Dapson in heterocyclic chemistry, part I: Novel synthesis of sulfone biscompounds for antimicrobial and antitumor activities

Article abstract of DOI:10.1080/10426500802505408

This article describes the synthesis of some novel sulfone bis-compounds bearing the biologically active thioether 3-6; thioureido 7, 8, 15, 16; triazole 10, 11; thiosemicarbazido 9, 12, 13; and 1,3,4-thiadiazole 14, 17 moieties starting with 4,4′-diisoth

Full text of DOI:10.1080/10426500802505408

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Phosphorus, Sulfur, and Silicon
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Dapson in Heterocyclic
Chemistry, Part I: Novel
Synthesis of Sulfone
Biscompounds for Antimicrobial
and Antitumor Activities
M. M. Ghorab a , N. M. H. Taha b , M. A. A. Radwan c
, N. E. Amin a , M. A. Shehab c & I. M. I. Faker c
a Department of Drug Radiation Research , National
Center for Radiation Research and Technology
(NCRRT) , Nasr City, Cairo, Egypt
b Organic Chemistry Department, Faculty of Science
for Girls , Al-Azhar University , Cairo, Egypt
c Applied Organic Chemistry Department , National
Research Center , Cairo, Egypt
Published online: 03 Nov 2008.
To cite this article: M. M. Ghorab , N. M. H. Taha , M. A. A. Radwan , N. E. Amin ,
M. A. Shehab & I. M. I. Faker (2008) Dapson in Heterocyclic Chemistry, Part I: Novel
Synthesis of Sulfone Biscompounds for Antimicrobial and Antitumor Activities,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:12, 2891-2905
To link to this article: http://dx.doi.org/10.1080/10426500802505408
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Phosphorus, Sulfur, and Silicon, 183:2891–2905, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802505408
Dapson in Heterocyclic Chemistry, Part I: Novel Synthesis
of Sulfone Biscompounds for Antimicrobial
and Antitumor Activities
M. M. Ghorab,1 N. M. H. Taha,2 M. A. A. Radwan,3
N. E. Amin,1 M. A. Shehab,3 and I. M. I. Faker3
1Department of Drug Radiation Research, National Center for
Radiation Research and Technology (NCRRT), Nasr City, Cairo, Egypt
2Organic Chemistry Department, Faculty of Science for Girls, Al-Azhar
University, Cairo, Egypt
3Applied Organic Chemistry Department, National Research Center,
Cairo, Egypt
This article describes the synthesis of some novel sulfone bis- compounds bear-
ing the biologically active thioether 3–6; thioureido 7, 8, 15, 16; triazole 10, 11;
thiosemicarbazido 9, 12, 13; and 1,3,4-thiadiazole 14, 17 moieties starting with
4,4ꢀ-diisothiocyanato-1,1-diphenylsulfone 2. The structures of newly synthesized
compounds were confirmed by elemental analysis, IR,1 H-NMR and mass spectral
data. Compound 3 was found to be the most active compound against Escherichia
coli. Also, compound 15 acted as potent cytotoxic agent.
Keywords Antimicrobial and antitumor agents; sulfone derivatives
INTRODUCTION
Bisheterocyclic compounds are currently an important group of organic
compounds that are used as bactericides,1 fungicides,2,3 antitumor
agents,4 and for their radioprotective effects.5 In addition, sulfone
derivatives are known to possess interesting biological properties
that show antitumor6 and antimicrobial7 activities. In addition, sev-
eral types of compounds containing thioether, thioreado, triazole,
thiosemicarbazido, and 1,3,4-thiadiazole have been shown to possess
antitumor and antimicrobial8–10 properties. The interesting antitumor
and antimicrobial properties of sulfone derivatives prompted us to
Received 30 September 2007; accepted 11 December 2007.
Address correspondence to M. M. Ghorab, Department of Drug Radiation Research,
National Center for Radiation Research and Technology (NCRRT), P.O. Box 29, Nasr
City, Cairo, Egypt. E-mail: mmsghorab@yahoo.com
2891

