New types of mono and bis sulfonamides, tosylamino acids and thiosulfonic ester derived from xanthotoxin, bergapten and visnagin with biological interest

Article abstract of DOI:10.1080/10426500701263521

Xanthotoxin, bergapten, and visnagin sulfonyl chlorides have been reacted with diamines, hydrazine, amino acides, and imidazolidineiminothiones to produce the corresponding mono-, bis-sulfonamide, and tosylamino acid derivatives. Interaction of xanthotoxi

Full text of DOI:10.1080/10426500701263521

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New Types of Mono and Bis
Sulfonamides, Tosylamino Acids
and Thiosulfonic Ester Derived
from Xanthotoxin, Bergapten
and Visnagin with Biological
Interest
A. M. Sh. El-Sharief a & S. Y. Al-Raqa a
a Chemistry Department, Faculty of Science , Taibah
University , Madinah Munawwarah, Saudi Arabia
Published online: 07 Jun 2007.
To cite this article: A. M. Sh. El-Sharief & S. Y. Al-Raqa (2007) New Types of Mono and
Bis Sulfonamides, Tosylamino Acids and Thiosulfonic Ester Derived from Xanthotoxin,
Bergapten and Visnagin with Biological Interest, Phosphorus, Sulfur, and Silicon and
the Related Elements, 182:7, 1557-1580, DOI: 10.1080/10426500701263521
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Phosphorus, Sulfur, and Silicon, 182:1557–1580, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701263521
New Types of Mono and Bis Sulfonamides, Tosylamino
Acids and Thiosulfonic Ester Derived from Xanthotoxin,
Bergapten and Visnagin with Biological Interest
A. M. Sh. El-Sharief
S. Y. Al-Raqa
Chemistry Department, Faculty of Science, Taibah University,
Madinah Munawwarah, Saudi Arabia
Xanthotoxin, bergapten, and visnagin sulfonyl chlorides have been reacted with
diamines, hydrazine, amino acides, and imidazolidineiminothiones to produce the
corresponding mono-, bis-sulfonamide, and tosylamino acid derivatives. Interac-
tion of xanthotoxin-4-sulfonyl chloride with thiohydantoin furnished the respective
thiosulfonic ester. The new products exhibited better antibacterial and antifungal
activities.
Keywords Bergapten; imidazolineiminothiones; tosylamino acids; thiohydantoin; vis-
nagin; xanthotoxin
INTRODUCTION
The furanocumarins (xanthotoxin, bergapten, ammajin, and psoralen),
which were isolated from Ammi majus L.1,2 are well known to be very
helpful, not only for plants as antifungal and antibacterial factors,3 but
also for human disease treatment.4 Elicitation of secondary metabolites
in vitro cultures of Ammi majus L. have been studied.5 This group of sec-
ondary metabolites has been successfully and effectively used because
of its photoreactive properties in the treatment of leucoderma, vitiligo,
and psoriasis diseases,6 as well as in neurology-symptomatic treatment
of demyelinating diseases, particularly in multiple sclerosis.7 Xantho-
toxin and bergapten could be also isolated and purified from Cnidium
monnieri (L.) Cusson by high-speed counter-current chromatography.8
Received September 20, 2006; accepted December 29, 2006.
The authors wish to express their thanks and sincere gratitude to Prof. Dr. M. M.
El-Nozhah, president of Taibah University and Dr. A. A. El-Harby, Dean of Faculty of
Science, Taibah University for their great help to Research programs.
Address correspondence to A. M. Sh. El-Sharief, Chemistry Department, Fac-
ulty of Science, Taibah University, Madinah Munawwarah, Saudi Arabia. E-mail: al-
shreaf 2005@hotmail.com
1557

1558
A. M. Sh. El-Sharief and S. Y. Al-Raqa
Variation in xanthotoxin content in Ammi majus L. cultures during
in vitro flowering and fruiting has been also studied.9
4-Methoxy-7-methyl-5 δ H-furo [3,2-g δ] benzopyran-5-one (Visna-
gin) isolated from Ammi visnaga L. has long been used as an analgesic
and as strong coronary vasodilator for renal colic and renal stones. It
has also selective antispasmodic effect upon the ureter, bronchial, mus-
cles, and gall bladder, but its use appeared to be limited by undesirable
side effects,10 which attracted the authors to improve its activity. El-
Sharief et al.11,12 synthesized some xanthotoxin, bergapten, and am-
majin derivatives with potential biological activities. They also,13−15
prepared some visnagin derivatives containing biologically active units
and some metal complexes of these ligands.16,17
Since, a considerable number of bis heterocyclic compounds exhib-
ited much better activities including (antibacterial, antifungal, tuber-
culostatic, and plant-growth regulative properties) than heterocyclic
compounds,18,19 the authors, in the present article, synthesized some
heterocyclic compounds containing bis (xanthotoxin, bergapten, and
visnagin) moieties linked together by a sulfonamide group, which have
remarkable biologicaly static activities.20 Thus, xanthotoxin -4-sulfonyl
chloride 121 has been reacted with ethylenediamine (1:1 ratio) to pro-
duce bis-xanthotoxinsulfonamide derivative 2 which was characterized
by elemental and spectral data (Scheme 1).
SCHEME 1
The 1H nmr spectrum of II showed the expected signals assigned to
2 CH2, 2 OCH3 and 8 Ar H. The 2 NH appeared as broad signal and
disappeared after the addition of D2O. Fragmentation pattern of 2 is
illustrated in Figure 1. Similarly, bergapten-9-sulfonyl chloride 311 has
been reacted with ethylenediamine to yield the bis-heterocyclic product
4 (Scheme 2).
1
The IR and H nmr spectra were consistent with structure 4. Mass
spectrum exhibited a fragment peak at m/z(308;0.5%,M./2); also, the
fragments of bergapten and ethylenediamine were indicated. In a simi-
lar fashion, xanthotoxin, and bergapten sulfonyl chlorides 1 and 3 were
reacted with 1,4-diaminobutane to give the bis heterocycles 5 and 6, re-
spectively (Scheme 3).

