Dicationic DNA-targeted antiprotozoal agents: Naphthalene replacement of benzimidazole

Article abstract of DOI:10.1016/j.bmc.2006.07.024

A series of naphthalene analogues of highly active benzimidazole diamidines were synthesized using sequential Stille and Suzuki coupling reactions for preparation of the bis-nitrile intermediates. All of the diamidines showed strong DNA affinities as judged by high ΔT_m values with poly(dA-dT). The dicationic compounds were quite active in vitro versus Trypanosoma brucei rhodesiense (T. b. r.) exhibiting IC₅₀ values ranging from 4 to 98 nM. These compounds were also active versus Plasmodium falciparum (P. f.) giving IC₅₀ values ranging from 4 to 33 nM. Two of the compounds showed good activity in vivo in the STIB900 model for acute African trypanosomiasis; one gave 3/4 cures and the other gave 4/4 cures on ip dosage of 20 mg/kg for 4 days. The amidoxime prodrugs of the naphthalene analogues were essentially ineffective.

Full text of DOI:10.1016/j.bmc.2006.07.024

Bioorganic & Medicinal Chemistry 14 (2006) 7434–7445
Dicationic DNA-targeted antiprotozoal agents:
Naphthalene replacement of benzimidazole
Sarah Chackal-Catoen,a Yi Miao,a W. David Wilson,a Tanja Wenzler,b
Reto Brunb and David W. Boykina,*
aDepartment of Chemistry and Center for Biotechnology and Drug Design, Georgia State University, Atlanta, GA 30303-3083, USA
bSwiss Tropical Institute, Basel CH4002, Switzerland
Received 14 June 2006; revised 3 July 2006; accepted 7 July 2006
Available online 2 August 2006
Abstract—A series of naphthalene analogues of highly active benzimidazole diamidines were synthesized using sequential Stille and
Suzuki coupling reactions for preparation of the bis-nitrile intermediates. All of the diamidines showed strong DNA affinities as
judged by high DTm values with poly(dA–dT). The dicationic compounds were quite active in vitro versus Trypanosoma brucei
rhodesiense (T. b. r.) exhibiting IC50 values ranging from 4 to 98 nM. These compounds were also active versus Plasmodium
falciparum (P. f.) giving IC50 values ranging from 4 to 33 nM. Two of the compounds showed good activity in vivo in the STIB900
model for acute African trypanosomiasis; one gave 3/4 cures and the other gave 4/4 cures on ip dosage of 20 mg/kg for 4 days. The
amidoxime prodrugs of the naphthalene analogues were essentially ineffective.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
molecules, most probable for trypanosomes, seems
likely to involve uptake by amidine transporters11
and appears to involve initial concentration in kineto-
plast DNA.1b Compound III a benzimidazole ana-
logue of IIa and numerous related dicationic
benzimidazoles exhibit significant activity against a
variety of protozoan diseases.12 However, because
the diamidines are charged at physiological pH these
molecules have limited bioavailability. Bioavailability
has been significantly improved by prodrug approach-
es for a number of classes of diamidines,13 however,
potential prodrugs reported to date for benzimidazole
compounds have not functioned effectively.14 An
alternate strategy for capitalizing on this type dicat-
ionic system is to replace the benzimidazole ring with
other ring systems, which may yield functional pro-
drugs. We decided to make a substantial change in
the physical properties of the ring system without
too large change in overall geometry by replacing
the benzimidazole unit with a naphthalene ring and
determine if biological activity was retained. The lead
compound would have the framework illustrated by
VI. Early results on these type systems gave excellent
activity. We now report the synthesis of several novel
naphthalene-based dications and their initial evalua-
tion as minor-groove binders and antiprotozoan
agents (see Fig. 1).
Aromatic diamidines have been studied since the
1930s when they were first reported to have signifi-
cant antiprotozoan activity.1 Despite extensive studies
of various classes of dications, pentamidine (I),
reported in 1942,2 is the only compound from
this class which has seen significant human use. Pent-
amidine is used against early stage human African
trypanosomiasis (HAT), antimony-resistant leishmani-
asis, and for AIDS-related P. jiroveci pneumonia.1
Furamidine (IIa) and analogues have been demon-
strated to have significant antiprotozoan activities
and pafuramidine (IIb), an orally effective prodrug
of IIa, is currently in Phase II clinical trials against
malaria, and Phase III trials against HAT and pneu-
mocystis pneumonia.1,3–6 It has been suggested that
these dicationic molecules act by binding in the min-
or groove of DNA at AT-rich sites.1 There is evi-
dence that minor-groove binding leads to inhibition
of DNA-dependent enzymes or possibly direct inhibi-
tion of transcription.1,7–10 The selectivity of these
Keywords: Antiprotozoal agents; Diamidines; Minor-groove binders;
Prodrugs.
*
Corresponding author. Tel.: +1 404 6513798; fax: +1 404 651 1416;
e-mail: dboykin@gsu.edu
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.07.024

S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
7435
O
O
NR
O
RN
H2N
HN
NH
NH2
NH2
NH2
(I)
IIa R = H
IIb R = OMe
N
N
O
HN
H2N
HN
H2N
HN
HN
NH
NH2
NH
NH2
III
IV
N
HN
H2N
O
NH
NH2
N
H
VI
V
Figure 1. Structures of important dicationic antiprotozoan agents and lead naphthalene framework.
2. Results and discussion
dehydration product 7 but the unexpected chloro ana-
logue 6, however, the latter derivative was readily
hydrolyzed to alcohol 7. Treatment of 5 in aqueous
HCl over an extended period produced a mixture of 5,
6, and 7. Using manganese dioxide and ammonia in
2-propanol–THF, containing magnesium sulfate at
room temperature, we carried out the direct conversion
of the primary alcohol 7 into the corresponding nitrile 8.
This step proceeds via an in situ oxidation–imination–
aldimine oxidation sequence. Numerous attempts,
including [(DDQ, dioxane/benzene or xylene), and
(SeO2, AcOH), (NBS, benzoyl peroxide, CCl4), (10%
Pd/C, xylene), (S, Pd/C, xylene), and (S, Pd/C)], to dehy-
2.1. Chemistry
A retrosynthetic approach for obtaining the key bis-ni-
trile needed for preparation of VI is shown in Scheme
1. This approach is envisioned to involve sequential
Stille and Suzuki coupling reactions to synthesize the de-
sired triaryl systems.
Initially, we attempted to make 7-bromo-2-cyanonaph-
thalene needed to introduce the naphthalene ring by a
conventional Hayworth-type synthesis as outlined in
Scheme 2. The starting material, 3-(4-bromobe-
nzoyl)propionic acid, was converted to 1 using a modi-
fied Wolff–Kishner procedure.15,16 Cyclization of 1 with
polyphosphoric acid15 gave the tetralone 2, which was
treated with ethyl formate to yield the b-ketoester 3.
The expected selective reduction of 3 into the alcohol-
ester 4 failed using many of the procedures described
previously17 for analogous compounds. The NaBH4 ap-
proach, according to previous reports, was expected to
lead to the desired reduced compound 4 in good yield.
But in our case, the fully reduced compound 5 in 82%
yield was obtained. Recently, a heterogeneous Pd-ethyl-
enediamine complex catalyst has been developed.18 This
catalyst possesses less activity than Pd/C because the
coordinated ethylenediamine acts as a mild catalyst-poi-
son. We tried to use this catalyst to selectively reduce the
ketone 3 into alcohol 4 without reduction of the ester
function but this method only afforded the recovery of
starting material. On heating 5 at reflux in 1,4-dioxane
with hydrochloric acid it did not produce the
drogenate
failed.
8 to yield 7-bromo-2-cyanonaphthalene
Having the bromonitrile 8 in hand, we decided to make
the dihydro analogue of the target structure VI and eval-
uate its biological properties (vide infra). The bis-nitrile
10 was synthesized from intermediate 8, which under-
went a Stille coupling reaction with 2-tributylstannylfu-
ran to give 9, followed by a Heck reaction of the latter
with p-bromobenzonitrile (Scheme 3).
Returning to the initial target structure VI, we noted
that 7-cyanonaphthalene-2-yl triflate has been described
in the literature19 and we decided to use it in place of
7-bromo-2-cyanonaphthalene for synthesis of the sys-
tem VI. The approach outlined in Scheme 4 differs in
certain steps from that previously described.19 Commer-
cially available 2-hydroxy-7-methoxynaphthalene was
first converted to triflate 11 by using a Tf2O/pyridine
system instead of the expensive previously described
O
O
NC
Br
CN
CN
CN
Scheme 1. Approach to key naphthalene intermediate.