2892
M. M. Ghorab et al.
investigate in some detail this relatively unexplored class of potential
antitumor and antimicrobial agents. Here we report the synthesis of
some biscompounds bearing sulfone groups with the above-mentioned
biologically active moieties to evaluate their antitumor and antimicro-
bial activities.
RESULTS AND DISCUSSION
Treatment of dapson 1 with thiophosgene at room temperature in the
presence of dilute hydrochloric acid9 furnished the corresponding 4,4ꢀ-
diisothiocyanato-1,1-diphenylsulfone 2. The IR spectrum of compound
2 showed the absence of (NH2) bands and presence of bands at 3090
–1
–1
–1
cm (CH arom.), 2102 cm (NCS), 1318, and 1146 cm (SO2).
The reactivity of diisothiocyanate 2 toward some oxygen and nitro-
gen nucleophiles was investigated. The reaction of diisothiocyanate 2
with methanol, ethanol, propanol, and/or butanol yielded the corre-
sponding thiocarbamate derivatives (3–6) (Scheme 1). The structure of
compounds 3–6 was proved by analytical and spectral data.
The IR spectrum of compound 3 showed the absence of a N C S
–1
–1
–1
band and showed the presence of bands at 3278 cm (NH), 2944 cm
–1
1
(CH aliph.), 1360, 1146 cm (SO2), and 1288 cm (C S). H-NMR
spectrum of (3 in DMSO-d6) revealed signals at 3.9 [s, 3H, 2OCH3], 7.4–
8.0 [m, 8H, Ar H], and 11.4 [s, 2H, 2NH]. Mass spectrum of compound
3 showed a molecular ion peak m/z 396 (M+, 27.03%) with a base peak
at 57 (100%), and other significant peaks appeared at 378 (40.54%), 243
O
S
O
1
O
S
CSCl2
H2N
NH2
S
C
N
N
C
S
O
2
ROH
S
C
S
C
O
S
N
N
H
OR
RO
H
O
3, R = CH3
4, R = C2H5
5, R = C3H7
6, R = C4H9
SCHEME
1

