Novel furanylarylene arylsulfonylindolesulfonamides: Synthesis and their antibacterial evaluation

Article abstract of DOI:10.1248/cpb.57.591

An array of furanylarylene arylsulfonylindolesulfonamides was synthesized through multi-step synthetic protocols involving bromination, stannylation, Stille cross coupling, reduction, arylsulfonylation, chlorosulfonylation, and condensation reactions. As

Full text of DOI:10.1248/cpb.57.591

June 2009
Notes
Chem. Pharm. Bull. 57(6) 591—596 (2009)
591
Novel Furanylarylene Arylsulfonylindolesulfonamides: Synthesis and
Their Antibacterial Evaluation
Chennan RAMALINGAN, In-Sook LEE, and Young-Woo KWAK*
Department of Chemistry, Kyungpook National University; Taegu 702–701, Korea.
Received August 26, 2008; accepted February 21, 2009; published online March 10, 2009
An array of furanylarylene arylsulfonylindolesulfonamides was synthesized through multi-step synthetic
protocols involving bromination, stannylation, Stille cross coupling, reduction, arylsulfonylation, chlorosulfonyla-
tion, and condensation reactions. As a preliminary evaluation, these analogs were tested for antibacterial activity
against a series of bacterial strains such as Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus,
Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae using a two-fold serial dilution assay.
Whereas analogs possessing unsubstitution, bromosubstitution, or methyl substitution on the benzene ring of
benzenesulfonyl group were less active/inactive, the methoxy and chloro substituted counterparts were demon-
strated to be comparatively more active. A few of them were found to exhibit better activity than the standard,
streptomycin against selective organisms.
Key words diarylfuran; indole; chlorosulfonylation; Stille cross coupling; condensation; antibacterial activity
Considering the increased incidence of severe dissemi- Results and Discussion
nated infections produced by bacteria in immunocompro-
The synthetic pathway for the construction of target fu-
mised hosts, there is an emerging need for new antibacterial ranylarylene arylsulfonylindolesulfonamides is furnished in
agents with potent activity. Consequently, the search for new Chart 1. Diaminodiarylfurans (5) were synthesized from
antimicrobial agents always remains as an important and readily available furan (1) by adopting bromination followed
challenging task for medicinal chemists. The development of by stannylation, Stille cross coupling, and reduction reac-
sulfonamides is a fascinating and informative area in medici- tions. Initially, furan (1) was treated with bromine in N,N-di-
nal chemistry, highlighting the role of skillful planning and methylformamide (DMF) to afford 2,5-dibromofuran (2).
serendipity in drug research. Sulfonamide derivatives are 2,5-Di(tributylstannyl)furan (3), resulting from 2,5-dibromo-
widely used in various conditions including gastrointestinal furan (2) by lithiation using n-butyllithium in ether followed
and urinary tract infections.1,2) Many representatives of by tributylstannylation, on treatment with 1-bromo-4-ni-
this class of compounds were reported to have antibacterial troarenes in the presence of catalytic amount of tetrakis-
activity.3—7) A few of them are human immunodeficiency (triphenylphosphine)palladium and cesium fluoride in 1,4-
virus (HIV) protease inhibitors,8—11) carbonic anhydrase in- dioxane, 2,5-bis(4-nitroaryl)furans (4) were obtained. The
hibitors,12—17) antiepileptic agents,18—20) and anticonvulsant nitro groups of 2,5-bis(4-nitroaryl)furans (4) were reduced to
agents.21—24) However, the most common side effects of this amino groups to yield 2,5-bis(4-aminoaryl)furans (5) using
class of drugs are diarrhea, anorexia, nausea, vomiting, and stannous chloride in ethanol/dimethyl sulfoxide (DMSO). On
hypersensitivity reaction.25)
the other hand, 1-arylsulfonylation of indole (6) with various
Being a structural building block in many natural products arylsulfonyl chlorides was carried out under phase-transfer
and biopertinent chemical targets, the indole ring is one of catalytic conditions to give their corresponding 1-arylsul-
the most commonly encountered heterocycles in medicinal fonyl-1H-indoles (7), which upon treatment with chlorosul-
chemistry.26,27) A careful perusal of literature revealed that fonic acid, the corresponding 3-chlorosulfonylated indole de-
indole based chemical entities possess diverse biological ac- rivatives (8) were obtained. Eventually, condensation be-
tivities including antibacterial and antifungal activities.28—37) tween the 2,5-bis(4-aminoaryl)furans (5) and the 3-chloro-
Particularly, indole carrying sulfonamide- or sulfone moi- sulfonylated indole derivatives (8) in the presence of triethyl-
eties at carbon-3 has attracted considerable interest. For amine in DMF afforded their corresponding target sulfon-
instance, a few indole 3-sulfonamides have been investigated amides, N,Nꢀ-[4,4ꢀ-(furan-2,5-diyl)bis(4,1-arylene)]bis[1-
as inhibitors of HIV-1 reverse transcriptase,38,39) while a (arylsulfonyl)-1H-indole-3-sulfonamides] (9) as pure solids
series of closely related sulfones has been shown to possess after column chromatographic separation.
activity against resistant HIV-1 mutants.40) Recently, short
As a preliminary evaluation, target sulfonamides 9a—j
peptide derivatives have been demonstrated to exhibit in vitro were assayed for their in vitro antibacterial activity against a
activity against HIV-1 wild type and mutants possessing non- panel of bacterial strains such as Bacillus subtilis, Enterococ-
nucleoside reverse transcriptase inhibitor resistance.41) On cus faecalis, Staphylococcus aureus, Pseudomonas aerugi-
the other hand, various target chemical entities with diarylfu- nosa, Escherichia coli, and Klebsiella pneumoniae using a
ran scaffold have been claimed to exhibit appreciable biolog- two-fold serial dilution method. Standard antibiotic and sol-
ical activity.42,43) In this article, we present synthesis of a vent control used were streptomycin and N,N-dimethyl for-
series of novel heterocyclic sulfonamides possessing indole mamide (DMF), respectively and the media used were Nutri-
and diarylfuran scaffolds together as antibacterial agents.
