H). ¹³C
NMR (100 MHz, CDCl3): δ = 21.0, 21.2,
46.4, 126.3, 127.4, 128.9, 129.1, 129.1, 129.3, 130.0, 132.0, 136.3,
137.5, 141.7, 142.3, 161.5, 188.2. HRMS (ESI+): m/z [M + H]+ calcd
for C23H22N3O2S3:
468.0859; found: 468.0857. The purity of the product was confirmed
by HPLC using the same two conditions used for 6b.
The retention time of the product under conditions A was 14.1 min
(98% purity) and under conditions B was 16.5 min
(>99% purity).
Compound
6d: ¹H NMR (400 MHz, CDCl3): δ = 2.65-2.80 (m,
2 H), 3.12-3.33 (m, 2 H), 4.30 (d, J = 12.0 Hz,
1 H), 4.34 (d, J = 12.0 Hz,
1 H), 6.70-6.82 (m, 2 H), 6.96-7.03 (m,
4 H), 7.17-7.37 (m, 7 H). ¹³C
NMR (100 MHz, CDCl3): δ = 30.1, 30.2,
46.4, 126.4, 126.8, 127.3, 127.4, 128.0, 128.4, 128.8, 129.2, 129.4,
130.4, 131.9, 134.1, 135.3, 142.2, 143.1, 161.5, 188.5. HRMS (ESI+): m/z [M + H]+ calcd
for C23H20N3O2S3:
466.0712; found: 466.0700. The purity of the product was confirmed
by HPLC using the same two conditions used for 6b.
The retention time of the product under conditions A was 12.7 min
(96% purity) and under conditions B was 15.1 min
(98% purity).
Compound 5d: ¹H
NMR (400 MHz, CDCl3): δ = 2.76-2.92 (m,
2 H), 3.34-3.49 (m, 2 H), 6.05 (br s,
2 H), 7.18-7.52 (m, 8 H). ¹³C
NMR (100 MHz, CDCl3): δ = 30.0, 30.5,
126.7, 127.8, 128.3, 129.1, 129.3, 130.0, 131.7, 135.7, 136.9, 140.1,
143.7, 183.3. HRMS (ESI+): m/z [M + H]+ calcd
for C15H15N2S: 255.0951; found:
255.0951. HPLC conditions A: MeCN/H2O with 0.1% AcOH
and conditions B: MeOH/H2O with 0.1% AcOH.
The following gradient was used: 35% organic solvent for
3 min, 35-95% organic solvent over 15 min,
95% organic solvent for 2 min at 1.0 mL/min.
The retention time of the product under conditions A was 6.6 min (>99% purity)
and under conditions B was 10.5 min (>99% purity).
Crystal Data: CCDC 838607.²² C15H14N3S;
MW = 254.34; monoclinic; a = 7.3785 (10) Å, b = 15.847 (3) Å, c = 11.1495 (16) Å, β = 101.204 (14)˚; U = 1278.8
(3) ų; T = 298
(2) K; space group P 21/n (#14); λ = 0.71073 Å; Z = 4;
Dc = 1.321 Mg/m³; F(000) = 536;
colorless; dimensions 0.20 × 0.20 × 0.50 mm; µ = 0.235 mm-¹;
3.32 < Θ < 32.23˚, 7898 reflection
measured, 4179 unique reflections, R
int = 0.0773. R1 = 0.2121,
0.3045, wR2 = 0.2746,
0.3530, 1.772 goodness of fit on F². Crystals are
invariably twinned. The structure was solved by direct methods with
SHELXS-86 and refined by full-matrix least-squares with SHELXL-97.
In each case, non-hydrogen atoms were found in the initial E-maps.
All non-hydrogen atom positions and anisotropic vibrational parameters
were
refined in the developed models, which included contributions from
the hydrogen atoms placed in calculated positions and assigned Uiso values
equal to 120% of the Ueq of the adjacent atom.
McGuire, J. R.; Zoellner, R. W. preliminary unpublished computational data.