Sulfone Biscompounds
2893
(43.24%), 153 (35.14%), 94 (45.95%), and 78 (37.84%). The IR spectrum
–1 –1
of compound 4 revealed bands at 3252 cm (NH), 3040 cm (CH
–1 –1
arom.), 2946, 2850 cm (CH aliph.), 1320, 1156 cm (SO2), and 1200
–1
1
cm (C S). H-NMR spectrum of (4 in DMSO-d6) showed signals at
1.39 [t, 6H, 2CH3], 4.6 [q, 4H, 2CH2], 7.6–8.0 [m, 8H, Ar-H], and 11.4
[s, 2H, 2NH]. Mass spectrum of compound 4 exhibited a molecular ion
peak m/z at 424 (M-CH3, 9.7%) with a base peak at 57 (100%), and other
significant peaks appeared at 350 (92.9%), 317 (66.1%), 290 (60.7%),
182 (74.9%), 150 (59.5%), 108 (73.7%), 90 (46.9%), and 76 (26.1%). IR
spectrum of 5 showed bands at 3240 cm–1 (NH), 3276 cm–1 (CH arom.),
–1
–1
–1
2970, 2840 cm (CH aliph.), 1337, 1186 cm (SO2), and 1289 cm
1
(C S). H NMR spectrum of (5 in DMSO-d6) revealed signals at 0.9
[t, 6H, 2CH3], 1.7 [m, 4H, 2CH2], 4.4 [t, 4H, 2CH2O], 7.5–8.0 [m, 8H,
Ar-H], and 11.5 [s, 2H, 2NH]. IR spectrum of compound 6 exhibited
–1
–1
–1
bands at 3278 cm (NH), 3100 cm (CH arom.), 2958, 2870 cm
–1
–1
1
(CH aliph.), 1330, 1146 cm (SO2), and 1288 cm (C S). H-NMR
spectrum of (6 in DMSO-d6) exhibited signals at 0.9 [t, 6H, 2CH3], 1.3,
1.7 [m, 8H, 4CH2], 4.4 [t, 4H, 2OCH2], 7.4–8.0 [m, 8H, Ar-H], and 11.4
[s, 2H, 2NH].
The novel thioureido derivatives 7 and 8 were synthesized when
diisothiocyanate 2 was allowed to react with propylamine and/or buty-
lamine as nitrogen nucleophile (Scheme 2).
–1
The IR spectrum of compound 7 revealed bands at 3240 cm (NH),
–1
–1
3064 cm (CH arom.), 2960, 2930, 2874 cm (CH aliph.), 1318, 1154
cm−1 (SO2), and 1220 cm−1 (C S). 1H-NMR spectrum of (7 in DMSO-d6)
showed signals at 0.9 [t, 10H, 2CH3+ 2CH2N], 1.5 [m, 4H, 2CH2], 7.7,
7.9 [2d, 8H, Ar-H], and 9.9 [s, 2H, 2NH]. Mass spectrum of compound 7
revealed a molecular ion peak m/z at 450 (M+, 75%), with a base peak
at 291 (100%), and other significant peaks appeared at 324 (75%), 268
(68.75%), and 77 (75%). The IR spectrum of compound 8 revealed bands
S
S
O
S
R
NH2
R
R
N
H
N
H
N
H
N
H
O
7; R = n-propyl
8; R = n-butyl
(2)
S
S
N2H4. H2O
EtOH
O
S
NH2
H2N
N
H
N
H
N
H
N
H
O
(9)
SCHEME
2

2894
M. M. Ghorab et al.
–1
–1
–1
at 3246 cm (NH), 3062 cm (CH arom.), 2958, 2930, 2872 cm
–1
1
(CH aliph.), 1320, 1152 cm (SO2), and 1250 cm−1 (C S). H-NMR
spectrum of (8 in DMSO-d6) exhibited signals at 0.8 [t, 6H, 2CH3], 1.3
[q, 4H, 2CH2NH, 1.4–1.5 [m, 8H, 4CH2], 7.5–7.9 [2d, 8H, AB system],
and 9.9 [s, 2H, 2NH]. Mass spectrum of compound 8 showed a molecular
ion peak m/z at 478 (M+, 0.2%), with a base peak at 332 (100%), and
other significant peaks appeared at 477 (M-1, 0.5%), 446 (0.86%), 371
(4.19%), 290 (19.16%), 268 (3.24%), 182 (36.48%), 150 (15.64%), 134
(26.27%), 90 (3.67%), and 76 (0.19%).
It is observed from the literature that the thiosemicarbazide moiety
plays a vital role in many biological activities, such as antibacterial11
antitumor12 activities. Thus treatment of diisothiocyanate 2 with hy-
drazine hydrate in ethanol at room temperature afforded the corre-
sponding thiosemicarbazide derivative 9 (Scheme 2).
The IR spectrum of 9 revealed bands at 3372, 3278 cm–1 (NH, NH2),
–1
–1
–1
2926 cm (CH aliph.), 1382, 1174 cm (SO2), and 1224 cm (C S).
Mass spectrum of compound 9 exhibited a molecular ion peak m/z at
396 (M+, 0.50%), 395 (M−1, 0.84%) with a base peak at 108 (100%),
and other significant peaks appeared at 368 (8.76%), 313 (8.88%), 285
(5.51%), 248 (80.24%), 184 (10.33%), 140 (62.55%), 118 (8.18%), and 55
(71.08%).
1,2,4-triazole derivatives 10, 11 were obtained via a reaction of com-
pound 2 with thiosemicarbazide and/or thiocarbohydrazide. The reac-
tion progress was followed easily by testing for the evolution of hydro-
gen sulfide (lead acetate paper) (Scheme 3).
The IR spectrum of compound 10 revealed bands at 3436, 3352,
–1
–1
–1
3225 cm (NH, NH2), 1630 cm (C N), 1328, and 1142 cm (SO2).
S
S
S
O
S
H2N
NHNH2
HN
N
NH
N
N
N
O
NH2
H2N
(10)
(2)
S
HN
N
N
NH
O
S
H2NHN
NHNH2
S
N
N
N
S
N
H
H
NH2
NH2
O
(11)
SCHEME
3