7436
S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
O
COOEt
O
b
c
O
a
Br
Br
Br
Br
COOH
COOH
1 (90%)
2 (83%)
3 (83%)
CN
HO
OH
R
COOEt
HO
d
e
h
+
Br
Br
Br
Br
4 (10%)
5 (82%)
8 (76%)
R = Cl: 6 (88%)
R = OH: 7 (69%)
g
f
HO
OH
R
+
Br
Br
R = Cl: 6 (28%)
R = OH: 7 (18%)
5 (9%)
Scheme 2. Reagents and conditions: (a) NH2NH2, KOH, triethyleneglycol, reflux, 2 h; (b) PPA, 90 °C, 20 min; (c) NaH, (EtO)2CO, benzene, reflux,
3 h; (d) NaBH4, EtOH, rt, overnight; (e) HCl 37%, 1,4-dioxane, reflux, 2 h 30 min; (f) HCl 1 N, reflux, 3 days; (g) AgNO3, H2O, acetone, rt,
overnight; (h) MnO2, MgSO4, NH3–IPA, THF, rt, overnight.
CN
CN
CN
a
b
O
Br
O
NC
8
9 (70%)
10 (35%)
Scheme 3. Reagents and conditions: (a) 2-tributylstannylfuran, Pd(PPh3)4, 1,4-dioxane, reflux, 3 h; (b) p-bromobenzonitrile, Pd(PPh3)4, KOAc,
DMF, 120 °C, overnight.
OH
CN
OTf
a
b
MeO
MeO
RO
R = OMe: 12 (82%)
R = OH: 13 (80%)
R = OTf: 14 (79%)
11 (88%)
c
a
Scheme 4. Reagents and conditions: (a) Tf2O, pyridine, toluene, rt, 2 h; (b) Zn(CN)2, Pd(PPh3)4, DMF, 150 °C, 3 h; (c) BBr3, CH2Cl2, rt, 48 h.
PhN(SO2CF3)2/Et3N system. According to Kehr and
Neidlein,19 the conversion of triflate 11 by Zn(CN)2 into
nitrile 12 was readily completed in the presence of
Pd(OAc)2, PPh3, in NMP at 150 °C, however, we were
not successful with this approach. A recent study from
Kubota and Rice20 showed that DMF is an excellent
solvent for this kind of reaction. The catalysts were also
examined: neither Pd(PPh3)2Cl2 nor Pd(OAc)2 gave the
desired product, however, use of Pd(PPh3)4 worked very
well for this cyanation. By using Pd(PPh3)4 (0.02 equiv),
Zn(CN)2 (2 equiv), and DMF at 150 °C, we obtained 12
in 82% yield. The cleavage of the methylether 12 was
achieved using BBr3 at room temperature to afford 13,
which was converted to triflate 14 using Tf2O/pyridine.
As shown in Scheme 5 the bis-nitrile 17 was prepared
from intermediate 14 in three steps starting with a Stille
coupling to produce the furan analogue 15 in a good
yield. Bromination of 15 with NBS in DMF afforded
16 in a moderate yield. A subsequent Suzuki coupling

S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
7437
Scheme 5. Reagents and conditions: (a) 2-tributylstannylfuran, Pd(PPh3)4, 1,4-dioxane, reflux, 1 h; (b) NBS, DMF, rt, overnight; (c) 4-cynanophenyl
boronic acid, Pd(OAc)2, K2CO3, TBAF, DME/H2O, reflux, 1 h.
of 16 with 4-cyanophenyl boronic acid gave the desired
17 in very good yield.
2.2. Biology
The DNA affinities and in vitro evaluation of the newly
synthesized dicationic naphthalene analogues against T.
b. r. and P. f. are given in Table 1. We also include data
in Table 1 for IIa and the benzimidazole analogues III–
V for comparison. The DNA affinities for the diami-
dines as indicated by DTm values for their complexes
with poly(dA–dT) are reduced by 10–30% in compari-
son to the corresponding benzimidazole analogue with
the exception of 26b which gives a comparable value
to its benzimidazole analogue. The small drop in affinity
is likely due to the absence of the benzimidazole NH
hydrogen-bond donor. On comparison of the DTm val-
ues of 18 and 21 it is noted that the affinity for the dihy-
dro analogue is about 20% less than that of the fully
aromatic one. This is consistent with better van der
Waals contacts with the walls of the groove for the aro-
matic compound 21. Since the NH is known to play an
important role in the groove binding of V it is interesting
that the affinities of 26b and V are comparable despite
the absence of an NH H-bond donor for 26b.24 Thus,
26b merits further biophysical study to gain insight into
the details of its minor-groove binding.
Scheme 6 summarizes the conversion of the bis-nitriles
into the desired diamidines and their corresponding po-
tential prodrugs. The bis-nitrile 10 was converted to
amidine 18 by a classical Pinner sequence. For the con-
version of 17 into amidine 21 we used the more elegant
and simpler method of transforming nitrile into amidine
using LiN(TMS)2, followed by hydrolysis of the silyl
groups with ethanolic HCl work-up to yield the desired
compound.21 This method is faster than the Pinner one
and gave high yields. Treatment of 10 and 17 with
hydroxylamine hydrochloride, potassium tert-butoxide
in DMSO at room temperature allowed conversion of
the cyano group into amidoximes 19 and 22, respective-
ly, in excellent yield. The O-methylamidoxime 20 was
obtained in 39% yield by treating the amidoxime 19 with
dimethylsulfate in the presence of aqueous NaOH in 1,4-
dioxane. For the O-methylamidoxime 23, the method
involving the system LiOH, H2O/DMF22 was used and
gave 22 in a 69% yield.
Earlier, we have reported that diamidines of both linear
IV and curved V biphenylbenzimidazoles exhibit impres-
sive antiprotozoan activities.12 Consequently, we have
prepared the naphthalene analogues 26a,b for evaluation.
The synthesis of the compounds 26a,b–28a,b required the
corresponding bis-nitriles 25a,b and is outlined in Scheme
7. The preparation of 25a,b involved two consecutive Su-
zuki couplings with first 3- or 4-bromophenyl boronic
acid and then 4-cyanophenyl boronic acid. The diami-
dines 26a,b, diamidoximes 27a,b, and di-O-methoxyami-
doximes 28a,b were obtained as previously described
above for the furan analogues.
The IC50 values for the dicationic naphthalene deriva-
tives against T. b. r. range from 4 to 98 nM. For the
furan core systems, both 18 and 21 exhibit greater
activity against T. b. r than III, and with 21 approx-
imately 8-fold more active. For the biphenyl types,
26a shows lower activity than its benzimidazole IV
counterpart, whereas 26b shows somewhat improved
activity compared to its benzimidazole analogue V.
These naphthalene compounds were generally
somewhat more active in vitro versus P. f. giving
RN
CN
NH2
a) if 18 or b) if 21
c) if 19 and 22
RN
O
b
O
b
a
NC
a
H2N
R
a
b
%
10: a=CH2 ; b=CH2
17: a=CH ; b=CH
18
H
CH2 CH2 77
CH2 CH2 87
19 OH
d
20 OMe CH2 CH2 39
21
H
CH
CH
CH
CH
90
84
69
22 OH
e
23 OMe CH CH
Scheme 6. Reagents and conditions: (a) 1—EtOH/HCl, rt, 10 days; 2—EtOH/NH3, rt, 10 days; (b)1—LiN(TMS)2, THF, rt, overnight; 2—EtOH/
HCl, rt, 12 h; (c) NH2OH Æ HCl, KOtBu, DMSO, rt, overnight; (d) NaOH 2 N, dimethylsulfate, 1,4-dioxane, rt, overnight; (e) LiOH, dimethylsulfate,
H2O/DMF, rt, 72 h.

7438
S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
4
3
4
NC
CN
NC
CN
Br
TfO
a
b
3
24a: 3-Br (98%)
24b: 4-Br (88%)
25a: 3-cyanophenyl (89%)
25b: 4-cyanophenyl (88%)
14
4
NR
NR
c) if R=H or
d) if R=OH
H2N
3
NH2
R
position
%
26a
H
3
3
3
4
4
4
91
92
90
90
96
78
27a
OH
OMe
H
e
28a
26b
27b
OH
OMe
e
28b
Scheme 7. Reagents and conditions: (a) 3- or 4-bromophenyl boronic acid, Pd(OAc)2, K2CO3, TBAF, DME/H2O, rt, 1 h; (b) 4-cynanophenyl
boronic acid, Pd(OAc)2, K2CO3, TBAF, DME/H2O, reflux, 3 h; (c) LiN(TMS)2, THF, rt, overnight; 2 EtOH/HCl, rt, 12 h; (d) NH2OH Æ HCl,
KOtBu, DMSO, rt, overnight; (e) LiOH, dimethylsulfate, H2O/DMF, rt, overnight.
Table 1. DNA affinities and in vitro antiprotozoan activity
in vitro screens. The selectivity ratios of the diami-
a
c
Compound DTm
T. b. r.b
P. f.b
IC50
poly(dA–dT) IC50 (nM) IC50 (nM) L-6 cells (nM)
dines, based upon cytotoxicity in L-6 myoblast cells,
range from 200 to 6825. Consequently, these com-
pounds are promising candidates for animal model
studies.
IIa
III
IV
V
25
4.3
122
15.5
96
6,400
10,100
23,000
17,000
27,300
99,200
17,900
11,100
67,100
>160,000
11,100
15,100
161,000
6,600
24.6
25.6
4.4
7.7
27.5
0.5
>28
The results from evaluating these compounds in the
STIB900 mouse model for acute African trypanosoma-
sis are presented in Table 2. The four diamidines 18,
18
19
17.6
22.2
20.9
98
4
10.1K
14.1K
16
166
849
6
20
21
22
23
7.5K
6.1K
59
687
833
29
Table 2. In vivo antitrypanosomal activity of dicationic compounds in
the STIB900 mouse modela
26a
27a
28a
26b
27b
28b
c
Compound
Curesb
Survival (days)
11.4K
6.9K
4
6.5K
6.2K
33
IIa
III
IV
V
0/4
1/4
4/4
0/4
0/3
0/4
NT
3/4
0/4
0/4
1/4
0/4
0/4
4/4
1/4
0/4
52.5
>27.75
>60
>28
8.9K
2.7K
8.5K
5.2K
>179,000
15,900
>36.5
16.75
8.5
a DNA, poly(dA–dT); buffer MES10; compound/DNA ratio = 0.3.
For compounds with DTm values listed as >28 °C, no melting was
observed at the highest temperature of the experiment, 96 °C; all
prodrugs tested have insignificant DTm values.
18
19
20
21
NT
>54
b The T. b. r. strain employed was STIB900 and the P.f. strain was K1;
see Refs. 13b and 23. IC50 values are the average of duplicate
determinations.
22
23
14.5
7.25
>29.25
9
26a
27a
28a
26b
27b
28b
c Cytotoxicity was evaluated using cultured L-6 rat myoblast cells
using the Alamar Blue assay, see Ref. 23.
7.5
>60
IC50 values ranging from 4 to 33 nM. The two furan-
based compounds 18 and 21 were approximately 20-
fold more active than their benzimidazole parent III.
The curved biphenyl analogue 26a exhibited approxi-
mately the same activity as its benzimidazole predeces-
sor IV, whereas the linear analogue 26b was
significantly less active than its counterpart V. As
expected the potential prodrugs were inactive in the
>52
13.75
a See Refs. 13b and 25 for details of STIB900 model. Dosage for
diamidines was intraperitoneal at 20 mg/kg for 4 days. Dosage for
prodrugs was po at 100 mg/kg for 4 days.
b Number of mice that survive 60 days and are parasite free.
c Average days of survival; untreated controls died between day 7 and 8
post-infection.

