656
T. Phuonget al. / Bioorg. Med. Chem. Lett. 14 (2004) 653–656
geometry and their similarity (Fig. 1). The total FlexS
docking score (Total-Score) were obtained from ꢂ787.4
for compound 4a to ꢂ1298.9 for compound 3d. Despite the
difference of thiourea moiety position on the phenyl ring
(1,2-, 1,3-, 1,4-phenylenedithiourea), the flexible alignment
show the similarity of both pharmacophore and chemical
composition of all compounds. The FlexS in silico result
expresses a corresponding with in vitro antifungal activ-
ities by the ranking of structures. 1,3- and 1,2-phenylene-
dithiourea analogues get the high rank on the total
FlexS docking score. 1,4-phenylenedithiourea derivatives
have low rank on FlexS superposition and 4 compounds
4c–d, 4g–h were failed in FlexS flexible alignment
procedure when compound 6a was setup as reference
structure. Structure of compounds 3d, 3e, 3h, 5a, 6a–b
are placed high rank in flexible superposition ranking.
Filter and collect the precipitate and recrystallize it from
mixture EtOH–H2O 1:1, dry at 60 ꢀC to have 5a–b.
3.3. General procedure for synthesis of 1,2-phenylene-
dithioureas
Place 0.01mol of 1,2-phenylenediamine, 0.02mol of 4-
isothiocyanatobenzoic acid or 4-isothiocyanatosalicylic
acid and 20mL EtOH. Heat the mixture on water bath
at 50–60 ꢀC for 15 min. Keep the mixture at room tem-
perature for 24 h. The precipitate was filtered and
recrystallized from EtOH to afford 6a–b.
References and notes
1. Caujolle, R.; Amarouch, H.; Payard, M.; Luiseau, P. N.;
Bories, C.; Gayral, P.; Linas, M. D.; Seguela, J. P. Eur. J.
Med. Chem. 1995, 30, 801.
3. Experimental
2. (a) Truong, P.; Ngo, D. T. H. Vietnamese Pharm. J. 1999,
12, 14 (Chem. Abstr. 2000, 133, 263752. (b) Truong, P.;
Tran, P. Y. Vietnamese Pharm. J. 2000, 9, 9 (Chem.
Abstr. 2001, 135, 73923.
3. Hiroshi, K.; Keiko, T.; Masami, A.; Emiko, M.; Kayoko,
M.; Toshiyuki, A. Bioorg. Med. Chem. Lett. 1999, 9, 1347.
4. Uckun, F. M.; Mao, C.; Pendergrass, S.; Maher, D.; Zhu,
D.; Tuel-Ahlgren, L.; Venkatachalam, T. K Bioorg. Med.
Chem. Lett. 1999, 9, 2721.
5. Dong, Y.; Venkatachalam, T. K.; Narla, R. K.; Trieu,
V. N.; Sudbeck, E. A.; Uckun, F. M. Bioorg. Med. Chem.
Lett. 2000, 10, 87.
6. Murray, P. R.; Baron, E. J. et al. Manual of Clinical
Microbiology, 6th ed.; ASM Press: Washington, 1995.
7. Haugwitz, R. D.; Maurer, B. V.; U.S. Patent 4,218,396,
1980.
Melting points (mp) were determined by using a Gal-
lenkamp apparatus. physiochemical parameters UV and
IR were determined on UV spectrometry 3191 PC-Shi-
mazdu and IR spectrometry on FTIR 8101-Shimazdu.
NMR spectra were recorded in the given solvent with
Bruker AC200 spectrometer. Chemical shifts are repor-
ted as (d values in parts per million). The splitting pat-
tern abbreviations are as follows: m (multiplet), s
(singlet), d (doublet), t (triplet). All reported products
showed 1H NMR spectra in agreement with the
assigned structures. Elemental analyses were found sui-
table with calculated of elemental from structure.
3.1. General procedure for synthesis of 1,4-phenylene-
dithioureas and 1,3-phenylenedithioureas
8. Demuth, Jr.; Thomas P.; White, R. E.; U.S. Patent
5,631,256, 1997.
9. Sybyl, Computer Program, Version 6.8, Tripos Inc., St
Louis, MO, 2001.
In round-bottomed flask, place 0.01mol of 1,4-phenyl-
ene-diisothiocyanate 2a (or 1,3-phenylenediisothiocya-
nate 2b), 0.02 mol of amine and 30mL EtOH (or
MeOH, iso-propanol depend on the ester group of
amines). Heat the mixture on water bath at 50–60 ꢀC for
15 min and leave at room temperature for 24 h. Filter
and collect the precipitate and recrystallize from EtOH
(or MeOH) afforded compounds 3a–h, 4a–h.
10. Analytical data for compound 3d: mp (ꢀC) 154–155; UV
1
(nm) 301.0; IR (KBr) (cmꢂ1) 1721, 1604, 1335, 1109; H
NMR (d ppm) 1.32 (d, JCH3ꢂCH=7, 12H, CH3), 3.78 (m,
2H, CH), 7.66 (m, 12H, ArH), 10.07 (s, 4H, NH). Anal.
calcd for C28H30N4O4S2: N, 10.17; S, 11.65. Found: N,
10.14; S, 11.61.
11. Analytical data for compound 3h: mp (ꢀC) 180–181; UV
(nm) 316.2; IR (KBr) (cmꢂ1) 1312, 1343, 1219, 837; 1H
NMR (d ppm) 1.33 (d, JCH3ꢂCH=7, 12H, CH3), 3.88 (m,
2H, CH), 7.44 (m, 10H, ArH), 10.10 (s, 4H, NH), 10.60 (s,
2H, ArOH). Anal. calcd for C28H30N4O6S2: N, 9.62; S,
11.01. Found: N, 9.46; S, 11.00.
3.2. General procedure for synthesis of hydrazide deriv-
atives of 1,4-phenylenedithiourea
In a round-bottomed flask, place 0.01 mol of 4b or 4f
0.022 mol of phenylhydrazine and 30 mL MeOH, heat-
ing reflux the mixture on water bath at 60–70 ꢀC for 3 h,
and leave the mixture at room temperature for 8 h.
Remove excessive phenylhydrazine by using HCl 10%.
12. Analytical data for compound 5a: mp (ꢀC) 205–206; UV
(nm) 301.2; IR (KBr) (cmꢂ1) 3266, 1518, 1113, 841; 1H
NMR (d ppm) 7.65 (m, 22H, ArH), 10.09 (s, 8H, NH).
Anal. calcd for C34H30N8O2S2: N, 17.32; S, 9.92. Found:
N, 16.94; S, 9.72.