Diguanidino and "reversed" diamidino 2,5-diarylfurans as antimicrobial agents

Article abstract of DOI:10.1021/jm000413a

Dicationic 2,5-bis(4-guanidinophenyl)furans 5a-5f, 2,5-bis[4- (arylimino)aminophenyl]furans 6a-6b and 6e-6k, and 2,5-bis[4-(alkylimino)aminophenyl]furans 6c-6d have been synthesized starting from 2,5-bis[tri-n-butylstannyl]furan. Thermal melting studies w

Full text of DOI:10.1021/jm000413a

J . Med. Chem. 2001, 44, 1741-1748
1741
Digu a n id in o a n d “Rever sed ” Dia m id in o 2,5-Dia r ylfu r a n s a s An tim icr obia l
Agen ts
Chad E. Stephens,† Farial Tanious,† Susan Kim,†,‡ W. David Wilson,† Wiley A. Schell,§ J ohn R. Perfect,§
Scott G. Franzblau,# and David W. Boykin*,†
Department of Chemistry, Georgia State University, 1 University Plaza, Atlanta, Georgia 30303-3083, Department of Medicine,
Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, North Carolina 27710,
and Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612-7231
Received September 25, 2000
Dicationic 2,5-bis(4-guanidinophenyl)furans 5a -5f, 2,5-bis[4-(arylimino)aminophenyl]furans
6a -6b and 6e-6k , and 2,5-bis[4-(alkylimino)aminophenyl]furans 6c-6d have been synthesized
starting from 2,5-bis[tri-n-butylstannyl]furan. Thermal melting studies with poly dA•dT and
the duplex oligomer d(CGCGAATTCGCG)2 demonstrated high DNA binding affinities for a
number of the compounds. The binding affinities are highly dependent on structure and are
significantly affected by substituents both on the phenyl rings of the 2,5-diphenylfuran nucleus
and on the cationic centers. Of the 17 novel dicationic compounds synthesized, six (6a , 6b, 5b,
6f, 6h , 6i) exhibited MICs of 2 µg/mL or less versus Mycobacterium tuberculosis. Of the
compounds screened against Candida albicans, three gave MICs of 2 µg/mL or less (5b, 6h ,
6i), and two (5b, 6i) were fungicidal, unlike a standard antifungal drug fluconazole, which
was fungistatic. In addition, one of the tested compounds (6i) exhibited a MIC of <1 µg/mL
against Aspergillus fumigatus, while also being a fungicidal against this organism. Finally,
when evaluated against an expanded fungal panel, compound 6h showed good activity against
Cryptococcus neoformans and Rhizopus arrhizus.
In tr od u ction
found to be highly effective treatments in animal models
for Pneumocystis carinii and Cryptosporidium
parvum.8-10,34 Furthermore, these diamidines have
shown antifungal activity in vitro against Candida
albicans and Cryptococcus neoformans.15-17 In an effort
to improve upon this antifungal activity and to discover
other antimicrobial activities through continued broad-
screen evaluation, we have become interested in the
effect of structural variations on the cationic centers of
these compounds. For instance, although there are
reports of antimicrobial activity of guanidino com-
pounds,35 this class of cationic compounds has not been
studied as extensively as their amidino analogues and
has yet to be explored within the diarylfuran series.
Therefore, this report describes, for the first time, the
synthesis, DNA-binding affinities, and some in vitro
antimicrobial (antifungal, antimycobacterial) activitites
of diguanidino analogues in the 2,5-diphenylfuran
series. In addition, the synthesis, DNA-binding affini-
ties, and the same antimicrobial properties of 2,5-bis-
{[alkyl (or aryl) imino]aminophenyl}furans are also
detailed. These latter compounds have the imino group
of the amidine attached to an “anilino” nitrogen in
contrast to the original amidino furans in which the
imino group is directly attached to the aryl ring. These
compounds, hereafter, are referred to as “reversed”
amidines. Finally, this report also describes, for the first
time, some of the interesting effects of placing various
substituents on the central phenyl rings of the 2,5-
diphenylfuran framework.
The antimicrobial properties of dicationic molecules
have been studied since the 1930s.1 Compounds of this
type have typically utilized amidine groups as the
cationic moieties, and their activities against a number
of pathogens including Cryptosporidium parvum,2
Giardia lamblia,3 Leishmania sp.,4,5 Plasmodium sp.,4,6
Pneumocystis carinii,7-10 Toxoplasma gondii,11 Trypano-
soma sp.,12-14 Candida albicans,15-17 Aspergillus sp.,15-17
and Cryptococcus neoformans15-17 have been reported.
Despite the broad range of activity exhibited by
diamidines, only one compound of this chemical
type, pentamidine, has seen significant clinical use.
Pentamidine has been used clinically against African
trypanosomiasis,18 antimony-resistant leishmaniasis,19
and P. carinii pneumonia.7,20 A number of compounds
in this class of dicationic molecules has been shown to
bind to the minor-groove of DNA at AT-rich sites, and
the details of their interaction with the minor-groove
have been elucidated from biophysical studies21-24 and
from several crystal structures.8,25-27 It is hypothesized
that these types of molecules exert their biological
activity by first binding to DNA and then by inhibiting
one or more of several DNA dependent enzymes (i.e.,
topoisomerases, nucleases, etc.) or possibly by direct
inhibition of transcription.23,28-33
In previous work from our laboratories, 2,5-diphenyl-
furan and 2,4-diphenylfuran diamidines have been
* To whom correspondence should be addressed. Tel: 404 651 3798.
Fax: 404 651 1416. E-mail: dboykin@gsu.edu.
† Georgia State University.
Ch em istr y
‡Summer undergraduate student from Furman University.
§ Duke University Medical Center.
The syntheses for the target diguanidines 5 and
reversed diamidines 6 require the corresponding di-
#University of Illinois at Chicago.
10.1021/jm000413a CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/28/2001

1742 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Stephens et al.
Sch em e 1a
Sch em e 3a
a
(a) PhCOCl, TEA, MeCN; (b) SOCl2, DMF, CH2Cl2, ∆; (c) NH3,
EtOH.
Sch em e 4
pared by reaction of the diamines 3 with 2 equiv of a
nonodoriferous S-(2-naphthylmethyl)thioimidate39,40 in
EtOH/MeCN (Scheme 4). Analogous to the literature,39
this reaction gave good yields (60-80%) when the
diamine was unsubstituted or substituted with electron-
donating groups; however, when the diamine was
substituted with the deactivating chloro group, the yield
was reduced considerably (25%), and with the strongly
deactivating trifluoromethyl group, the diamidine could
not be isolated.
a
(a) Pd(PPh3)4, 1,4-dioxane, ∆; (b) H2, Pd/C, EtOAc, EtOH; (c)
SnCl2 dihydrate, EtOH, DMSO, ∆.