S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
7439
21, 26a, and 26b all extend the life of treated animals be-
yond that of the untreated controls. Compounds 21 and
26b are the most active in vivo giving 3/4 and 4/4 cures,
respectively, on ip dosage. The potential prodrugs are
generally ineffective, the only even moderately effective
one 27b provided just 1/4 cures and a significant increase
in average survival time of the treated animals on oral
dosage.
3.3.1. 4-(p-Bromophenyl)butanoic acid (1). Potassium
hydroxide (15.25 g, 0.27 mol) powder was added to a
well-stirred solution of 3-(4-bromobenzoyl)propionic
acid (20 g, 77.8 mmol) in triethyleneglycol (70 ml); then
hydrazine (8.5 ml, 0.27 mol) was added dropwise under
nitrogen. The mixture was refluxed for 2 h under nitro-
gen. After cooling to room temperature, the reaction
mixture was neutralized with 4 N HCl and extracted sev-
eral times with dichloromethane. The combined organic
layers were washed with water, saturated aqueous NaCl,
dried over MgSO4, and concentrated. The crude oily
product was subjected to column chromatography (sili-
ca gel, 50% ethyl acetate-hexanes). Removal of the sol-
vents afforded an oil, which precipitated in petroleum
ether. Filtration yielded 90% of 1 as a white powder;
mp 62.2 °C (heptane). 1H NMR (CDCl3) d 1.94 (p,
J = 7.6 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 2.63 (t,
J = 7.5 Hz, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.40 (dd,
J = 1.5, 8.1 Hz, 2H), 11.2 (br s, 1H); 13C NMR (CDCl3)
d 179.98, 140.08, 131.47, 130.23, 119.82, 34.34, 33.2,
25.99; EI-MS m/z: 244 (81BrM+, 26), 242 (79BrM+, 26),
184 (98), 182 (100), 171 (35), 169 (36); Anal. Calcd for
C10H11BrO2: C, 49.38; H, 4.52. Found: C, 49.19; H,
4.57.
The strategy to replace a benzimidazole ring with a
naphthalene one for these type minor-groove binders
worked quite well as judged from their DNA binding
affinity and intrinsic antiprotozoan activity. However,
the hope that the amidoxime prodrugs of these com-
pounds would be effective in mice was not realized.
The lack of efficacy of the amidoxime prodrugs of the
benzimidazole and naphthalene minor-groove binders
merits further study.
3. Experimental
3.1. Biology
In vitro assays with T. b. r. STIB 900 and P. f. K1 strain
as well as efficacy study in an acute mouse model for
T. b. r. STIB 900 were carried out as previously
reported.12,13,23,25
3.3.2. 7-Bromo-3,4-dihydro-2H-naphthalen-1-one (2).
Compound 1 (15 g, 61.72 mmol) was added portionwise
to stirred PPA (150 g) at 90 °C. After being stirred for
20 min, the dark orange mixture was poured into ice/
water. The yellow precipitate was collected, washed with
water, and dried under vacuum to afford 2 in 83% yield;
mp 77.5 °C (heptane). 1H NMR (CDCl3) d 2.13 (p,
J = 6.4 Hz, 2H), 2.65 (t, J = 6.3 Hz, 2H), 2.91 (t,
J = 6.0 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 7.57 (dd,
J = 2.1, 8.1 Hz, 1H), 8.15 (d, J = 2.1 Hz, 1H); 13C
NMR (CDCl3) d 196.98, 143.1, 136.06, 133.99, 130.61,
129.92, 120.58, 38.74, 29.11, 22.93; EI-MS m/z: 226
3.2. Tm measurements
Thermal melting experiments were conducted with a
Cary 300 spectrophotometer. For the experiment cuv-
ettes are mounted in a thermal block and the solution
temperatures are monitored by a thermistor in a refer-
ence cuvette. Temperatures are under computer
control and are increased at 0.5 °C/min. The experi-
ments were conducted in Mes 10 buffer (Mes
10 mM, EDTA 1 mM, and NaCl 100 mM) using
1 cm path length quartz cuvettes. The concentrations
of DNA were determined by measuring the absor-
bance at 260 nm. A ratio of 0.3 compound per base
was used for the complex and DNA with no com-
pound was used as a control.
(
81BrM+, 95), 224 (79BrM+, 100), 211 (18), 209 (19), 198
(76), 196 (77), 170 (53), 168 (55), 145 (22), 115 (35), 89
(45); Anal. Calcd for C10H9BrO: C, 53.33; H, 4.0.
Found: C, 53.46; H, 4.10.
3.3.3. 7-Bromo-1-oxo-1,2,3,4-tetrahydro-2-naphthoic acid
ethyl ester (3). Diethylcarbonate (43.1 ml, 0.35 mol) was
added to a suspension of NaH 60% (5.33 g, 0.13 mol) in
100 ml of dry benzene under nitrogen. This mixture was
heated to 65 °C, and a solution of 2 (10 g, 44.44 mmol)
in 50 ml of dry benzene was added dropwise over a peri-
od of 20 min. After the addition was completed, the mix-
ture was refluxed for 3 h. After cooling to room
temperature, acetic acid (10 ml) was added dropwise.
Then ice-cold water was added and the mixture was stir-
red until the solid material has been dissolved. Organic
layer was separated, and the aqueous layer was extract-
ed with ethyl acetate. The organic layers were washed
with ice-cold water, saturated aqueous NaCl, dried over
MgSO4, and concentrated. The residual material was
subjected to column chromatography (silica gel, 10%
ethyl acetate-hexanes). Removal of the solvents afforded
a dark pink oil, which precipitated in ice water. Precip-
itate was collected, washed with water, and dried to
yield 83% of 3 as a pale yellow powder; mp 67.6 °C
(petroleum ether). 1H NMR (DMSO-d6) d 1.19 (t,
3.3. Chemistry
Melting points were recorded using a Thomas–Hoover
(Uni-Melt) capillary melting point apparatus and are
uncorrected. TLC analysis was carried out on silica gel
60 F254 precoated aluminum sheets and detected with
UV light. 1H and 13C NMR spectra were recorded
employing a Varian Unity Plus 300 spectrometer, with
peak assignments relative to residual DMSO
(2.49 ppm) or CHCl3 (7.24 ppm). Mass spectra were
recorded on a VG analytical 70-SE spectrometer at the
Georgia Institute of Technology, Atlanta, GA. Elemen-
tal analyses were performed by Atlantic Microlab, Nor-
cross, GA. All chemicals and solvents (including
anhydrous) were purchased from Aldrich Chemical
Co., Fisher Scientific, Across, Frontier or Lancaster
and used as received. Ethanol (Mg/I2) was distilled from
the indicated drying agent.