Sulfone Biscompounds
2895
Mass spectrum of compound 10 revealed a molecular ion peak m/z at
446 (M+, 0.46%), with a base peak at 78 (100%), and other significant
peaks appeared at 381 (7.30%), 347 (8.11%), 290 (0.66%), 248 (48.82%),
192 (15.05%), 188 (0.88%), 140 (24.82%), 108 (34.84%), 92 (18.88%),
and 77 (5.20%). The IR spectrum of compound 11 showed bands at
–1
–1
–1
3450, 3368, 3200 cm (NH, NH2), 1630, cm (C N), 1408, 1146 cm
–1
(SO2), and 1290 cm (C S). Mass spectrum of compound 11 revealed
a molecular ion peak m/z at 476 (M+, 0.87%), with a base peak at
78 (100%), and other significant peaks appeared at 382 (0.78%), 332
(4.63%), 276 (8.38%), 248 (8.55%), 160 (20.11%), 108 (35.06%), and 77
(9.85%).
When compound 2 was allowed to react with phenyl hydrazine and/
or benzoyl hydrazine, the thiosemicarbazide derivatives 12 and 13 were
obtained (Scheme 4).
–1
–1
The IR spectrum of compound 12 revealed bands 3234, 3200 cm
–1
–1
(NH), 2924 cm (CH aliph.), 1300, 1148 cm (SO2), and 1274 cm
1
(C S). H-NMR spectrum of compound (12 in DMSO-d6) showed sig-
nals at 6.8–7.9 [m, 18H, Ar-H], 8.3, 10.1, and 10.3 [3s, 6H, 6NH). Mass
spectrum of compound 12 revealed a molecular ion peak m/z at 548 (M+,
5.58%), with a base peak at 66 (100%), and other significant peaks ap-
peared at 549 (M+1, 1.72%), 496 (5.04%), 438 (6.31%), 342 (10.04%),
250 (32.94%), 218 (38.13%), 156 (10.74%), and 78 (67.78%).
–1
The IR spectrum of 13 showed bands at 3348, 3250 cm (NH),
3100 cm (CH arom.), 2926 cm (CH aliph.), 1726 cm (C O), 1390,
–1
–1
–1
–1
–1
1146 cm (SO2), and 1290 cm (C S). Mass spectrum of compound
13 revealed a molecular ion peak m/z at 604 (M+, 1.87%), with a base
S
S
H
H
O
S
N
N
PhNHNH2
Ph
N
N
Ph
N
N
H
H
H
H
O
(12)
(2)
S
S
H
H
O
PhCONHNH2
Ph
N
N
Ph
N
N
S
N
N
H
H
H
H
O
O
O
(13)
SCHEME
4