Sch em e 2
Biologica l Resu lts
Melting temperatures were measured for the com-
pounds 5 and 6 bound to poly dA•dT to obtain a
qualitative evaluation of the DNA binding affinity of
these drug candidates (Table 1). Since several of the
compounds bound very strongly to poly dA•dT (Table
1), the interaction of these compounds with the Dick-
erson-Drew dodecamer d (CGCGAATTCGCG)2, a DNA
with a different and shorter AT sequence and different
groove characteristics, was also studied. The reduced
binding of the drugs to the dodecamer, reflected by the
lower ∆Tm values of the drug-dodecamer complexes
(Table 1), allowed for a better relative comparison of the
DNA binding affinity of these putative minor-groove
binding compounds. Although ∆Tm values provide only
a relative ranking of the compounds binding affinities,
we have found that they are directly correlated with
binding constants for a set of related diphenylfuran
dications.41
The parent diguanidino compound 5a showed a strong
affinity for DNA as judged by the ∆Tm values for both
poly dA•dT (21.6) and the dodecamer (10.8). These
values compare well to those (25 and 11.7, respectively)
previously reported8 for the parent diamidine, 2,5-bis-
[4-amidinophenyl]furan (furamidine), suggesting little
difference in affinity of the amidine and guanidine
cationic centers within the 2,5-diarylfuran system.
Based on the comparison of ∆Tm values for binding to
the dodecamer for the parent diguanidine 5a and for
the various parent reversed diamidines 6a -6d , several
interesting effects resulting from structural variation
of the terminal groups are noted. First, reversed diami-
dines bearing phenyl (6b) or cyclohexyl (6c) terminal
groups showed an increase in affinity over that of the
parent diguanidine 5a . In a related series of diamidines,
amino compounds 3 as a common precursor (Scheme 1).
The preparation of the diamino compounds 3 was
conveniently achieved in two steps starting with a Stille
coupling between 2,5-bis(tri-n-butylstannyl)furan and
a substituted 4-bromonitroarene to form the corre-
sponding 2,5-bis(4-nitrophenyl)furans 2. This general
reaction, which has been described by us in a communi-
cation,36 typically gave good yields (65-88%) of the
dinitro compounds, and, in contrast to previously re-
ported syntheses,37 allowed for the straightforward
incorporation of substituents onto the two phenyl rings
of the 2,5-diphenylfuran framework. Reduction of the
2,5-bis(4-nitrophenyl)furans 2 was achieved either by
catalytic hydrogenation or by the action of stannous
chloride and generally produced the desired diamino
compounds 3 in excellent overall yields. With the
diamines 3 in hand, the diguanidino analogues 5 were
prepared in a two-step process which involved first the
reaction of 3 with Boc-protected S-methylthiourea in the
presence of mercuric chloride (Scheme 2).38 Deprotection
of the Boc-protected guanidine analogues 4 was subse-
quently accomplished using anhydrous HCl in dichloro-
methane/EtOH to give the diguanidines in good overall
yield.
As shown in Scheme 3, the first of the reversed
diamidines (6b) was prepared from the corresponding
diamide via a two-step process which involved conver-
sion of the latter to the diimidoyl chloride using SOCl2,
followed by reaction with anhydrous ammonia.9 Unfor-
tunately, this approach gave inconsistent results in
other cases, apparently due to the low solubility of the
intermediate diamides and/or the sensitivity of the
furan nucleus to thionyl chloride. Alternatively, the
remainder of the diamidines 6 were conveniently pre-

2,5-Diarylfurans as Antimicrobial Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1743
Ta ble 1. In Vitro Antimicrobial Activities and DNA Binding Results for 2,5-Diarylfuran Dicationic Molecules 5 and 6c
C. albicans
A. fumigatus
MIC MFC
(µg/mL) (µg/mL) (µg/mL) MIC (µg/mL)
DNA affinityb
compd
no.
MIC
MFC
M. tub.
∆Tm
∆Tm
(oligo)
X1X2
R
(µg/mL)
(AT)
5a
6a
6b
6c
6d
5b
5c
5d
5e
5f
6e
6f
6g
6h
6i
X1 ) X2 ) H
X1 ) X2 ) H
X1 ) X2 ) H
X1 ) X2 ) H
X1 ) X2 ) H
X1 ) H, X2 ) CH3
NHAm
12.5
nt
25
25
nt
50
nt
nt
100
nt
nt
100
100
33.4
100
100
100
nt
nt
10
100
10
e1
>100
10
>100
nt
3.13
1.56
1.56
e6.25
nda
e1
16
4
8
nt
3.13
e1
nt
2
e1
8
21.6
19.6
28.6
26.7
15.9
17.8
15.2
26.1
5.9
10.8
7.5
15.0
12.8
6.0
6.9
2.8
4.7
0
1.4
7.8
8.9
1.1
10.8
7.8
0
NHC(dNH)-2-Pyr
NHC(dNH)Ph
NHC(dNH)-c-Hex
NHC(dNH)CH3
NHAm
nt
>100
>100
1.04
10
>100
>100
2.08
33.4
X1 ) H, X2 ) OCH3 NHAm
100
100
10
nt
6.25
10
100
10
100
100
100
nt
nt
100
nt
X1 ) H, X2 ) Cl
X1 ) H, X2 ) CF3
X1 ) X2 ) CH3
X1 ) H, X2 ) CH3
X1 ) H, X2 ) CH3
X1 ) H, X2 ) CH3
X1 ) H, X2 ) CH3
NHAm
NHAm
NHAm
NHC(dNH)Ph
NHC(dNH)-2-Pyr
NHC(dNH)-2-Qu
NHC(dNH)-2-Pyr-5-CH3
10
10
nt
3.12
10
100
e1
e1
100
10
6.25
0.25
2.7
24.9
22.6
7.5
24.3
19.0
5.2
>100
e1
X1 ) H, X2 ) OCH3 NHC(dNH)-2-Pyr
e1
6j
6k
X1 ) H, X2 ) Cl
X1 ) X2 ) CH3
furamidine
NHC(dNH)-2-Pyr
NHC(dNH)-2-Pyr
>100
>100
25
nt
>100
nt
5.7
25
1.2
11.7
nt
nt
fluconazole
NA
rifampin
0.062
a
b
No activity observed at 6.25 µg/mL. AT ) poly dA•dT; oligo ) d(CGCGAATTCGCG)2. c nt ) not tested; nd ) not determined.
such an increase in affinity with increasing bulk of
terminal groups was attributed to increased van der
Waals interactions of the terminal groups with the walls
of the minor-groove and such is likely the case in this
system.9 Interestingly, the ∆Tm value for the compound
with a terminal 2-pyridyl group (6a ) is significantly
lower than that for its phenyl counterpart 6b. The lower
affinity of 6a may suggest a different binding mode or
different base pair selectivity for the two closely related
dicationic analogues. However, introduction of a methyl
group onto each of the two central phenyl rings of the
amidine with a terminal phenyl group, 6e, resulted in
lowering of the ∆Tm value to one similar to that of its
pyridyl counterpart, 6f. Finally, the use of a small alkyl
terminal group, a methyl group as found in 6d , led to a
significant drop in binding affinity.