7440
S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 2.25H), 2.28 (m,
2H), 2.76 (m, 1.5H), 2.94 (m, 2H), 3.82 (m, 1H), 4.13
(q, J = 7.2 Hz, 2H), 4.24 (q, J = 7.2 Hz, 1.5H), 7.25 (d,
J = 8.1 Hz, 0.75H), 7.36 (d, J = 8.1 Hz, 1H), 7.58 (dd,
J = 2.1, 8.1 Hz, 0.75H), 7.73 (d, J = 2.1 Hz, 0.75H),
7.76 (dd, J = 2.1, 8.1 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H);
3.3.6. 7-Bromo-2-hydroxymethyl-3,4-dihydronaphthalene
(7). A solution of 6 (4.1 g, 15.88 mmol) in acetone
(30 ml) was added dropwise to a stirred suspension of
silver nitrate (4.05 g, 23.82 mmol) in acetone (60 ml)
and water (60 ml) at room temperature. After being stir-
red overnight, the mixture was filtered and the filtrate
was extracted with chloroform. Organic layer was
washed with water and brine, dried over MgSO4, and
concentrated. Oily residue was subjected to column
chromatography (silica gel, 30% ethyl acetate-hexanes).
Removal of the solvents yielded 69% of 7 as a white
13C NMR (DMSO-d6)
d 192.91, 172.59, 170.45,
162.85, 144.14, 139.09, 137.10, 133.98, 133.76, 132.35,
132.08, 130.62, 129.58, 126.75, 120.46, 120.18, 98.76,
61.55, 61.36, 54.23, 27.09, 26.99, 26.54, 20.64, 14.75;
EI-MS m/z: 296 (81BrM+, 96), 298 (79BrM+, 100), 269
(10), 267 (10), 252 (85), 250 (89), 224 (67), 222 (66),
198 (33), 196 (35), 170 (185), 143 (64), 115 (100), 89
(28); Anal. Calcd for C13H13BrO3: C, 52.52; H, 4.37.
Found: C, 52.32; H, 4.47.
1
powder; mp 92 °C (heptane). H NMR (DMSO-d6) d
2.15 (t, J = 8.7 Hz, 2H), 2.69 (t, J = 8.4 Hz, 2H), 4.01
(d, J = 4.8 Hz, 2H), 5.02 (t, J = 5.7 Hz, 1H), 6.39 (s,
1H), 7.05 (d, J = 8.7 Hz, 1H), 7.22 (dd, J = 2.1, 6.6 Hz,
2H), 7.24 (d, J = 1.8 Hz, 1H); 13C NMR (DMSO-d6) d
144.30, 136.55, 133.64, 129.17, 128.64, 127.74, 119.11,
119.08, 63.68, 26.52, 23.68; EI-MS m/z: 240 (81BrM+,
53), 238 (79BrM+, 54), 209 (24), 207 (22), 159(37), 141
(54), 128 (100), 115 (23); Anal. Calcd for C11H11BrO:
C, 55.23; H, 4.6. Found: C, 55.40; H, 4.67.
3.3.4. 7-Bromo-2-hydroxymethyl-1,2,3,4-tetrahydronaph-
thalen-1-ol (5). A solution of 3 (3 g, 10.10 mmol) in
EtOH (30 ml) was treated with NaBH4 (0.77 g,
20.20 mmol) overnight at room temperature. After
addition of saturated aqueous ammonium chloride,
followed by extraction with dichloromethane, organic
layer was washed with water, saturated aqueous NaCl,
dried over MgSO4, and concentrated. The oily residue
was purified by column chromatography (silica gel,
70% ethyl acetate-hexanes) to afford 5 in 82% yield as
a white powder and the partially reduced compound 4
in 10% yield; mp 127 °C (ethyl acetate). 1H NMR
(DMSO-d6) d 1.47 (m, 1/3H), 1.65 (m, 4H), 1.96
(m, 1/3H), 2.65 (m, 8/3H), 3.58 (m, 4/3H), 4.30
(t, J = 8.1 Hz, 1/3H), 4.41 (t, J = 8.1 Hz, 1H), 4.55
(m, 4/3H), 5.00 (d, J = 5.7 Hz, 1H), 5.35
(d, J = 6.9 Hz, 1/3H), 7.01 (d, J = 8.4 Hz, 1/3H), 7.04
(d, J = 8.1 Hz, 1H), 7.28 (dd, J = 2.4, 8.4 Hz, 1/3H),
7.32 (dd, J = 2.1, 8.1 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H),
7.5 (d, J = 2.1.8 Hz, 1/3H); 13C NMR (DMSO-d6) d
143.5, 142.3, 135.9, 135.8, 132.2, 130.7, 130.2, 129.6,
128.9, 118.5, 118.0, 68.0, 66.0, 62.4, 62.0, 43.8, 41.8,
27.7, 27.4, 23.5, 19.3; EI-MS m/z: 258 (81BrM+, 8), 256
3.3.7. 7-Bromo-2-cyano-3,4-dihydronaphthalene (8). A
2 M solution of ammonia in 2-propanol (15 ml) and
anhydrous magnesium sulfate (14.61 g, 0.12 mol) were
added to a stirred solution of 7 (1.94 g, 8.11 mmol) in
THF (40 ml). Activated manganese dioxide (10.6 g,
0.12 mol) was added to the solution. The resulting mix-
ture was stirred at room temperature overnight and then
diluted with dichloromethane. The mixture was filtered
through CeliteÒ, the CeliteÒ washed well with dichloro-
methane, and the filtrate concentrated. The solid residue
was purified by column chromatography (silica gel, 5%
ethyl acetate-hexanes). Removal of the solvents afforded
8 as a white powder in 76% yield; mp 93.5 °C (heptane).
1H NMR (DMSO-d6) d 2.49 (t, J = 8.4 Hz, 2H), 2.81 (t,
J = 7.8 Hz, 2H), 7.18 (d, J = 8.1 Hz, 1H), 7.42 (s, 1H),
7.45 (dd, J = 2.1, 8.1 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H);
13C NMR (DMSO-d6)
d 140.13, 134.57, 133.06,
(
79BrM+, 8), 240 (29), 238 (30), 209 (56), 207 (51), 128
132.45, 130.13, 129.92, 119.41, 119.26, 110.77, 25.21,
23.68; EI-MS m/z: 235 (81BrM+, 62), 233 (79BrM+, 65),
154 (100), 127 (37); Anal. Calcd for C11H8NBr: C,
56.41; H, 3.42. Found: C, 56.70; H, 3.39.
(100), 115 (18); Anal. Calcd for C11H13BrO2: C, 51.36;
H, 5.06. Found: C, 51.69; H, 5.20.
3.3.5. 7-Bromo-2-chloromethyl-3,4-dihydronaphthalene
(6). To a solution of 5 (4.61 g, 17.94 mmol) in 1,4-diox-
ane (10 ml) was added concd HCl (5.5 ml, 0.18 mol) and
the mixture was refluxed for 2 h 30 min. After cooling to
room temperature, reaction mixture was poured into
water. The precipitate was collected, washed with water,
dried, and subjected to column chromatography (silica
gel, 10% ethyl acetate-hexanes). After removal of the
solvents, oily product, which precipitated in water, was
collected and dried under vacuum to give 6 as a white
3.3.8. 2-(2-Cyano-3,4-dihydronaphthalen-7yl)furan (9).
To a solution of 8 (1.64 g, 7.0 mmol) and tetrakis(triphe-
nylphosphine)palladium (0.24 g, 0.21 mmol) in 1,4-diox-
ane (15 ml) was added 2-tributylstannylfuran (3.3 ml,
10.41 mmol) and the reaction mixture was refluxed for
3 h. After cooling to room temperature, the reaction
mixture was poured into ice/water and extracted with
ethyl acetate. The organic layer was washed with water
and brine, dried over MgSO4, and evaporated. The con-
centrate was purified by column chromatography (silica
gel, 20% ethyl acetate-hexanes). Removal of the solvent
yielded 70% of 9 as a white powder; mp 117 °C (hep-
1
powder in 88% yield; mp 86.3 °C (heptane). H NMR
(DMSO-d6)
d 2.32 (t, J = 8.4 Hz, 2H), 2.75 (t,
J = 8.1 Hz, 2H), 4.37 (s, 2H), 6.06 (s, 1H), 7.10 (d,
J = 8.4 Hz, 1H), 7.31 (dd, J = 2.4, 5.7 Hz, 2H); 13C
NMR (DMSO-d6) d 24.33, 26.44, 48.77, 119.16,
124.86, 128.53, 129.34, 128.87, 133.66, 135.46, 138.31;
EI-MS m/z: 258.5 (81BrM+, 53), 256.5 (79BrM+, 42), 223
(98), 221 (100), 142 (80), 128 (36), 115 (21); Anal. Calcd
for C11H10BrCl: C, 51.26; H, 3.88. Found: C, 51.66; H,
3.87.
1
tane). H NMR (DMSO-d6) d 2.49 (t, J = 7.8 Hz, 2H),
2.86 (t, J = 7.8 Hz, 2H), 6.58 (m, J = 1.8 Hz, 1H), 6.90
(d, J = 3.6 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.50 (s,
4H), 7.53 (d, J = 6.6 Hz, 2H), 7.74 (d, J = 1.5 Hz, 1H);
13C NMR (DMSO-d6)
d 153.13, 143.66, 142.03,
135.26, 132.16, 129.92, 129.19, 125.76, 123.56, 120.33,
112.81, 110.62, 106.58, 26.34, 24.66; ESI-MS m/z: 222