1559

1560
A. M. Sh. El-Sharief and S. Y. Al-Raqa
SCHEME 2
SCHEME 3
1
Structures 5 and 6 were elucidated by IR, H nmr, Mass spectra,
and elemental analyses. The 1H nmr spectra of both exhibited two sig-
nals for the methylene and one for the methoxy protons, while the aro-
matic protons appeared as complex multiplets. In the down field region,
a hump characteristic for 2 NH was observed and disappeared after
addition of D2O. The mass spectrum of V revealed fragments at m/z
428 (M.-xanthotoxin), 202 (base peak, 9-hydroxypsoralin) and 84 di-
aminobutane. Visnagine-9-sulfonyl chloride 7 (Scheme 4)13,15 was sim-
ilarly reacted with ethylenediamine and 1,4-diamobutane to produce
the bis-compounds 8 and 9, respectively (Scheme 5).
SCHEME 4
These structures of compounds 8 and 9 (Scheme 5) were confirmed
1
by IR, H nmr, mass spectra, and elemental analyses. The IR spec-
tra of 8 and 9 exhibited NH absorption at 3170 cm-1. The mass spec-
trum of 8 exhibited a fragment peak at m/z 322, M/2, and 216 (base

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1561
SCHEME 5
peak, visnagin-CH3); also, the 1H nmr showed the expected signals
for aliphatic, aromatic, and variable hydrogens. The mass spectrum of
9 showed fragment peaks at m/z 336, M/2, and 216, 100% base peak
(visnagin-CH3); 1H nmr showed the respective signals for 4H(2 × CH2-
C), 6H(2 × CH3-Ar), 4H(2 × CH2-N), 6H(2xOCH3), 6H(Ar H), and 2NH
(disappeared after addition of D2O), respectively.
It was reported22 that the interaction of hydrazine hydrate with xan-
thotoxin in boiling ethanol for longer reaction time (17 h) caused fission
of the α-pyran ring and gave the hydrazide 10 (Scheme 6).
SCHEME 6
In the present investigation, xanthotoxin-4-sulfonyl chloride 1 has
been reacted with hydrazine hydrate in boiling ether for one hr to give
the bis-compound 11 and not open the α-pyranone ring.
Similarly, bergaptin-9-sulfonyl chloride 3 has been reacted with hy-
drazine hydrate under the same conditions to give 12. The structures
11 and 12 were confirmed by elemental and spectral data (Scheme 7).
The mass spectra of 11 and 12 resembles the mass spectrum of most of
the synthesized bis-compounds, which exhibited half of the molecular
weight, also most of them (xanthotoxin & bergaptin) showed the psora-
line moiety as a base peak. Another type of bis-heterocyclic compounds
could be achieved through the reaction of xanthotoxin-4-sulfonyl chlo-
ride 1 with 2,4-diaminotoluene (2:1) where the obtained product was
consistent with structure 13 (Scheme 8).

1562
A. M. Sh. El-Sharief and S. Y. Al-Raqa
SCHEME 7
SCHEME 8
1H NMR of 13 showed in the up field region two singlets for the
methyl and the two methoxy protons. The aromatic protons appeared
as multiplets while the remaining hydrogens (2 NH) showed up as broad
signal and disappeared after addition of D2O. The fragmentation pat-
tern of 13 is illustrated in Figure 2.
Attempted reaction of bergaptin-9-sulphonyl chloride 3 or Visnagin-
9-sulphonyl chloride 7 with 2,4-diaminotoluene hopping to obtain bis-
heterocyclic compounds was unsuccessful, and instead, one amino
group only reacted with the sulfonyl chloride while the other was oxi-
dized by the atmospheric oxygen under the reaction conditions to the
nitro group where bergapten and visnagin-9-sulphonamides 1423 and
15 were obtained, respectively (Scheme 9).
SCHEME 9

1563

1564
A. M. Sh. El-Sharief and S. Y. Al-Raqa
The structures 14 and 15 were established by IR, 1H nmr, mass spec-
tra, and elemental analyses. Similarly, reacting p-phenylenediamine
with xanthotoxin-4-sulfonyl chloride 1 or visnagin-9-sulfonyl chloride
7 to obtain bis-heterocyclic compounds was also unsuccessful, and in-
stead, the corresponding p-nitrophenylaminosulfonyl derivatives 16
and 17 were obtained which were confirmed by elemental and spectral
data (Scheme 10). Authentic samples of the nitro compounds 16 and
17 could be prepared through interaction of xanthotoxinsulfonyl chlo-
ride 1 and visnaginsulfonyl chloride 7 with p-nitroaniline in benzene
as solvent and pyridine as catalyst (m.p. and m.m.p.).
SCHEME 10
Also, reaction of α,α-diamino-p-xylene with xanthotoxin-4-sulfonyl
chloride 1 or with bergaptin-9-sulfonyl chloride 3 failed to give bis-
heterocyclic products and instead one amino group reacted with the sul-
fonyl chloride and the other was oxidized to yield p-nitromethylphenyl
derivatives 18 and 19, respectively (Scheme 11). IR, 1H nmr, mass spec-
tra and elemental analyses corroborated these structures.
SCHEME 11
The mass spectrum of 18, exhibited M+, M-1, M-2 and M-CH3; the
1H nmr of 18 and 19 showed three singles for the aliphatic protons (two
types of CH2 and one for the methoxyl protons). The eight aromatic
protons appeared as multiplets and the NH as hump underneath the
aromatic protons which disappeared after addition of D2O.