2896
M. M. Ghorab et al.
N
N
N
N
O
S
HCOOH
(9)
S
N
N
S
H
H
O
(14)
SCHEME
5
peak at 248 (100%), and other significant peaks appeared at 605 (M+1,
1.71%), 603 (M−1, 4.10%), 578 (12.10%), 552 (8.22%), 368 (38.10%), 313
(1.25%), 178 (22.38%), 108 (83.81%), and 78 (3.20%).
We also investigated the reactivity of compound 9 toward acid. Thus,
compound 9 was reacted with formic acid to produce the corresponding
the 1,3,4-thiadiazole derivative 14 (Scheme 5).
The IR spectrum of compound 14 exhibited absorption bands at 3370
–1
–1
–1
1
cm (NH), 1592 cm (C N), 1310, and 1146 cm (SO2). H-NMR
spectrum of compound (14 in DMSO-d6) revealed signals at 7.7–8.0 [m,
8H, Ar-H], 9.0 [s, 2H, 2NH], and 11.0 [s, 2H, 2N CH]. Mass spectrum
of compound 14 exhibited a molecular ion peak m/z at 416 (M+, 1.15%),
with a base peak at 108 (100%), and other significant peaks appeared
at 417 (M+1, 0.38%), 418 (M+2, 0.23%), 374 (5.73%), 332 (47.78%), 290
(13.07%), 276 (31.18%), 192 (10.08%), 141 (12.08%), 90 (12.88%), and
59 (81.88%).
Also, when diisothiocyanate derivative 2 was treated with glycine
as another nucleophile, the corresponding 4,4ꢀ-bis(3-carboxymethy-
thioureido)-1,1ꢀ-diphenylsulfone was obtained. The structure of 15 was
proved on the basis of elemental analyses as well as spectroscopic data
(Scheme 6).
–1
The IR spectrum of 15 revealed bands at 3422 cm (br, NH, OH),
–1
–1
–1
1
1720 cm (C O), 1314, 1150 cm (SO2), and 1250 cm (C S). H-
NMR spectrum of (15 in DMSO-d6) exhibited signals at 6.7 [d, 4H,
2CH2], 7.4–8.0 [m, 8H, Ar-H], 10.0 [s, 2H, 2NH], 10.9 [s, 2H, 2OH].
Finally, the Schiff’s base 16 was achieved by condensing compound 9
with benzaldehyde in ethanol under reflux, while the cyclic compound
OH
S
S
H2N
O
S
O
HOOC
N
N
COOH
N
N
(2)
H
H
H
H
O
(15)
SCHEME
6

Sulfone Biscompounds
2897
S
S
O
EtOH
AcOH
HN
N
N
S
N
NH
N
H
H
Ph
Ph
O
Ph
PhCHO
(16)
(9)
HN
N
N
NH
Ph
O
S
Fused
sod. acetate
S
S
N
N
H
H
O
(17)
SCHEME
7
17 was obtained via reaction of 9 with benzaldehyde in acetic acid in
presence of fused sodium acetate (Scheme 7).
–1
–1
The IR spectrum of 16 showed bands at 3306 cm (NH), 1592 cm
–1
–1
(C N), 1320, 1148 cm (SO2), and 1280 cm (C S). Mass spectrum
of 16 revealed a molecular ion peak m/z 573 (M+1, 6.04%) with a base
peak at 77 (100%). IR spectrum of compound 17 exhibited bands at
–1
–1
–1
3234 cm (NH), 1594 cm (C N), 1326, and 1144 cm (SO2). Mass
spectrum of compound 17 showed a molecular ion peak m/z 572 (M+,
13.24%) with a base peak at 52 (100%) (Chart 1).
Antimicrobial Activity
Some of the newly synthesized compounds were screened for their an-
timicrobial activity using the diffusion agar technique.13 The tested
compounds were dissolved in N, N-dimethylformamide (DMF), which
showed no inhibition zones. Tables 1 and 2 list the screening results of
the tested compounds against the Gram-negative bacteria Escherichia
coli and Salmonella typhi, Gram-positive bacteria Staphylococcus au-
reus and Bacillus subtillus, and pathogenic fungi Aspergillus niger and
Aspergillus flavus. The reference antibiotic chloramphenicol and fungi-
cide Grisofluvine were used as positive controls for comparison. The
fungi cultures were maintained on Czapek’s Dox agar media.
Diphenylsulfone bearing thiocarbamic acid o-methyl ester 3 was
found to be the most active compound against Gram-negative bacte-
ria Es-cherichia coli. The results indicated that the biologically active
compound 3 was almost as potent as the standard antibiotic chloram-
phenicol as positive control.