ent broth (NB). Microdilution panels were prepared contain-
ing two-fold dilutions of the compounds and standard drug in
DMF ranging from 100 to 12.5 mg mlꢁ1. The inhibition con-
∗ To whom correspondence should be addressed. e-mail: ywkwak@knu.ac.kr
© 2009 Pharmaceutical Society of Japan

592
Vol. 57, No. 6
Chart 1. Synthesis of Target Heterocyclic Sulfonamides
Table 1. Minimum Inhibitory Concentration (MIC in mg/ml) of Target Sulfonamides 9a—j and Standard against Bacterial Strains
Bacillus
subtilis
Enterococcus
faecalis
Staphylococcus
aureus
Pseudomonas
aeruginosa
Escherichia
coli
Klebsiella
pneumoniae
Compound
9a
9b
9c
9d
9e
9f
9g
9h
25
50
—
25
25
—
—
100
—
—
—
25
50
25
50
25
12.5
12.5
100
100
—
100
100
100
50
12.5
25
100
100
—
25
12.5
100
100
—
100
100
100
100
—
—
50
100
50
—
100
100
—
—
25
50
50
100
100
25
50
12.5
100
100
50
25
25
9i
9j
50
12.5
50
25
Streptomycin
centration of the commonly used antibiotic, streptomycin and moiety (9c, 9d) and the analogs with methyl group on 4-posi-
the target sulfonamide analogs 9a—h were compared. The tion of the aryl group of 1-arylsulfonyl moiety (9g, 9h) did
results are summarized in Table 1.
not show any antibacterial activity against B. subtilis, E. fae-
Using this reliable assay, it was found that target sulfon- calis and S. aureus except 9c and 9d against S. aureus which
amides bearing methoxy substituent on 4-position of the aryl exhibited activity at the highest concentration. While the
group of 1-arylsulfonyl moiety (9a, 9b) were the most active bromo analog 9f was inactive only against E. faecalis, the
among the target sulfonamides against P. aeruginosa, E. coli bromo analog 9e did not exhibit activity against P. aerugi-
and K. pneumoniae except 9b against E. coli and notably, nosa, E. coli and K. pneumoniae. Of the sulfonamides pos-
these compounds were markedly active than the standard an- sessing chloro groups 9i and 9j, the analog 9i was less active
tibiotic streptomycin against P. aeruginosa and K. pneumo- compared to standard antibiotic against all the organisms
niae except 9a against K. pneumoniae, which showed similar except E. faecalis and S. aureus and, against these couple of
activity as the standard. Against E. coli, 9a exerted similar organisms, it displayed similar activity with that of standard.
activity with that of the standard while 9b showed less activ- Furthermore, the chloro analog 9j exerted less activity com-
ity. Furthermore, the sulfonamide 9b was more active than pared to its chloro counterpart 9i against all the organisms
the standard against S. aureus while 9a exhibited similar except P. aeruginosa and K. pneumoniae. Against the former,
activity. Against B. subtilis, these 9a and 9b showed less ac- the minimum inhibitory concentration of 9j was similar to
tivity compared to the standard while against E. faecalis, that of 9i, while against the latter, the minimum inhibitory
these targets showed similar activity.
concentration of 9j was two-fold lower than that of 9i.
Among the sulfonamides 9c—h, the analogs without any
substituent on 4- position of the aryl group of 1-arylsulfonyl

June 2009
593
thus obtained was purified by column chromatography over silica gel using
n-hexane/dichloromethane (1 : 1) as an eluent. Yield 1.13 g, 91%. mp 269—
271 °C. 1H-NMR (400 MHz, DMSO-d6, 25 °C) d: 8.30 (4H, d, Jꢃ8.4 Hz),
8.10 (4H, d, Jꢃ8.6 Hz), 7.51 (2H, s).
Conclusion
A series of heterocyclic sulfonamides, N,Nꢀ-[4,4ꢀ-(furan-
2,5-diyl)bis(4,1-arylene)]bis[1-(arylsulfonyl)-1H-indole-3-
sulfonamides] was synthesized by adopting a multi-step syn-
thetic strategy involving bromination, stannylation, Stille
cross coupling, reduction, arylsulfonylation, chlorosulfonyla-
tion, and condensation reactions. As a preliminary evaluation
of their antimicrobial activity, these analogs were tested
against a series of bacterial strains such as B. subtilis, E. fae-
calis, S. aureus, P. aeruginosa, E. coli, and K. pneumoniae
using a two-fold serial dilution technique. Among them, the
more active compounds were identified as the sulfonamides
with methoxy or chloro substituents on the benzene ring of
benzenesulfonyl moiety and some of them were more active
2,5-Bis(2-methyl-4-nitrophenyl)furan (4b)45) This compound was syn-
thesized from 2-bromo-5-nitrotoluene (1.73 g, 8.0 mmol) and 2,5-bis(tri-
butylstannyl)furan (2.6 g, 4.0 mmol) by adopting the method akin to the syn-
thesis of 2,5-bis(4-nitrophenyl)furan. Yield 1.24 g, 92%. mp 240—241 °C.