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1565
In conclusion, (xanthotoxin, bergapten, and visnagin) sulfonyl chlo-
rides 1, 3, and 7 have been reacted with aliphatic diamines (ethylenedia-
mine and 1,4-diaminobutane), aromatic diamines (p-phenylenediamine
and 2,4-diaminotoluene), as well as aralkyl diamines (α,α-diamino-
p-xylene) and hydrazine, hoping to obtain bis-heterocyclic com-
pounds. It was found that aliphatic diamines and hydrazine gave
bis products, while aromatic diamines and aralkyl diamines gave the
mono sulphonamido products. Xanthotoxin-4-sulfonyl chloride and 2,4-
diaminotoluene yielded a bis-product, which could be attributed to the
fact that it is the most isolatable one. In the case of the diamines, which
furnished mono sulfonamide, the other amino group was oxidized by
the atmospheric oxygen under the reaction conditions to nitro group.24
The use of amino acids as starting materials for the design and
synthesis of new potent biologically active compounds is the subject
of interest25 El-Sharief et al.26 reported a facile synthesis for several
heterocyclic compounds containing six, seven, and eight member rings
fused to quinazoline moiety starting from amino acids. They also27 syn-
thesized a number of novel triazoles, triazolothiadiazoles, triazoloth-
iadiazines, and triazolotriazines starting from amino acids. Thus, our
interest in the chemistry of amino acids26,27and the chemistry of (xan-
thotoxin, bergapten, and visnagin)11−17 led us to couple both in one
moiety through a sulfonamide linkage hopping to obtain products with
better activities. Thus, interaction of xanthotoxin-4-sulfonyl chloride 1
with L-alanine, DL-phenylalanine and L-tyrosine in presence of NaOH
solution (10%) with subsequent acidification furnished the tosylamino
acid derivatives 20 (Scheme 12).
SCHEME 12
The MS of 20a showed M+ at m/z 367(8.71%),M+1 368 (1.46%)
and base peak 215 (100%, xanthotoxin), also the mass spectra of
1
20b,c were compatible with their structures. H nmr spectrum of 20b

1566
A. M. Sh. El-Sharief and S. Y. Al-Raqa
exhibited in the aliphatic region (d, t, and s) corresponding to methy-
lene, methyne and methoxy protons, respectively, while aromatic region
exhibited (m and two broad s), which were characteristic for Ar H and
the reaining hydrogens (disappeared after addition of D2O). Imidazoles
and their fused derivatives are key components of many bioactive com-
pounds of both natural and synthetic origin.28 Hydantoin derivatives
are used in theraby as anticonvalsants and chemotherapeutics,29 also
biological and pharmacological activities were stated among deriva-
tives of thiohydantoins.30−33 Due to these activities and our interest
in the chemistry of imidazoles,34−38 and thiohydantoins,39−42 we cou-
pled xanthotoxin with imidazole and with thiohydantoin derivatives
through a sulfonamide and thiosulfonic ester linkage, respectively, hop-
ing to obtain new products with better biological and pharmacological
activities. Thus, interaction of xanthotoxin-4-sulfonyl chloride 1 with
imidazolidineiminothiones 21a–c43 proceeded easily through elimina-
tion of HCl to give 22a–c respectively (Scheme 13). The IR spectrum
of 22 revealed the absence of NH, also the 1H nmr, mass spectrum and
elemental analyses were compatible with structure 22.
SCHEME 13
El-Sharief et al.42 reacted thiohydantoin with chloroacetic acid and
its derivatives through elimination of HCl to give the S-alkyl deriva-
tives. In the present investigation thiohydantoin 2343 has been reacted
successfully with xanthotoxin-4-sulfonyl chloride 1 to produce the thio-
sulfonic acid ester derivative 24 which its structure was elucidated by
elemental and spectral data (Scheme 14).

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1567
SCHEME 14
ANTIMICROBIAL ACTIVITY
Most of the synthesized compounds were evaluated for their antimicro-
bial activity using agar diffusion technique (Cooper, 1972), 1 mg/ml solu-
tion in dimethylformamide was used. The tested organisms were Gram
negative bacteria (Escherichia coli, NCTC-10416 and Salmonella typhi,
ATCC1331), Gram positive bacteria (Staphylococcus aureus, NCTC-
7447 and Bacillus subtilis, NCIB-3610) and Fungi (Aspergillus terrus,
Ferm-BAM C-21and Aspergillus flavus, Ferm-BAM C-22). The bacte-
ria and fungi were maintained on nutrient agar and Czapek’s Dox agar
medium, respectively, DMF showed on inhibition zones. The agar media
were inocubated with different test microorganisms. After 24 h of incu-
bation at 30◦C for bacteria and 48 h of incubation at 28◦C for fungi, the
diameter of the inhibition zone (mm) was measured. Chloramphenicol
and Grisofluvine were used as a standard reference for antibacterial
and antifungal activities, respectively. The minimal inhibitory concen-
tration (MIC) of most of the tesed compounds was measured by two fold
serial dilution method.
Antibacterial Activity
Most of the synthesized compounds were found to possess various an-
tibacterial activity towards all the used bacterial strains.
Gram Negative Bacteria
Compounds 1,4-bis (Xanthotoxin-4-sulfonamido) butane (5) and
Xanthotoxin-4-sulfonamido derivative (18) possess a very high antibac-
terial activity towards (E. coli, NCTC-10416) they have the same ef-
fect as the standard chloramphenicol at all concentrations (1, 2.5, and

1568
A. M. Sh. El-Sharief and S. Y. Al-Raqa
5 mg/ml). The bis compounds 6, 8, and 13, the mono sulfonamido deriva-
tive, which contain nitrophenyl group 15, 16, 17 and 19, and the tosyl
amino acid derivative (20c) showed a high antibacterial activity against
the same organisms (E. coli, NCTC-10416); the compounds exhibited
the same effect as the standard chloramphenicol at MIC (1 g/ml). The
bis xanthotoxin sulfonamides 2 and 5 exhibited a high antibacterial
activity against the gram negative bacteria (Salmonella typhi, ATCC-
13311). They exhibited the same effect as standard chloramphenicol
at MIC (2.5 g/ml). Also, compound 14 exhibited moderate antibacte-
rial activity against the same organism at all concertrations used (1,
2.5, and 5 g/ml). Compounds 4, 6, 8, 11, 12, 18, 19, 20a, and 20b, also
showed moderate activity against the same organism (Salmonella ty-
phi, ATCC-13311) at MIC 1 and 2.5 mg/ml. The results of antibacterial
activity against Gram negative bacteria are summarized in Table I.
Gram Positive Bacteria
Most of the synthesized compounds exhibited various antibacterial
activities towards the bacterial strains used (Staphylococcus aureus,
NCTC-7447 and Bacillus subtilis, NCIB-3610). Thus, compounds 17
and 20c possess the highest activity against(Staphylococcus aureus,
NCTC-7447) at MIC(2.5 g/ml), also, compounds 9, 15, 17, and 20c
showed the same activity against the same organism at MIC (5 g/ml).
Compounds 2, 4, 8, and 11 also exhibited the highest activity against
(Bacillus subtilis, NCIB -3610) at MIC (2.5 and 5 mg/ml). All the syn-
thesized compounds used, except No. 20c, showed moderate activity
against the same organism (Bacillus subtilis) at MIC (1 mg/ml). How-
ever, none of the tested compounds showed superior activity compared
with the reference antibiotic. The results are represented in Table II.
AntiFungal Activity
Most of the prepared compounds were tested for their antifungal activ-
ity using (Aspergillus terrus, Ferm-BAM-C21 and Aspergillus flavus,
Ferm-BAM-C22). The results of the antifungal activity and (MIC) are
summarized in Table III. Some of the synthesized compounds exhib-
ited various antifungal activities towards the two test fungus used.
Compound (28) showed the highest activity against (Aspergillus flavus,
Ferm—BAM - C22) at MIC 5 mg/ml. Also, compounds 4, 12, 17, 20a, c
exhibited moderate antifungal activities against both the two tested
fungus used in all concentration (1, 2.5, and 5 mg/ml), while com-
pound (20b) showed moderate activity against (Aspergillus terrus,
Ferm-BAM-C21) at MIC (1 mg/ml).