S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
7441
(M+H)+, 443 (2M+H)+; Anal. Calcd for C15H11NO: C,
81.44; H, 4.97. Found: C, 81.34; H, 4.96.
9.0 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.60 (dd, J = 1.8,
8.4 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H), 8.02 (d,
J = 8.4 Hz, 1H), 8.04 (d, J = 1.5 Hz, 1H); 13C NMR
(DMSO-d6) d 159.08, 134.17, 133.44, 130.60, 130.31,
129.80, 124.81, 122.59, 120.05, 109.55, 107.17, 56.17;
EI-MS m/z: 183 (M+, 85), 153 (26), 140 (100), 126 (5),
113 (13), 84 (39), 49 (64); Anal. Calcd for C12H9NO:
C, 78.68; H, 4.91. Found: C, 78.79; H, 4.90.
3.3.9. 2-(2-Cyano-3,4-dihydronaphthalen-7yl)-5-(4-cyan-
ophenyl)furan (10). To a solution of 9 (1.3 g, 5.88 mmol)
in DMF (15 ml) was added p-bromobenzonitrile (1.6 g,
8.82 mmol),
tetrakis(triphenylphosphine)palladium
(0.2 g, 0.17 mmol), and potassium acetate (0.86 g,
8.82 mmol). The mixture was heated at 120 °C under
nitrogen overnight. The reaction mixture was poured
onto ice/water and the precipitate was collected, washed
with water, hexanes, and ether, dried, and purified by
column chromatography (silica gel, 30–50% dichloro-
methane-hexanes). Removal of the solvents gave 10 as
a yellow powder in 35% yield; mp 208.5 °C (butan-1-
3.3.12. 7-Hydroxy-2-cyanonaphthalene (13). In an ice
bath, a solution of BBr3 (9.77 ml, 0.1 mol) in dichloro-
methane (35 ml) was added to a solution of 12 (7.57 g,
41.36 mmol) in dichloromethane (45 ml). After 48 h at
room temperature, the mixture was poured into water
and the suspension filtered. The precipitate was washed
with dichloromethane, dried, and purified by column
chromatography (silica gel, 20% ethyl acetate-hexanes).
The filtrate was extracted several times with ethyl ace-
tate. The combined organic layer was washed with
brine, dried over MgSO4, and concentrated. The dark
residue was purified by column chromatography (silica
gel, 20% ethyl acetate-hexanes). Removal of the solvents
yielded 13 (80%) as a white crystalline powder; mp
187.1 °C (water/acetic acid). 1H NMR (DMSO-d6) d
7.25 (s, 1H), 7.27 (dd, J = 2.4, 7.8 Hz, 1H), 7.50 (dd,
J = 1.8, 8.1 Hz, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.95 (d,
J = 8.4 Hz, 1H), 8.33 (s, 1H), 10.18 (s, 1H); 13C NMR
(DMSO-d6) d 156.69, 133.67, 132.34, 129.73, 129.06,
128.97, 123.05, 121.93, 119.49, 109.17, 108.55; EI-MS
m/z: 169 (M+, 100), 140 (49), 114 (17); Anal. Calcd for
C11H7NO: C, 78.10 ; H, 4.14. Found: C, 78.16; H, 3.99.
1
ol). H NMR (DMSO-d6) d 2.50 (t, J = 7.8 Hz, 2H),
2.89 (t, J = 7.8 Hz, 2H), 7.12 (d, J = 3.3 Hz, 1H), 7.32
(d, J = 7.5 Hz, 1H), 7.36 (d, J = 3.3 Hz, 1H), 7.51 (s,
1H), 7.79 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H),
7.98 (d, J = 8.4 Hz, 2H); 13C NMR (DMSO-d6) d
153.55, 150.76, 141.09, 135.25, 133.80, 132.86, 131.48,
128.49, 128.42, 125.37, 123.77, 123.14, 119.50, 118.85,
111.7, 110.02, 109.23, 108.62, 25.62, 23.85; EI-MS m/z:
322 (M+, 100), 190 (10), 130 (19), 102 (14); Anal. Calcd
for C22H14N2O: C, 81.98; H, 4.34. Found: C, 81.81; H,
4.31.
3.3.10. 7-Methoxynaphthalene-2-yl trifluoromethanesulf-
onate (11). Triflic anhydride (21.24 ml, 0.13 mol) was
added dropwise to a suspension of 7-methoxy-2-naph-
thol (20 g, 0.11 mol) and pyridine (9.28 ml, 0.11 mol)
in toluene (150 ml). After stirring for 2 h at room tem-
perature, the solution was poured onto water and
extracted several times with ethyl acetate. The combined
organic layer was washed with brine, dried over MgSO4,
and concentrated. The dark oily residue was purified by
column chromatography (silica gel, 15% ethyl acetate-
hexanes). Removal of the solvents afforded 11 as an
3.3.13. 7-Cyanonaphthalene-2-yl trifluoromethanesulfo-
nate (14). Triflic anhydride (6.65 ml, 39.57 mmol) was
added dropwise to
a suspension of 13 (6.08 g,
35.97 mmol) and pyridine (2.9 ml, 35.97 mmol) in tolu-
ene (50 ml). After stirring for 2 h at room temperature,
the solution was poured onto water and extracted sever-
al times with ethyl acetate. The combined organic layer
was washed with brine, dried over MgSO4, and concen-
trated. The dark oily residue was purified by column
chromatography (silica gel, 10% ethyl acetate-hexanes).
Removal of the solvents gave an oil that precipitated
in heptane to give 14 as a beige powder in 79% yield;
1
oil in 88% yield; H NMR (DMSO-d6) d 3.88 (s, 3H),
7.25 (dd, J = 2.7, 9.0 Hz, 1H), 7.40 (dd, J = 2.4,
9.0 Hz, 1H), 7.49 (d, J = 2.7 Hz, 1H), 7.93 (d,
J = 9.3 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 8.04 (d,
J = 9.0 Hz, 1H); 13C NMR (DMSO-d6) d 158.49,
147.34, 134.71, 130.60, 129.42, 127.53, 120.10, 117.96,
116.82, 116.15, 106.29, 55.34; EI-MS m/z: 306 (M+,
25), 173 (10), 145 (100), 130 (12), 102 (34), 69 (15); Anal.
Calcd for C12H9F3O4S Æ 0.1EtOAc: C, 47.27; H, 3.13.
Found: C, 47.62; H, 2.93.
1
mp 75.1 °C (CH2Cl2/heptane). H NMR (DMSO-d6) d
7.84 (dd, J = 2.4, 9.0 Hz, 1H), 7.92 (dd, J = 1.8,
8.7 Hz, 1H), 8.26 (t, J = 9.6 Hz, 2H), 8.30 (s, 1H), 8.71
(s, 1H); 13C NMR (DMSO-d6) d 147.65, 134.51,
133.46, 132.06, 131.52, 129.61, 127.95, 123.05, 120.16,
119.58, 118.67, 110.32; EI-MS m/z: 301 (M+, 20), 168
(37), 140 (100), 113 (16), 69 (23); Anal. Calcd for
C12H6F3NO3S: C, 47.84; H, 1.99. Found: C, 47.87; H,
1.84.
3.3.11. 7-Methoxy-2-cyanonaphthalene (12). To a sus-
pension of 11 (32.19 g, 0.11 mol) and Zn(CN)2
(24.70 g, 0.21 mol) in deoxygenated dry DMF (80 ml)
was added Pd(PPh3)4 (2.43 g, 2.1 mmol) in DMF
(60 ml). The mixture was then stirred at 150 °C under
nitrogen atmosphere for 3 h. After cooling to room tem-
perature, the reaction mixture was partitioned between
saturated sodium bicarbonate solution and ethyl ace-
tate. The organic layer was washed with brine, dried
over MgSO4, and evaporated. The residue was purified
by column chromatography (silica gel, 10% ethyl ace-
tate-hexanes). Removal of the solvents gave 12 as a
3.3.14. 2-(2-Cyanonaphthalen-7-yl)furan (15). To a solu-
tion of 14 (2 g, 6.64 mmol) and Pd(PPh3)4 (0.23 g,
0.19 mmol) in 1,4-dioxane (20 ml) was added 2-tribut-
ylstannylfuran (3.14 ml, 9.96 mmol) and the reaction
mixture was refluxed for 1 h. After cooling to room tem-
perature, the reaction mixture was poured into ice/water
and extracted with ethyl acetate. The organic layer was
washed with water and brine, dried over MgSO4, and
evaporated. The concentrate was purified by column
1
white powder in 82% yield; mp 81.7 °C (heptane). H
NMR (DMSO-d6) d 3.88 (s, 3H), 7.35 (dd, J = 2.7,