1H-NMR (400 MHz, DMSO-d6, 25 °C) d: 8.26 (2H, d, Jꢃ1.5 Hz), 8.20—
8.17 (2H, m), 8.14 (2H, d, Jꢃ8.6 Hz), 7.35 (2H, s) 2.70 (6H, s).
Synthesis of 2,5-Bis(4-aminophenyl)furan (5a)44) Tin chloride (SnCl2·
2H2O; 4.1 g, 18.0 mmol) was added to a suspension of 2,5-bis(4-nitro-
phenyl)furan (0.93 g, 3.0 mmol) in absolute ethanol/dimethyl sulfoxide
(85 : 15) under nitrogen atmosphere and the mixture was heated to 85 °C for
5 h. After the completion of the reaction, it was cooled and the pH of the so-
lution was raised between 7 and 8 by the addition of aqueous sodium hy-
droxide. The combined extracts after extraction with ethyl acetate (50 mlꢂ5)
than the standard, streptomycin as well. The interesting anti- were washed with water (50 mlꢂ2) followed by brine (50 mlꢂ2). Evapora-
tion of the solvent after dried with sodium sulfate afforded a crude mass
which was crystallized from benzene/hexane to give pure 2,5-bis(4-
bacterial activity of these novel heterocyclic sulfonamides in-
duced us for further investigation to establish their mode of
action and will be carried out in due course. Besides, the in-
formation gained in this study would be useful in the design
of structurally similar analogs with improved efficacy.
aminophenyl)furan as a brownish yellow solid. Yield 0.59 g, 78%. mp 217—
219 °C. 1H-NMR (400 MHz, DMSO-d6, 25 °C) d: 7.35 (4H, d, Jꢃ8.6 Hz),
6.54 (4H, d, Jꢃ8.0 Hz), 6.49 (2H, s), 5.19 (4H, br s). 13C-NMR (100 MHz,
DMSO-d6, 25 °C) d: 152.57, 148.41, 124.67, 119.18, 114.31, 104.15. GC/MS
(m/z): 250 (Mꢄ; C16H14N2O).
2,5-Bis(4-amino-2-methylphenyl)furan (5b)45) This compound was
synthesized from its corresponding 2,5-bis(2-methyl-4-nitrophenyl)furan
(1.0 g, 3 mmol) by using a method as described for the synthesis of 2,5-
bis(4-aminophenyl)furan. Yield 0.63 g, 75%. mp 176—178 °C. 1H-NMR
(400 MHz, DMSO-d6, 25 °C) d: 7.39 (2H, d, Jꢃ8.0 Hz), 6.49 (4H, dd, Jꢃ
10.6, 2.5 Hz), 6.44 (2H, s), 5.19 (4H, br s), 2.35 (6H, s). 13C-NMR (100
MHz, DMSO-d6, 25 °C) d: 151.85, 148.11, 134.66, 127.59, 118.27, 116.26,
112.00, 107.56, 22.04. GC/MS (m/z): 278 (Mꢄ; C18H18N2O).
Experimental
All the solvents were distilled prior to use and all reagents were reagent
grade and were used without further purification. Thin layer chromatography
was performed on Silica gel 60 F plates eluting with the solvents indicated.
Column chromatography was performed on Silica gel 230—400 mesh slurry
packed in glass columns with the eluent system as indicated. All the re-
ported melting points were measured in open capillaries and are uncor-
1
rected. H- and 13C-NMR spectra were acquired at 400 MHz and 100 MHz,
respectively (Bruker Avance) using either DMSO-d6 or CDCl3 as a solvent
and tetramethylsilane (TMS) as an internal standard. Infrared spectra were
measured on Mattson Galaxy 7020A (KBr pellet). Mass spectra were meas-
ured on Shimadzu QP5000. Elemental analyses were acquired on Fisone,
EA 1106. The abbreviations br s, s, d, dd, dt, and m stand for the resonance
multiplicities broad singlet, singlet, doublet, doublet of doublet, doublet of
triplet, and multiplet, respectively.
Synthesis of 2,5-Dibromofuran (2) To a stirring solution of furan
(7.3 ml, 100 mmol) in N,N-dimethylformamide (100 ml) at 15—20 °C, was
added bromine (10.3 ml, 200 mmol) carefully in a dropwise fashion. After
the addition was completed, the resulting dark solution was further stirred
for over night while not allowing the temperature to rise above 25 °C. Then
the mixture was poured into water (500 ml) and extracted with diethyl ether
(50 mlꢂ5). The combined ether layers were washed with saturated sodium
bicarbonate (50 mlꢂ2) followed by water (50 mlꢂ2). After drying with
magnesium sulfate, the solvent was evaporated and the concentrated mixture
was subjected to vacuum distillation to afford 2,5-dibromofuran as a viscous
liquid (yield 14 g, 62%) which was used directly for the next step.
Synthesis of 2,5-Bis(tributylstannyl)furan (3) To a stirring cooled
(ꢁ78 °C) solution of 2,5-dibromofuran (7.9 g, 35.0 mmol) in diethyl ether
(140 ml), was added n-BuLi (30.4 ml, 76 mmol). After the stirring was con-
tinued for 1 h. while attaining the reaction temperature ambient, the mixture
was again cooled to ꢁ78 °C. After the dropwise addition of tributyltin chlo-
ride (21.5 ml, 76 mmol), the temperature of the reaction was allowed to
reach ambient. Then the mixture was refluxed for 10 h, cooled and water
(400 ml) was added. The organic layer was separated and the aqueous layer
was extracted with diethyl ether (100 mlꢂ2). After drying over magnesium
sulfate, the combined organic layers were evaporated under reduced pres-
sure. Vacuum distillation of the residue afforded 2,5-bis(tributylstan-
nyl)furan as a viscous liquid. Yield 16.74 g, 74%. 1H-NMR (400 MHz,
CDCl3, 25 °C) d: 6.59 (2H, s), 1.61—1.50 (12H, m), 1.38—1.24 (12H, m),
1.10—0.98 (12H, m), 0.87 (18H, t, Jꢃ7.2 Hz).