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1569
TABLE I Antimicrobial Activity Against (Gram Negative Bacteria)
Test organisms/concentration (mg/ml)
E. Coli
Salmonella typhi
Sample
no.
1
2.5
5
1
2.5
5
2
4
5
6
8
+
+
+
++
+++
++
++
++
+
++
++
+
+
+
+
+
0
+
+
0
++
+
++
+
+
+
+
+
0
++
+
++
++
++
+
+++
++
++
+
++
+
9
++
+
11
12
13
14
15
16
17
18
19
20a
20b
20c
22d
St.
+
++
+
+
+
++
+
++
+
++
++
++
++
++
+++
++
++
+
++
0
++
+
+
++
++
++
++
++
++
+
++
0
0
+
++
0
0
0
0
++
+
+
+
+
+
0
+
+++
++
+
+
+
+
0
+
+
++
+
+
++
+
++
++
++
++
++
+++
++
+
+++
+++
+
+
++
+++
++
++
The organisms were tested against the activity of different concentrations of the
sample. St. = Reference standard; Chlorampfenicol was used as a standard
antibacterial agent and Grisofluvine was used as standard antifungal agent. The
test was done using the diffusion agar technique. Well diameter. 1 cm . . . (100 ul of
each conc. was tested). Inhibition values = 0.1–0.5 cm beyond control = +; inhibition
values = 0.6–1.0 cm beyond control = ++; inhibition values = 1.1–1.5 cm beyond
control = +++; 0 = not detected.
CONCLUSION
The sulphonyl chloride derivatives (1, 3, and 7) of xanthotoxin,
bergapten, and visnagin were reacted with various diamines. Most
of these reactions produced the expected bis sulfonamides, while the
others gave unexpected products due to the formation of mono sulfon-
amides with oxidation of the other amino group to nitro, which could be
attributed to atmospheric oxygen oxidation under the reaction condi-
tions. Xanthotoxinsulfonyl chloride (1) was also reacted with different
amino acids, imidazole, and thiohydantoin derivatives. Many of the new
products exhibited activity against (E. Coli) as the reference standard

1570
A. M. Sh. El-Sharief and S. Y. Al-Raqa
TABLE II Antimicrobial Activity Against (Gram Positive Bacteria)
Test organisms/concentration (mg/ml)
Staphylococcus aureus
Bacillus subtillus
Sample
no.
1
2.5
5
1
2.5
5
2
4
5
6
8
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
0
++
++
+
++
++
+
+
+
+
+
+
+
+
+
+
+
+
++
+
++
+
9
+
+
++
+
11
12
13
14
15
16
17
18
19
20a
20b
20c
22c
St.
+
+
++
+
++
++
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
++
+
+
+
+
+
+
+
+
++
+
++
+
+
+
+
+
+
+
+
+
+
+
0
0
+
+
+
0
0
+
+
+
+
++
++
++
+++
+
+
+
+
+
++
+++
++
+++
+++
+++
++
The organisms were tested against the activity of different concentrations of the
sample. St. = Reference standard; Chlorampfenicol was used as a standard
antibacterial agent and Grisofluvine was used as standard antifungal agent. The test
was done using the diffusion agar technique. Well diameter. 1 cm . . . (100 ul of each
conc. was tested). Inhibition values = 0.1–0.5 cm beyond control = +; inhibition values
= 0.6–1.0 cm beyond control = ++; inhibition values = 1.1–1.5 cm beyond control =
+++; 0 = not detected.
chloramphinicol. Antiviral and antitumor activities of these products
will be tested, and the results will be reported in due course.
EXPERIMENTAL
All melting points are uncorrected and were determined on an elec-
trothermal STUART melting point apparatus (SCIENTIFIC Co. Ltd.,
UK). IR spectra (cm−1) were determined with a Jacso FT/IR 5300 spec-
1
trophotometer using KBr technique. H NMR spectra were measured
using a Jeol FX-100 spectrometer 60 MHz and a Varian Gemini 200 in-
strument 200 MHz (Cairo Univ.) and 250&300 MHz using TMS as an in-
ternal standard, DMSO-d6 as solvent and chemical shift were expressed

