Communications
Table 2. Anodic peak potentials (Epa) of flupirtine (1) and derivatives 9a–h and 10a–d, EC50 and Emax values towards KV7.2/3 channels in HEK293 cells and
LD50 (24 h exposure) and LD25 values (48 h exposure) in TAMH cells and HEP-G2 cells as well as toxicity/activity ratios.
1
2
3
Entry
Epa[a] [mV]
logD7.4
EC50[b][μM]
Emax [%]
LD50[c] [μM]
LD25 [μM][c]
Tox./Act.[c]
LD50[d] [μM]
LD25 [μM][d]
Tox./Act.[d]
0.918�0.099[e]
0.26�0.082
0.253�0.042
>10
>10
>10
100
487�51
>30
>63
>250
>1000
>125
>500
>7.5
>10
>100
>63
>500
>500
103�47
13�04
14�13
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
6�03
>10
112
50
55
547�111
8�3
74�40
4�1
81
15
4
5
6
7
8
9
1
9a
9b
9c
9d
9e
350
442
452
450
499
573
573
631
855
628
654
442
n.o.[g]
2.96
3.90
4.34
3.61
2.62
3.00
2.04
4.27
3.85
3.24
3.72
2.81
3.02
100�23
69�9
>250
134�22
831�149
>250
>500
>10
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
4�4
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
267
–
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
400
–
–
–
9f
>10
9g
9h
10a
10b
10c
10d
0.015�0.002
0.269�0.031
>10
>10
>10
147�9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
129�3
-
>30
>125
>63
>500
>500
25�16
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
93
–
–
–
–
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
n.d. [f]
>10
[a] Determined with 1.0 mM compound in 100 mM TRIS-buffer (pH 7.4); [b] EC50- and LD50-values are means and standard deviations of 4–5 independent
determinations; [c] determined using TAMH cells; [d] determined using HEP-G2 cells; [e] flupirtine maleate salt was used; [f] not determined; [g] non-
oxidizable.
Experimental Section
Keywords: medicinal chemistry · ion channels · oxidation ·
structure-activity relationships · sulfides
N-[6-(Benzylthio)-2-(methylamino)
pyridin-3-yl]-2-(3,5-difluorophenyl)acetamide (9g)
Compound 8g (2.8 mmol, 771 mg), iron powder (28 mmol, 1.57 g)
and ammonium chloride (28 mmol, 1.5 g) were suspended in 15 mL
[1] C. Gomis-Perez, M. V. Soldovieri, C. Malo, P. Ambrosino, M. Taglialatela,
P. Areso, A. Villarroel, Front. Mol. Neurosci. 2017, 10, 117.
[2] E. Scheuch, K. Methling, P. J. Bednarski, S. Oswald, W. Siegmund, J.
[3] A. Douros, E. Bronder, F. Andersohn, A. Klimpel, M. Thomae, H.-D.
459; and (Erratum) 2015, 71, 387.
°
ethanol 20%. The suspension was stirred at 100 C for 2 hours,
filtered over diatomaceous earth, and the filter washed with ethyl
acetate. The filtrate was poured into water. The collected precip-
itate was washed with ethyl acetate. 2,6-Dichlorophenyl acetic acid
(2.8 mmol, 600 mg) and O-(7-azabenzotriazole-1-yl)-N,N,N’,N’-tetra-
methyluroniumhexafluorophosphate (HATU, 5.6 mmol, 2.1 g) were
°
added and the mixture was stirred at 40 C overnight. The product
was separated using silica gel chromatography (solvent: ethyl
acetate/hexane). The combined product containing fractions were
evaporated to dryness. The residue was dissolved in ethanol and
water was added to precipitate the product. Lavender colored solid
[5] T. Garin Shkolnik, H. Feuerman, E. Didkovsky, I. Kaplan, R. Bergman, L.
Pavlovsky, E. Hodak, JAMA Dermatol. 2014, 150, 984–989.
[6] a) W. Siegmund, C. Modeß, E. Scheuch, K. Methling, M. Keiser, A. Nassif,
Urban, S. A. Coulthard, E. S. Bjornsson, I. Cascorbi, A. Floratos, T.
Stammschulte, U. Gundert-Remy, M. R. Nelson, G. P. Aithal, A. K. Daly,
Pharmacogenet. Genomics, 2016, 26, 218–224.
[7] a) DE 102018212006.4; b) C. Bock, K. Beirow, A. S. Surur, L. Schulig, A.
[8] C. Bock, A. Link, Fut. Med. Chem. 2019, 11, in press.
(yield=8%); purity 100%; mp: 201–202 C; 1H NMR (400 MHz,
°
DMSO-d6): δ=9.25 (s, 1H), 7.40 (m, 2H), 7.30 (m, 4H), 7.13 (m, 3H),
6.41 (d, J=7.8 Hz, 1H), 6.23 (d, J=4.6 Hz, 2H), 4.38 (s, 2H), 3.70 (s,
2H), 2.89 (d, J=4.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): δ=168.7,
163.4 (dd, J=13 Hz, J=244 Hz, 2 C), 153.2, 151.6, 140.4 (t, J=10 Hz,
1 C), 138.9, 133.2, 128.6 (2 C), 128.3 (2 C), 126.8, 115.1, 112.7 (dd, J=
6 Hz, J=17 Hz, 2 C), 107.9, 102.2 (t, J=26 Hz, 1 C), 41.8, 33.3, 27.9;
~
IR: v=3442, 3404, 3269, 1652, 1591, 1496, 1389, 1230, 1119, 991,
[9] C. J. Lemmerhirt, M. Rombach, A. Bodtke, P. J. Bednarski and A. Link,
696 cmÀ 1; HRMS-ESI m/z [MÀ H]À calcd for C14H16N4O2S: 398.1144,
found: 398.1157. For synthetic details of other compounds see
supporting information.
[10] A. Bottoni, M. Calvaresi, A. Ciogli, B. Cosimelli, G. Mazzeo, L. Pissani, E.
[11] J. D. Turner, R. Sharma, G. Al Jayoussi, H. E. Tyrer, J. Gamble, L. Hayward,
R. S. Priestley, E. A. Murphy, J. Davies, D. Waterhouse, D. A. N. Cook, R. H.
Clare, A. Cassidy, A. Steven, K. L. Johnston, J. McCall, L. Ford, J.
Hemingway, S. A. Ward, M. J. Taylor, Proc. Natl. Acad. Sci. USA 2017, 114,
E9712-E9721.
[12] a) V. Barrese, F. Miceli, M. V. Soldovieri, P. Ambrosino, F. A. Iannotti, M. R.
Cilio, M. Taglialatela, Clin. Pharmacol. 2010, 2, 225–236; b) A. S. Surur, L.
Schulig, A. Link, Arch. Pharm. Chem. Life Sci. 2019, 352: e1800248..
[13] a) A. Van Summeren, J. Renes, F. G. Bouwman, J.-P. Noben, J. H. M. van
b) M. Davis, B. D. Stamper, BioMed Res. Int. 2016, DOI: 10.1155/2016/
4780872.
Acknowledgements
AS is thankful for support for the article processing charge from
the DFG (German Research Foundation, 393148499) and the Open
Access Publication Fund of the University of Greifswald. CB was
supported by DFG grant LI 765/7-1, KB by DFG BE 1287/6-1.
Conflict of Interest
Manuscript received: November 6, 2018
Revised manuscript received: November 26, 2018
Version of record online: ■■■, ■■■■
The authors declare no conflict of interest.
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