General Procedure for the Synthesis of 1-(Arylsulfonyl)-1H-indole
(7a—e) In a two neck flask under nitrogen atmosphere, was added finely
powdered sodium hydroxide (10 mmol), tetrabutylammonium hydrogensul-
fate (TBAHS) (0.1 mmol) and dichloromethane (15 ml). The mixture was
stirred for 10 min while cooling in an ice bath (0—5 °C) and then indole
(3.3 mmol) was added at the same temperature. After stirring for a couple of
minutes, a solution of corresponding arylsulfonyl chlorides (3.3 mmol) in
dichloromethane (10 ml) was added dropwise over a period of 15 min while
not allowing the temperature to surpass ambient temperature. The stirring
was continued further for 3 h and the mixture was filtered and concentrated
after rinsing the solid with dichlormethane (10 ml). The obtained solid was
subjected to column chromatographic separation over silica gel using n-
hexane–ethyl acetate (100 : 15) as an eluent to afford their corresponding 1-
(arylsulfonyl)-1H-indoles as pure solids.
1-(4-Methoxyphenylsulfonyl)-1H-indole (7a)46) Yield 88%. mp 110—
111 °C. 1H-NMR (400 MHz, CDCl3, 25 °C) d: 7.98 (1H, d, Jꢃ8.4 Hz),
7.79—7.76 (3H, m), 7.54—7.52 (1H, m), 7.27—7.25 (1H, m), 7.14 (1H, t,
Jꢃ2.4 Hz), 6.94—6.91 (1H, m), 6.86—6.84 (1H, m), 6.63 (1H, t,
Jꢃ2.4 Hz), 3.74 (3H, s). 13C-NMR (100 MHz, CDCl3, 25 °C) d: 128.7,
128.3, 127.6, 126.4, 124.3, 123.9, 123.5, 121.5, 120.9, 120.1, 114.2, 109.1,
55.8.
1-(Phenylsulfonyl)-1H-indole (7b)47) Yield 94%. mp 78—79 °C. 1H-
NMR (400 MHz, CDCl3, 25 °C) d: 7.99 (1H, dt, Jꢃ0.8, 8.0 Hz), 7.88—7.85
(2H, m), 7.58 (1H, d, Jꢃ3.59 Hz), 7.52—7.50 (2H, m), 7.42—7.40 (2H, m),
7.31—7.30 (1H, m), 7.22—7.19 (1H, m), 6.64 (1H, d, Jꢃ3.59 Hz). 13C-
NMR (100 MHz, CDCl3, 25 °C) d: 138.4, 133.9, 130.9, 129.4, 126.9, 126.5,
124.8, 123.5, 121.6, 115.3, 113.7, 109.4.
1-(4-Bromophenylsulfonyl)-1H-indole (7c)46) Yield 92%. mp 73—
1
74 °C. H-NMR (400 MHz, CDCl3, 25 °C) d: 8.08 (1H, dt, Jꢃ1.2, 8.0 Hz),
7.76 (1H, d, Jꢃ3.6 Hz), 7.66—7.63 (1H, m), 7.42—7.40 (3H, m), 7.24—
7.21 (3H, m), 6.66 (1H, d, Jꢃ3.6 Hz). 13C-NMR (100 MHz, CDCl3, 25 °C)
d: 136.2, 134.9, 131.5, 130.5, 128.3, 128.0, 124.5, 123.5, 121.9, 121.7,
113.2, 107.6.
Synthesis of 2,5-Bis(4-nitrophenyl)furan (4a)44) In a two-neck round
bottom flask equipped with reflux condenser under nitrogen atmosphere,
was taken 1-bromo-4-nitrobenzene (1.6 g, 8.0 mmol), 2,5-bis(tributylstan-
nyl)furan (2.6 g, 4 mmol), cesium fluoride (2.4 g, 16 mmol), tetrakis-(tri-
phenylphosphine palladium (0.28 g, 0.24 mmol) and 1,4-dioxane (40 ml).
Then the mixture was heated to 100 °C with periodical stirring and main-
tained for 12 h. After evaporating the solvent, dichloromethane (50 ml) was
added. The obtained organic fraction after aqueous workup was passed
through a short silica gel column. The solvent was removed and the product
1-(4-Methylphenylsulfonyl)-1H-indole (7d)48) Yield 90%. mp 87—
88 °C. 1H-NMR (400 MHz, CDCl3, 25 °C) d: 7.98 (1H, d, Jꢃ8.4 Hz), 7.75—
7.73 (2H, m), 7.56 (1H, d, Jꢃ3.6 Hz), 7.50 (1H, d, Jꢃ8.4 Hz), 7.24—7.20
(4H, m), 6.64 (1H, d, Jꢃ3.6 Hz), 2.30 (3H, s). 13C-NMR (100 MHz, CDCl3,
25 °C) d: 145.1, 130.1, 130.0, 127.0, 126.5, 124.7, 124.1, 123.4, 121.5,
120.9, 113.7, 109.2, 21.7.