2898
M. M. Ghorab et al.
A
N
B
O
NH
HN
N
-S
+H
m/z 540 (14.71%)
HN
S
NH
Ph
Ph
-32
S
S
O
m/z 573 (13.24%)
m/z C28H24N6O2S3
572 (13.24%)
- B
-A
CH-NH
O
S
HN
N
N
HN
NH
Ph
S
S
O
m/z C7H7N 105 (17.25 %)
- NH
m/z 467 ( 26.18%)
-NCS
-15
m/z 90 (25.00%)
- CH
- 58
O
HN
N
-13
NH
S
NH
Ph
S
O
- CS
- 44
m/z 409 (11.76%)
m/z 77 (33.25 %)
- 24 - C2
-15
-NH
C
H
D
C
S
Ph
N
O
m/z 53 (30.88%)
- H
- D
S
HN
S
NH
O
m/z 121 (17.65%)
m/z 394 (11.76%)
- C
m/z 52 ( 100 %)
base peak
O
S
O
N
- CN
- 26
N
NH
HN
S
NH
O
O
m/z 273 (14.25 %)
m/z 247 (19.12%)
- 2NH
- 30
SO2
O
S
- C6H4
- 76
- O
m/z 125 (23.53%)
- 16
O
m/z 141 ( 12.15 %)
m/z 217 (14.71%)
-C6H4
- 76
- SO2
- 64
m/z 65 (58.82%)
m/z 77 (27.94%)
SCHEME Mass fragmentation pattern of compound 17.

Sulfone Biscompounds
2899
TABLE I Antibacterial Activity of Some Synthesized Compounds
E.
coli
Salmonella
typhi
Staphylococcus
aureus
Bacillus
subtillus
Compd No.
1
2.5
5
1
2.5
5
1
2.5
5
1
2.5
5
2
3
7
++ ++ ++
++ +++ +++
+
+
0
+
+
+
0
+
+
++
+
+
+
0
+
++ ++
+
++ ++
+
+
++ ++ +++
0
+
+
0
0
+
+
+
+
+
+
10
12
16
DMF
++ ++ ++
++
+
+
0
+
++ ++ ++ ++ ++ ++ ++ ++
+
+
0
++
++ ++ ++
0
0
0
0
+
0
0
0
0
0
0
++ ++
0
0
0
0
0
0
Chloramphenicol ++ +++ +++ +++ +++ +++ ++ ++ +++ ++ +++ +++
Well diameter 1 cm (100 mL of each conc. was tested.
Inhibition values = 0.1–0.5 cm beyond control =
+
Inhibition values = 0.6–0.1 cm beyond control = ++
Inhibition values = 1.1–1.5 cm beyond control = +++
Inhibition values = > 1 cm beyond control = ++++, 0 = not detected.
Antitumor Activity (In Vitro Study)
Reagents
1) RPMI 1640 medium (sigma).
2) Ehrlich Ascites Carcinoma cells (EAC) suspension (2.5 × 105 mL).
TABLE II Antifungal Activity of Some Synthesized Compounds
Aspergillusniger
Aspergillus vlavus
Compd. No.
1
2.5
5
1
2.5
5
2
3
7
10
12
16
DMF
+
+
+
++
0
++
++
+
+
+
0
+
+
+
++
+
0
0
+
+
++
++
+
+
++
++
++
++
0
+
++
+
++
+
++
+
+
0
0
0
0
0
Grisofluvine
+++
+++
+++
+++
+++
+++
Well diameter 1 cm (100 mL of each conc. was tested.
Inhibition values = 0.1–0.5 cm beyond control =
+
Inhibition values = 0.6–0.1 cm beyond control = ++
Inhibition values = 1.1–1.5 cm beyond control = +++
Inhibition values = > 1 cm beyond control = ++++, 0 = not detected.

