Microwave-assisted solvent-free synthesis of bis(dihydropyrimidinone) benzenes and evaluation of their cytotoxic activity: Research article

Article abstract of DOI:10.1111/j.1747-0285.2009.00937.x

An effective one-pot synthesis of bis(dihydropyrimidinonoe)benzenes using chlorotrimethylsilane (TMSCl) through Biginelli condensation reaction of terephthalic aldehyde, 1,3-dicarbonyl compounds and (thio)urea or guanidine under microwave irradiation cond

Full text of DOI:10.1111/j.1747-0285.2009.00937.x

ª 2010 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2009.00937.x
Chem Biol Drug Des 2010; 75: 375–380
Research Article
Microwave-Assisted Solvent-Free Synthesis of
Bis(dihydropyrimidinone)benzenes and Evaluation
of their Cytotoxic Activity
Javad Azizian1, Mohammad K.
MCR condensations involve three or more compounds reacting in a
single one-pot reaction, but consecutively to form a new product,
which contains the essential parts of all the starting materials. The
search and discovery for new MCR's on one hand (7), and the full
Mohammadi1, Omidreza Firuzi2,
Behrooz Mirza3 and Ramin Miri2,*
1Department of chemistry, Faculty of Science, Science and Research
exploitation of already known multicomponent reactions on the other
hand, is therefore of considerable current interest. One such MCR
that belongs in the latter category is the venerable Biginelli dihydro-
pyrimidine synthesis. A few years ago, Pietro Biginelli reported on the
one-pot cyclocondensation reaction of an aldehyde, a b-ketoester,
and urea (or thiourea), a procedure known as the Biginelli reaction, is
receiving increased attention. More than a century ago, Biginelli intui-
tively anticipated the synthetic potential of multicomponent reactions
by combining in a single flask the reactants of two different reactions
having one component in common (8). The result of the three-compo-
nent reaction was a new product that was correctly characterized as
a substituted 3,4-dihydropyrimidine-2(1H)-one (DHPM).
Branch, Islamic Azad University, P.O. Box 11365-4435 Tehran, Iran
2Medicinal & Natural Products Chemistry Research Centre, Shiraz
University of Medical Science, P.O. Box 3288-71345 Shiraz, Iran
3Department of chemistry, Faculty of science, South Tehran Branch,
Islamic Azad University, P.O. Box 11365-4435 Tehran, Iran
*Corresponding author: Prof. Ramin Miri, mirir@sums.ac.ir
An effective one-pot synthesis of bis(dihydropyr-
imidinonoe)benzenes using chlorotrimethylsilane
(TMSCl) through Biginelli condensation reaction of
terephthalic aldehyde, 1,3-dicarbonyl compounds
and (thio)urea or guanidine under microwave irra-
diation conditions is described. Excellent yields of
the products and simple work-up are attractive
features of this green protocol. Then, the cyto-
toxic activities of these compounds were evalu-
ated on five different human cancerous cell lines
(Raji, HeLa, LS-180, SKOV-3 and MCF7). Their cyto-
toxic study indicated that they possessed a weak
to moderate activity. Furthermore, the higher
activity of compound 4b bearing sulfur in C2
position of pyrimidinone ring showed the impor-
tance of this site for cytotoxic activity of these
compounds.
3,4-Dihydropyrimidinones (DHPMs) constitute a very important class
of organic compounds because of their attractive pharmacological
properties, including antiviral, antitumour, antibacterial activities [For
a review, see (9); references cited therein (10)].
They have emerged as integral backbones of several calcium chan-
nel blockers, antihypertensive agents, a-1a-antagonists, and neuro-
peptide Y (NPY) antagonists (11–13). Moreover, several alkaloids
containing the dihydropyrimidine core unit have been isolated from
marine sources, which also exhibit interesting biologic properties.
Most notably, among these are the batzelladine alkaloids, which
were found to be potent HIV gp-120-CD4 inhibitors (14–16). In the
frame work of our program to develop the chemistry of heterocyclic
compounds and in connection with our ongoing interests in MCRs
(17–22). We would like to introduce a facile procedure for the syn-
thesis of bis(dihydropyrimidinone)benzenes via one-pot condensation
of terephthalic aldehyde or isophthalic aldehyde with (thio)urea,
guanidine, and 1,3- dicarbonyl compounds (Scheme 1). Furthermore,
the cytotoxic activity of synthesized compound was checked in five
different cell lines.
Key words: Biginelli reaction, cytotoxicity, dihyropyrimidinone,
microwave irradiation, multicomponent, terephthalic aldehyde, TMSCl
Received 21 September 2009, revised 24 November 2009 and accepted
for publication 26 November 2009
Multicomponent reactions (MCRs) can be distinguished from classi-
cal, sequential two-component chemistry synthesis processes in that
they use three or more chemical starting materials as the input for
product formation. Up to seven starting components have been
used, and MCRs have often been shown to produce higher product
yields than classical chemistry (1–3).
Experimental
General
The reactions were carried out with a microwave oven (2.45 GHz,
1500 w; Microsynthesis, Milstone). Melting points were measured
on the Electrothemal 9100 apparantus and are uncorrected. IR
spectra were measured on a Bomem FT-IR-MB 100 spectrometer
Multicomponent reactions are finding increasing use in the discov-
ery process of new drugs and agrochemicals (4–6) and offer signifi-
cant advantages over conventional linear-type syntheses.
375

Azizian et al.
R2
R1
HN
OHC
O
X
X
O
O
TMSCl
HN
R1
R2
+
+
H2N
NH2
NH
R1
MWI/100 °C
NH
1a-e
x = O,S,NH
CHO
X
O
1
2
1a: R = R = Me
R2
3
2a-c
1
2
1b: R = Me, R = OEt
4a-g
1
2
1c: R = Me, R = Ph
Scheme 1: General synthetic
pathway for derivatives used in
this study.
1
2
1d: R = CF , R = Me
3
1
2
1e: R = CF , R = 2-thienyl
3
1
(ABB Bomem Inc, QC, Canada). H and 13C NMR spectra were mea-
sured with a Bruker DRX-300 Avance spectrometer (Bruker, Ettlingen,
Germany) in DMSO-d6 at 300 and 75 MHz using tetra methyl sylan
as internal standard. Chemical shifts are reported (d) relative to
TMS, and coupling constant (J) is reported in hertz (Hz). Mass spec-
tra were recorded on a MS model 5973 Network apparatus at ioniza-
tion potential of 70 eV. Elemental analysis for C, H, and N was
performed using a Thermo Finnigan Flash EA 1112 (Thermo Fisher
Scientific Inc, USA) instrument. All other reagents were purchased
from commercial sources and were freshly used after being purified
by standard procedures.
2.16 (s, 6H, Me). 13C NMR (DMSO-d6): 193.5, 174.6, 148.9, 144.2,
127.4, 110.6, 54.5, 31.2, 19.80. MS: (m ⁄ z) (%) 414 (M+,6), 325(11),
314(17), 274(19), 140(94), 59(100).
1,1¢-(4,4¢-(1,4-phenylene)bis(2-imino-6-methyl-1,2,
3,4-tetrahydropyrimidine-5,4-diyl)) diethanone
(4c)
Yield 85%, m.p. 298–300 ꢀC (dec). IR (KBr): kmax = 3353, 3220,
2973, 1694, 1606, 1374 cm-1. 1H NMR (DMSO-d6): 9.99 (sbr, 2H,
NH), 7.95 (s 2H, NH), 7.21 (s, 4H, Ar), 6.28 (sbr, 2H, NH), 5.23 (s,
2H, CH), 2.23 (s, 6H, COMe), 2.06 (s, 6H, Me). 13C NMR (DMSO-d6):
193.4, 178.2, 154.3, 144.6, 127.6, 109.5, 53.2, 31.1, 20.1. MS: (m ⁄ z)
(%) 380 (M+,9), 351(11), 307(19), 267(25), 183(78), 59(81), 43(100).
Anal. Calcd for C20H24N6O2: C, 63.14; H, 6.36; N, 22.09. Found: C,
63.41, H, 6.71; N, 21.97.