1-(4-Chlorophenylsulfonyl)-1H-indole (7e)46) Yield 91%. mp 78—
1
79 °C. H-NMR (400 MHz, CDCl3, 25 °C) d: 8.11 (1H, dd, Jꢃ1.8, 7.8 Hz),

594
Vol. 57, No. 6
7.79 (1H, d, Jꢃ3.6 Hz), 7.64—7.61 (2H, m), 7.40—7.37 (3H, m), 7.23— (2H, dd, Jꢃ8.5, 2.0 Hz), 7.01 (2H, d, Jꢃ2.0 Hz), 6.92 (4H, d, Jꢃ9.0 Hz),
7.21 (2H, m), 6.68 (1H, d, Jꢃ3.6 Hz). 13C-NMR (100 MHz, CDCl3, 25 °C)
6.75 (2H, s), 3.49 (6H, s), 2.37 (6H, s). 13C-NMR (100 MHz, DMSO-d6) d:
d: 136.1, 134.4, 131.7, 130.3, 128.0, 127.9, 122.3, 121.9, 121.8, 121.6, 164.5, 151.5, 136.9, 135.3, 134.1, 131.6, 130.1, 127.7, 127.4, 126.6, 125.1,
113.1, 107.5.
125.0, 124.7, 121.1, 120.6, 120.0, 116.5, 115.4, 113.8, 110.8, 55.9, 22.2. IR
(KBr), cmꢁ1: 3446.1, 1594.3, 1496.9, 1445.1, 1381.5, 1267.2, 1168.6,
1151.0, 1110.7, 1092.6, 1020.9, 944.6, 832.9, 756.7, 715.8, 671.4, 621.7,
General Procedure for the Synthesis of 1-(Arylsulfonyl)-1H-indole-3-
sulfonyl Chloride (8a—e) In a two-neck flask equipped with air con-
denser, was taken 1-(arylsulfonyl)-1H-indole (1.5 mmol) and acetonitrile 567.0, 544.3. Anal. Calcd for C48H40N4O11S4: C, 59.00; H, 4.13; N, 5.73; S,
(7 ml). After cooling (0—5 °C) in an ice bath, chlorosulfonic acid (6.0
mmol) was added carefully in a dropwise fashion and the dark brown solu-
13.13. Found: C, 59.05; H, 4.15; N, 5.72; S, 13.16.
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(4,1-phenylene)]bis[1-(phenylsulfonyl)-
tion was allowed to reach ambient temperature over a couple of hours, and 1H-indole-3-sulfonamide] (9c) Yield, 88%. mp 163—164 °C. 1H-NMR
was stirred for 48 h while maintaining the reaction temperature between (400 MHz, DMSO-d6) d: 10.71 (2H, br s), 8.41 (2H, s), 8.02—8.00 (4H, m),
35—40 °C. Then the mixture was poured into crushed ice (200 g) and ex-
7.94 (2H, d, Jꢃ8.0 Hz), 7.89 (2H, d, Jꢃ8.0 Hz), 7.61 (4H, d, Jꢃ8.0 Hz),
tracted with dichloromethane (20 mlꢂ5). The combined organic layers were 7.53—7.49 (6H, m), 7.45—7.38 (4H, m), 7.15 (4H, d, Jꢃ8.0 Hz), 6.93 (2H,
washed with saturated aqueous sodium hydrogencarbonate (25 mlꢂ2) fol- s). 13C-NMR (100 MHz, DMSO-d6) d: 152.3, 136.3, 134.2, 130.3, 127.5,
lowed by brine (25 mlꢂ2). Removal of the solvent under vacuum after dry- 126.8, 125.2, 124.8, 124.6, 124.5, 120.7, 120.6, 119.9, 119.8, 113.8, 107.9.
ing over magnesium sulfate gave their corresponding 1-(arylsulfonyl)-1H- IR (KBr), cmꢁ1: 3446.4, 1612.4, 1587.8, 1528.3, 1502.8, 1449.1, 1391.9,
indole-3-sulfonyl chlorides as solids. An analytically pure sample was ob- 1272.0, 1190.4, 1153.9, 1135.5, 1111.3, 1086.1, 1072.1, 1005.7, 948.2,
tained after crystallization from acetonitrile.
825.4, 745.9, 703.9, 615.3, 562.1, 467.6. Anal. Calcd for C44H32N4O9S4: C,
1-(4-Methoxyphenylsulfonyl)-1H-indole-3-sulfonyl
Chloride
(8a) 59.45; H, 3.63; N, 6.30; S, 14.43. Found: C, 59.42; H, 3.67; N, 6.32; S,
Yield 74%. mp 157—158 °C. 1H-NMR (400 MHz, DMSO-d6, 25 °C) d: 14.42.
7.97—7.91 (3H, m), 7.78 (1H, d, Jꢃ8.0 Hz), 7.62 (1H, s), 7.37 (1H, t, Jꢃ
7.8 Hz), 7.28 (1H, t, Jꢃ7.5 Hz), 7.09 (2H, dd, Jꢃ9.0, 2.5 Hz), 3.78 (3H, s).
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(3-methyl-4,1-phenylene)]bis[1-(phenyl-
sulfonyl)-1H-indole-3-sulfonamide] (9d) Yield, 86%. mp 126—127 °C.