The placement of a single substituent on each of the
two phenyl rings of the 2,5-diphenylfuran framework
produced striking differences in ∆Tm values for both
the diguanidine and reversed diamidine series. For the
diguanidine series, it is noted that placement of single
substituent of roughly the same size but of differing
electronic properties (e.g., Me, OMe, Cl, CF3) on the
phenyl rings resulted in a lowering of the ∆Tm values;
compare the values of 5a with 5b-5e. The most
dramatic effect was observed for the strongest electron-
withdrawing group, the CF3 of 5e, which reduced the
∆Tm value (dodecamer) to zero. This seems likely to be
a pK effect and may reflect the presence of nonproto-
nated quanidinium groups under the test conditions,
which would greatly affect the DNA binding affinity.
The introduction of two methyl groups on the aryl rings
(5f) also dramatically reduced the ∆Tm value from that
of the parent diguanidine 5a . The presence of two
methyl groups on each aryl ring of these furan systems
is thus not well accommodated in the DNA minor
groove, perhaps because of the torsional twist that such
substitution would induce on the system.
The ∆Tm values for a series of reversed diamidines
with terminal 2-pyridyl groups (6a , 6f, 6h -k ) showed
a different sensitivity to substituents. In this case, the
introduction of a single substituent on each of the two
phenyl rings of the 2,5-diarylfuran framework caused
little effect on the ∆Tm values when the substituent was
methyl (6f) or methoxy (6i). However, introduction of a
chloro group (6j) resulted in significant reduction of the
value, perhaps in part due to a pK effect. Interestingly,
the detrimental effect of the chloro group on the ∆Tm
was much greater for the pyridyl derivative 6j than for
the analogous guanidine 5d , perhaps due to the lower
basicity of the reversed amidine in comparison to the
guanidine. In agreement with the results from the
diguanidine series, the introduction of two methyl
groups on each of the core phenyl rings (6k ) also
dramatically reduced the DNA affinity. Interestingly,
replacement of the terminal 2-pyridyl with a 2-quinolyl
group (6g) resulted in a significant reduction of the
∆Tm, suggesting definite limits on the dimensions of
the terminal group. On the other hand, the introduction
of a methyl group on the terminal pyridyl ring (6h )
slightly enhanced the binding affinity.
The antimicrobial data for these compounds are also
summarized in Table 1. The greatest activity among the
diguanidino compounds was found for 5b, which showed
good in vitro activity against both C. albicans and M.
tuberculosis. These compounds gave MIC values of
approximately 1 µg/mL against both organisms and was
fungicidal against C. albicans. The reversed amidines
bearing a terminal alkyl group (6c-d ), in general, did
not show significant antimicrobial activity, although
compound 6c, with the larger cyclohexyl group, did
exhibit some activity against M. tuberculosis. In con-

1744 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Stephens et al.
Ta ble 2. Evaluation of 6h Against an Expanded Fungus
agents. Finally, the clinical potential of these types of
compounds awaits the results of additional structure-
activity studies and the in vivo evaluation of their
efficacies.
Panela
genus, species, isolate number MIC 80% MIC 100%
MFC
>100
Aspergillus flavus 194.99
Aspergillus flavus 107.96
Aspergillus flavus 141.88
Aspergillus fumigatus 168.95
Aspergillus fumigatus 182.99
Aspergillus fumigatus 119.00
Aspergillus fumigatus 165.86
Aspergillus fumigatus 153.90
Fusarium solani 152.89
3.12
3.12
3.12
10
3.12
3.12
6.25
50
>100
>100
>100
>100
>100
>100
>100
50
1.56
>100
3.12
6.25
>100
3.12
25
50
50
50
50
50
50
50
Exp er im en ta l Section
The difference in thermal melting values (∆Tm) were
determined, and DNA samples were prepared as previously
described.9,10
50
3.12
3.12
0.78
1.56
0.79
0.78
1.56
1.56
0.78
1.56
1.56
Mycoba cter iu m tu ber cu losis Su scep t ib ilit y Test in g.
The compounds were tested against M. tuberculosis H37Rv
in BACTEC 12B medium using a fluorometric broth micro-
dilution assay, the Microplate Alamar Blue Assay (MABA).41
Compounds were initially assessed at 6.25 ug/mL, and those
effecting a reduction in fluorescence of at least 90% relative
to untreated cultures were further evaluated for MIC by
testing at lower concentrations. The MIC was defined as the
lowest concentration of compound effecting a reduction of
g90% of the relative fluorescence units relative to a control
culture. Antimycobacterial data were provided by the Tubercu-
losis Antimicrobial Acquisition and Coordinating Facility
(TAACF)) through a research and development contract with
the U.S. National Institute of Allergy and Infectious Diseases.
An tifu n ga l Test Or ga n ism s. The fungi used in this study
for all the compounds in Table 1 included two reference strains,
C. albicans A39 and A. fumigatus (strain 168.95). Expanded
studies on 6h -i employed the fungi listed in Table 2.
Med iu m . Antifungal susceptibility testing was performed
with RPMI 1640 medium (Sigma Chemical Co., St. Louis, MO)
with glutamine, but without sodium bicarbonate, and was
buffered at pH 7.0 with 0.165 M morpholinopropanesulfonic
acid.
An tifu n ga l in Vitr o Su scep tibility Testin g. Experiments
for determination of MICs of yeasts were performed by the
broth macrodilution method according to the recommendations
of the National Committee for Clinical Laboratory Standards.42
The only difference compared to the standardized method was
the choice of drug dilutions, which ranged from 100 to 0.09
µg/mL. Briefly, this method specifies the use of an inoculum
grown at 35 °C and adjusted to a concentration of 0.5 × 103 to
2.5 × 103 CFU/mL, incubation of the culture at 35 °C, and
reading at 48 h for all yeasts except for C. neoformans, for
which the results are interpreted at 72 h. The MIC was defined
as the culture with the lowest drug concentration in which a
visual turbidity less than or equal to 80% inhibition compared
to that produced by the growth control tube was observed.
The minimum fungicidal concentration (MFC) was deter-
mined by plating 100 µL aliquots from tubes showing complete
inhibition of growth on Sabouraud agar plates. The lowest drug
concentration that yielded three or fewer colonies was recorded
as the MFC.
Rhizopus arrhizus 117.89
Candida albicans 116.98
Candida albicans 159.95
Candida albicans 149.97
Candida albicans 156.97
Candida albicans 126.97
Candida albicans 117.00
Candida albicans A39
1.56
1.56
1.58
1.56
3.15
3.12
3.12
1.56
1.56
25
Cryptococcus neoformans H99
>100
a
MIC and MFC values are µg/mL. MIC 80% ) 80% of inoculum
is inhibited. MIC 100% ) 100% of inoculum is inhibited. MFC )
minimum fungicidal concentration.
trast, the amidines bearing a terminal phenyl group (6b,
6e) showed good activity against M. tuberculosis (MIC
) 1.56 and 3.13 µg/mL, respectively) as well as some
antifungal activity. In addition, four of the compounds
containing a terminal pyridyl group (6a , 6f, 6h , and 6i)
showed promising activity against M. tuberculosis, with
MIC values ranging from 1.0 to 2.0 µg/mL. Compounds
6h and 6i also showed activity at the MIC level of e
1.0 µg/mL against C. albicans, and 6i showed a similar
level of activity against Aspergillus fumigatus. Finally,
it is of interest to note that the pyridyl-substituted
compounds which exhibited the greatest antimicrobial
activity also showed at least moderate DNA affinity, a
correlation which may offer insight into the mode of
action of these compounds.