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1571
TABLE III Antifungal Activity
Test organisms/concentration (mg/ml)
Aspergillus terrus Aspergillus flavus
2.5
Sample
no.
1
5
1
2.5
5
2
4
5
6
8
9
11
12
13
14
15
16
17
18
19
20a
20b
20c
22c
St.
0
+
0
0
0
0
+
+
0
0
+
0
+
+
0
+
+
+
+
+
+
+
+
+
+
0
0
0
0
+
0
0
+
+
+
+
+
+
0
+
+
0
+
+
+
+
+
0
+
+
+
0
+
+
+
0
0
0
+
+
+
+
0
+
0
0
+
+
+
+
0
+
+
+
—
+++
+
+
+
+
0
+
+
+
+
+
+
0
+
+
++
+
0
0
+
+
+
+
—
++
+
+
+
+
+
0
+
+
+
+
—
+++
+
+
+
—
+++
+
+++
+++
The organisms were tested against the activity of different concentrations of
the sample. St. = Reference standard; Chlorampfenicol was used as a standard
antibacterial agent and Grisofluvine was used as standard antifungal agent. The
test was done using the diffusion agar technique. Well diameter. 1 cm . . . (100 ul of
each conc. was tested). Inhibition values = 0.1–0.5 cm beyond control = +;
inhibition values = 0.6–1.0 cm beyond control = ++; inhibition values = 1.1–1.5
cm beyond control = +++; 0 = not detected.
in δ values. Mass spectra were obtained by use of a Schimadzu–GC
MS−QP 1000EX instrument using the direct inlet system. Elemental
analyses were determined using a Perkin–Elmer 240 (Microanalyses)
instrument, at Cairo University. Antibacterial and antifungal activities
of the synthesized products were carried out by Fermentation Biotech-
nology & Applied microbiology (FERM–BAM) Center, Al-Azhar Univer-
sity, Cairo, Egypt, and are shown in Tables I–III. Physical data of these
compounds are shown in Table IV.
Condensation of (1, 3, or 7) with Aliphatic Diamines
A mixture of (1, 3; 3.14 g or 7; 3.28 g; 10 m moles); ethylenediamine (0.6
g; 10 m moles) or 1,4-diaminobutane (0.88 g; 10 m moles) in dry ether

1572
A. M. Sh. El-Sharief and S. Y. Al-Raqa
TABLE IV Physical Data of the Synthesized Compounds
Elemental analyses
Calcd./found [%]
Compd. Yield
M.P.
[◦C]
Cryst.
solvent
Mol. formula
(Mol. wt.)
no.
(%)
C
H
N
S
Cl
—
2
20 171–173 E/W
(1:1)
23 183–185 E/W
(1:1)
23 160–162 E/W
(1:1)
25 191–192 E/W
(1:1)
C26H20N2O12S2
(616)
50.65 3.25 4.55 10.39
50.40 3.30 4.60 10.50
50.65 3.25 4.55 10.39
50.80 3.20 4.50 10.50
49.41 3.53 4.12 9.41
49.50 3.60 4.10 9.30
49.41 3.53 4.12 9.41
49.30 3.50 4.10 9.50
52.17 3.73 4.35 9.94
52.30 3.70 4.40 9.70
53.57 4.17 4.17 9.52
53.70 4.20 4.00 9.40
48.98 2.72 4.76 10.88
49.00 2.70 4.70 10.70
48.98 2.72 4.76 10.88
49.00 2.80 4.60 10.90
54.87 3.24 4.13 9.44
55.00 3.20 4.00 9.50
54.05 3.60 6.31 7.21
54.00 3.70 6.30 7.10
51.92 2.89 6.73 7.69
52.10 2.90 6.60 7.60
53.02 3.26 6.51 7.44
53.10 3.10 6.70 7.30
54.05 3.60 6.31 7.21
54.00 3.70 6.30 7.10
54.05 3.60 6.31 7.21
54.20 3.50 6.30 7.10
45.05 3.54 3.82 8.72
4
5
C
26H20N2O12S2
(616)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
C
28H24N2O12S2
(680)
6
C28H24N2O12S2
(680)
C28H24N2O12S2
(644)
C30H28N2O12S2
(672)
8
15 205–207
E
9
20 175–173
E
11
12
13
15
16
17
18
19
20a
20b
20c
22a
22b
22c
24
15 167–169 E/W
(1:1)
15 215–217 E/W
(1:1)
C
C
C
24H16N2O12S2
(588)
24H16N2O12S2
(588)
31H22N2O12S2
(678)
25 221–223
20 240–242
23 287–289
20 277–279
25 235–237
25 222–224
E
E
E
E
E
E
E
E
E
E
E
E
E
C20H16N2O8S
(444)
C
C
C
18H12N2O8S
(416)
19H14N2O8S
(430)
20H16N2O8S
(444)
C20H16N2O8S
(444)
20
25
23
>250
>250
>250
C
15H13N O8S
(367)
45.10 3.50 3.9
8.60
C
21H17N O8S
(443)
56.88 3.84 3.16 7.22
57.00 3.70 3.10 7.20
50.91 4.24 2.82 6.47
51.00 4.10 2.80 6.50
C
21H21N O11
(495)
S
30 178–180
35 220–222
30 188–190
25 188–190
C
27H15N3O7S2Cl2 51.59 2.39 6.69 10.19 11.30
(628) 51.70 2.40 6.60 10.00 11.40
27H15N3O7S2ClBr 48.18 2.23 6.25 9.52
(672.5) 48.00 2.20 6.30 9.70
C29H20N3O8S2Cl 54.59 3.14 6.59 10.04 5.57
(637.5) 54.70 3.10 6.50 10.00 5.70
27H16N2O7S2ClBr 49.13 2.43 4.25 9.70
(659.5) 49.00 2.40 4.30 9.70
C
—
C
—
B = Benzene; C = chloroform; D= Dioxane; E = Ethanol; H = n-Hexane; W = water.