13C-NMR (100 MHz, DMSO-d6, 25 °C) d: 164.3, 134.4, 130.5, 129.6, 128.6, 1H-NMR (400 MHz, DMSO-d6) d: 10.75 (2H, br s), 8.49 (2H, s), 8.05 (4H,
127.5, 125.2, 124.2, 123.6, 122.1, 115.5, 113.3, 56.2.
d, Jꢃ7.5 Hz), 7.96 (2H, d, Jꢃ8.0 Hz), 7.91 (2H, d, Jꢃ7.6 Hz), 7.59 (2H, d,
1-(Phenylsulfonyl)-1H-indole-3-sulfonyl Chloride (8b)49) Yield 82%. Jꢃ8.6 Hz), 7.54 (2H, d, Jꢃ7.5 Hz), 7.50—7.46 (6H, m), 7.42 (2H, d, Jꢃ
mp 143—144 °C. 1H-NMR (400 MHz, CDCl3, 25 °C) d: 8.40 (1H, s),
7.5 Hz), 7.07—7.00 (4H, m), 6.76 (2H, s), 2.37 (6H, s). 13C-NMR (100
8.05—7.96 (4H, m), 7.70—7.65 (1H, m), 7.60—7.44 (4H, m). 13C-NMR MHz, DMSO-d6) d: 151.4, 136.3, 135.5, 135.3, 134.2, 131.5, 130.3, 127.7,
(100 MHz, CDCl3, 25 °C) d: 136.9, 135.5, 134.5, 131.2, 130.2, 127.6, 127.3, 127.5, 126.8, 125.3, 125.2, 124.7, 121.4, 120.7, 116.8, 113.8, 110.9, 22.1. IR
125.8, 125.2, 123.9, 120.6, 114.0.
(KBr), cmꢁ1: 3446.0, 3322.9, 1611.3, 1528.6, 1496.5, 1447.1, 1375.0,
1-(4-Bromophenylsulfonyl)-1H-indole-3-sulfonyl Chloride (8c) Yield 1326.3, 1269.4, 1187.9, 1151.6, 1112.0, 1090.7, 1052.0, 965.4, 947.0,
78%. mp 149—150 °C. 1H-NMR (400 MHz, DMSO-d6, 25 °C) d: 7.99— 867.7, 796.4, 746.0, 730.8, 703.7, 684.3, 621.8, 566.2, 548.8. Anal. Calcd
7.93 (3H, m), 7.85—7.81 (3H, m), 7.71 (1H, s), 7.42—7.38 (1H, m), 7.35— for C46H36N4O9S4: C, 60.25; H, 3.96; N, 6.11; S, 13.99. Found: C, 60.29; H,
7.32 (1H, m). 13C-NMR (100 MHz, DMSO-d6, 25 °C) d: 136.4, 134.4, 3.96; N, 6.14; S, 13.95.
133.4, 133.2, 130.9, 129.5, 129.0, 127.6, 125.5, 124.2, 124.0, 122.2, 113.3.
Nꢀ,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(4,1-phenylene)]bis[1-(4-bromophenyl-
1-(4-Methylphenylsulfonyl)-1H-indole-3-sulfonyl Chloride (8d)49) sulfonyl)-1H-indole-3-sulfonamide] (9e) Yield, 79%. mp 152—153 °C.
Yield 76%. mp 159—160 °C. 1H-NMR (400 MHz, CDCl3, 25 °C) d: 8.38 1H-NMR (400 MHz, DMSO-d6) d: 10.76 (2H, br s), 8.48 (2H, s), 7.98—
(1H, s), 8.04—8.01 (1H, m), 7.98—7.95 (1H, m), 7.89 (2H, d, Jꢃ8.5 Hz),
7.54—7.43 (2H, m), 7.35 (2H, d, Jꢃ8.5 Hz), 2.40 (3H, s). 13C-NMR (100
7.93 (8H, m), 7.69 (4H, d, Jꢃ8.5 Hz), 7.66 (4H, d, Jꢃ8.5 Hz), 7.49—7.42
(4H, m), 7.19 (4H, d, Jꢃ8.5 Hz), 6.96 (2H, s). 13C-NMR (100 MHz, DMSO-
MHz, CDCl3, 25 °C) d: 147.1, 134.5, 133.9, 131.2, 130.8, 127.7, 127.2, d6) d: 152.3, 136.8, 135.4, 134.2, 133.4, 131.7, 130.0, 129.4, 126.9, 126.2,
125.7, 125.0, 123.9, 120.5, 114.0, 21.9.
125.3, 124.8, 124.7, 120.8, 119.6, 113.8, 108.0. IR (KBr), cmꢁ1: 3446.2,
1-(4-Chlorophenylsulfonyl)-1H-indole-3-sulfonyl Chloride (8e) Yield 1616.5, 1574.5, 1530.1, 1503.8, 1473.3, 1445,4, 1393.2, 1318.8, 1270.7,
79%. mp 168—169 °C. 1H-NMR (400 MHz, DMSO-d6, 25 °C) d: 8.06 (2H, 1188.0, 1151.2, 1137.6, 1110.8, 1089.1, 1070.2, 1009.8, 945.9, 822.9,
d, Jꢃ8.5 Hz), 7.93 (1H, d, Jꢃ8.6 Hz), 7.81 (1H, d, Jꢃ7.5 Hz), 7.70—7.66 745.9, 708.5, 618.4, 565.8, 425.2. Anal. Calcd for C44H30Br2N4O9S4: C,
(3H, m), 7.41—7.37 (1H, m), 7.34—7.30 (1H, m). 13C-NMR (100 MHz,
50.48; H, 2.89; N, 5.35; S, 12.25. Found: C, 50.50; H, 2.91; N, 5.32; S,
DMSO-d6, 25 °C) d: 140.3, 136.0, 134.4, 131.1, 130.5, 129.1, 127.6, 125.5, 12.28.
124.1, 124.0, 122.2, 113.2.