To evaluate the spectrum of antifungal activity of
these compounds, pyridyl-substituted diamidines 6h
and 6i were selected for studies against other patho-
genic fungi (Table 2). Compound 6h was quite effective
against an expanded panel of C. albicans, while exhibit-
ing fungicidal activity against several strains. This
compound was also quite active against Cryptococcus
neoformans and Rhizopus arrhizus, while being fungi-
cidal against the latter. In contrast, 6h was not very
active gainst the mold Fusarium solani or the two
Aspergillus species. Compound 6i did not show signifi-
cant activity in the expanded fungus panel.
In conclusion, the data presented in this report
indicate that both the diguanidines and the reversed
diamidines in the 2,5-diarylfuran series have strong
DNA binding properties, which are highly dependent
on structure. Substituents on the central phenyl rings
of the 2,5-diarylfuran framework as well as on the
terminal cationic centers have significant influences on
DNA-binding affinity. It seems likely that the different
series bind by different modes; an understanding of
these differences in DNA interactions awaits the results
of various biophysical studies that are in progress.
Compounds from both of these new classes of dicationic
antimicrobial agents show promising in vitro results.
It is striking that compounds in these classes show both
antifungal and antimycobacterial activity. In addition,
they show the potential to be broad-spectrum antifungal
Moulds were tested by the same method,42 but with the
following modifications. Isolates were grown on Sabouraud
dextrose agar at 30 °C; after adequate sporulation occurred
(4-14 days), conidia were harvested by flooding the colonies
with a sterile solution of 0.85% NaCl and 0.05% Tween 80 in
sterile distilled water. Inocula were prepared with a hemo-
cytometer for counting and were then diluted with RPM1 1640
medium to obtain a final inoculum size of approximately 0.5
× 103 to 2.5 × 103 CFU/mL. The inoculum size was verified
by plating an aliquot of the inoculum. The cultures were
incubated at 30 °C for 48 to 72 h or until growth in the control
tube was visible.
Ch em istr y. Melting points were determined with a Mel-
Temp 3.0 capillary melting point apparatus and are uncor-
1
rected. H nuclear magnetic resonance spectra were recorded
on a Varian Unity+300 or a Varian VRX 400 instrument, with
peak assignments relative to residual DMSO (2.49 ppm) or
CHCl3 (7.24 ppm). Mass spectra were recorded on a VG
Instruments 70-SE spectrometer at the Georgia Institute of
Technology, Atlanta, GA. Elemental analyses were performed
by Atlantic Microlab, Norcross, GA. Unless otherwise stated,
all reagent chemicals and solvents (including anhydrous

2,5-Diarylfurans as Antimicrobial Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1745
solvents) were purchased from Aldrich Chemical Co., Fisher
Scientific, or Lancaster Synthesis and used as received.
Acetonitrile (CaH2), triethylamine (CaH2), and ethanol (Mg/
I2) were distilled from the indicated drying agent. 2,6-Di-
methyl-4-nitrobromobenzene44,45 and S-(2-naphthylmethyl) thio-
acetimidate39 were prepared according to the literature.
P r ep a r a tion of 2,5-Bis(4-n itr op h en yl)fu r a n s 2. The
following representative procedure is a slight variation of that
previously described.36
2,5-Bis(2-m eth yl-4-n itr op h en yl)fu r a n (2b). To a solution
of 2-bromo-5-nitrotoluene (4.32 g, 20 mmol) and tetrakis-
(triphenylphospine)palladium(0) (0.40 g) in anhydrous 1,4-
dioxane (50 mL) was added 2,5-bis(tri-n-butylstannyl)furan
(6.46 g, 10 mmol), and the mixture was heated overnight under
nitrogen at 95-100 °C. The resulting orange suspension was
diluted with hexanes (15 mL), cooled to room-temperature, and
filtered to give, after rinsing with hexanes, an orange solid
(3.10 g), mp 241-243 °C. The product was recrystallized from
DMF (100 mL) to give a bright orange fluffy solid (2.87 g, 85%),
mp 242-243 °C. 1H NMR (DMSO-d6): 2.69 (s, 6H), 7.31 (s,
2H), 8.12 (m, 4H), 8.23 (s, 2H). Anal. Calcd. for C18H14N2O5
(338.31): C, H, N.
2,5-Bis(4-a m in o-2,6-d im eth ylp h en yl)fu r a n (3f). Yield:
99%; white fluffy solid; mp 144.5-146 °C. 1H NMR (DMSO-
d6): 2.01 (s, 6H), 5.06 (br s, 4H), 6.24 (s, 2H), 6.29 (s, 4H). MS
(EI): m/z 306 (M+).
2,5-Bis(4-a m in o-2-ch lor op h en yl)fu r a n (3d ). To a sus-
pension of the corresponding bis-nitro derivative 2d (1.22 g,
3.2 mmol) in dry EtOH (100 mL) and DMSO (20 mL) was
added SnCl2‚2H2O (5.80 g, 25.7 mmol), and the mixture was
heated under nitrogen at 80 °C. After 4-5 h, TLC showed that
starting material had been consumed, and thus the mixture
was cooled, neutralized with NaOH (aq), and extracted with
EtOAc. The extract was washed with water and brine, then
dried (Na2SO4), and concentrated. The resulting oil was
crystallized from benzene/hexane with partial concentration
to give a light brown solid (0.74 g, 71%), mp 191.5-193 °C.
1
Catalytic hydrogenation was not explored. H NMR (DMSO-
d6): 5.60 (br s, 4H), 6.61 (dd, J ) 8.6, 2.2 Hz, 2H), 6.68 (d, J
) 2.2 Hz 2H), 6.82 (s, 2H), 7.56 (d, J ) 8.6 Hz, 2H). MS (EI):
m/z 318 (M+).
P r ep a r a tion of 2,5-Bis(4-N,N′-d i-BOCgu a n id in op h en -
yl)fu r a n Der iva tives 4 (Sch em e 2). The following experi-
mental is representative. The yields ranged from 62 to 89%.
2,5-Bis(4-n itr op h en yl)fu r a n (2a ). Yield: 88%; orange
2,5-Bis(4-N,N′-d i-BOCgu a n id in op h en yl)fu r a n (4a ). To
a room-temperature solution of 2,5-bis(4-aminophenl)furan
(0.626 g, 2.5 mmol) and 1,3-bis(tert-butoxycarbonyl)-2-methyl-
2-thiopseudourea (1.56 g, 5.3 mmol) in anhydrous DMF was
added triethylamine (1.59 g, 15.7 mmol) followed by mercury-
(II) chloride (1.57 g, 5.8 mmol), and the resulting suspension
was stirred at room-temperature for 22 h. After diluting with
CH2Cl2 and sodium carbonate solution, the suspension was
filtered over Celite, and the filtrate was washed well with
water (3×) and finally with brine. After drying (Na2SO4), the
solvent was removed in vacuo, and the residue was diluted
with MeOH to give the BOC-protected bis-guanidine as a pale
yellow solid. The collected product was purified by reprecipi-
tation from CH2Cl2/MeOH (with partial concentration) to give
fluffy solid; mp 269-270 °C lit.46 mp 270-272 °C.
