´
C. Proenc¸a, M. L. Serralheiro, M. E. Araujo, T. Pamplona, S. Santos, M. S. Santos, and F. Fraza˜o Vol 48
1292
Benzoxazole-2-thiol (1 g, 10 mmol) was dissolved in 5 mL
pH ¼ 8, their geometry, partition coefficients, and polar
surface areas suggest that they may permeate membranes
to exert their action inside the cells, rendering them promis-
ing lead structures in the search for new AChE inhibitors.
The inhibitory activity profiles found for all the sulfe-
namides synthesized can be reasoned in terms of a bal-
ance between partition toward a hydrophobic anionic
environment, polar surface area, and deviations of
XACSN dihedral angles from colinearity, which emerges
as a factor potentially coupled to enzyme specificity. Fur-
thermore, the integrity of the sulfenamide molecules,
throughout enzyme inhibition assays, implies a noncova-
lent interaction with the enzyme.
of NaOH 2M. This solution and 22.5 mL of 13% sodium hy-
pochlorite were dropped slowly at equal rates into 18 mL of
concentrated ammonium hydroxide (25%v/v). The mixture
was stirred during addition and cooled in ice-bath (5–10ꢀC)
until stabilization of pH between 12.2 and 12.0. The precipi-
tate obtained was washed with cold water until free from alkali
and crystallized from pentane; yield 49%.
Synthesis of N-ethyl-2-benzoxazolylsulfenamide (7) is
described as an example of the procedure followed for prepa-
ration of N-substituted sulfenamides:
Benzoxazole-2-thiol (2.5 g, 1.65 mmol) was dissolved in 68.8
mL of NaOH 0.48M. To this solution, 26.5 mL of a 70% aqueous
solution of ethylamine and iodine (8.39 g, 0.033 mol) dissolved in
55 mL of a 0.5M aqueous solution of potassium iodide were added
dropwise. The pH was kept between 12.2 and 12.0 until precipita-
tion of the sulfenamide, which was washed with cold water and
crystallized from petroleum ether; yield 80.9%.
In summary, these results suggest that compounds 8
and 9 could be considered as new leads for further
optimization.
2-Benzothiazolylsulfenamide (1). Yellow crystals g 87%.
Mp 124–126ꢀC dec. (lit. [20] 127–128ꢀC). IR (KBr); mmax/cmꢂ1
3323, 3198, 1461, 1429, 1313, 1242, 1031, 692. RMN H (400
:
1
EXPERIMENTAL
MHz; CDCl3) d 7.82 (2H, m, H-5, H-6); 7.43 (1H, m, H-4); 7.31
(1H, m, H-7); 3.32 (2H, s, NH2); NMR 13C (100 MHz; CDCl3)
d 178.3 (C-2, C); 154.6 (C-9, C); 135.0 (C-8, C); 126.0 (CH,
C-4); 123.8 (CH, C-7); 121.6 (CH, C-5); 121.2 (CH, C-6).
N-Ethyl-2-benzothiazolylsulfenamide (2). Yellow crystals
Melting points were measured in a Stuart Scientific-melting
point apparatus SMP3. IR spectra were obtained using a Hita-
chi 270–50 spectrophotometer on KBr pastille and only diag-
nostic bands are reported on a cmꢂ1 scale. 1H NMR and 13C
NMR spectra were acquired in a Brucker Avance 400 apparatus
at 400 and 100.4 MHz, respectively, using chloroform-d or d6
DMSO as solvents. The chemical shifts are reported in parts per
million (ppm, d), using the appropriate signal for residual solvent
protons as reference. Coupling constants are reported to the near-
est 0.1 Hz. HRMS were recorded on a Finnigan FT/MS 2001-
DT mass spectrometer. Column chromatography used silica-gel
60, 0.040–0.063 lm (Merck 9385). Thin layer chromatography
(TLC) and preparative TLC were performed on precoated silica-
gel 60 F254 (Merck 5554 and Merck 5717, respectively).
g 62%. Mp 54.5–55.7ꢀC (lit. [20] 55–57ꢀC). IR (KBr); mmax/cmꢂ1
:
3225, 2920, 2880, 1458, 1427, 1238, 1022, 752. RMN H (400
1
MHz; CDCl3) d 7.84 (1H, d, J ¼ 8.4 Hz, H-4); 7.82 (1H, d, J ¼ 7.6
Hz, H-7); 7.42 (1H, ddd, J ¼ 8.4; 7.6; 1.2 Hz, H-5); 7.29 (1H, ddd
J ¼ 7.6; 1.2 Hz, H-6); 3.32 (1H, sb, NH); 3.22 (2H, dq, J ¼ 7.2; 5.6
Hz, H-10); 1.27 (3H, t, J ¼ 7.2 Hz, H-20). NMR 13C (100 MHz;
CDCl3) d 178.6 (C-2, C); 154.9 (C-9, C); 135.0 (C-8, C); 125.9
(CH, C-4); 123.7 (CH, C-7); 121.6* (CH, C-5); 121.1* (CH, C-6);
47.5 (CH2, C-10); 15.7 (CH3, C-20).