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(3-methyl-4,1-phenylene)]bis[1-(4-bro-
General Procedure for the Synthesis of N,Nꢀ-[4,4ꢀ-(Furan-2,5-
diyl)bis(4,1-arylene)]bis[1-(arylsulfonyl)-1H-indole-3-sulfonamides] (9a—
mophenylsulfonyl)-1H-indole-3-sulfonamide] (9f) Yield, 75%. mp
140—141 °C. 1H-NMR (400 MHz, DMSO-d6) d: 10.76 (2H, br s), 8.50 (2H,
j) To a solution of 2,5-bis(4-aminoaryl)furan (0.4 mmol) in N,N-dimethyl- s), 7.97 (4H, d, Jꢃ8.5 Hz), 7.94—7.91 (4H, m), 7.65 (4H, d, Jꢃ8.5 Hz),
formamide (8.0 ml) under nitrogen atmosphere, was added 1-(arylsulfonyl)- 7.61 (2H, d, Jꢃ8.6 Hz), 7.49—7.41 (4H, m), 7.07 (2H, dd, Jꢃ8.6, 2.0 Hz),
1H-indole-3-sulfonyl chloride (0.8 mmol). The mixture was stirred at ambi- 6.98 (2H, d, Jꢃ2.0 Hz), 6.76 (2H, s), 2.37 (6H, s). 13C-NMR (100 MHz,
ent temperature for 6 h. after the addition of triethyl amine (0.86 mmol), and DMSO-d6) d: 151.6, 136.7, 135.4, 135.3, 134.2, 133.4, 131.6, 130.0, 129.3,
was extracted with ethyl acetate (10 mlꢂ5) after adding water (50 ml). The 127.7, 126.9, 125.3, 124.8, 121.3, 120.9, 120.8, 116.6, 113.8, 110.9, 22.2. IR
combined organic fractions were washed with water (15 mlꢂ2), dried over (KBr), cmꢁ1: 3446.2, 1574.9, 1473.1, 1445.2, 1392.7, 1188.0, 1151.3,
magnesium sulfate and evaporated under reduced pressure. Column chro- 1110.7, 1089.1, 1070.1, 1010.0, 945.5, 745.8, 708.2, 618.6, 565.9. Anal.
matographic separation of the obtained crude solid over silica gel using n- Calcd for C46H34Br2N4O9S4: C, 51.40; H, 3.19; N, 5.21; S, 11.93. Found: C,
hexane/ethyl acetate (40 : 60) as an eluent afforded their corresponding pure
N,Nꢀ-[4,4ꢀ-(furan-2,5-diyl)bis(4,1-arylene)]bis[1-(arylsulfonyl)-1H-indole-
3-sulfonamides] as solids.
51.44; H, 3.18; N, 5.24; S, 11.91.
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(4,1-phenylene)]bis[1-(4-methylphenyl)-
1H-indole-3-sulfonamide] (9g) Yield, 82%. mp 170—171 °C. 1H-NMR
(400 MHz, DMSO-d6) d: 10.70 (2H, br s), 8.36 (2H, s), 7.90 (4H, dd, Jꢃ7.5,
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(4,1-phenylene)]bis[1-(4-methoxyphenyl-
sulfonyl)-1H-indole-3-sulfonamide] (9a) Yield, 89%. mp 141—142 °C. 1.5 Hz), 7.81 (4H, d, Jꢃ8.0 Hz), 7.63 (4H, d, Jꢃ9.0 Hz), 7.45—7.36 (4H,
1H-NMR (400 MHz, DMSO-d6) d: 10.74 (2H, br s), 8.40 (2H, s), 7.94— m), 7.20 (4H, d, Jꢃ8.0 Hz), 7.16 (4H, d, Jꢃ9.0 Hz), 6.95 (2H, s), 1.93 (6H,
7.88 (8H, m), 7.63 (4H, d, Jꢃ8.6 Hz), 7.46—7.37 (4H, m), 7.16 (4H, d, s). 13C-NMR (100 MHz, DMSO-d6) d: 152.3, 146.5, 136.9, 134.1, 133.2,
Jꢃ8.5 Hz), 6.95—6.93 (6H, m), 3.47 (6H, s). 13C-NMR (100 MHz, DMSO-
131.8, 130.7, 127.5, 126.7, 126.0, 125.1, 124.7, 124.6, 120.6, 120.0, 119.5,
d6) d: 164.5, 152.3, 136.9, 134.1, 131.6, 130.1, 127.3, 126.6, 126.0, 125.0, 113.8, 107.9, 20.9. IR (KBr), cmꢁ1: 3446.1, 3301.0, 1596.1, 1504.0, 1473.6,
124.7, 124.6, 120.6, 119.9, 119.5, 115.4, 113.8, 107.9, 55.9. IR (KBr), 1445.5, 1379.4, 1338.3, 1190.7, 1176.4, 1150.8, 1109.2, 1089.4, 1052.7,
cmꢁ1: 3446.3, 1594.3, 1498.4, 1445.3, 1381.2, 1267.1, 1190.9, 1168.3,
944.9, 904.5, 843.8, 812.6, 755.4, 711.9, 665.7, 617.5, 563.4, 533.9. Anal.
1150.8, 1110.7, 1092.5, 1021.9, 944.9, 833.6, 804.6, 756.1, 715.2, 671.7, Calcd for C46H36N4O9S4: C, 60.25; H, 3.96; N, 6.11; S, 13.99. Found: C,
618.7, 566.6, 543.2. Anal. Calcd for C46H36N4O11S4: C, 58.21; H, 3.82; N, 60.28; H, 3.97; N, 6.09; S, 14.05.
5.90; S, 13.51. Found: C, 58.25; H, 3.79; N, 5.94; S, 13.49.