2,5-Bis(2-m eth oxy-4-n itr oph en yl)fu r an (2c). Yield: 77%;
bright orange granular solid; mp 308-310 °C (DMF).1H NMR
(DMSO-d6): 4.10 (s, 6H), 7.37 (s, 2H), 7.90 (s, 2H), 7.94
(d, 2H), 8.22 (d, 2H). Anal. Calcd. for C18H14N2O7‚0.1H2O
(372.11): C, H, N.
2,5-Bis(2-ch lor o-4-n itr op h en yl)fu r a n (2d ). Yield: 71%;
fluffy orange solid; mp 247-247.5 °C (DMF/MeOH).1H NMR
(DMSO-d6): 7.70 (s, 2H), 8.29 (dd, J ) 8.8, 2.2 Hz, 2H), 8.36
(d, J ) 8.8 Hz, 2H), 8.43 (d, J ) 2.2 Hz, 2H). Anal. Calcd. for
C
16H8Cl2N2O5 (379.15): C, H, N.
2,5-Bis(4-n it r o-2-t r iflu or om et h ylp h en yl)fu r a n (2e).
Yield: 74%; fluffy golden needles; mp 158.5-159 °C (EtOH).
1H NMR (DMSO-d6): 7.38 (s, 2H), 8.24 (d, J ) 8.7 Hz, 2H),
8.57 (d, J ) 2.4 Hz, 2H), 8.62 (dd, J ) 8.6, 2.4 Hz, 2H). Anal.
Calcd. for C18H8F6N2O5 (446.26): C, H, N.
1
a fluffy yellow solid (1.25 g, 68%), mp >400 °C dec. H NMR
(CDCl3): 1.50 and 1.53 (2s, 36H), 6.65 (s, 2H), 7.66 (s, 8H),
10.38 (br s, 2H), 11.61 (br s, 2H).
Dep r otection of N,N′-Di-BOCgu a n id in es. The following
procedure is representative.
2,5-Bis(2,6-dim eth yl-4-n itr oph en yl)fu r an (2f). Yield: 65%;
yellow needles; mp 156.5-157.5 °C (DMF/EtOH/H2O). 1H
NMR (DMSO-d6): 2.34 (s, 12H), 6.85 (s, 2H), 8.04 (s, 4H). Anal.
Calcd. for C20H18N2O5 (366.36): C, H, N.
P r ep a r a tion of 2,5-Bis(4-a m in op h en yl)fu r a n s 3. The
following procedure is representative.
2,5-Bis(4-a m in o-2-m eth ylp h en yl)fu r a n (3b). To a sus-
pension of the bis-nitro derivative 2b (2.87 g) in EtOAc (90
mL) and dry EtOH (10 mL) was added Pd/C (10%) (0.40 g),
and the mixture was hydrogenated on a Parr apparatus at an
initial pressure of ∼50 psi. After the uptake of hydrogen
subsided (generally 3-6 h), the resulting solution was filtered
over Celite, and the pale yellow to colorless filtrate was
concentrated in vacuo to near dryness to give, after dilution
with hexanes, the pure diamine as a pale yellow/tan solid (2.17
g, 91%), mp 174-176 °C, which required no purification. 1H
NMR (DMSO-d6): 2.33 (s, 6H), 5.15 (br s, 4H), 6.42 (s, 2H),
6.46 (m, 4H), 7.35 (d, 2H). MS (EI): m/z 278 (M+).
2,5-Bis(4-gu an idin oph en yl)fu r an Dih ydr och lor ide (5a).
A solution of the corresponding N,N′-di-BOCguanidine (1.19
g, 1.62 mmol) in CH2Cl2 (15 mL) was diluted with dry EtOH
(10 mL) and saturated at ice-water bath temperature with
anhydrous HCl. The solution was then stirred at room-
temperature for 2-3 days (drying tube), with the product
slowly precipitating (shorter reaction times generally gave
incomplete deprotection). After removing the solvent, the solid
was dissolved in hot EtOH, and the solution was filtered and
then concentrated to near dryness to give a suspension. After
dilution with ether, the solid was collected and dried in vacuo
at 50-60 °C for 2 days to yield the bis-guanidine dihydro-
chloride as an off-white/tan solid (0.66 g, quantitative), mp
1
>300 °C dec. H NMR (DMSO-d6): 7.12 (s, 2H), 7.31 (d, 4H),
7.58 (br s, 8H), 7.86 (d, 4H), 10.09 (br s, 2H). MS (FAB,
thioglycerol): m/z 335.3 (MH+, 100). Anal. Calcd. for C18H18N6O‚
2HCl‚0.25EtOH (407.30): C, H, N. In some cases, the product
only solidified after completely removing the solvent and
placing the residue under high vacuum.
2,5-Bis(4-a m in op h en yl)fu r a n (3a ). Yield: 94%; pale yel-
low/tan solid; mp 218-221 °C, lit.46 mp 213-216 °C. MS (EI):
m/z 250 (M+).
2,5-Bis(4-gu a n id in o-2-m et h ylp h en yl)fu r a n Dih yd r o-
ch lor id e (5b). Tan solid, mp 265-271 °C dec. 1H NMR
(DMSO-d6): 2.53 (s, 6H), 6.93 (s, 2H), 7.17 (m, 4H), 7.56 (br s,
8H), 7.82 (d, 2H), 10.06 (br s, 2H). MS (FAB, thioglycerol): m/z
363.3 (MH+, 100). Anal. Calcd. for C20H22N6O‚2HCl‚1.5H2O‚
0.66EtOH (496.93): C, H, N.
2,5-Bis(4-a m in o-2-m eth oxyp h en yl)fu r a n (3c). The origi-
nal oil was reconcentrated with benzene to give a yellow/tan
solid which was triturated with ether. Yield: 79%; mp 201-
202.5 °C. 1H NMR (DMSO-d6): 3.80 (s, 6H), 5.25 (br s, 4H),
6.24 (dd, J ) 8.3, 2.0 Hz, 2H), 6.30 (d, J ) 1.9 Hz 2H), 6.56 (s,
2H), 7.48 (d, J ) 8.4 Hz, 2H). MS (EI): m/z 310 (M+).
2,5-Bis(4-gu a n id in o-2-m eth oxyp h en yl)fu r a n Dih yd r o-
ch lor ide (5c). Light brown hygroscopic solid. 1H NMR (DMSO-
d6): 3.95 (s, 6H), 6.92 (dd, 2H), 6.99 (d, 2H), 7.02 (s, 2H), 7.58
(br s, 8H), 7.95 (d, 2H), 10.08 (br s, 2H). MS (EI): m/z
352 (M+ - NH2CN, 38.0), 310 (100), 267 (38.9), 251 (8.8), 155
(18.7). Anal. Calcd. for C20H22N6O3‚2HCl‚1.0H2O‚0.33EtOH
(500.57): C, H, N.