15
Compound 6e: ¹H
NMR (400 MHz, CDCl3): δ = 3.11 (s, 0.5 H),
3.60 (s, 2.5 H), 4.33 (s, 1.7 H), 4.35 (s, 0.3 H),
6.79-6.83 (m, 2 H), 6.89-6.94 (m, 2 H),
7.05-7.56 (m, 6 H). HRMS (ESI+): m/z [M + H]+ calcd
for C16H16N3O2S3: 378.0399;
found: 378.0391. The purity of the product was confirmed by HPLC
using the same two conditions used for 5d.
The retention time of the product under conditions A was 11.4 min
(95% purity) and under conditions B was 13.3 min (98% purity).
Compound 6f: ¹H NMR
(400 MHz, CDCl3): δ = 0.80 (t, J = 7.1 Hz,
0.93 H), 1.19 (t, J = 7.1 Hz,
2.07 H), 3.52 (q, J = 7.1 Hz,
0.62 H), 4.13 (q, J = 7.1 Hz,
1.38 H), 4.32 (s, 1.35 H), 4.36 (s, 0.65 H),
6.76-6.82 (m, 1 H), 6.83-6.88 (m, 1 H),
7.08-7.18 (m, 4 H), 7.22-7.58 (m, 4 H).
HRMS (ESI+): m/z [M + H]+ calcd
for C17H18N3O2S3:
392.0556; found: 392.0546. The purity of the product was confirmed by
HPLC using the same two conditions used for 5d.
The retention time of the product under conditions A was 16.5 min
(98% purity) and under conditions B was 14.2 min (98% purity).
Compound 6g: ¹H
NMR (400 MHz, CDCl3): δ = 4.31 (s, 1.25 H),
4.33 (s, 0.75 H), 4.74 (s, 0.76 H), 5.36 (s, 1.24 H), 6.61-6.66
(m, 1 H), 6.68-6.72 (m, 1 H), 6.82-6.88
(m, 1 H), 6.97-7.41 (m, 12 H). HRMS (ESI+): m/z [M + H]+ calcd
for C22H20N3O2S3:
454.0712; found: 454.0703. The purity of the product was confirmed
by HPLC using the same two conditions used for 5d.
The retention time of the product under conditions A was 17.9 min
(99% purity) and under conditions B was 15.7 min
(95% purity).
Compound 6h: ¹H
NMR (400 MHz, CDCl3): δ = 0.64-0.81 (m,
1 H), 0.81-1.15 (m, 3 H), 1.27-1.46
(m, 2 H), 1.46-1.63 (m, 2 H), 1.64-1.78
(m, 1 H), 1.87-2.02 (m, 1 H), 4.22 (tt, J = 3.5, 11.9 Hz,
0.5 H), 4.29 (s, 1.3 H), 4.33 (s, 0.7 H),
5.07 (tt, J = 3.5,
11.9 Hz, 0.5 H), 6.64-6.78 (m, 2 H),
6.98-7.05 (m, 1 H), 7.05-7.28 (m, 4 H),
7.28-7.59 (m, 3 H). HRMS (ESI+): m/z [M + H]+ calcd
for C21H24N3O2S3:
466.1025; found: 446.1015. The purity of the product was confirmed by
HPLC using the same two conditions used for 6b.
The retention time of the product under conditions A was 15.0 min
(>99% purity) and under conditions B was 16.9 min
(97% purity).