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1573
(30 ml) was heated under reflux on a water bath for 3 h. The reaction
mixture was concentrated and the product was purified by dissolving in
dil. NaOH and precipitated by dil. HCl then crystallized from the proper
solvent to give bis (xanthotoxin, bergapten, or visnagin)sulfonamide
derivatives (2, 5), (4, 6), and (8, 9), respectively, (Table IV).
1,2-Bis (Xanthotoxin-4-sulfonamido)ethane (2)
1
IR; 3170(NH), 2950(CH-aliph.), 1735(CO), and 1350,1170 (SO2-N). H
NMR; δ = 2.75(4H, s, 2 × CH2,), 4.50(6H, s, 2 × OCH3), 6.33(2H, d, J
= 9.7 Hz, 2 × C-3H), 7.35(2H, d, J = 2.1 Hz, 2 × C-5H), 7.85(2H, d, J =
2.1 Hz, 2 × C-6H), 8.15(2H, d, J = 9.7 Hz, 2 × C-2H) and 10.05–10.25
ppm (2H, broad s, 2 × NH, disappeared after addition of D2O). Mass
spectrum of 2 (C26H20N2O12S2) showed M+ at m/z 616(0.16%) and base
peak (202, 9-hydroxypsoralen, 100%). Fragmentation pattern of 2 is
illustrated in Figure 1.
1,2-Bis (Bergapten-9-sulfonamido)ethane (4)
IR spectrum; 3175(NH), 2960(CH-aliph.), 1740(CO), and 1350,
1165(SO2-N). 1H NMR; δ = 2.90(4H, s, 2 × CH2), 4.37(6H, s, 2 × OCH3),
6.32(2H, d, J = 9.9 Hz, 2 × C-3H), 7.14(2H, d, J = 2.3 Hz, 2 × C-5H),
7.75 (2H, d, J = 2.3 Hz, 2 × C-6H), 8.18 (2H, d, J = 9.9 Hz, 2 × C-2H)
and 9.85–9.95 ppm (2H, broad s, 2 × NH, disappeared after addition of
D2O). Mass spectrum of 4 (C26H20N2O12S2) exhibited at m/z 308(0.5%;
M/2), 309(0.36), 310(2.40), 311 (0.55), 216(68.23, bergapten), 217(9.89),
the base peak at 202(4-hydroxypsoralen, 100), and 50(14.9, ethlenedi-
amine).
1,4-Bis (Xanthotoxin-4-sulfonamido)butane (5)
IR; 3190(NH), 2970–2930(CH-aliph.), 1745(CO), and 1350,1160(SO2-
N). 1H NMR; δ = 1.70(4H, t, 2 × C-CH2-C), 2.82(4H, app q, 2 ×
CH2-N, after addition of D2O it is appeared as t), 4.50 (6H, s, 2 ×
OCH3), 6.50–8.10 (8H, m, Ar H), and 9.90–10.10 ppm (2H, hump, 2
× NH, disappeared following the addition of D2O). Mass spectrum of
5 (C28H24N2O12S2) showed a peak at m/z 428(1.29%, M-xanthotoxin),
with a base peak at m/z 202(9-hydroxypsoralen). Other significant
peaks appeared at m/z 203 (12.87), 215(8.17), and 216(7.36).
1,4-Bis (Bergapten-9-sulphonamido)butane (6)
IR and 1H NMR of 6 revealed approximately the same bands as
those of 5. Mass spectrum of 6 (C28H24N2O12S2) exhibited a peak
at m/z 428(0.57%, M-bergapten), with a base peak at m/z 202

1574
A. M. Sh. El-Sharief and S. Y. Al-Raqa
(9-hydroxypsoralen). Other significant peaks appeared at m/z
203(13.05), 204(1.44), 215(1.80), 216(21.40), and 217(3.20).
1,2-Bis (Visnagin-9-sulphonamido)ethane (8)
IR; 3175(NH), 2930–2890(CH-aliph.), 1715(CO), and 1360,1170(SO2-
N). 1H NMR; δ = 2.45(6H, s, 2 × CH3-C), 2.75(4H, s, 2 × CH2-N),
4.25(6H, s, 2 × OCH3), 6.20(2H, S, 2 × CH= of γ -chromon), 7.85 (4H,
q, two AB system, JAB = 2.6 Hz), and 8.75(2H,broad s, 2 × NH, disap-
peared after addition of D2O). Mass spectrum of 8(C28H24N2O12S2) re-
vealed a peak at m/z 322(0.1% M/2), with a base peak at m/z 216(100%,
visnagin-CH3). Other significant peaks appeared at m/z 295(1.72) and
280(1.19).
1,4-Bis (Visnagin-9-sulfonamido)butane (9)
IR; 3170(NH), 2950–2830(CH-aliph.), 1710(CO) and 1365,1170(SO2-
1
N). H NMR; δ = 1.72(4H, t, 2 × C-CH2-C), 2.50(6H, s, 2 × CH3-C),
2.79 (4H, app q, 2 × CH2-N; after addition of D2O it is appeared as t),
4.30(6H, s, 2 × OCH3), 6.25(2H, s, 2 ×–CH=), 7.90(4H, q, two AB sys-
tem, JAB = 2.7 Hz), and 9.10–9.30 ppm (2H, hump, 2 × NH, disappeared
following the addition of D2O). Mass spectrum of 9 (C30H28N2O12S2)
showed peaks at m/z 428(1.2%, M-vinagin-CH3), 336(0.11%, M/2), and
216(100%, base peak,visnagin-CH3).
Codensation of (1 and 3) with Hydrazine Hydrate
A mixture of (1 or 3) (3.14 g; 10 m moles) and hydrazine hydrate (0.5 g;
10 m moles) in dry ether (30 ml) was heated under reflux for one h. The
reaction mixture was concentrated and the obtained product crystal-
lized to give bis(xanthotoxin and bergapten)sulfonamides (11 and 12),
respectively (Table IV).
Bis Xathotoxin-4-sulphonamide (11)
IR; 3230(NH), 1740(CO) and 1370,1175(SO2-N). 1H NMR; δ = 4.55(6H,
s, 2 × OCH3), 6.70–8.30(8H, m, Ar H), and 9.50–10.50 ppm (2H, broad
s, 2 × NH, disappeared after addition of D2O). Mass spectrum of 11
(C24H16N2O12S2) exhibited a peak at m/z 294(1.81%, m/2), base peak
at 268(100%), and other significant peaks at 248(22.33), 225(34.33),
205(28.83), and 194 (15.54).
Bis Bergapten-9-sulfonamide (12)
1
IR and H NMR spectra of 12 revealed approximately the same data
as those of 11. Mass spectrum of 12 (C24H16N2O12S2) exhibited a peak