7442
S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
chromatography (silica gel, 10% ethyl acetate-hexanes).
Removal of the solvent yielded 15 as a yellow powder
in 86% yield; mp 120.5 °C (heptane). 1H NMR
(DMSO-d6) d 6.73 (m, J = 1.8 Hz, 1H), 7.17 (d,
J = 3.3 Hz, 1H), 7.4 (dd, J = 1.5, 8.4 Hz, 1H), 7.86 (d,
J = 1.8 Hz, 1H), 8.07 (s, 3 H), 8.33 (s, 1H), 8.6 (s, 1H);
times with dry ether and dried under vacuum. NH3
gas was then passed through an anhydrous (freshly dis-
tilled EtOH) ethanolic solution (15 ml) of imidate and
the mixture was stirred at room temperature for another
10 days. After evaporation of the solvent, the solid was
washed several times with dry ether and dried under vac-
uum to afford 18 (free base) as a yellow powder in 77%
13C NMR (DMSO-d6)
d 152.26, 143.92, 134.42,
1
133.45, 132.23, 129.28, 128.82, 126.39, 125.40, 121.60,
119.19, 112.50, 109.19, 107.92; EI-MS m/z: 219 (M+,
100), 190 (65); Anal. Calcd for C15H9NO: C, 82.19; H,
4.10. Found: C, 82.00; H, 3.87.
yield; mp >260 °C (EtOH/ether). H NMR (DMSO-d6)
d 2.58 (t, J = 8.1 Hz, 2H), 2.92 (t, J = 8.1 Hz, 2H),
7.17 (d, J = 3.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.39
(d, J = 3.1 Hz, 1H), 7.52 (s, 1H), 7.83 (m, 2H), 7.92 (d,
J = 8.7 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 8.93 (br s,
1H), 9.06 (br s, 2H), 9.12 (br s, 2H), 9.43 (br s, 1H);
3.3.15. 2-Bromo-5-(2-cyanonaphthalen-7-yl)furan (16).
To a solution of 15 (0.8 g, 3.65 mmol) in DMF (5 ml)
cooled to 0 °C was added NBS (0.72 g, 4.01 mmol)
and the reaction mixture was stirred overnight at room
temperature. The reaction mixture was poured into
ice/water. The precipitate was filtered, washed with
water and hexanes, dried under vacuum, and purified
by column chromatography (silica gel, 10% ethyl ace-
tate-hexanes). Removal of the solvent afforded 16 as a
pale yellow powder in 55% yield; mp 131.9 °C (butan-
13C NMR (DMSO-d6)
d 165.85, 164.83, 153.50,
151.01, 136.15, 135.10, 134.57, 131.77, 128.93, 128.49,
128.35, 127.56, 125.87, 125.35, 123.62, 123.33, 111.49,
108.62, 26.16, 22.72; (18, hydrochloride salt) ESI-MS
m/z: 357 (M+H)+, 358 (M+2H)2+, 179 (M/2+H)+; Anal.
Calcd for C22H20N4O Æ 2HCl Æ 1.3H2O: C, 58.36; H,
5.47; N, 12.37; Cl, 15.66. Found: C, 57.97; H, 5.18; N,
12.46; Cl, 16.03.
1
1-ol). H NMR (DMSO-d6) d 6.79 (d, J = 3.3 Hz, 1H),
3.3.18. 2-(2-N-Hydroxyamidino-3,4-dihydronaphthalen-
7-yl)-5-(4-N-hydroxyamidinophenyl)furan hydrochloride
salt (19). A suspension of hydroxylamine hydrochloride
(1.72 g, 24.84 mmol) in anhydrous DMSO (30 ml) un-
der nitrogen was cooled to 5 °C and potassium t-bu-
toxide (2.79 g, 24.84 mmol) was added portionwise.
The mixture was stirred for 30 min. The bis-cyano
derivative 10 (0.4 g, 1.24 mmol) was added at once
and the reaction mixture was stirred overnight at
room temperature. It was then slowly poured into
ice/water and stirred for about 30 min. The precipitate
was collected, washed with water, dichloromethane,
ether, and hexanes, and dried under vacuum to afford
19 (free base) as a yellow powder in 87% yield; mp
>260 °C (EtOH/ether). 1H NMR (DMSO-d6) d 2.52
(t, J = 8.1 Hz, 2H), 2.76 (t, J = 7.5 Hz, 2H), 5.53 (br
s, 2H), 5.86 (br s, 2H), 7.02 (d, J = 3.6 Hz, 1H), 7.07
(s, 1H), 7.11 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 7.8 Hz,
1H), 7.57 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.75 (m,
J = 8.7 Hz, 4H), 9.70 (s, 1H), 9.85 (s, 1H); 13C
NMR (DMSO-d6) d 152.86, 151.94, 151.09, 150.38,
135.18, 134.15, 132.43, 132.09, 130.36, 128.44, 127.84,
125.81, 123.89, 122.95, 122.46, 121.39, 108.72, 107.71,
26.92, 21.72; (19, hydrochloride salt) ESI-MS m/z:
389 (M+H)+, 390 (M+2H)2+, 195 (M/2+H)+, 777
(2M+H)+; Anal. Calcd for C22H20N4O3 Æ 2HCl Æ 1/
3H2O: C, 56.66; H, 4.86; N, 12.01; Cl, 15.02. Found:
C, 56.79; H, 4.89; N, 11.63; Cl, 14.72.
7.23 (d, J = 3.6 Hz, 1H), 7.76 (dd, J = 1.5, 8.7 Hz, 1H),
8.03 (dd, J = 1.5, 8.7 Hz, 1H), 8.09 (d, J = 8.4 Hz, 2H),
8.31 (s, 1 H), 8.62 (s, 1H); 13C NMR (DMSO-d6) d
154.39, 134.48, 133.58, 132.11, 129.25, 128.91, 128.14,
126.63, 124.83, 122.59, 121.55, 119.11, 114.45, 110.48,
109.28; EI-MS m/z: 299 (81BrM+, 45), 297 (79BrM+, 42),
190 (100); Anal. Calcd for C15H8NOBr Æ 0.1H2O: C,
60.06; H, 2.75. Found: C, 60.01; H, 2.49.
3.3.16.
2-(4-Cyanobiphenyl)-5-(2-cyanonaphthalen-7-
yl)furan (17). A mixture of 16 (0.94 g, 3.15 mmol),
4-cyanophenyl boronic acid (0.65 g, 4.42 mmol), tetra-
butylammonium fluoride (1.33 g, 3.73 mmol), palladium
acetate (14.2 mg, 0.06 mmol), and potassium carbonate
(0.87 g, 6.30 mmol) in a mixture of water/DME (10 ml/
10 ml) was refluxed and stirred vigorously for 1 h. After
cooling to room temperature, the mixture was poured
into water and extracted with ethyl acetate. The organic
layer was washed with brine, dried over MgSO4, and
concentrated. The crude product was purified by column
chromatography (silica gel, 30–60% dichloromethane-
hexanes). Removal of solvents afforded 17 (92%) as a
yellow powder; mp 239.6 °C (butan-1-ol). 1H NMR
(DMSO-d6) d 7.36 (d, J = 3.6 Hz, 1H), 7.43 (d,
J = 3.6 Hz, 1H), 7.77 (dd, J = 1.5, 8.4 Hz, 1H), 7.93 (d,
J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 8.10 (d,
J = 8.7 Hz, 2H), 8.18 (dd, J = 1.5, 8.7 Hz, 1H), 8.54 (s,
1H), 8.60 (s, 1H); 13C NMR (DMSO-d6) d 116.19,
114.47, 97.11, 96.53, 96.50, 95.66, 94.99, 92.05, 91.60,
91.40, 89.31, 88.12, 86.85, 85.22, 81.73, 81.55, 74.60,
73.20, 72.43, 72.13; EI-MS m/z: 320 (M+, 100), 190
(31), 160 (38); Anal. Calcd for C22H12N2O: C, 82.22;
H, 3.54. Found: C, 82.50; H, 3.75.
3.3.19. 2-(2-N-Methoxyamidino-3,4-dihydronaphthalen-
7-yl)-5-(4-N-methoxyamidinophenyl)furan hydrochloride
salt (20). Bis-amidoxime 19 (240 mg, 0.62 mmol) was
dissolved in 1,4-dioxane (10 ml) and cooled to 0–5 °C.
Aqueous 2 N NaOH solution (9 ml) was slowly added
followed by dimethylsulfate (0,6 ml, 6.2 mmol) dropwise
in 1,4-dioxane (5 ml). After addition was completed, the
mixture was stirred at room temperature for overnight.
The reaction mixture was poured into water and extract-
ed with ethyl acetate. Organic layer was washed with
brine, dried over MgSO4, and evaporated. The concen-
trate was purified by column chromatography (silica
3.3.17. 2-(2-Amidino-3,4-dihydronaphthalen-7-yl)-5-(4-
amidinophenyl)furan hydrochloride salt (18). HCl gas
was passed through an ethanolic solution (15 ml) of 10
(0.17 g, 0.53 mmol) and the mixture was stirred at room
temperature for 10 days. After evaporation of the sol-
vent, intermediate imidate ester was washed several