N-Ethenyl-2-benzothiazolylsulfenamide (3). Pale yellow
:
HPLC studies were carried out in isocratic mode (methanol/
water 8:2, 1 mL minꢂ1) using a Surveyor Plus HPLC system
(Thermo Finnigan) equipped with a Surveyor Autosampler
Plus with a 100 lL loop, a quaternary pump Surveyor LC
Pump Plus, and a diode-array detector Surveyor PDA Plus. A
crystals g 34.1%. Mp 38.5–40.0ꢀC. IR (KBr); mmax/cmꢂ1
3191, 3079, 3001, 2881, 1454, 1428, 1311, 1241, 1007, 754,
1
725. NMR H (400 MHz; CDCl3) d 7.84 (1H, d, J ¼ 8.4 Hz,
H-4); 7.82 (1H, d, J ¼ 7.6 Hz, H-7); 7.42 (1H, ddd J ¼ 8.4;
7.8; 1.2 Hz, H-5); 7.30 (1H, ddd J ¼ 7.4; 1.2 Hz, H-6); 5.99
(1H, ddd, J ¼ 17.2; 10.2; 1.2 Hz, H-20); d 5.30 (1H, dd, J ¼
17.0; 1.2 Hz, H-30a); 5.24 (1H, dd, J ¼ 10.2; 1.2 Hz, H-30b);
3.37 (2H, t, J ¼ 6.0 Hz, H-10); 3.43 (1H, tb, NH). HRMS
[M]þ m/z 222.02790 (calcd. for C10H10N2S2 222.02799).
N-Benzyl-2-benzothiazolylsulfenamide (4). Yellow crystals
g 42%. Mp 115.0–116.5ꢀC dec. (lit. [20] 117ꢀC). IR (KBr);
stainless-steel Thermo Electron Hypersil GOLD C18 column
R
(100 ꢁ 4.6 mm2, particle size 5 lm) or a Merck PurospherV
Star RP-18 endcapped column (125 ꢁ 4 mm2, particle size 5
lm) were used.
CMCs were determined in thermostatic vessels at 25.0 6
0.1ꢀC with a Kru¨ss K100M2 tensiometer coupled to a Met-
rohm 765 Dosimat automatic burette.
UV–vis scans were performed at 25ꢀC with Shimadzu UV
1603–visible spectrophotometer coupled to a Shimadzu CPS
240A peltier module.
All purchased starting materials and reagents were used
without further purification unless stated otherwise. All chemi-
cals were of analytical grade. AChE type VI-S, from electric
eel 349 U mgꢂ1 solid, 411 U mgꢂ1 protein, 5,50-dithiobis[2-
nitrobenzoic acid] (DTNB), acetylthiocholine iodide (AChI),
tris[hydroxymethyl]aminomethane (tris buffer) and sodium do-
decyl sulfate were obtained from Sigma.
m
max/cmꢂ1: 3081, 3025, 1467, 1429, 1311, 1238, 1079, 1005,
696. NMR 1H (400 MHz; CDCl3) d 7.87 (2H, m, H-4, H-7);
7.44 (5H, m, H-20, H-30, H-40, H-50, H-60); 7.34 (2H, m, H-6,
H-5); 4.37 (2H, d, J ¼ 8 Hz, CH2N); 3.67 (1H, s, NH). NMR
13C (100 MHz; CDCl3) d 177.4 (C-2, C); 154.9 (C-9, C);
138.5 (C-10, C); 135.2 (C-8, C); 128.7 (C-20, CH); 128.5 (C-30,
CH); 128.0 (C-40, CH); 126.0 (C-4, CH); 123.8 (C-7, CH);
121.7 (C-5, CH); 121.2 (C-6, CH); 57.1 (CH2N).
N-Acetyl-2-benzothiazolylsulfenamide (5). White crystals g
31.5%. Mp 133.8–135.8ꢀC (lit. [20] 135–136ꢀC). IR (KBr);
General procedure for the synthesis of compounds
1–9. Synthesis of 2-benzoxazolylsulfenamide (6) is described
as an example of the procedure followed for preparation of
N-unsubstituted sulfenamides:
m
max/cmꢂ1: 3394, 3177, 3064, 2877, 2733, 1685, 1482–1426,
1308, 1255). NMR 1H (400 MHz; CDCl3) d 10.35 (1H, s,
H-11); 8.02 (1H, d; J ¼ 8 Hz, H-4); 7.84 (1H, d; J ¼ 8 Hz,
H-7); 7.47 (1H, t, J ¼ 8 Hz, H-5); 7.36 (1H, t, J ¼ 8 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet