Synthesis of potent antitumor and antiviral benzofuran derivatives

Article abstract of DOI:10.1016/j.bmcl.2009.03.069

A new series of potent antitumor and antiviral benzofuran derivatives was synthesized by the reaction of the furochromone-6-carboxaldehydes 1 and 2 with different heterocyclic amines to yield the benzofuran-5-carbonyl derivatives 4-11. The synthesized compounds 1, 3-11 were tested against twelve different human cancer cell lines and all of the compounds were more potent than the comparative standards. The HIV inhibitory activity of the tested compounds 1, 3-11 showed that they have higher potency than Atevirdine. Moreover, compound 6 was significantly potent with wider therapeutic index. The HIV-1 RT inhibitory activity showed that compounds 10, 11, 3 and 4 were notably potent but with lower therapeutic index than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed that they have weaker potency and less therapeutic index than VX-950, although compounds 1, 4, 9 and 6, respectively exhibited significant activity.

Full text of DOI:10.1016/j.bmcl.2009.03.069

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2420–2428
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of potent antitumor and antiviral benzofuran derivatives
a,*
a
b
a
Shadia A. Galal , Amira S. Abd El-All , Mohamed M. Abdallah , Hoda I. El-Diwani
a
Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Cairo, Egypt
Univet Pharmaceuticals Ltd, Balteem, Egypt
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of potent antitumor and antiviral benzofuran derivatives was synthesized by the reaction of
Received 30 October 2008
Revised 18 February 2009
Accepted 18 March 2009
Available online 21 March 2009
the furochromone-6-carboxaldehydes 1 and 2 with different heterocyclic amines to yield the benzofuran-
5-carbonyl derivatives 4–11. The synthesized compounds 1, 3–11 were tested against twelve different
human cancer cell lines and all of the compounds were more potent than the comparative standards.
The HIV inhibitory activity of the tested compounds 1, 3–11 showed that they have higher potency than
Atevirdine. Moreover, compound 6 was significantly potent with wider therapeutic index. The HIV-1 RT
inhibitory activity showed that compounds 10, 11, 3 and 4 were notably potent but with lower therapeu-
tic index than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed
that they have weaker potency and less therapeutic index than VX-950, although compounds 1, 4, 9 and
6, respectively exhibited significant activity.
Keywords:
Furochromones
Benzofuran
Heterocyclic amines
Antitumor activity
Cytotoxicity
Ó 2009 Elsevier Ltd. All rights reserved.
Antiviral activity
HIV and HIV-1 RT inhibitory activity
HCV NS3-4A protease inhibitor activity
1
5
Of the various human diseases, cancer, human immunodefi-
ciency virus (HIV) and hepatitis C virus (HCV) are scourges on
humanity. Therefore, identification of novel potent, selective, and
less toxic anticancer and antiviral agents remains one of the most
are useful for treating cell proliferation and viral infections con-
ditions (Fig. 2).
1
6
The main purpose of this work consists of designing and synthe-
sizing novel polycyclic compounds containing the benzofuran scaf-
fold linked by a carbonyl group in the 5-position to the
1
–3
pressing health problems. Benzofurans and furochromones
are
very interesting heterocycles, which are ubiquitous in nature and
show a wide range of biological activities. Recently, the anticancer
pharmacologically interesting moieties having pyrimidine nucleus
and studying the influence of these moieties on antitumor, anti-
HIV and anti-HCV activities of the synthesized compounds.
The naturally occurring furochromones namely as khellin (VIIa)
and visnagin (VIIb) are very sensitive to alkali and the solvent used
in the reaction has great effect on the obtained products, for exam-
ple, aqueous alkaline hydrolysis of VIIa and VIIb using potassium
hydroxide afforded khellinone (VIIIa) and visnaginone (VIIIb),
4
and antiviral activities of the natural cyclopenta[b]benzofurans
5
and furochromones have been reported, the same as for a variety
of benzofuran derivatives. For example, 1-[(benzofuran-2-yl)phen-
ylmethyl]imidazoles (I) had a potent, reversible, non-selective
aromatase-inhibitory effect6 and 2-{4-[(benzofuran-2-yl)car-
bonyl]piprazin-1-yl}-3-propylpyridine (II) exhibited good anti-HIV
7
17
activity. In the process of new drug discovery, benzofuran deriva-
respectively. Whereas, alcoholic hydrolysis of VIIa and VIIb with
tives III and IV were obtained by screening for anticancer agents dis-
potassium hydroxide gave different product known as
ellinone (IXa) and x-acetovisnaginone (IXb). The hydrolysis
x
-acetokh-
1
8
playing selective cytotoxicity against a tumorigenic cell line
8
–10
(Fig. 1).
products are important molecules for the synthesis of new furochr-
omones. Compounds VIIIa and VIIIb are used in the synthesis of 5-
oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (1) and (2) directly
On the other hand, pyrimidine nucleus is the main constituent
of different antiviral and antitumor agents.1
1–13
Several promising
1
9,20
antitumor active derivatives were found to contain the fused benz-
imidazole and pyrimidine system as a series of 3,4-dihydro-
benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (V, VI).14 Further-
more, compounds derived from fused pyridines and pyrimidines
via Vielsmeier-Haack reaction (c.f. Scheme 1).
of chromones, known as ring opening reaction or
The hydrolysis
-pyrone ring fis-
c
sion, was previously investigated by ab initio and density func-
2
1
tional theory methods by Kó nˇ a et al. The calculations of ROR
mechanism of khellin VIIa have been performed recently by Ati
2
2
et al.
An efficient way for synthesis of new benzofuran derivatives
has been developed in this work, based upon ROR of chromones
*
Corresponding author. Tel.: +20 233371718; fax: +20 233370931.
E-mail address: sh12galal@yahoo.com (S.A. Galal).
0
960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.069

S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
2421
R
N
N
CH CH CH
2
2
3
CH3
N
O
N
N
O
O
II
I, R = Cl, F
OMe
OMe
OH
CH3
OH
CH3
OEt
O
R
O
O
O
III, R = H, F
IV
Figure 1.
R
R
tively, characterized by the spectral and elemental analyses. The
H NMR spectrum of compound 4 indicated the absence of the
1
O
N
O
(
2
CH ) singlet as well as the presence of two singlets at d 9.25 and
H
H
N
1
2.75 ppm corresponding to NH and OH, which disappeared by
N
CH
3
D
2
O. Also, the IR spectrum showed the presence of two bands at
N
Cl
N
N
ꢀ1
3
504 and 3415 cm of the phenolic OH and NH of benzimidazole,
N
respectively, which confirming the unexpected pyrone ring open-
ing, although the pyrone ring was known to be stable enough in
N
2
4
the presence of mild basic condition.
V, R = H, NO , OCH
V I, R = H, NO , OCH
2 3
2
3
Compound 4 or 5 was formed probably via the formation of the
Schiff base 12 or 13 followed by a nucleophilic attack of the benz-
imidazole nitrogen at C-7 of compound 1 or 2 to cause pyrone ring
opening and intramolecular cyclization affording 4 or 5, respec-
tively (c.f. Scheme 2).
Compounds 6–11 were obtained by the reaction of furochro-
mone 1 with the following heterocyclic amines, 2-aminobenzimid-
azole, 2-aminopyridine, 2-aminopyrazine, 2-aminothiazole,
Figure 2.
in alkaline medium and the reaction of furochromones (1 or 2)
with heterocyclic amines in mild basic conditions.
The reaction of (1H-benzimidazol-2-yl) methanamine dihydo-
2
3
chloride (3) with compounds 1 and 2 was studied by using a cat-
alytic amount of triethyl amine or piperidine to give unexpected
benzimidazo[1,2-a][1,4]diazepinyl derivatives 4 and 5, respec-
3
-amino-5-methyloxazole, and 4-aminopyridine, respectively, in
the presence of alcoholic KOH (c.f. Scheme 3).
OMe O
O
OMe O
POCl / DMF
3
H
KOH/ H O
CH3
OH
2
O
O
O
R
OMe O
R
VIIIa = OMe
VIIIb = H
1 = OMe
2 = H
O
CH3
O
R
O
OMe O
VIIa = OMe
VIIb = H
CH3
KOH/ C H OH
O
2
5
OH
R
IXa = OMe
IXb = H
Scheme 1.

2
422
S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
OMe
O
CHO
N
N
T.E.A / methanol
OMe
+
.
2 HCl
NH2
O
O
H
R
O
O
3
1
2
, R =OMe
, R =H
N
N
O
H
N
R
1
1
2, R =OMe
3, R =H
OMe
O
N
OMe
O
N
H
O
H
OH
N
N
H
N
R
O
OH
N
R
4
5
, R =OMe
, R =H
Scheme 2.
The synthesis of compounds 6–11 probably took place via addi-
the standard drug used, was less active than the tested compounds,
6
7
ꢀ5
tion of hydroxyl ion to C –C bond of furochromone derivative
which had comparative activity with IC50 = 2.55 ꢁ 10
lM to
2
1,22
ꢀ5
1
followed by a nucleophilic attack of the reacted amine on
the intermediate A, formed by alcoholic hydrolysis of compound
, and finally, in the case of compounds 6–10, the intramolecular
3.00 ꢁ 10
lM.
On non-small lung cancer (NCl H460) and colonadenocarcino-
1
ma (RKOP 27) cell lines, all the tested compounds were more po-
ꢀ
3
cyclization took place (c.f. Scheme 4). Whereas, in the synthesizing
of compound 11, the intramolecular cyclization could not be oc-
curred, the suggested mechanism of the reaction to afford 11 is ex-
plained in Scheme 4.
tent than Gencitabine hydrochloride (IC50 = 2.13 ꢁ 10
l
M) and
ꢀ3
Capecitabine (IC50 = 4.33 ꢁ 10
lM), the standard drugs used,
respectively.
The study of the cytotoxicity on leukemia (HL60) cell line
ꢀ
5
The cytotoxicity of the tested compounds 1, 3–11 was deter-
indicated that, compounds
4
(IC50 = 3.25 ꢁ 10
lM) and 1
2
5
ꢀ5
mined by using MTT assay according to Mosmann’s method on
different human cancer cell lines (c.f. Tables 1 and 2), including:
cervical carcinoma (KB), ovarial carcinoma (SKOV-3), CNS cancer
(IC50 = 3.13 ꢁ 10
lM) were the least potent compounds but more
ꢀ3
active than Doxorubicin (IC50 = 1.13 ꢁ 10
lM).
ꢀ5
On leukemia(U937) cellline, compound 11(IC50 = 2.63 ꢁ 10
lM)
(
(
SF-268), non-small lung cancer (NCl H460), colonadenocarcinoma
RKOP 27), anti-leukemia (HL60, U937, K562), melanoma (G361,
was the most potent, whereas, 4 showed the least bioactivity
ꢀ
5
3
(IC50 = 3.33 ꢁ 10
l
l
M), but with higher bioactivity than Doxorubicin
ꢀ
SK-MEL-28), neuroblastoma (GOTO, NB-1). The cytotoxic effect
of the tested compounds over normal human fetal lung fibroblast
WI 38 cell line was also tested. The results were expressed as the
IC50, which is the concentration of the drugs inducing a 50% inhibi-
tion of cell growth of treated cells when compared to the growth of
control cells.
(IC50 = 4.45 ꢁ 10
M).
On leukemia (K562) cell line, compound 1 (IC50 = 2.58 ꢁ
ꢀ5
10
lM) was the most potent among the other synthesized ben-
zofuran derivatives, followed by compound 11 with (IC50
=
ꢀ5
2.63 ꢁ 10
l
M), whereas compound 9 was the least potent one
ꢀ5
with (IC50 = 4.64 ꢁ 10
l
lM).
M), but was more potent than Doxorubi-
ꢀ3
Screening the cytotoxicity of the tested compounds on cervical
carcinoma (KB), where Fluorouracil was used as standard drug
cin (IC50 = 6.66 ꢁ 10
Estimation of the cytotoxicity on melanoma (G361) cell line
showed that compounds 1, 6 and 11 have the lowest IC50
ꢀ
3
(
IC50 = 4.46 ꢁ 10
lM), showed that the tested compounds were
ꢀ
5
more potent than the standard, with exception of compound 7
(2.63 ꢁ 10
l
M) among the tested compounds, whereas com-
ꢀ3
ꢀ5
(
IC50 = 3.28 ꢁ 10
lM) which had comparative activity with Fluo-
pound 7 showed the highest one (IC50 = 4.81 ꢁ 10
lM). On the
rouracil. Compounds 4 and 5 were the most potent compounds
other hand, comparing the IC50 of compound 7 to that of Aldesleu-
ꢀ
ꢀ
5
5
ꢀ3
(
(
IC50 = 2.55 ꢁ 10
l
M) and more potent than compounds
1
kin (6.66 ꢁ 10
lM), the standard drug used, indicated that com-
ꢀ5
IC50 = 3.78 ꢁ 10
lM) and 3 (IC50 = 2.77 ꢁ 10
lM).
pound 7 was potent with over than 100 times.
On ovarian carcinoma (SKOV-3) cell line, compounds 4, 5 and 10
On melanoma (SK-MEL-28) cell line, Aldesleukin (IC50
=
ꢀ
5
ꢀ5
were the most significantly potent compounds (IC50 = 2.55 ꢁ 10
lM)
3.45 ꢁ 10
lM), the standard drug used, was the least potent com-
and more potent than both Doxorubicin used as standard drug
pound. The potency of the tested compounds can be arranged in
descending order as follows: 6, 8, 1, 11, 9, 3, 5,7, 4, and 10.
On neuroblastoma (GOTO) and (NB-1) cell lines, compound 11
ꢀ
3
ꢀ5
(
IC50 = 4.16 ꢁ 10
l
M) and compound 1 (IC50 = 3.28 ꢁ 10
l
M).
ꢀ3
Compounds 6 and 9 with (IC50 = 3.28 ꢁ 10
lM) showed less activity
ꢀ5
than compound 1 but still have more activity than Doxorubicin.
was the most potent compound with (IC50 = 2.53 ꢁ 10 M) and
M), respectively whereas, the IC50(s) of Doxo-
rubicin, the standard drug used on both cell lines, were
l
ꢀ5
Studying the cytotoxicity of tested compounds on CNS cancer
(IC50 = 2.50 ꢁ 10
l
3
(
SF-268) cell line, showed that Cytarabine (IC50 = 7.68 ꢁ 10ꢀ
lM),

S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
2423
OMe
O
N
O
N
OH
OMe
OMe
O
OMe
OMe
O
7
N
N
O
N
OH
O
N
OH
N
b
OMe
N
H
8
6
OMe
O
O
c
a
f
CHO
+
KOH / methanol
O
OMe
d
1
OMe
O
N
e
OMe
OMe
O
N
H
N
O
O
OH
N
OH
S
OMe
OMe
O
11
N
9
O
OH
N
OMe
O
N
CH3
a = 2-aminobenzimidazole
b = 2-aminopyridine
c = 2-aminopyrazine
d = 2-aminothiazole
10
e =3-amino-5-methyl-oxadiazole
f = 4-aminopyridine
Scheme 3.
ꢀ
3
ꢀ3
(
4.73 ꢁ 10
l
M) and (5.15 ꢁ 10
l
M), respectively. By compar-
selectivity toward tumor cell lines over WI 38 normal cell line.
The other starting material 3, 2-aminonethylbenzimidazole, is
one of the most potent compound against RKOP27 cell line with
low selectivity to the tumor cell lines. The imidazodiazepine moi-
ety on the compounds 4 and 5 has positive influence on the activ-
ity, where 4 and 5 are among the most active compounds for cell
lines KB, SKOV-3 and NClH460. Moreover, compound 5 is one of
the most potent for SF-268 and RKOP27 cell lines. Compound 4
is relatively selective for tumor cell lines over WI 38 cell line, while
5 showed no selectivity. Compound 6 with imidazopyrimidine
moiety have a great bioactivity against SK-MEL-28 and G361cell
lines with selectivity to tumor cell lines. Pyridopyrimidine moiety
in compound 7 increases the activity against SF-268 cell line but
with the absence of selectivity over WI 38 cell line. Whereas, com-
pound 8 with pyrazinopyrimidine moiety improve the activity
among the tumorigenic SF-268 and NClH460 cell lines and selec-
tivity over non-tumorigenic WI 38 cell line. The thiazolopyridine
and oxadiazolopyrimidine moieties represent in compounds 9
and 10, respectively raises the potency toward NCI H460 cell line
with little selectivity over WI 38 cell line. Besides, compound 9 is
the most active compound against HL60 cell line with selectivity
ing the bioactivity of the synthesized compounds with compound
, it was found that compounds 11 and 8 were more potent than
compound 1, whereas compounds 9 and 10 were less potent than
while compound 6 and 1 have the same bioactivity, in addition,
1
1
compounds 4 and 5 were less potent than 3.
On neuroblastoma (NB-1) cell line, comparison of the potency
of furochromone 1 with the other tested compounds indicated that
formation of compounds 11 and 8 caused increasing in the po-
tency, whereas, compounds 7, 4, 6 and 9 have lower bioactivity
than 1. On the other hand, compounds 4 and 5 have less potency
than compound 3.
The previous screening of the bioactivity of the tested com-
pounds on the presented panel cell lines indicated that, they were
more significantly potent than the comparative standards used.
The starting material 1 and the products 4–11 have in common
the benzofuran moiety related to a carbonyl group in the 5-posi-
tion, but the activity varied slightly on the heterocyclic moiety re-
lated to the carbonyl group for compounds 4–10 or the side chain
in case of compound 11. Compound 1 is one of the most potent
compounds against SF-268, RKOP27, K562 and G361 with slight

2
424
S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
OMe O
H
OMe O
H
+
H
O
O
OH
H
O
+
O
O
O
OH
OMe
OMe
OMe O
O
H
NH2
H
H
O
O
O
O
OMe
H
OMe
N
N
-
H O
2
O
N
OH
- H O
OH
OMe
2
H N
2
N
H
O
OMe
OMe
N
OMe O
-
H O
O
2
H
N
O
O
H
OH
O
N
OMe O
OH
OMe
N
A
N
O
OH
N
OMe
6
-10
N
N
OMe O
N
OMe O
OMe O
N
N
N
O
OH
N
H
O
N
O
N
OH
OH
OMe
-
OMe
O
H
N
OMe
OH
O
H
N
H
B
N
C
-
OMe O HN
N
OMe O
N
N
+
H
O
OH
O
OH
OMe
OMe
7
Scheme 4.
over WI 38 cell line. On the other hand, compound 10 is one of the
most potent compounds against SKOV-3 cell line with minor selec-
tivity over the normal cell line WI 38. For compound 11, the pyri-
dine nucleus is related to the 5-carbonylbenzofuran derivative
through an amino propen-linker, which seems to increase the
activity, but at the same time does not conserve the selectivity.
Compound 11 gave the most potent activity on these cell lines
RKOP27, U937, G361, GOTO and NB-1 cell lines but unfortunately
showed no selectivity on WI 38 cell line with lower or almost the
Antiviral activity: HIV inhibitory activity and reverse transcriptase
inhibition with therapeutic windows. CEM-SS cells, laboratory-de-
rived virus isolates (including drug-resistant virus isolates), and
low-passage clinical virus isolates used in these evaluations were
previously described in detail. The inhibitory activities of the
tested compounds 1, 3–11 against HIV were evaluated by microti-
ter anti-HIV assays with CEM-SS cells or fresh human peripheral
blood mononuclear cells (PBMCs); these assays quantify the ability
of a compound to inhibit HIV-induced cell killing or HIV replica-
tion. Quantification was performed by the tetrazolium dye XTT as-
2
6
same IC50
.

S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
2425
Table 1
The cytotoxicity activity of synthesized compounds was determined by using MTT assay according to the Mosmann’s method25 on different human cancer cell lines
Compound #
IC50a
lM Tumor cell growth inhibition (%)
KB
SK OV-3
SF-268
NCI H460
RKOP27
ꢀ
ꢀ
ꢀ
ꢀ
5
5
5
5
5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ3
ꢀ5
ꢀ5
ꢀ3
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
1
3
4
5
6
7
8
9
3.78 ꢁ 10
2.77 ꢁ 10
2.55 ꢁ 10
2.55 ꢁ 10
3.28 ꢁ 10
2.84 ꢁ 10
2.55 ꢁ 10
2.55 ꢁ 10
3.28 ꢁ 10
2.77 ꢁ 10
2.84 ꢁ 10
3.28 ꢁ 10
2.55 ꢁ 10
3.20 ꢁ 10
2.55 ꢁ 10
2.84 ꢁ 10
3.20 ꢁ 10
2.55 ꢁ 10
2.55 ꢁ 10
2.77 ꢁ 10
2.77 ꢁ 10
2.55 ꢁ 10
2.55 ꢁ 10
2.55 ꢁ 10
2.84 ꢁ 10
2.55 ꢁ 10
2.55 ꢁ 10
2.77 ꢁ 10
2.55 ꢁ 10
2.77 ꢁ 10
2.77 ꢁ 10
2.84 ꢁ 10
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
2.84 ꢁ 10
ꢀ5
2.77 ꢁ 10
ꢀ5
2.55 ꢁ 10
ꢀ
ꢀ5
2.8 ꢁ 10
3.00 ꢁ 10
ꢀ3
ꢀ5
ꢀ5
ꢀ5
5
ꢀ5
3.28 ꢁ 10
2.60 ꢁ 10
2.77 ꢁ 10
2.77 ꢁ 10
2.55 ꢁ 10
ꢀ5
2.55 ꢁ 10
ꢀ5
ꢀ5
3.3 ꢁ 10
2.8 ꢁ 10
ꢀ5
ꢀ5
ꢀ5
1
1
0
1
2.8 ꢁ 10
2.60 ꢁ 10
2.55 ꢁ 10
ꢀ
ꢀ5
4.5 ꢁ 10
2.84 ꢁ 10
ꢀ
3
Fluorouracil
Doxorubicin
Cytarabine
Gemcitabine HCl
Capecitabine
4.46 ꢁ 10
4.16 ꢁ 10ꢀ
3
7.68 ꢁ 10ꢀ
3
2.13 ꢁ 10ꢀ
3
4.33 ꢁ 10ꢀ
3
Table 2
The cytotoxicity activity of synthesized compounds was determined by using MTT assay according to the Mosmann’s method25 on different human cancer cell lines
Compound #
IC 50a
lM Tumor cell growth inhibition (%)
Leukaemia
U937
Melanoma
Neuroblastoma
NB-1
Normal cells
WI 38
HL60
K562
G361
SK-MEL-28
GOTO
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ3
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ3
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
1
3
4
5
6
7
8
9
3.13 ꢁ 10
2.91 ꢁ 10
3.25 ꢁ 10
3.05 ꢁ 10
2.60 ꢁ 10
2.75 ꢁ 10
2.66 ꢁ 10
2.55 ꢁ 10
2.81 ꢁ 10
2.63 ꢁ 10
1.13 ꢁ 10
2.91 ꢁ 10
2.58 ꢁ 10
3.13 ꢁ 10
3.38 ꢁ 10
2.98 ꢁ 10
2.69 ꢁ 10
4.46 ꢁ 10
3.21 ꢁ 10
4.46 ꢁ 10
2.84 ꢁ 10
2.63 ꢁ 10
6.66 ꢁ 10
2.63 ꢁ 10
3.05 ꢁ 10
3.16 ꢁ 10
3.13 ꢁ 10
2.63 ꢁ 10
4.81 ꢁ 10
2.98 ꢁ 10
3.84 ꢁ 10
2.87 ꢁ 10
2.63 ꢁ 10
2.66 ꢁ 10
3.01 ꢁ 10
3.21 ꢁ 10
3.05 ꢁ 10
2.53 ꢁ 10
3.05 ꢁ 10
2.60 ꢁ 10
2.84 ꢁ 10
3.38 ꢁ 10
2.81 ꢁ 10
2.78 ꢁ 10
2.63 ꢁ 10
3.29 ꢁ 10
2.91 ꢁ 10
2.78 ꢁ 10
3.29 ꢁ 10
2.58 ꢁ 10
2.81 ꢁ 10
2.84 ꢁ 10
2.53 ꢁ 10
3.16 ꢁ 10
2.78 ꢁ 10
3.33 ꢁ 10
2.91 ꢁ 10
3.97 ꢁ 10
3.21 ꢁ 10
2.78 ꢁ 10
4.31 ꢁ 10
3.25 ꢁ 10
2.50 ꢁ 10
3.21 ꢁ 10
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
ꢀ5
2.98 ꢁ 10
2.69 ꢁ 10
ꢀ5
ꢀ5
3.33 ꢁ 10
3.33 ꢁ 10
ꢀ5
ꢀ5
3.01 ꢁ 10
2.84 ꢁ 10
ꢀ5
ꢀ5
2.72 ꢁ 10
4.72 ꢁ 10
ꢀ5
ꢀ5
2.98 ꢁ 10
2.55 ꢁ 10
ꢀ5
ꢀ5
2.84 ꢁ 10
3.73 ꢁ 10
ꢀ5
ꢀ5
2.84 ꢁ 10
2.84 ꢁ 10
ꢀ5
ꢀ5
1
1
0
1
3.29 ꢁ 10
2.81 ꢁ 10
ꢀ5
ꢀ5
2.63 ꢁ 10
2.53 ꢁ 10
ꢀ3
Doxorubicin
Aldesleukin
Doxorubicin
4.45 ꢁ 10
6.66 ꢁ 10ꢀ
3
3.45 ꢁ 10ꢀ3
4.73 ꢁ 10ꢀ
3
5.15 ꢁ 10ꢀ3
say (CEM-SS, 174 ꢁ CEM, MT2, and AA5 cell-based assays), which
is metabolized to a colored formazan product by viable cells. Anti-
viral and toxicity data were reported as the quantity of drug re-
quired to inhibit virus-induced cell killing or virus production by
Table 3
The HIV inhibitory activity and reverse transcriptase inhibition with therapeutic
windows of the tested compounds and standard
*
Ma
*
Mb
Therapeutic indexc
Compounds #
EC50 /
l
IC50 /
l
5
0% (EC50). The compounds 1, 3–11 were tested for RT inhibitory
1
3
4
5
6
7
8
9
2 ꢁ 10-5
17.53
5.1
9.44
47.55
25.66
16.3
32,567
1755
ꢀ
5
activity against purified recombinant HIV-1 RT using the cell-free
Quan-T-RT assay system (Amersham Corp., Arlington Heights, IL),
which utilizes the scintillation proximity assay (SPA) principle.
IC50[RT] values (concentration at which the compound inhibits re-
combinant RT by 50%) were calculated by comparing the measure-
ments to untreated sample.
Results of HIV and HIV-RT inhibitory activity of the tested com-
pounds and standard were evaluated (c.f. Table 3). For comparison,
Atevirdine was used as standard drug. The EC50 values listed in Ta-
ble 3 showed that, all of tested compounds were more potent than
1 ꢁ 10
ꢀ
5
3
35 ꢁ 10
21,678
23,458
1,140,000
23,498
20,000
22,567
7689
ꢀ
2
7,28
6 ꢁ 10
ꢀ5
2 ꢁ 10
3 ꢁ 10
9 ꢁ 10
4 ꢁ 10
4 ꢁ 10
1 ꢁ 10
ꢀ5
ꢀ
ꢀ
ꢀ
ꢀ
5
5
5
5
14.6
15.26
–4
1
1
0
1
3 ꢁ 10
4.8
1263
100,000
ꢀ4
Atevirdine
10 ꢁ 10
10
a
Compound concentration required to inhibit the virus induced cell killing by
ꢀ
4
50%.
Atevirdine (EC50 = 10ꢁ10
l
M). Only the imidazopyrimidinyl
b
Compound concentration required to achieve 50% inhibition of recombinant
ꢀ5
derivative 6 (EC50 = 2 ꢁ 10
lM) had much better therapeutic in-
HIV-1 RT activity.
c
dex (TI = 1,140,000) than the standard (TI = 100,000). Studying the
bioactivity of new synthesized compounds with respect to furochr-
omone 1, indicated that compound 11 had higher potency,
whereas compound 6 possessed the same bioactivity as compound
Therapeutic index is the toxic dose of a drug for 50% of the population (TD50)
divided by the minimum effective dose for 50% of the population (ED50).
*
EC50 and IC50 values were estimated by logistic regression analysis. One way
ANOVA (P < 0.01) was used to test treatment difference in EC50 and IC50. After
significant factor by ANOVA, individual group differences were analyzed using
Holm-Sidak’s procedure for multiple comparisons versus control.
1
9
with wider therapeutic index. On the other hand, compounds 7,
, 10, 8 and 4 have less bioactivity with respect to furochromone 1.
Screening of HIV-1 reverse transcriptase inhibition of the tested
compounds showed that the oxadiazolopyrimidinyl derivative 10
(IC50 = 5.1
(IC50 = 9.44
dine (IC50 = 10
l
l
M), which was more potent than compound
M). These compounds were more potent than Atevir-
M). On the other hand, compounds
4
–
4
was the most potent compound with striking IC50 (3 ꢁ 10
l
M),
followed by compound 11 (IC50 = 4.8 M), then compound 3
l
l
1

2
426
S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
(
(
IC50 = 17.53
IC50 = 16.3
l
M),
8
(IC50 = 14.6
(IC50 = 25.66
l
M),
9
(IC50 = 15.26
l
M),
l
7
M),
lines showed that, the synthesized compounds possess high po-
tency against all cell lines and the hetero-moieties included into
bezofuranylcarbonyl skeleton via ROR, mostly have positive effect
on the activity and selectivity.
The HIV inhibitory activity of the tested compounds, 1, 3–11,
indicated that all the compounds were more active than Atevir-
dine and compound 6 having imidazopyrimidine as heterocyclic
moiety has 20 times active as Atevirdine with higher therapeutic
index. Testing of the HIV-RT inhibitory activity of compounds,
showed that compound 10 was the most potent one but with low-
er therapeutic index than the standard.
l
M),
6
l
M) and
5
(IC50 = 47.55
respectively, showed significant activity but less than the standard.
Hepatitis C Virus (HCV) NS3-4A protease inhibitor activity. Hepati-
tis C virus (HCV) NS3-4A protease inhibitor activity of the com-
pounds 1, 3–11 was tested. Cells were identical in sequence to
0
29
the I377neo/NS3-3 /wt replicon described by Lohmann et al.
Determination of 50% inhibitory concentration (IC50), 90% inhibi-
tory concentration (IC90), and 50% cytotoxic concentration (CC50
of all the tested compounds in HCV replicon cells was performed
)
using a quantitative RT-PCR (QRT-PCR) assay.3
0,31
The cytotoxicity
of the tested compounds was measured under the same experi-
mental settings using a tetrazolium (MTS)-based cell viability as-
say (Promega, Madison, WI) for comparison was used as standard
drug. The results of HCV NS3-4A protease inhibitor activity and
the cytotoxic activity of the tested compounds and standard were
listed (c.f. Table 4).
The evaluation of hepatitis C virus (HCV) NS3-4A protease
inhibitor activities showed that compound 1 was the most active
compound. Only compound 9 having the thiazolopyridine as heter-
omoiety is nearly active as VX-950 with regarding to the cytotox-
icity on hepatocyte cell lines. Unfortunately, none of the tested
compounds was more potent and had wider therapeutic index
than VX-950, the standard drug used.
Screening of the 90% inhibitory concentration (IC90) values revealed
that compounds 1 (IC90 = 0.796 ± 0.08
l
M), 4 (IC90 = 0.955 ± 0.08
(IC90 = 1.32 ± 0.13 M), 3(IC90 = 2.12
M), and 11(IC90 = 2.31 ± 0.2 M), respectively, showed signifi-
l
M),
All the synthesized derivatives can serve as lead compounds for
further investigations or may constitute a basis of new class of
antitumor and antiviral active agents.
9
±
(IC90 = 1.12 ± 0.12
0.12
lM),
6
l
l
l
cant activity but less active than VX-95. Whereas, compounds 5, 7, 8
(11H-Benzo[4,5]imidazo[1,2-a][1,4]diazepin-4-yl)(6-hydroxy-4,7-
and 10 were inactive.
Regarding to the cytotoxicity on hepatocyte cell lines, the stan-
dard drug used was also the most potent compound (CC50
dimethoxy-benzofuran-5-yl)methanone (4). Yield: 83%, mp 315–
1
317 °C. H NMR (500 MHz, DMSO-d
6
): 3.94(s, 3H, CH
3
), 4.00(s,
0
3
3H, CH ), 7.14(d, 1H, J = 1.5 Hz, H3 benzofuran), 7.47 (m, 2H, H8
0
=
90 ± 1.2
nificant potency among the synthesized compounds followed by
compounds 1 and 6 with the same bioactivity (CC50 = 234 ± 6 M),
then compounds 4 (CC50 = 256 ± 13 M), 3 (CC50 = 345 ± 12) and
1 (CC50 = 435 ± 15 M). On the other hand, the bioactivity of com-
l
M). Compound 9 (CC50 = 127 ± 9
l
M) had the most sig-
and H9 benzimidazodiazepine), 7.56(d, 1H, J = 1.5 Hz, H2 benzofu-
ran), 7.72(m, 4H, H1, H3, H7 and H10 diazepinobenzimidazole),
7.91(s, 1H, H5 benzimidazodiazepine), 9.23(br, NH, D O exchange-
2
l
l
1
l
pounds 7, 8 and 10 almost decayed. Studying the therapeutic index
of the tested compound, revealed that none of the tested com-
pound has wider therapeutic index than VX-950.
Table 5
The median lethal dose of the tested
a
* **
(LD50 ± SD ) mg/kg
Compound no.
The median lethal dose LD50 of the tested compounds was deter-
32–34
1
3
4
5
6
7
8
9
113.29 ± 1
146.6 ± 1
mined according to the procedure described by Lorke.
The re-
sults of the LD50 in mg/kg of the synthesized compounds were
listed (c.f. Table 5). Screening the median lethal dose (LD50) of
the tested compounds 1, 3–11 showed that, all the compounds
165.65 ± 1
121.16 ± 1
177.14 ± 1
124.67 ± 1
150.09 ± 1
133.14 ± 1
125.98 ± 1
152.13 ± 1
were found to have higher LD50 than compound
1
(
LD50 = 113.29 ± 1 mg/kg). These results indicated that the heter-
omoieties included into benzofuranyl skeleton decreased the toxic-
ity of the starting material 1.
10
11
In conclusion, the reaction of furochromone 1 or 2 with hetero-
cyclic amines afforded antitumor and antiviral active agents via
ring opening reaction. The cytotoxicity studies of compounds 1,
a
Dose required to kill half the members of the tested population.
Data expressed as means ± SD for three independent experiments.
The median lethal dose of the tested compounds was determined according to
*
**
3
–11 against 12 human cancer and the non-tumorigenic WI 38 cell
the procedure described by Lorke.
Table 4
HCV NS3-4A protease inhibitory activity and the cytotoxic activity of the tested compounds and standard
a
*
b
*
CC50c ( ± SD*)
lM
Therapeutic indexd
Compound no.
IC50 ( ± SD )
lM after 48 h
IC90 ( ± SD )
lM after 48 h
1
3
4
5
6
7
8
9
0.421 ± 0.03
0.876 ± 0.09
0.444 ± 0.04
>100
0.564 ± 0.04
>100
>100
0.342 ± 0.03
>100
0.796 ± 0.08
2.12 ± 0.12
0.955 ± 0.08
—
1.32 ± 0.13
—
234 ± 5
451 ± 12
256 ± 13
—
234 ± 6
—
555.81948
514.84018
576.57658
—
414.89362
—
—
—
—
1.12 ± 0.12
—
2.31 ± 0.2
127 ± 9
—
435 ± 15
90 ± 1.2
371.34503
—
441.17647
1200
1
1
0
1
0.986 ± 0.08
0.20 ± 0.0001
e
VX-950
0.45 ± 0.0003
a
Compound concentration required to achieve 50% inhibition of HCV NS3-4A protease activity.
Compound concentration required to achieve 90% inhibition of HCV NS3-4A protease activity.
Compound concentration required to reduce the cell viability by 50% as determined by MTT method.
Therapeutic index is the toxic dose of a drug for 50% of the population (TD50) divided by the minimum effective dose for 50% of the population (ED50).
The standard used in comparison.
b
c
d
e
*
Data expressed as means ± SD for three independent experiments.

S. A. Galal et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428
2427
O exchangeable), IR (cm 1): 3503.75
ꢀ
(6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)(2-methyl-3aH-[1,2,4]-
able), 12.75(s, 1H, OH, D
2
(
OH), 3415.73 (NH), 3064.93(CH, aromatic), 2970.36 (CH, ali-
phatic), 3164.74–2655.42 (intermolecular H bonded OH and NH),
oxadiazolo[2,3-a]pyrimidin-6-yl)methanone (10). Yield: 75%, mp 225–
1
227 °C. HNMR(500 MHz, DMSO-d
6
):1.52(s, 3H,CH
), 3.92(s, 3H, OCH ), 3.75(s, 1H, H3a,
oxadiazolopyrimidine), 6.23(s, 1H, H7 oxadiazolopyrimidine),
3
, oxadiazolopyr-
+
1
4
641.1(C@O), 1608.45 (C@N), 1540.45(C@C). MS: m/z 403 (M ,
17 3 5
5%).220 (m , 100%), 183 (m , 93%), Anal. Calcd for C22H N O :
imidine), 3.85(s, 3H, OCH
3
3
1
2
0
0
C, 65.50; H, 4.25; N, 10.42. Found: C, 65.43; H, 4.29; N, 10.40.
11H-Benzo[4,5]imidazo[1,2-a][1,4]diazepin-4-yl)(6-hydroxy-4-meth-
oxy-benzofuran-5-yl)methanone (5). Yield: 63%, mp 323–325 °C. H NMR
7.16(d, 1H, J = 1.5 Hz, H3 benzofuran), 7.61(d, 1H, J = 1.5 Hz, H2 ben-
(
zofuran), 7.81(s, 1H, H5 oxadiazolopyrimidine), 12.65(s, 1H, OH, D
2
O
1
ꢀ1
exchangeable). IR (cm ): 3402.31(br, OH and NH), 1639.34(C@O),
0
+
(500 MHz, DMSO-d
6
): 3.96(s, 3H, CH
3
), 7.16(s, 1H, J = 1.5 Hz, H3 benzo-
1617.81(C@N). MS: m/z 335(M , 65.12%), 132 (m
1
, 100%). Anal. Calcd
0
furan), 7.20 (m, 3H, H7 benzofuran, H8 and H9 benzimidazodiazepine),
7
for C17
11.86.
H N O : C, 57.14; H, 4.23; N, 11.76. Found: C, 57.22;H, 4.17;N,
15 3 6
0
.48(d, 1H, J = 1.5 Hz, H2 benzofuran),7.73(m, 4H, H1, H3, H7 and H10
diazepinobenzimidazole), 8.1(s, 1H, H5 benzimidazodiazepine),
.23(br, NH, D O exchangeable), 12.752(s, 1H, OH, D O exchangeable),
IR (cm ): 3520.35(OH), 3404.21(NH), 3034.88(CH, aromatic),
974.50(CH, aliphatic), 1639.73(C@O), 1608.33 (C@N). MS: m/z
(E)-1-(6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)-3-(pyridin-4-
ylamino)prop-2- en-1-one (11). Yield: 60%, mp 295–297 °C. H NMR
1
9
2
2
ꢀ
1
(500 MHz, DMSO-d
6
): 3.85(s, 3H, OCH
3
), 3.93(s, 3H, OCH
3
), 6.42(d,
0
0
0
2
1H, J = 18.5 Hz, H2 propenone), 7.2(d, 1H, J = 2 Hz, H3 benzofu-
ran), 7.42(d, 2H, J = 7.5 Hz, H3 and H5 pyridine), 7.53(d, 1H,
+
15 3 4
373(M , 100%). Anal. Calcd for C21H N O : C, 67.56; H, 4.05; N, 11.25.
0
0
0
Found: C, 67.53; H, 4.12; N, 11.11
J = 18.5 Hz, H3 propenone), 7.76(d, 1H, J = 2 Hz, H2 benzofuran),
8.30(d, 2H, J = 7.5 Hz, H2 and H6 pyridine), 10.56(s, 1H, NH, D
(
6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)(benzo[4,5]imidazo[1,2-
2
O
1
ꢀ1
a]pyrimidin-3-yl)methanone (6). Yield: 65%, mp >330 °C. H NMR
exchangeable), 12.96(s, 1H, OH, D
2
O exchangeable). IR (cm ):
(
500 MHz, DMSO-d
6
) 3.84(s, 3H, CH
3
), 3.93(s, 3H, CH
3
), 7.15 (m 3H,
3513.00 (OH), 3350.62(NH), 1655.65(C@O), 1611.12(C@N). MS:
m/z 340 (M , 55%), 220(m , 100%). Anal. Calcd for C18H N O : C,
1 16 2 5
63.52; H, 4.74; N, 8.23. Found: C, 63.55; H, 4.79; N, 8.12.
0
+
H3 benzofuran, H7 and H8 benzimidazopyrimidine), 7.64 (m, 1H,
H9 benzimidazopyrimidine), 7.70(d, 1H, J = 1.5 Hz, H2 benzofuran),
0
8
.28(m, 1H, H6 benzimidazopyrimidine), 8.51(s, 1H, H4 benzimi-
dazopyrimidine), 8.87(s, 1H, H2 benzimidazopyrimidine), 13.02(s,
Acknowledgments
ꢀ
1
1
2
H, OH, D Oexchangeable). IR(cm ):3571.52(OH), 3050.33(CH, aro-
matic), 2975.33(CH, aliphatic), 3200.74–2600.55(intermolecular H
bonded OH), 1642.09(C@O), 1606.8(C@N), 1537.35(C@C). MS: m/z
The authors express their deep thanks to ‘SANOFI-AVENTIS
(Paris, FR)’ for the evaluation of: the cytotoxicity on 13 different
human cell lines, the HIV & HIV RT inhibitory activity, the HCV
NS3-4A protease inhibitor activity and the median lethal dose of
the synthesized compounds. We thank ‘the US-Egypt Joint Science
and Technology Board Fund’ administered through the USDA
(BIO9-002-015).