S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
7443
gel, 20% ethyl acetate-hexanes). Removal of the solvents
afforded 20 (free base) as a pale yellow powder in 39%
yield; mp >260 °C (EtOH/ether). H NMR (DMSO-d6)
(0.45 ml, 4.73 mmol). After addition was completed,
the mixture was stirred at room temperature for 72 h.
The reaction mixture was poured into water and the pre-
cipitate was collected, washed with water and heptane to
afford 23 (free base) as a yellow powder in 69% yield; mp
1
d 2.51 (t, J = 8.1 Hz, 2H), 2.75 (t, J = 7.8 Hz, 2H),
3.72 (s, 3H), 3.75 (s, 3H), 5.76 (br s, 2H), 6.10 (br s,
2H), 7.03 (d, J = 3.6 Hz, 1H), 7.12 (s, 1H), 7.13 (d,
J = 3.6 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H),
7.61 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.79
(d, J = 8.4 Hz, 2H); 13C NMR (DMSO-d6) d 152.93,
151.86, 151.12, 150.64, 135.31, 133.93, 131.66, 131.22,
130.76, 128.43, 127.88, 126.19, 124.91, 122.96, 122.74,
121.55, 108.78, 107.81, 60.68, 60.61, 26.84, 21.80; (20,
hydrochloride salt) ESI-MS m/z: 417 (M+H)+, 418
(M+2H)2+; Anal. Calcd for C24H24N4O3 Æ 1.5HCl Æ 0.6-
H2O: C, 59.80; H, 5.58; N, 11.62; Cl, 11.03. Found: C,
59.92; H, 5.61; N, 11.24; Cl, 11.25.
1
>260 °C (1,4-dioxane). H NMR (DMSO-d6) d 3.76 (s,
3H), 3.79 (s, 3H), 6.12 (br s, 3H), 6.19 (br s, 3H), 7.21
(d, J = 3.3 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 7.77 (m,
J = 8.4 Hz, 3H), 7.88 (m, J = 8.4 Hz,3H), 7.98 (s, 2H),
8.32 (s, 1H), 8.38 (s, 1H); 13C NMR (DMSO-d6) d;
(23, hydrochloride salt) ESI-MS m/z: 415 (M+H)+;
Anal. Calcd for C24H22N4O3 Æ 2HCl Æ 1/2H2O: C,
58.82; H, 5.33; N, 10.97. Found: C, 58.84; H, 4.99; N,
10.62.
3.3.23. 7-(3-Bromophenyl)-2-cyanonaphthalene (24a). A
mixture of triflate 14 (2 g, 6.64 mmol), 3-bromophenyl
boronic acid (1.6 g, 7.97 mmol), tetrabutylammonium
fluoride (2.10 g, 6.64 mmol), palladium acetate (30 mg,
0.13 mmol), and potassium carbonate (1.82 g,
13.28 mmol) in water/DME mixture (25 ml/25 ml) was
stirred vigorously for about 1 h at room temperature.
The precipitate was filtered, washed with water, dried
under vacuum, and purified by column chromatography
(silica gel, 50% dichloromethane-hexanes). Removal of
the solvents afforded 24a as a white powder in 98% yield;
3.3.20. 2-(2-Amidinonaphthalen-7-yl)-5-(4-amidinophe-
nyl)furan hydrochloride salt (21). A solution of com-
pound 17 (300 mg, 0.94 mmol) in THF (8 ml) was
treated with LiN(TMS)2 1 M in THF (5 ml), stirred
overnight at room temperature, treated with ethanolic
HCl (10 ml), and stirred for another 12 h. The precipi-
tate was then filtered, washed with ether, and dried.
The salt of 21 was put into water, basified with aqueous
NaOH 10%, and stirred vigorously. The precipitate was
then filtered, washed with water, ether, and dried to af-
ford 21 (free base) as a yellow powder in 90% yield; mp
1
mp 147.3 °C (butan-1-ol). H NMR (DMSO-d6) d 7.49
(t, J = 7.8 Hz, 1H), 7.64 (m, J = 0.9, 8.1 Hz, 1H), 7.83
(m, J = 1.8, 9.0 Hz, 2H), 8.03 (t, J = 1.8 Hz, 1H), 8.08
(dd, J = 1.8, 8.7 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H), 8.42
(s, 1H), 8.61 (s, 1H); 13C NMR (DMSO-d6) d 141.54,
137.52, 134.72, 133.73, 132.16, 131.25, 130.84, 129.64,
129.16, 128.85, 128.25, 126.74, 126.33, 126.20, 122.59,
119.15, 108.95; EI-MS m/z: 309 (81BrM+, 90), 307
1
>260 °C (EtOH/ether). H NMR (DMSO-d6) d 7.40 (d,
J = 3.6 Hz, 1H), 7.45 (d, J = 3.6 Hz, 1H), 7.83 (dd,
J = 1.5, 8.7 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 8.09–
8.17 (m, 4 H), 8.20 (dd, J = 1.5, 8.4 Hz, 1H), 9.27 (br
s, 2H), 9.40 (br s, 2H), 9.51 (br s, 2H), 9.60 (br s, 2H);
13C NMR (DMSO-d6)
d 166.73, 165.77, 154.14,
152.62, 135.25, 135.15, 132.74, 130.39, 129.68, 129.37,
129.31, 129.19, 126.90, 125.83, 124.62, 124.30, 123.69,
112.31, 110.98; (21, hydrochloride salt) ESI-MS m/z:
178 (M/2+H)+, 355 (M+H)+, 356 (M+2H)2+; Anal.
Calcd for C22H18N4O Æ 2HCl Æ H2O: C, 59.33; H, 4.97;
N, 12.58. Found: C, 59.32; H, 4.66; N, 12.32.
(
79BrM+, 90), 227 (50), 100 (48); Anal. Calcd for
C17H10NBr: C, 66.23; H, 3.24. Found: C, 66.21; H, 3.14.
3.3.24.
7-(40-Cyanobiphenyl-3-yl)-2-cyanonaphthalene
(25a). A mixture of compound 24a (2.05 g, 6.65 mmol),
4-cyanophenyl boronic acid (1.37 g, 9.32 mmol), tetra-
butylammonium fluoride (2.52 g, 7.98 mmol), palladium
acetate (30 mg, 0.13 mmol), and potassium carbonate
(1.84 g, 13.31 mmol) in water/DME mixture (25 ml/
25 ml) was refluxed for about 3 h. After cooling to room
temperature, the mixture was poured into water and the
precipitate was filtered, washed with water, dried under
vacuum, and purified by column chromatography (silica
gel, 50% dichloromethane-hexanes). Removal of the sol-
vents afforded 25a as a white powder in 89% yield; mp
3.3.21. 2-(2-N-Hydroxyamidinonaphthalen-7y-l)-5-(4-N-
hydroxyamidinophenyl)furan hydrochloride salt (22).
The same procedure described for 19 was used starting
from 17. Free base of 22, yield 84%; mp >260 °C
1
(EtOH/ether). H NMR (DMSO-d6) d 3.64 (br s, 3H),
7.39 (d, J = 3.6 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.74
(dd, J = 1.2, 8.7 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H),
8.07–8.20 (m, 5H), 8.46 (s, 1H), 8.57 (s, 1H), 9.07 (br
s, 3H), 11.28 (s, 1H), 11.33 (s, 1H); 13C NMR
(DMSO-d6) d 159.28, 158.61, 153.27, 151.84, 134.09,
133.99, 132.08, 129.34, 128.81, 128.67, 128.38, 124.86,
124.15, 123.86, 123.65, 122.73, 111.44, 110.36; (22,
hydrochloride salt) ESI-MS m/z: 194 (M/2+H)+, 387
1
201.8 °C (butan-1-ol). H NMR (DMSO-d6) d 7.67 (t,
J = 7.8 Hz, 1H), 7.79 (m, J = 1.8, 8.4 Hz, 2H), 7.90 (d,
J = 7.8 Hz, 1H), 8.03 (q, J = 8.7 Hz, 4H), 8.16 (m,
4H), 8.5 (s, 1H), 8.61 (s, 1H); 13C NMR (DMSO-d6) d
144.25, 139.88, 139.02, 138.63, 134.32, 133.41, 132.61,
132.55, 132.07, 129.71, 128.89, 128.46, 128.29, 127.64,
127.19, 126.51, 126.19, 125.97, 125.64, 118.83, 118.53,
110.15, 108.74; EI-MS m/z: 330 (M+, 80); Anal. Calcd
for C24H14N2 Æ 1/4H2O: C, 86.07; H, 4.36. Found: C,
86.16; H, 4.11.
(M+H)+,
388
(M+2H)2+
;
Anal.
Calcd
for
C22H18N4O3 Æ 2HCl Æ 1/2H2O: C, 56.42; H, 4.51; N,
11.96. Found: C, 56.15; H, 4.76; N, 11.56.
3.3.22. 2-(2-N-Methoxyamidinonaphthalen-7-yl)-5-(4-N-
methoxyamidinophenyl)furan hydrochloride salt (23). To
a solution of 22 (730 mg, 1.89 mmol) in DMF (15 ml)
was slowly added lithium hydroxide hydrate
(317.5 mg, 7.56 mmol) followed by dimethylsulfate
3.3.25. 7-(40-Amidinobiphenyl-3-yl)-2-amidinonaphtha-
lene hydrochloride salt (26a). The same procedure de-
scribed for 21 was used starting from 25a. Free base