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(3-methyl-4,1-phenylene)]bis[1-(4-
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(3-methyl-4,1-phenylene)]bis[1-(4- methylphenyl)-1H-indole-3-sulfonamide] (9h) Yield, 87%. mp 125—
methoxyphenylsulfonyl)-1H-indole-3-sulfonamide] (9b) Yield, 90%. mp 126 °C. 1H-NMR (400 MHz, DMSO-d6) d: 10.74 (2H, br s), 8.45 (2H, s),
115—116 °C. 1H-NMR (400 MHz, DMSO-d6) d: 10.73 (2H, br s), 8.44 (2H,
7.93—7.90 (4H, m), 7.85 (4H, d, Jꢃ8.0 Hz), 7.62 (2H, d, Jꢃ8.6 Hz), 7.46—
s), 7.96—7.89 (8H, m), 7.61 (2H, d, Jꢃ8.5 Hz), 7.46—7.38 (4H, m), 7.06 7.38 (4H, m), 7.17 (4H, d, Jꢃ8.5 Hz), 7.06 (2H, dd, Jꢃ8.3, 2.2 Hz), 7.01

June 2009
595
(2H, d, Jꢃ2.0 Hz), 6.77 (2H, s), 2.37 (6H, s), 1.91 (6H, s). 13C-NMR (100
MHz, DMSO-d6) d: 151.5, 146.5, 136.9, 135.2, 134.2, 133.3, 131.7, 130.6,
127.7, 127.4, 126.7, 125.2, 125.1, 124.8, 121.3, 120.7, 120.2, 116.6, 113.8,
110.9, 22.2, 20.9. IR (KBr), cmꢁ1: 3445.6, 3277.7, 1615.0, 1529.9, 1495.7,
1445.8, 1382.6, 1330.4, 1271.0, 1225.8, 1190.7, 1177.4, 1150.9, 1110.2,
1089.9, 1053.3, 1017.5, 969.3, 944.9, 812.3, 755.7, 711.3, 666.1, 621.8,
566.1, 535.0. Anal. Calcd for C48H40N4O9S4: C, 61.00; H, 4.27; N, 5.93; S,
13.57. Found: C, 60.97; H, 4.27; N, 5.96; S, 13.53.
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(4,1-phenylene)]bis[1-(4-chlorophenyl-
sulfonyl)-1H-indole-3-sulfonamide] (9i) Yield, 81%. mp 137—138 °C.
1H-NMR (400 MHz, DMSO-d6) d: 10.76 (2H, br s), 8.47 (2H, s), 8.05 (4H,
d, Jꢃ8.6 Hz), 7.95—7.89 (4H, m), 7.62 (4H, d, Jꢃ8.5 Hz), 7.54 (4H, d, Jꢃ
8.5 Hz), 7.48—7.40 (4H, m), 7.15 (4H, d, Jꢃ8.5 Hz), 6.94 (2H, s). 13C-NMR
(100 MHz, DMSO-d6) d: 152.2, 140.8, 136.8, 134.9, 134.2, 131.8, 130.5,
129.4, 126.9, 126.1, 125.3, 124.8, 124.6, 120.7, 120.6, 119.5, 113.8, 108.0.
IR (KBr), cmꢁ1: 3446.5, 3296.0, 1584.5, 1530.4, 1503.8, 1476.5, 1445.7,
1388.4, 1337.4, 1270.5, 1220.4, 1186.4, 1151.3, 1137.8, 1110.9, 1086.5,
1053.3, 1013.3, 946.4, 911.5, 828.6, 757.4, 710.2, 630.0, 566.2, 480.5. Anal.
Calcd for C44H30Cl2N4O9S4: C, 55.17; H, 3.16; N, 5.85; S, 13.39. Found: C,
55.19; H, 3.15; N, 5.88; S, 13.34.
N,Nꢀ-[4,4ꢀ-(Furan-2,5-diyl)bis(3-methyl-4,1-phenylene)]bis[1-(4-
chlorophenylsulfonyl)-1H-indole-3-sulfonamide] (9j) Yield, 83%. mp
135—137 °C. 1H-NMR (400 MHz, DMSO-d6) d: 10.76 (2H, br s), 8.50 (2H,
s), 8.06 (4H, d, Jꢃ9.0 Hz), 7.96 (2H, d, Jꢃ8.0 Hz), 7.92 (2H, d, Jꢃ7.0 Hz),
7.60 (2H, d, Jꢃ8.5 Hz), 7.50 (4H, d, Jꢃ9.0 Hz), 7.47—7.40 (4H, m), 7.06
(2H, dd, Jꢃ8.5, 2.0 Hz), 6.99 (2H, d, Jꢃ2.0 Hz), 6.76 (2H, s), 2.37 (6H, s).
13C-NMR (100 MHz, DMSO-d6) d: 149.8, 139.1, 134.9, 133.4, 133.1, 132.3,
129.7, 128.5, 127.5, 125.8, 125.0, 123.4, 122.9, 119.4, 119.0, 118.9, 114.8,
111.9, 109.0, 20.3. IR (KBr), cmꢁ1: 3446.1, 1576.6, 1530.1, 1495.6, 1476.6,
1445.5, 1387.2, 1332.0, 1271.0, 1186.9, 1151.8, 1110.7, 1086.5, 1053.1,
1013.2, 945.8, 827.2, 757.5, 709.9, 634.0, 566.3, 480.3. Anal. Calcd for
C46H34Cl2N4O9S4: C, 56.04; H, 3.48; N, 5.68; S, 13.01. Found: C, 56.08; H,
3.51; N, 5.64; S, 13.05.
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Antibacterial Evaluation The in vitro antibacterial activities were ex-
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Acknowledgements Financial support from Korea Research Foundation
(KRF-2006-005-J02401) is gratefully acknowledged.
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