Crystal Data for 6e: CCDC 838606.²² C16H15N3O2S3; MW = 377.49; orthorhombic; a = 16.708 (4) Å, b = 18.397 (3) Å, c = 5.6729 (8) Å, β = 90˚; U = 1743.7 (6) ų; T = 300(2) K; space group P n a 21 (#33); λ = 0.71073 Å; Z = 4; D c = 1.438 Mg/m³; F(000) = 784; yellow; dimensions 0.69 × 0.06 × 0.03 mm; µ = 0.439 mm-¹; 3.54 < Θ < 29.19˚, 9073 reflection measured, 4001 unique reflections, R int = 1163. R1 = 0.0625, 0.1818, wR2 = 0.0656, 0.0781, 0.877 goodness of fit on F². The structure was solved by direct methods and refined as described above. Compound 6f: CCDC 838608.²² C17H17N3O2S3; MW = 391.54; triclinic; a = 10.2747 (5) Å, b = 11.2638 (5) Å, c = 18.1559 (8) Å, β = 80.766 (4)˚; U = 1866.99 (15) ų; T = 299 (2) K; space group P-1; λ = 0.71073 Å; Z = 4; D c = 1.393 Mg/m³; F(000) = 816; yellow; dimensions 0.46 × 0.32 × 0.05 mm; µ = 0.413 mm-¹; 3.35 < Θ < 30.59˚, 21500 reflection measured, 11234 unique reflections, R int = 0.0342. R1 = 0.0407, 0.1264, wR2 = 0.0482, 0.0515, 1.005 goodness of fit on F². The structure was solved by direct methods and refined as described above.
17Compound 6i: ¹H NMR (400 MHz, CDCl3): δ = 0.78 (t, J = 7.2 Hz, 1.8 H), 1.17 (t, J = 7.1 Hz, 1.2 H), 2.78 (s, 1 H), 3.21-2.28 (m, 3.3 H), 3.81 (q, J = 7.2 Hz, 0.7 H), 4.35 (s, 0.8 H), 4.36 (s, 1.2 H), 7.36-7.42 (m, 2 H), 7.45-7.53 (m, 3 H). HRMS (ESI+): m/z [M + H]+ calcd for C12H16N3O2S3: 330.0399; found: 330.0399. The purity of the product was confirmed by HPLC using the same two conditions used for 6b. The retention time of the product under conditions A was 8.6 min (97% purity) and under conditions B was 10.3 min (96% purity). Crystal Data: CCDC 838605.²² C12H15N3O2S3; MW = 329.47; monoclinic; a = 5.2548 (4) Å, b = 15.8241 (13) Å, c = 17.885 (2) Å, β = 97.681 (9)˚; U = 1473.8 (2) ų; T = 150 (2) K; space group P 21/n (#14); λ = 0.71073 Å; Z = 4; D c = 1.485 Mg/m³; F(000) = 688; colorless; dimensions 0.62 × 0.04 × 0.01 mm; µ = 0.507 mm-¹; 3.45 < Θ < 27.59˚, 10662 reflection measured, 3285 unique reflections, R int = 0.0831. R1 = 0.0637, 0.1217, wR2 = 0.1185, 0.1248, 1.008 goodness of fit on F². The structure was solved by direct methods and refined as described above.
19Compound 6j: ¹H NMR (400 MHz, CDCl3): δ = 2.87 (s, 3 H), 3.31 (s, 3 H), 4.37 (s, 2 H), 7.37-7.43 (m, 2 H), 7.47-7.54 (m, 3 H). ¹³C NMR (100 MHz, CDCl3): δ = 39.6, 42.0, 46.5, 129.5, 129.6, 130.1, 132.7, 161.3, 185.2. HRMS (ESI+): m/z [M + H]+ calcd for C11H14N3O2S3: 316.0243; found: 316.0243. The purity of the product was confirmed by HPLC using the same two conditions used for 5d. The retention time of the product under conditions A was 8.7 min (>99% purity) and under conditions B was 10.1 min (99% purity).
20Cytotoxicity analyses were performed by using the assay developed for determining dehydrogenase activities in metabolically active cells as described in ref. 1.
21Fifty percent effective (EC50) concentrations of compounds against WNV were determined by evaluation of cytopathic effects (CPE) in Vero cells by limiting dilution, as described in ref. 1.
22Crystallographic data for structures 5d, 6e, 6f, and 6i have been deposited with the Cambridge Crystallographic Data Centre (CCDC 838607, 838606, 838608, and 838605, respectively). Copies of the data can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, United Kingdom [Fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].