7444
S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
1
of 26a, yield 91%; mp >260 °C (EtOH/ether). H NMR
137.77, 134.72, 133.67, 132.96, 132.30, 129.21, 128.89,
128.24, 127.83, 127.52, 126.62, 125.94, 119.22, 118.94,
110.21, 108.96; EI-MS m/z: 330 (M+, 100%), 165 (45),
151 (38); Anal. Calcd for C24H14N2: C, 87.27; H, 4.24.
Found: C, 96.94; H, 4.30.
(DMSO-d6)
d 7.69 (t, J = 7.8 Hz, 1H), 7.85 (d,
J = 8.7 Hz, 2H), 7.92 (d, J = 7.8 Hz, 1H), 8.01 (d,
J = 8.7 Hz, 2H), 8.09 (d, J = 8.7 Hz, 2H), 8.18–8.21
(m, 4H), 8.53 (s, 1H), 8.61 (s, 1H), 9.29 (br s, 3H),
9.38 (br s, 1H), 9.53 (br s, 3H), 9.61 (br s, 1H); 13C
NMR (DMSO-d6) d 165.96, 165.19, 145.03, 140.18,
139.31, 138.65, 134.35, 132.10, 130.08, 129.88, 128.84,
128.62, 128.51, 128.35, 127.35, 126.90, 126.76, 125.95,
123.96; (26a, hydrochloride salt) ESI-MS m/z: 365
(M+H)+; Anal. Calcd for C24H20N4 Æ 2HCl Æ 1.7H2O:
C, 61.59; H, 5.47; N, 11.97. Found: C, 61.72; H, 5.08;
N, 11.60.
3.3.30. 7-(40-Amidinobiphenyl-4-yl)-2-amidinonaphtha-
lene hydrochloride salt (26b). The same procedure de-
scribed for 21 was used starting from 25b. Free base
of 26b, yield 90%; mp >260 °C (EtOH/ether). 1H
NMR (DMSO-d6) d 7.82 (dd, J = 1.8, 8.4 Hz, 1H),
7.93–8.05 (m, 9H), 8.14 (dd, J = 1.8, 8.7 Hz, 1H),
8.20 (d, J = 8.4 Hz, 1H), 8.47 (s, 1H), 8.59 (s, 1H),
9.15 (br s, 3H), 9.25 (br s, 1H), 9.44 (br s, 3H),
9.55 (br s, 1H); 13C NMR (DMSO-d6) d 165.92,
165.20, 144.43, 139.37, 138.09, 137.79, 134.35,
132.10, 129.92, 128.90, 128.74, 128.51, 127.96,
127.80, 126.93, 126.85, 126.38, 126.02, 124.01; (26b,
hydrochloride salt) ESI-MS m/z: 365 (M+H)+; Anal.
Calcd for C24H20N4 Æ 2HCl Æ 3.5H2O: C, 57.60; H,
5.84. Found: C, 57.79; H, 5.63.
3.3.26. 7-(40-N-Hydroxyamidinobiphenyl-3-yl)-2-N-hy-
droxyamidinonaphthalene hydrochloride salt (27a). The
same procedure described for 19 was used starting from
25a. Free base of 27a, yield 92%; mp >260 °C (EtOH/
ether). 1H NMR (DMSO-d6) d 5.88 (br s, 2H), 5.93
(br s, 2H), 7.78–8.09 (m, 12H), 8.27 (s, 1H), 8.32 (s,
1H), 9.70 (s, 1H), 9.79 (s, 1H); 13C NMR (DMSO-d6)
d 159.09, 158.89, 144.88, 141.04, 140.22, 139.29,
134.58, 133.02, 130.64, 129.62, 129.23, 129.10, 128.45,
127.97, 127.21, 126.45, 126.06, 125.21, 124.68; (27a,
hydrochloride salt) ESI-MS m/z: 397 (M+H)+, 398
(M+2H)2+; Anal. Calcd for C24H20N4O2 Æ 2HCl Æ 0.1-
H2O: C, 61.18; H, 4.75; N, 11.89. Found: C, 61.12; H,
4.93; N, 11.49.
3.3.31. 7-(40-N-Hydroxyamidinobiphenyl-4-yl)-2-N-hy-
droxyamidinonaphthalene hydrochloride salt (27b). The
same procedure described for 19 was used starting from
25b. Free base of 27b, yield 96%; mp >260 °C (EtOH/
ether). 1H NMR (DMSO-d6) d 5.89 (br s, 2H), 5.96
(br s, 2H), 7.78–7.94 (m, 11H), 8.02 (d, J = 8.7 Hz,
1H), 8.25 (s, 1H), 8.31 (s, 1H), 9.71 (s, 1H), 9.81 (s,
1H); 13C NMR (DMSO-d6) d 158.96, 158.60, 143.76,
139.30, 138.05, 137.86, 133.98, 132.22, 129.29, 128.67,
128.46, 127.73, 127.58, 127.33, 126.95, 126.18, 124.74,
124.09, 123.92; (27b, hydrochloride salt) ESI-MS m/z:
3.3.27. 7-(40-N-Methoxyamidinobiphenyl-3-yl)-2-N-me-
thoxyamidinonaphthalene hydrochloride salt (28a). The
same procedure described for 23 was used starting from
27a with additional purification by column chromatog-
raphy (silical gel, 30% ethyl acetate-hexanes). Free base
397 (M+H)+, 398 (M+2H)2+
;
Anal. Calcd for
1
of 28a, yield 90%; mp >260 °C (EtOH/ether). H NMR
C24H20N4O2 Æ 2HCl Æ 1.8H2O: C, 57.44; H, 5.14; N,
11.16. Found: C, 57.36; H, 4.74; N, 10.77.
(DMSO-d6) d 3.76 (s, 3H), 3.79 (s, 3H), 6.13 (br s, 2H),
6.20 (br s, 2H), 7.61–8.09 (m, 12H), 8.34 (s, 1H), 8.35 (s,
1H); 13C NMR (DMSO-d6) d 156.48, 156.20, 143.68,
140.44, 139.66, 138.41, 133.68, 132.50, 130.10, 128.61,
128.23, 127.47, 127.25, 127.17, 126.56, 126.50, 125.96,
125.75, 124.10, 62.98, 62.75; (28a, hydrochloride salt)
ESI-MS m/z: 425 (M+H)+; Anal. Calcd for
C26H24N4O2 Æ 2HCl Æ EtOH Æ 0.7H2O: C, 60.47; H, 6.05;
N, 10.07. Found: C, 60.31; H, 6.07; N, 10.00.
3.3.32. 7-(40-N-Methoxyamidinobiphenyl-4-yl)-2-N-me-
thoxyamidinonaphthalene hydrochloride salt (28b). The
same procedure described for 23 was used starting from
27b with additional purification by column chromatog-
raphy (silical gel, 30% ethyl acetate-hexanes). Free base
1
of 28b, yield 78%; mp >260 °C (EtOH/ether). H NMR
(DMSO-d6) d 3.76 (s, 3H), 3.80 (s, 3H), 6.11 (br s, 2H),
6.19 (br s, 2H), 7.78–7.94 (m, 11H), 8.03 (d, J = 8.7 Hz,
1H), 8.28 (s, 1H), 8.32 (s, 1H); 13C NMR (DMSO-d6) d
157.00, 156.95, 143.36, 139.31, 137.92, 137.85,
133.77, 132.33, 128.65, 128.50, 128.18, 127.71,
127.67, 127.23, 126.78, 126.08, 125.62, 125.17, 124.12,
63.17, 62.97; (28a, hydrochloride salt) ESI-MS m/z:
425 (M+H)+; Anal. Calcd for C26H24N4O2 Æ 2HCl Æ
EtOH: C, 60.47; H, 6.05; N, 10.07. Found: C, 60.38;
H, 5.97; N, 10.03.
3.3.28. 7-(4-Bromophenyl)-2-cyanonaphthalene (24b).
The same procedure described for 24a was used starting
from 14 with 4-bromophenyl boronic acid. Yield 88%;
mp 178.8 °C (butan-1-ol). H NMR (DMSO-d6) d 7.73
(m, 5H), 8.3 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.1 Hz,
2H), 8.36 (s, 1H), 8.6 (s, 1H); 13C NMR (DMSO-d6) d
138.31, 137.91, 134.67, 133.62, 132.22, 132.06, 129.19,
128.90, 128.14, 126.64, 125.91, 121.71, 119.16, 108.97;
EI-MS m/z: 309 (81BrM+, 92), 307 (79BrM+, 90), 227
(50), 100 (51); Anal. Calcd for C17H10NBr Æ H2O: C,
62.59; H, 3.70. Found: C, 62.87; H, 3.37.
1
Acknowledgments
3.3.29.
7-(40-Cyanobiphenyl-4-yl)-2-cyanonaphthalene
This work was supported by an award from the Bill
and Melinda Gates Foundation and NIH Grants
GM61587 and AI46365. The technical assistance with
the in vivo experiments by Guy Riccio is greatly
appreciated.
(25b). The same procedure described for 25a was used
starting from 24b. Yield 88%; mp 199.9 °C (butan-1-
ol). 1H NMR (DMSO-d6) d 7.8 (dd, J = 1.5, 8.7 Hz,
1H), 7.96 (m, 8H), 8.15 (m, 3H), 8.46 (s, 1H), 8.63 (s,
1H); 13C NMR (DMSO-d6) d 143.89, 139.33, 138.29,

S. Chackal-Catoen et al. / Bioorg. Med. Chem. 14 (2006) 7434–7445
7445
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