Typical procedure for the preparation of (4a–4g)
Microwave irradiation conditions (MWI) method
A mixture of dialdehyde (1 mmol), 1,3-dicarbonyl compounds (2 mmol),
(thio)urea or guannidine (3 mmol), and TMSCl (0.3 mmol, 15 mol %)
were mixed and sealed with a cap containing a septum. The loaded
vial was then placed into the cavity of the microwave reactor and
heated at 100 ꢀC for 4–6 min. After completion of the reaction (moni-
tored by TLC, the ethyl acetate ⁄ n- hexane), reaction mixture was
poured into cold water (25 mL) and stirred for 5–10 min. The precipi-
tates were filtered and washed with cold water (2 · 15 mL) and then
with 90% ethanol (2 · 10 mL) to give pure products. Products were
characterized by analyzing their 1H and 13C NMR, and the mass spec-
tra and their purity were confirmed by elemental analysis.
Diethyl4,4¢-(1,4-phenylene)bis(6-methyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate) (4d)
Yield 95%, m.p. 315–317 ꢀC (dec). IR (KBr): kmax = 3326, 3105,
1
2975, 1702, 1236 ⁄ cm. H NMR (DMSO-d6): 9.09 (sbr, 2H, NH), 7.67
(s, 2H, NH), 7.16 (s, 4H, Ar), 5.11 (d, J = 3.3 Hz, 2H, CH), 3.87 (q,
J = 7.2 Hz, 4H, OCH2CH3), 2.21 (s, 6H, Me), 1.05 (t, J = 7.2 Hz, 6H,
OCH2CH3). 13C NMR (DMSO-d6): 166.2, 152.9, 149.2, 144.7, 127.2,
100.1, 60.1, 51.5, 18.6, 14.9. MS: (m ⁄ z) (%) 442 (M+,7), 398(9),
296(21), 256(54), 183(73), 59(100).
Spectral data
(4,4¢-(1,4-phenylene)bis(6-methyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5,4-diyl))bis (phenylmetha-
none) (4e)
4,4¢-(1,4-phenylene)bis(5-acetyl-6-methyl-
3,4-dihydropyrimidin-2(1H)-one) (4a)
Yield 91%, m.p. 295–298 ꢀC (dec). IR (KBr): kmax = 3312, 3110,
1
Yield 91%, m.p. 315-317 ꢀC (dec). IR (KBr): kmax = 3279, 3103,
2923, 1706, 1601, 1326 ⁄ cm. 1H NMR (DMSO-d6): 9.17 (sbr, 2H,
NH), 7.78 (sbr, 2H, NH), 7.18 (s, 4H, Ar), 5.21 (d, J = 3 Hz, 2H, CH),
2.27 (s, 6H, COMe), 2.10 (s, 6H, Me). 13C NMR (DMSO-d6): 195.0,
152.9, 148.9, 144.3, 127.4, 110.5, 54.3, 31.3, 19.7. MS: (m ⁄ z) (%)
382 (M+,7), 354(10), 259(17), 183(100), 155(45), 43(95).
2923, 1702, 1667 ⁄ cm. H NMR (DMSO-d6): 9.15 (s, 2H, NH), 7.75
(sbr, 2H, NH), 7.49-7.38 (m, 10H, COPh), 7.13 (s, 4H, Ar), 5.23 (d,
J = 2.5 Hz, 2H, CH), 1.64 (s, 6H, Me). 13C NMR (DMSO-d6): 195.1,
152.9, 146.5, 144.1, 141.9, 132.3, 129.4, 128.5, 127.2, 110.2, 55.7,
19.3. MS: (m ⁄ z) (%) 506 (M+,5), 450(7), 410(100), 318(71), 242(85),
126(31), 116(41), 57(26). Anal. Calcd for C30H26N4O4: C, 71.13; H,
5.17; N, 11.06. Found: C, 71.49; H, 5.11; N, 11.13.