2,5-Bis(4-a m in o-2-t r iflu or om et h ylp h en yl)fu r a n (3e).
Original red oil crystallized from EtOAc/hexanes in two crops
as a red/orange solid. Combined yield: 81%; mp (first/major
crop) 89.5-91 °C; mp (second crop) 91.5-92 °C. 1H NMR
(DMSO-d6): 5.79 (br s, 4H), 6.52 (s, 2H), 6.82 (dd, J ) 8.4, 2.4
Hz, 2H), 6.98 (d, J ) 2.2 Hz, 2H), 7.43 (d, J ) 8.4 Hz, 2H). MS
(EI): m/z 386 (M+).

1746 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Stephens et al.
2,5-Bis(2-ch lor o-4-gu a n id in op h en yl)fu r a n Dih yd r o-
ch lor id e (5d ). Tan solid, mp 300-304 °C dec. 1H NMR
(DMSO-d6): 7.31 (s, 2H), 7.33 (d, 2H), 7.47 (s, 2H), 7.72 (br s,
8H), 8.04 (d, 2H). MS (DCI, ammonia): m/z 365, 363, 361 (MH+
- NH2CN, 8, 52, 78), 323, 321, 319 (11, 66, 100). Anal. Calcd.
for C18H16Cl2N6O‚2HCl‚0.5H2O (485.21): C, H, N, Cl.
6H), 6.60 (br s, 4NH), 6.77 (s, 2H), 6.87 (m, 4H), 7.55 (dd, 2H),
7.74 (d, 2H), 7.95 (m, 2H), 8.31 (d, 2H), 8.63 (d, 2H).
To prepare the hydrochloride salt, the free base was
suspended in EtOH (40 mL) and treated with dry HCl gas for
5-10 min at ice-bath temperature. The resulting solution was
then concentrated in vacuo to near dryness to give an orange
suspension which was diluted with ether (40 mL) and filtered
2,5-Bis(4-gu a n id in o-2-tr iflu or om eth ylph en yl)fu r a n Di-
1
1
to yield an orange powder (0.40 g), mp >180 °C dec. H NMR
h yd r och lor id e (5e). Orange/red hygroscopic solid. H NMR
(DMSO-d6): 2.62 (s, 6H), 7.08 (s, 2H), 7.44 (d, 2H), 7.47 (s,
2H), 7.85 (dd, 2H), 7.99 (d, 2H), 8.22 (t, 2H), 8.49 (d, 2H), 8.89
(d, 2H), 9.36 (br s, 2H), 10.13 (br s, 2H), 11.88 (br s, 2H). MS
(EI): m/z 486 (M+, 100), 382 (77.9), 278 (12.8), 104 (20.0), 78
(8.8), 43 (28.9). Anal. Calcd. for C30H26N6O‚3.5HCl‚0.5H2O
(623.20): C, H, N, Cl.
(DMSO-d6): 6.99 (s, 2H), 7.63 (d, 2H), 7.69 (s, 2H), 7.79
(br s, 8H), 7.91 (d, 2H), 10.37 (br s, 2H). MS (CI, isobutane):
m/z 471 (MH+, 14), 429 (100), 387 (19). Anal. Calcd. for
C20H16F6N6O‚2HCl‚0.67H2O‚0.67EtOH (586.24): C, H, N.
2,5-Bis(4-gu a n id in o-2,6-d im et h ylp h en yl)fu r a n
Di-
1
h yd r och lor id e (5f). Off-white solid, mp 296-300 °C dec. H
NMR (DMSO-d6): 2.20 (s, 12H), 6.56 (s, 2H), 7.01 (s, 4H), 7.57
(br s, 8H), 10.09 (br s, 2H). MS (FAB, thioglycerol): m/z
391.2 (MH+, 100). Anal. Calcd. for C22H26N6O‚2HCl‚0.5H2O
(472.41): C, H, N.
2,5-Bis[4-(2-pyr idylim in o)am in oph en yl]fu r an (6a). Free
base: yellow crystalline solid, mp 221-223 °C (DMF/EtOH/
H2O). Yield: 65% 1H NMR (DMSO-d6): 6.80 (br s, 4NH), 6.94
(s, 2H), 7.03 (d, 4H), 7.56 (m, 2H), 7.77 (d, 4H), 7.96 (m, 2H),
8.32 (d, 2H), 8.64 (m, 2H). Hydrochloride: Orange powder, mp
The original route to the reversed amidines (which was used
to prepare 6b) is as follows (Scheme 3).
1
>175 °C dec H NMR (DMSO-d6): 7.26 (s, 2H), 7.58 (d, 4H),
7.85 (dd, 2H), 8.03 (d, 4H), 8.22 (t, 2H), 8.52 (d, 2H), 8.89 (d,
2H), 9.39 (br s, 2H), 10.16 (br s, 2H), 11.91 (br s, 2H). MS
(EI): m/z 458 (M+, 100), 354 (49.1), 250 (27.6), 221 (8.9), 130
(9.4), 105 (13.6), 78 (8.6). Anal. Calcd. for C28H22N6O‚3.5HCl
(586.12): C, H, N, Cl.
2,5-Bis[4-(ben zim id oyla m in o)p h en yl]fu r a n Dih yd r o-
ch lor id e (6b). To a chilled solution of 2,5-bis(4-aminophenyl)-
furan (0.25 g, 1.0 mmol) in dry acetonitrile (10 mL) was added
triethylamine (0.22 g, 2.1 mmol) followed dropwise by benzoyl
chloride (0.30 g, 2.1 mmol), and the resulting suspension was
stirred at room-temperature for 3 h. Water (10 mL) was then
added, and the precipitate was collected, rinsed with water,
followed by MeOH, and finally dried in vacuo to give 2,5-bis-
(4-benzamidophenyl)furan as a tan solid (0.44 g, 96%), mp
312-314.5 °C. 1H NMR (DMSO-d6): 6.98 (s, 2H), 7.52-7.62
(m, 6H), 7.80 (d, 4H), 7.89 (d, 4H), 7.97 (d, 4H), 10.33 (br s,
2H).
2,5-Bis[4-(cycloh exylim in o)a m in op h en yl]fu r a n (6c).
Free base: pale yellow needles, mp 242-243 °C dec (EtOAc).