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1575
at m/z 294 (5.14%, M/2), base peak at 202(100%, 9- hydroxypsoralen),
and 216(82.88%, 9-methoxypsoralen).
Reaction of (1, 3, and 7) with 2,4-diaminotoluene
A mixture of (1, 3; 3.14 g or 7; 3.28 g; 10 m moles); 2,4-diaminotoluene
(1.22 g; 10 m moles) and pyridine (0.5 ml) in dry benzene (30 ml)
was heated under reflux for 3 h. The reaction mixture was then con-
centrated cooled and 20 ml. of cold dil. HCl (1:1) was added. The
product was dissolved in dil NaOH, filtered, precipitated by dil. HCl
and crystallized to give bis xanthotoxinsulfonamide derivative (13),
and (bergapten and visnagin)sulfonamide derivatives (1423 and 15)
(Table IV).
Tolyl-2,4-bis(xanthotoxin-4-sulfonamide, Derivative (13)
IR;
3250(NH),
3070–3020(CH-arom.),
2950–2900(CH-aliph.),
1
1735(CO), and 1375, 1170 cm−1(SO2-N). H NMR of 13; δ = 2.30(3H,
s, CH3-Ar), 4.50(6H, s, 2 × OCH3), 6.50–8.30(11H, m, Ar H), and
9.50–10.10 ppm(2H, broad s, 2 x NH, disappeared after addition of
D2O). Mass spectrum of 13 is shown in Figure 2, which exhibited M+,
base peak, and the fragmentation pattern.
Bergapten-9-sulfonamido-(1-yl-3-nitro-4-methylbenzene) (14)
1
IR; 3230(NH), 1735(CO), 1540,1335(NO2), and 1350,1160(SO2-N). H
NMR; δ = 2.30(3H, s, CH3-Ar), 4.35(3H, s, OCH3), 6.35–8.15(7H, m,
Ar H), and 10.10 ppm(1H, hump, disappeared following the addi-
tion of D2O). Mass spectrum (C19H14N2O8S) showed the following
peaks; at m/z 414 (1.01%, M-O), 399(0.72%, M-OCH3), base peak
at 202(100%, 9-hydroxypsoralen) and 216(9.69%, 9-methoxypsoralen),
(m.p. and m.m.p. with authentic sample prepared according to Attia et
al.23).
Visnagin-9-sulfonamido-(1-yl-3-nitro-4-methylbenzene) (15)
1H NMR; δ = 2.35(3H, s, CH3-Ar), 2.55(3H, s, CH3, γ -chromone),
4.35(3H, s, OCH3), 6.25(1H, s, CH, γ -chromone), 7.35–8.35(5H, m,
Ar H), and 9.85(1H, broad s, NH,disappeared after addition of D2O).
Mass spectrum (C20H16N2O8S) exhibited the following peaks at m/z
443(0.07%, M-1), 442(0.18, M-2), 429(0.13, M-CH3), 428(M-O), 413(0.26,
M-OCH3), 310(0.29, visnaginsulfonamide), 230(1.16, visnagin), and
215(base peak, 100, Visnagin-CH3).

1576
A. M. Sh. El-Sharief and S. Y. Al-Raqa
Interaction of Xanthotoxin-4-sulfonyl Chloride,
Bergapten-9-sulfonyl Chloride or Visnagin-9-sulfonyl Chloride
(1, 3, and 7) with p-Phenylenediamine and
α,α-Diamino-p-xylene
A mixture of (1, 3; 3.14 g or 7; 3.28 g; 10 m moles); and p-
phenylenediamine (0.54 g; 5 m moles) or α,α-diamino-p-xylene (0.68
g; 5 m moles), and pyridine (0.5 ml) in dry benzene (30 ml) was heated
under reflux for 3 h and treated as above to give the corresponding
xanthotoxin, bergapten or visnagin sulfonamides (16–19), respectively,
(Table IV).
Xanthotoxin-4-sulfonamido-(1-yl-4-nitrobenzene) (16)
1H NMR; δ = 4.40(3H, s, OCH3), 6.50–8.30(8H, m, Ar H), and 9.85 ppm
(1H, hump, NH, disappeared after addition of D2O). Mass spec-
trum (C18H12N2O8S) exhibited the following peaks at m/z 415(0.30%,
M+), 418(0.18, M+2), 419(0.27, M+3), 415(0.24, M-1), 414(0.70, M-2),
400(3.87, M-O), 386(13.63, M-OCH3), and 107(100, base peak, ni-
trosobenzene).
An authentic sample of 16 was prepared as follows: a mixture of
xanthotoxin-4-sulfonyl chloride (1; 3.14 g, 10 m moles), p-nitroaniline
(1.38 g, 10 m moles), and pyridine (0.5 ml) in dry benzene (30 ml) was
heated under reflux for 5 h and treated as above to give (16; m.p. and
m.m.p.)
Visnagin-9-sufonamido-(1-yl-4-nitrobenzene) (17)
IR;
3220(NH),
3020(CH-arom.),
2950(CH-aliph.),
1720(CO),
1545,1345(NO2) and 1335,1135(SO2-N). 1H NMR; δ = 2.45(3H, s,
CH3-Ar), 4.45 (3H, s, OCH3), 6.15(1H, s, CH, γ -chromone), 7.35–
8.35(6H, m, Ar H), and 9.75 ppm(1H, hump, NH, disappeared after
addition of D2O). Mass spectrum (C19H14N2O8S) exhibited at m/z
430(0.84%, M+), 429(1.56, M-1), 428(6.28, M-2), 415(1.29, M-CH3), and
135(100, base peak).
An authentic sample of 17 was prepared as follows: a mixture of
Visnagin-9-sulfonyl chloride (7, 3.28 g, 10 m moles), p-nitroaniline (1.38
g, 10 m moles), and pyridine (0.5 ml) in dry benzene (30 ml), was heated
under reflux for 5 h and treated as above to give (17; m.p. and m.m.p.).
Xanthotoxin-4-sulfonamidomethyl-(1-yl-4-nitrotoluene) (18)
IR; 3170(NH), 3010(CH-arom.), 2950(CH-aliph.), 1740(CO), 1535, 1335
(NO2) and 1330,1135(SO2-N). 1H NMR; δ = 4.25(2H, s, N-CH2-Ar),