2900
M. M. Ghorab et al.
3) Trypan blue dye: A stock solution was prepared by dissolving 1 g
of the dye in distilled water (100 mL). The working solution was
then prepared by diluting 1 mL of the stock solution with 9 mL of
distilled water. The stain was used then for staining the dead EAC
cells.
4) The compounds tested were (2–15).
Procedure
1) EAC cells were obtained by needle aspiration of the ascetic fluid
from preinoculated mice under aseptic conditions.14
2) The cells were tested for viability and contamination by staining a
certain cell volume of this fluid with an equal volume of the working
solution of trypan blue dye.15,16
3) The ascetic fluid was diluted with saline (1:10) to contain 2.5 × 106
mL cells on a hemocytometer.
4) In a set of sterile test tubes, 0.1 mL of tumor cells suspension,
0.8 mL RPMI 1640 media, and 0.1 mL of each tested compound
(corresponding to 100, 50, and 25 µg/mL) were mixed. The test tubes
were incubated at 37◦C for 2 hr. A trypan blue exclusion test15,16 was
carried out to calculate the presence of nonviable cells. Compounds
producing more than 70% nonviable cells are considered active.16
No. of non viable
Total No. of cells
% of non-viable cells =
× 100
(1)
The relationship between surviving fraction and drug concentration
was plotted to obtain the survival curve of EAC cells. The response
parameter calculated was the IC50 value, which corresponds to the
compound concentration causing 50% mortality in net cells (Table 3).
The results indicated that biologically active compound 15 was al-
most more active than the reference drug (Doxorubicin). From these
results it was found that diphenylsulfone having carboxymethylth-
ioureido moiety 15 exhibited nonviable cells of about 90% at a con-
centration of 50 µg/mL.
EXPERIMENTAL
Melting points were uncorrected. IR spectra were recorded (KBr) on a
Perkin Elmer 1650 spectrophotometer. 1H-NMR spectra were recorded
on varian Gemini spectrometer 200 (200 MHz) using DMSO-d6 as a
solvent, and TMS as internal standard chemical shifts were expressed
as δ ppm units. Mass spectra were recorded on a gas chromatography

Sulfone Biscompounds
2901
TABLE III In Vitro Antitumor Activity of Some Newly Synthesized
Compounds
Non-viable cells (%)
Concentration (µg/mL)
Compound No.
100
50
25
ICa50
2
4
7
8
9
11
14
15
0
20
10
20
0
0
10
0
0
0
0
0
0
0
0
0
0
85
20
>100
>100
>100
>100
>100
>100
>100
0.5
0
0
20
100
100
10
90
55
Doxorubicin
52
aIC50 >100 Mg/mL is considered to be inactive.
GC-MS 9p 100 Ex (schiumadzu instrument) at 70 ev. Microanalytical
data were obtained from the Microanalytical Data Unit at Cairo Uni-
versity.
4,4’-Diisothiocyanato-1,1‘-diphenylsulfone (2)
Dapson 1 (0.01 mol) was dissolved in 200 mL of H2O containing 50
mL concentrated HCl. To this 0.02 mol of CSCl2 was added in one
portion. Stirring began immediately and continued until all of the red
color of CSCl2 had disappeared (1 hr) and the product was precipitate
as white crystals. The resulting precipitate was filtered off, dried, and
recrystallized from acetone to give (2, Table 4).
4,4’-Bis[thiocarbamic acid-O-methyl
ester]-1,1’-diphenylsulfone (3), 4,4’-Bis[thiocarbamic
acid-O-ethyl ester]-1,1’-diphenylsulfone (4),
4,4’-bis[thiocarbamic acid-O-propylester]-1,1’-diphenylsulfone
(5), and 4,4’-Bis[thiocarbamic acid-O-butyl
ester]-1,1’-diphenylsulfone (6)
A solution of 2 (0.01 mol) in alcohol (methyl, ethyl, propyl, butyl) (20
mL) was refluxed for 8 hr. The solid obtained was recrystallized from
dioxane to give (3–6), respectively (Table 4).