Yield: 17%. 1H NMR (DMSO-d6): 1.18-1.90 (m, 20H), 2.14
(m, 2H), 5.71 (br s, 4NH), 6.82 (s, 2H), 7.63 (d, 4H). [In
addition, a 41% yield of the monoamidine/monoamine (free
base: yellow solid, mp 195-196 °C) was isolated by chromatog-
raphy on silica (EtOAc-MeOH, 9:1). The insoluble nature of
the reaction medium was the likely cause of the incomplete
reaction.] Dihydrochloride: tan/peach solid, mp 244-248 °C
The intermediate bis(benzamide) (0.44 g, 0.96 mmol) was
suspended in anhydrous dichloromethane (40 mL) and treated
with freshly distilled thionyl chloride (0.68 g, 5.7 mmol) along
with 2 drops of DMF, and the mixture was refluxed with
vigorous stirring until a solution was obtained (20 h). The
solution was then concentrated in vacuo to give a yellow solid,
which was coevaporated with dry benzene. The obtained
imidoyl chloride was dissolved in anhydrous dichloromethane
(40 mL), and the solution was saturated at ice/water-bath
temperature with anhydrous ammonia and sealed. After
stirring overnight at room-temperature, the turbid mixture
was concentrated to give a yellow solid, which was triturated
with 0.5 N NaOH, collected, and air-dried. This free-base (0.44
g, 100%) was dissolved in boiling EtOH (50 mL), filtered, and
at ice-bath temperature was treated with dry HCl. After
dilution with ether, the solution was concentrated (high
vacuum) to give the dihydrochloride as an orange hygroscopic
solid, mp 242-248 °C. 1H NMR (DMSO-d6): 7.26 (s, 2H), 7.58
(d, 4H), 7.67 (t, 4H), 7.78 (t, 2H), 7.95 (d, 4H), 8.03 (d, 4H),
9.12 (br s, 2H), 9.94 (br s, 2H), 11.66 (br s, 2H). MS (EI): m/z
456 (M+, 100), 353 (63), 250 (62), 221 (16), 130 (15), 103 (41),
76 (14), 44 (22). Anal. Calcd. for C30H24N4O‚2HCl‚0.5H2O‚0.1-
(C2H5)2O (545.87): C, H, N.
1
dec. H NMR (DMSO-d6): 1.27 (m, 6H), 1.63-1.96 (m, 14H),
2.72 (m, 2H), 7.22 (s, 2H), 7.40 (d, 4H), 7.96 (d, 2H), 8.60 (br
s, 2H), 9.34 (br s, 2H), 11.39 (br s, 2H). MS (FAB, thio-
glycerol): m/z 469.4 (MH+, 100). Anal. Calcd. for C30H38N4O‚
2HCl‚0.75EtOH‚0.25H2O (580.60): C, H, N.
2,5-Bis[4-(b en zim id oyl)a m in o-2-m et h ylp h en yl]fu r a n
(6e). Free base: yellow crystalline solid. Yield: 60%. 1H NMR
(DMSO-d6): 2.48 (s, 6H), 6.50 (br s, 4NH), 6.75 (s, 2H), 6.84
(s, 4H), 7.44 (m, 6H), 7.71 (d, 2H), 7.95 (d, 4H). Hydro-
chloride: orange/yellow hygroscopic solid. 1H NMR (DMSO-
d6): 2.61 (s, 6H), 7.03 (s, 2H), 7.38-7.44 (m, 4H), 7.63-7.68
(m, 4H), 7.75-7.80 (m, 2H), 7.94 (d, 6H). MS (EI): m/z 484
(M+, 100), 381 (87.2), 278 (37.9), 235 (5.4), 218 (3.1), 190 (5.5),
144 (11.1), 103 (32.8), 76 (9.3). Anal. Calcd. for C32H28N4O‚2HCl‚
0.66H2O (569.39): C, H, N.
2,5-Bis[2-m e t h yl-4-(2-q u in olylim in o)a m in op h e n yl]-
fu r a n (6g). Free base: orange powdery crystals, mp 168-169
°C (EtOH). Yield: 52%. 1H NMR (DMSO-d6): 2.54 (s, 6H), 6.80
(s, 2H), 6.95 (m, 4H), 7.69 (m, 2H), 7.78 (d, 2H), 7.84 (m, 2H),
8.07 (d, 2H), 8.12 (d, 2H), 8.44 (d, 2H), 8.50 (d, 2H). Dihydro-
1
chloride: orange solid, mp >185 °C dec. H NMR (DMSO-d6):
2.65 (s, 6H), 7.10 (s, 2H), 7.50 (m, 4H), 7.85 (m, 2H), 8.01 (m,
2H), 8.20 (d, 2H), 8.26 (d, 2H), 8.46 (d, 2H), 8.80 (d, 2H), 9.44
(br s, 2H), 10.21 (br s, 2H), 11.98 (br s, 2H). MS (FAB,
thioglycerol): m/z 587.2 (MH+, 100). Anal. Calcd. for C38H30N6O‚
2.0HCl‚1.75H2O (691.13): C, H, N, Cl.
Alter n a tive P r ep a r a tion of Bis{[a lk yl(or a r yl)im in o]-
a m in op h en yl}fu r a n Der iva tives 6 (Sch em e 4). The fol-
lowing experimental is representative. In some cases, the
product was purified by recrystallization.
2,5-Bis[2-m et h yl-4-(5-m et h yl-2-p yr id ylim in o)a m in o-
p h en yl]fu r a n (6h ). Free base: yellow crystalline solid, mp
156-158 °C (Et2O/hexanes). Yield: 74%. 1H NMR (DMSO-
d6): 2.37 (s, 6H), 2.50 (s, 6H), 6.55 (br s, 4NH), 6.75 (s, 2H),
6.85 (m, 4H), 7.70-7.76 (m, 4H), 8.18 (d, 2H), 8.45 (s, 2H).
Hydrochloride: orange solid, mp >175 °C dec. 1H NMR
(DMSO-d6): 2.49 (s, 6H), 2.62 (s, 6H), 7.08 (s, 2H), 7.43 (d,
2H), 7.47 (s, 2H), 7.85 (dd, 2H), 7.98 (d, 2H), 8.03 (d, 2H), 8.42
(d, 2H), 8.74 (s, 2H), 9.29 (br s, 2H), 10.07 (br s, 2H), 11.83 (br
s, 2H). MS (EI): m/z 514 (M+, 19.2), 396 (100), 278 (34.5), 144
(8.0), 118 (33.6), 91 (13.6), 43 (22.8). Anal. Calcd. for
2,5-Bis[2-m e t h yl-4-(2-p yr id ylim in o)a m in op h e n yl]-
fu r a n (6f). To a solution of 2,5-bis(4-amino-2-methylphenyl)-
furan (0.30 g, 1.08 mmol) in dry MeCN (5 mL) was added dry
EtOH (15 mL), and the solution was chilled briefly in an ice-
water bath. S-(2-Naphthylmethyl)thiobenzimidate hydro-
bromide (0.815 g, 2.27 mmol) was then added, and the mixture
was stirred overnight at room-temperature. The resulting
solution was concentrated to an oil, which was triturated with
ether to give a yellow solid. The solid was collected, dissolved
in EtOH, and basified with NaOH (1 N), and the free base
was extracted into EtOAc. After drying (Na2SO4) and partially
concentrating, the resulting suspension was diluted with ether
to give a fluffy yellow solid (0.36 g, 69%), mp 188-189 °C,
which required no purification.1H NMR (DMSO-d6): 2.51 (s,
C
32H30N6O‚3.25HCl‚0.75H2O (646.62): C, H, N, Cl.