+
3
C
1
89(M , 10.5%), 221(m
1
, 77%), 169(m
2
, 100%). Anal. Calcd for
21
H
15
N
3 5
O : C, 64.78; H, 3.88; N, 10.79. Found: C, 64.58; H, 3.91; N,
0.83.
6-hydroxy-4,7-dimethoxybenzofuran-5-yl)(9aH-pyrido[1,2-a]pyr-
imidin-3-yl)methanone (7). Yield: 77%, mp >340 °C.
500 MHz, DMSO-d ): 3.88(s, 3H, CH ), 3.96(s, 3H, CH ), 4.59(s, 1H,
H9a pyridopyrimidine), 6.17(m, 1H, H9 pyridopyrimidine), 6.45(m,
(
1
H NMR
(
6
3
3
Supplementary data
1
6
H, H8 pyridopyrimidine), 6.62(m, 1H, H6 pyrimidobenzimidazole),
0
.96(m,1H, H7 pyridopyrimidine), 7.17(d, 1H, J = 1.5 Hz,H3 benzofu-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.069.
0
ran), 7.69(d, 1H, H2 benzofuran), 7.79(m, 1H, H2 pyrimidobenzimi-
dazole), 7.95(s, 1H, H4 pyrimidobenzimidazole), 12.75(s, 1H, OH,
D O exchangeable). IR (cm ): 3532.67(OH), 3035.18(CH, aromatic),
2
ꢀ1
References and notes
2
1
8
972.10(CH, aliphatic), 3200–2600 (intermolecular H bonded OH),
639.2, (C@O), 1607.38(C@N), 1547.21(C@C). MS: m/z 352(M ,
0.12%), 220 (m , 95%), 132(m , 100%). Anal. Calcd for C19H N O :
1 2 16 2 5
+
1. Hou, X. L.; Yang, Z.; Wong, H. N. C. Furans and Benzofurans. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford,
2002; Vol. 14, p 139.
C, 64.77; H, 4.58; N, 7.95. Found: C, 64.69; H, 4.62; N, 7.85.
6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)(8H-pyrazino[1,2-a]pyr-
2.
Mustafa, A. Furopyrans and Furopyrones; John Wiley and Sons: N.Y., N.Y., 1967.
(
Chapter III: Furochromones, pp 102–159.
3. Gammill, R. B.; Hyde, B. R. J. Org. Chem. 1983, 48, 3863.
1
imidin-3-yl)methanone (8). Yield: 75%, mp 215–217 °C (dec.). H NMR
500 MHz, DMSO-d ): 2.80(s, 1H, NH, D O exchangeable), 3.85(s, 3H,
CH ), 3.92(s, 3H, CH ), 5.95(s, 1H, H9 pyrzinopyrimidine), 6.22(m, 2H,
4.
Kim, S.; Salim, A. A.; Swanson, S. M.; Kinghorn, A. D. Anticancer Agents
Med.Chem. 2006, 6, 319.
(
6
2
3
3
5. Hudson, J.; Towers, G. H. N. Drugs Future 1999, 24, 295.
6. Whomsley, R.; Fernandez, E.; Nicholls, P. J.; Smith, H. J.; Lombardi, P.; Pestellini,
V. J. Steroid Biochem. Mol. Biol. 1993, 44, 675.
0
H6 and H7 pyrzinopyrimidine),7.09(d, 1H, J = 1.5 Hz,, H3 benzofuran),
.60(d, 1H, J = 1.5 Hz, H2 benzofuran), 7.68(s, 1H, H2 pyrzinopyrimi-
0
7
7.
Romero, D.; Thomas, R.; May, P.,; Poel, T, US Appl., 354,925, 1994; Chem. Abstr.
1996, 125, 142777g.
2
dine), 7.82(s, 1H, H4 pyrzinopyrimidine), 13.09(s, 1H, OH, D O
ꢀ
1
8. Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.; Naruto, S.; Sugano, Y.
exchangeable). IR (cm ): 3574.37(OH), 3241.64(NH), 1645.34(C@O),
+
Bioorg. Med. Chem. Lett. 2004, 14, 455.
1
597.84(C@N). MS: m/z 353 (M , 65.12%), 220(m
1 1
, 87%), 132(m ,
9.
Hayakawa, I.; Shioya, R.; Agatsuma, T.; Sugano, Y. Chem. Pharm. Bull. 2005, 53,
1
00%). Anal. Calcd for C18 : C, 61.19; H, 4.28; N, 11.89. Found:
H
15
N
3
O
5
638.
10. Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.; Naruto, S.; Sugano, Y.
Bioorg. Med. Chem. Lett. 2004, 14, 4383.
C, 61.22; H, 4.17; N, 11.86.
6-Hydroxy-4,7-dimethoxybenzofuran-5-yl)(8aH-thiazolo[3,2-a]pyrimi-
(
1
1. Prekupec, S.; Makuc, D.; Plavec, J.; Suman, L.; Kralj, M.; Pavelic, K.;
Balzarini, J.; De Clercq, E.; Mintas, M.; Raic-Malic, S. J. Med. Chem. 2007,
50, 3037.
1
dine-6-yl)methanone (9). Yield: 75%, mp >340 °C. H NMR (500 MHz,
DMSO-d ): 3.88(s, 3H, CH ), 3.92(s, 3H, CH ), 4.52(s, 1H, H8a thiazolopyr-
6
3
3
12. Gadhachanda, V. R.; Wu, B.; Wang, Z.; Kuhen, K. L.; Caldwell, J.;
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1
7
H, H3 thiazolopyrimidine), 7.16(d, 1H, J = 1.5 Hz, H3 benzofuran),
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0
.53(m, 2H, H7 thiazolopyrimidine), 7.61(d, 1H, J = 1.5 Hz, H2 benzofu-
ran), 7.81(s, 1H, H5 thiazolopyrimidine), 13.23(s, 1H, OH, D O exchange-
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+
1
611.12(C@N). MS: m/z358 (M , 98%), 220(m
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H, 3.88; N, 7.89; S, 8.95.
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