2902

Sulfone Biscompounds
2903
4,4’-Bis(3-propyl-2-thioxo)-1,1’-diphenylsulfone (7) and
4,4’-bis(3-butyl-2-thioxo)-1,1’-diphenylsulfone(8)
A mixture of 2 (0.01 mol) and propylamine and/or butyl amine (0.02
mol) in dioxane (30 mL) containing few drops of triethylamine was
refluxed for 6 hr. The solid that formed upon heating was recrystallized
from dioxane to give (7, 8), respectively (Table 4).
4,4’-Bis(thiosemicarbazid-4-yl)-1,1’-diphenylsulfone(9)
A solution of 2 (0.01 mol) and hydrazine hydrate (0.02 mol) in ethanol
(30 mL) was stirred for 3 hr. The solid that formed was collected and
recrystallized from ethanol to give (9), (Table 4).
4,4’-Bis(5-amino-3-thioxo-2,4-dihydro,1,2,4-triazol-4-yl)-1,1’-
diphe-nylsulfone 10 and
4,4’-Bis[1-(5-mercapto-4-amino)-4H-1,2,4-triazolo-3-
yl)thiosemicarbazid-4-yl)-1,1’-diphenylsulfone(11)
A mixture of 2 (0.01 mol) and thiosemicarbazide and/or thiocarbohy-
drazide (0.02 mol) in ethanol (30 mL) containing a few drops of triethy-
lamine was refluxed until evolution of hydrogen sulfide had stopped (8
hr). The solid product was collected and recrystallized from ethanol to
give (10, 11), respectively (Table 4).
4,4’-Bis(phenylthiosemicarbazide-4-yl)-1,1’-diphenylsulfone
(12) and 4,4’-Bis(benzoylthiosemicarbazide-4-yl)-1,1’-
diphenylsulfone(13)
A solution of 2 (0.01 mol) and phenyl hydrazine and/or benzoyl hy-
drazine (0.02 mol) in dioxane (30 mL) was refluxed for 3 hr. The solid
obtained was recrystallized from acetic acid to give (12) and (13), res-
pectively (Table 4).
4,4’-Bis(1,3,4-thiadiazolylamino)-1,1’-diphenylsulfone (14)
A solution of compound 9 (0.01 mol) in formic acid (20 mL) was heated
under reflux for 4 hr. After cooling, the precipitate was filtered off and
recrystallized from dioxane to give (14) (Table 4).

2904
M. M. Ghorab et al.
4,4’-Bis(3-carboxymethyl-thioureido)-1,1’-diphenylsulfone (15)
A mixture of 2 (0.01 mol) and glycine (0.02 mol) in dioxane (30 mL)
containing 3 drops of triethylamine was refluxed for 6 hr. The obtained
solid was recrystallized from dioxane to give (15) (Table 4).
4,4’-Bis(1-benzylidene-thiosemicarbazide-4-yl)-1,1’-
diphenylsulfone
(16)
A mixture of 9 (0.01 mol) and benzaldehyde (0.02 mol) in ethanol (50
mL) was refluxed for 5 hr. The obtained solid was recrystallized from
ethanol to give (16) (Table 4).
4,4’-Bis[(5-phenyl-4,5-dihydro[1,3,4]thiadiazol-2-yl)amino]-1,1’-
diphenylsulfone
(17)
A mixture of 9 (0.01 mol) and benzaldehyde (0.02 mol) in acetic acid
(30 mL) containing 1 g fused sodium acetate was refluxed for 10
hr. The reaction mixture was poured into ice water. The obtained
solid was recrystallized from dimethylformamide/ethanol to give (17)
(Table 4).
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Sulfone Biscompounds
2905
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