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1577
4.50(3H, s, OCH3), 4.65(2H, s, CH2-NO2), 6.50–8.10(8H, m, Ar H), and
9.95 ppm (1H, hump, NH, disappeared following the addition of D2O).
Mass spectrum; (C20H16N2O8S) revealed the following peaks at m/z
444(0.2%, M+), 448(0.9, M+4), 443(0.3, M-1), 442(0.6, M-2) 428(1.2, M-
O), 413(3.2, M-OCH3), and 202(100, base peak, 9-hydroxypsoralen).
Bergapten-9-sulfonamidomethyl-(1-yl-4-nitrotoluene) (19)
IR and 1H NMR of 19 exhibited approximately the same bands as those
of 18. Mass spectrum (C20H16N2O8S) showed at m/z 444(0.2%, M+),
428(1.2, M-O), 429(1.1, M-CH3), 413 (3.2, M-OCH3), and 202 (100, base
peak, xanthotoxin).
General Procedure for Synthesis of Tosylamino Acids (20a–c)
The tosylamino acid derivatives (20a–c) were prepared similar to the
reported methods,24,25 whereby the amino acid (alanine, 0.89 g; pheny-
lalanine, 1.65 g; or tyrosine, 1.81 g; 10 m moles) was dissolved in 1N
sodium hydroxide (25 ml), and over a period of 15 min, a solution of
xanthotoxin -4-sulfonyl chloride (1, 3.14 g, 10 m moles) in dry benzene
(30 ml) was added in portions. The mixture was stirred at room tem-
perature for 3 h. The excess of sufonyl chloride was separated off, and
the solution was treated with 2N HCl until acidic to Congo red (pH
5). Cooling and acidification caused precipitation of the product, which
was filtered off, washed with water, air dried and crystallized to give
(20a–c) (Table IV).
Tosylalanine Derivative (20a)
IR; 3200–2750(-COOH overlapped with NH, arom., and aliph.CH),
1720,1650(2 CO), and 1350,1130(SO2-N).1H NMR; δ = 1.50(3H, d, CH3-
C), 4.45(3H, s, OCH3), 4.65(1H, q, N-CH : CH3. COOH), 6.20(1H, d,
J=9.8 Hz, C-3H), 7.30(1H, d, J = 2.3 Hz, C-5H), 7.75(1H, d, J = 2.3
Hz, C-6H), 8.05(1H, d, J = 9.8 Hz, C-2H), and 10.10, 11.35 ppm (2H,
2 broad s, NH & OH, disappeared after addition of D2O). Mass spec-
trum (C15H13NO8S) showed M+ at m/z 367(8.71%,) with a base peak
at m/z 215(100, xanthotoxin). Other significant peaks were observed at
m/z 368(1.64, M+1), 369(0.8, M+2), 352 (59.51, M-CH3), and 295(2.34,
xanthotoxin-4-sulfonamide).
Tosylphenylalanine Derivative (20b)
IR measurements are approximately as those of (20a). 1H NMR;
δ = 2.85(2H, d, CH2), 4.40(3H, s, OCH3), 4.75(1H, t, N-CH-COOH),
6.20–8.00(9H, m, Ar H), and 10.05, 11.30(2H, 2 broad s, NH and OH,
disappeared after addition of D2O).

1578
A. M. Sh. El-Sharief and S. Y. Al-Raqa
Tosyl-L-Tyrosine Derivative (20c)
IR; 3450–3350(OH), 3250–2750(broad band due to overlap of ν NH,
COOH, arom., and aliph. CH), and 1720,1630(2 CO). Mass spectrum
(C21H21NO11S) showed the following peaks at m/z 495(4.90, M + 2 H2O),
462(5.9, M+3), and 216(100, base peak, xanthotoxin).
Synthesis of the Sulfonamide Derivatives (22a–c)
A mixture of the iminothione (21a, 1.75 g; 21b, 1.97 g or 21c, 1.80 g;
5 m mols), xanthotoxin-4-sulfonyl chloride (1, 1.57 g, 5 m moles) and
pyridine (0.5 ml) in dry benzene (30 ml) was refluxed for 3 h. The reac-
tion mixture was treated with cold dil. HCl and the obtained product
was filtered off, washed with water, and then crystallized to give 22a–c
(Table IV).
Sulfonamide Derivative (22a)
IR; 3030 (CH-arom.), 2950 (CH-aliph.), 1740,1680 (2 CO), 1485, 1170
1
(CS-N), and 1355,1170 (SO2-N). H NMR; δ = 4.45(3H, s, OCH3) and
6.70–8.10 (12H, m, Ar H). Mass spectrum of 22a (C27H15N3O7S2Cl2)
exhibited a peak at m/z 602 (9.7%, M-C2H2), 248(100, base peak),
350(8.2, imidazolineiminothione), and 215(10.5, 9-methoxypsoraline).
Synthesis of (22b)
IR and 1H NMR spectra showed approximately the same bands as those
of 22a. Mass spectrum (C27H15N3O7S2ClBr) revealed a peak at m/z
460(1.5%, M-p-Br.C6H4.NCS), 462(42.1), 463(40.8), 216(38.8, xantho-
toxin), 173(51.3, p-Br.C6H4.NH2), 136(3.9, p-Cl-.C6H4NC), and 86(100,
base peak).
Synthesis of (22c)
IR; 3020(CH-arom.), 2950–2850(CH-alph.), 1730,1670(2 CO),
1490,1175(CS-N), and 1350,1160(SO2-N). 1H NMR, δ = 1.1(3H,
t, CH3-C), 4.45(3H, s, CH3-O), 5.1(2H, q, CH2-O), and 6.6–8.10
ppm (12H, m, Ar H). Mass spectrum (C29H20N3O8S2Cl) showed
a peak at m/z 636(80.1%, M-1), 359(100, base peak, the cor-
responding imidazolidineiminothione), 346(27.3, the respective
thiohydantoin), 179(77.1, p-ethoxyisothiocyanate), and 153(27.3,
p-chlorophenylisocyanate).

Sulfonamides, Tosylamino Acids, and Thiosulfonic Esters
1579
Synthesis of the Thiosulfonicacid Ester (24)
A mixture of the thiohydantoin 23 (0.80 g, 2 m moles), xanthotoxin-4-
sulfonyl chloride 1 (0.63 g, 2 m moles), and sodium ethoxide (2 m moles)
in absolute ethanol (30 ml) was refluxed for 6 h. The reaction mixture
was poured on to cold dil. HCl, and the obtained product was crystallized
to give 24 (Table IV). 1H NMR spectrum exhibited the following signals
at δ = 4.51(3H, s, CH3-O), 6.3(1H, s, CH-N), and 6.90–8.30 ppm (12H,
m, Ar H).
REFERENCES
[1] (a) I. R. Fahmy, H. Abu-Shady, A. Schonberg, and A. Sina, Nature (London), 60, 468
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