2,5-Bis[2-m et h oxy-4-(2-p yr id ylim in o)a m in op h en yl]-
fu r a n (6i). Free base: Bright yellow crystalline solid, mp 196-

2,5-Diarylfurans as Antimicrobial Agents
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1747
1
197 °C (EtOAc/Et2O). Yield: 75%. H NMR (DMSO-d6): 3.92
S -(2-N a p h t h y lm e t h y l)-2-p y r id y lt h io im id a t e ‚H B r .
Yield: 58%. White fluffy solid, mp 192 °C dec. 1H NMR
(DMSO-d6): 4.80 (s, 2H), 7.53-7.57 (m, 2H), 7.59-7.62 (dd,
1H), 7.76-7.79 (m, 1H), 7.90-7.97 (m, 3H), 8.05 (s, 1H), 8.10-
8.14 (m, 1H), 8.26 (d, 1H), 8.78-8.80 (m, 1H).
(s, 6H), 6.64 and 6.67 (d, 2H and s, 2H, overlapping a broad
NH signal), 6.89 (s, 2H), 7.55 (dd, 2H), 7.86 (d, 2H), 7.95 (m,
2H), 8.32 (d, 2H), 8.63 (d, 2H). Dihydrochloride: brick orange
solid, mp >180 °C dec. 1H NMR (DMSO-d6): 4.00 (s, 6H), 7.16
(s, 2H), 7.18 (d, 2H), 7.34 (s, 2H), 7.85 (dd, 2H), 8.13 (d, 2H),
8.22 (t, 2H), 8.49 (d, 2H), 8.89 (d, 2H), 9.39 (br s, 2H), 10.15
(br s, 2H), 11.89 (br s, 2H). MS (EI): m/z 518 (M+, 100), 414
(90.0), 371 (13.3), 310 (12.7), 267 (9.7), 155 (6.02), 104 (25.9),
77 (9.6), 43 (13.6). Anal. Calcd. for C30H26N6O‚2.0HCl‚2.0H2O
(627.51): C, H, N, Cl.
2,5-B is[2-c h lor o -4-(2-p y r id y lim in o )a m in o p h e n yl]-
fu r a n (6j). Free base: orange crystalline solid, mp 189-190
°C (EtOH). Yield: 25%. 1H NMR (DMSO-d6): 6.85 (br s, 4NH),
7.02 (dd, 2H), 7.08 (d, 2H), 7.17 (s, 2H), 7.56 (m, 2H), 7.93-
7.98 (m, 4H), 8.29 (d, 2H), 8.64 (m, 2H). Dihydrochloride:
yellow/orange solid, mp >180 °C dec. 1H NMR (DMSO-d6):
7.45 (s, 2H), 7.60 (d, 2H), 7.80 (s, 2H), 7.86 (dd, 2H), 8.23 (m,
4H), 8.50 (d, 2H), 8.90 (d, 2H), 9.54 (br s, 2H), 10.23 (br s,
2H), 11.98 (br s, 2H). MS (EI): m/z 530, 528, 526 (M+, 13.2,
69.8, 100), 426, 424, 422 (7.9, 48, 72.4), 322, 320, 318 (2.6, 17.4,
26.6). Anal. Calcd. for C28H20Cl2N6O‚2.0HCl‚1.5H2O (627.35):
C, H, N, Cl.
S-(2-Na p h th ylm eth yl)-5-m eth yl-2-p yr id ylth ioim id a te‚
1
HBr . Yield: 65%. White fluffy solid, mp 190-191 °C dec. H
NMR (DMSO-d6): 2.42 (s, 3H), 4.79 (s, 2H), 7.53-7.57 (m, 2H),
7.59-7.62 (dd, 1H), 7.90-7.97 (m, 4H), 8.05 (s, 1H), 8.17 (d,
1H), 8.64 (s, 1H).
S -(2-Na p h t h ylm e t h yl)-2-q u in olylt h ioim id a t e ‚H Br .
Yield: 23%. Light tan fluffy solid, mp 184-186 °C dec. 1H
NMR (DMSO-d6): 4.73 (s, 2H), 7.53-7.55 (m, 2H), 7.62-7.64
(dd, 1H), 7.78 (t, 1H), 7.87-7.97 (m, 4H), 8.07 (s, 1H), 8.12 (d,
2H), 8.28 (d, 1H), 8.66 (d, 1H). Quinoline-2-thiocarboxamide
was prepared from quinoline-2-carbonitrile according to the
general method of Taylor.47
Ack n ow led gm en t. This work was supported by
NIH Grants NIAID RO1AI 46365-01A2 and
RO1GN61587 and an award from Immtech Interna-
tional, Inc. Awards by the Chemical Instrumental
Program of NSF (CHE 8409599) and the Georgia
Research Alliance provided partial support for acquisi-
tion of the NMR spectrometers used in this work.
2,5-Bis[2,6-d im eth yl-4-(2-p yr id ylim in o)a m in op h en yl]-
fu r a n (6k ). Free base: pale yellow crystals, mp 206-207 °C
(EtOH). Yield: 80%. H NMR (DMSO-d6): 2.19 (s, 12H), 6.47
1
(s, 2H), 6.55 (br s, 4NH), 6.69 (s, 4H), 7.54 (m, 2H), 7.94 (m,
2H), 8.29 (d, 2H), 8.62 (d, 2H). Hydrochloride: fluffy yellow
solid. 1H NMR (DMSO-d6): 2.28 (s, 12H), 6.68 (s, 2H), 7.28 (s,
4H), 7.84 (m, 2H), 8.21 (t, 2H), 8.48 (d, 2H), 8.88 (d, 2H), 9.37
(br s, 2H), 10.12 (br s, 2H), 11.87 (br s, 2H). MS (EI): m/z 514
(M+, 8.5), 410 (38.7), 306 (100), 291 (16.0), 148 (45.4), 104
(56.3). Anal. Calcd. for C32H30N6O‚3.75HCl‚0.5H2O (660.35):
C, H, N, Cl.
2,5-Bis[4-(a cet im id oyl)a m in op h en yl]fu r a n Dih yd r o-
br om id e (6d ). This compound was purified and characterized
as the HBr salt without conversion to the free base. Fluffy tan/
orange solid, mp 307-309.5 °C dec (MeOH/EtOAc). Yield:
57%. 1H NMR (DMSO-d6, 70 °C): 2.37 (s, 6H), 7.17 (s, 2H),
7.40 (d, 4H), 7.94 (d, 4H), 8.52 (br s, 2H), 9.43 (br s, 2H), 11.13
(br s, 2H). MS (FAB, thioglycerol): m/z 333.2 (MH+, 100). Anal.
Calcd. for C20H20N4O‚2.0HBr (494.23): C, H, N.
1
Su p p or tin g In for m a tion Ava ila ble: Yields, mp, and H
NMR data for 2,5-bis(4-N,N′-di-BOCguanidinophenyl)furans
4b-f. This material is available free of charge via the Internet
at http://pubs.acs.org.
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