1,1¢-(4,4¢-(1,4-phenylene)bis(6-methyl-2-thioxo-
1,2,3,4-tetrahydropyrimidine-5,4-diyl))
diethanone (4b)
4,4¢-(1,4-phenylene)bis(5-acetyl-6-(trifluoro-
methyl)-3,4-dihydropyrimidin-2(1H)-one) (4f)
Yield 85%, m.p. 328–330 ꢀC (dec). IR (KBr): kmax = 3324, 2962,
Yield 87%, m.p. 310-312 ꢀC (dec). IR (KBr): kmax = 3384, 3176,
1
1
2981, 1615, 1447 ⁄ cm. H NMR (DMSO-d6): 10.23 (s, 2H, NH), 9.66
1710, 1645, 1231 ⁄ cm. H NMR (DMSO-d6): 9.48 (s, 2H, NH), 7.76
(s, 2H, NH), 7.17 (s, 4H, Ar), 5.24 (s, 2H, CH), 2.29 (s, 6H, COM),
(s, 2H, NH), 7.31 (s, 4H, Ar), 5.14 (s, 2H, CH), 2.25 (s, 6H, Me). 13C
376
Chem Biol Drug Des 2010; 75: 375–380

Synthesis of Bis(dihydropyrimidinone)benzenes
NMR (DMSO-d6): 193.9, 152.6, 144.4, 132.5, 129.1, 125.9, 107.8,
50.5, 27.6. MS: (m ⁄ z) (%) 490 (M+, 11), 256(100), 69(85), 57(81),
43(63). Anal. Calcd for C20H16F6N4O4: C, 48.99; H, 3.29; N, 11.43.
Found: C, 49.76; H, 3.21; N, 11.51.
wells was 0.5%. Cells were further incubated for 72 h, except
for HeLa cells, which were incubated for 96 h. At the end of
the incubation time, the medium was removed and MTT was
added to each well at a final concentration of 0.5 mg ⁄ mL and
plates were incubated for another 4 h at 37 ꢀC. Then formazan
crystals were solubilized in 200 lL DMSO. The optical density
was measured at 570 nm with background correction at 655 nm
using a Bio-Rad microplate reader (Model 680). The percentage
of viability compared to control wells was calculated for each
concentration of the compound and IC16 and IC50 values (26)
were calculated with the software CurveExpert version 1.34 for
Windows. Each experiment was repeated 3–4 times. Data are
presented as mean € S.D.
4,4¢-(1,4-phenylene)bis(5-(thiophene-2-carbonyl)-
6-(trifluoromethyl)-3,4-dihydropyrimidin -2(1H)-
one) (4g)
Yield 87%, m.p. 218–220 ꢀC (dec). IR (KBr): kmax = 3157, 3089,
1
2912, 1658, 1603, 1205 ⁄ cm. H NMR (DMSO-d6): 9.92 (s, 2H, NH),
7.89(d, J = 4.5 Hz, 2H, thienyl), 7.78 (d, J = 3.9 Hz, 2H, thienyl),
7.69 (s, 2H, NH), 7.50(s, 4H, Ar), 7.16 (dd, J = 3.9, 4.5 Hz, 2H, thie-
nyl), 5.61 (s, 2H, CH). 13C NMR (DMSO-d6): 182.3, 154.5, 146.1,
142.4, 140.9, 138.9, 137.0, 130.7, 129.3, 123.2, 104.5, 54.6. MS:
(m ⁄ z) (%) 626 (M+,5), 542(11), 446(15), 397(21), 350(50), 268(71),
222(55), 111(100), 69(91). Anal. Calcd for C26H16F6N4O4S2: C, 49.84;
H, 2.57; N, 8.94. Found: C, 49.89; H, 2.69; N, 9.09.
Results and Discussion
The original Biginelli protocol for the preparation of the DHMPs
consisted of heating a mixture of the three components (alde-
hyde, b-keto-ester, and urea) in ethanol containing a catalytic
amount of HCl [For a review, see (9); references cited therein
(10)]. The major drawback associated with this protocol is the
low yields, particularly for substituted aromatic and aliphatic
aldehydes (27,28). This has led to the development of multistep
synthetic strategies (29–34), involving combinations of Lewis
acids and transition metal salts, e.g. BF3.OEt2, polyphosphate
esters, and reagents like CuI, InCl3, Mn(OAc)3, trimethylsilyltri-
flate, LaCl3.7H2O, CeCl3.7H2O, LiClO4, Yb(OTf)3, clays, etc. How-
ever, many of these methods involve expensive reagents, long
reaction times, and high stoichiometric amount of catalysts, and
difficult to handle especially on a large scale. Therefore, the dis-
covery of a new and an inexpensive catalyst for the preparation
of dihydropyrimidin-2-(1H)-ones under mild and efficient conditions
is of prime importance. For the increasing environmental and
economical concerns in recent years, it is now essential for
chemists to search environmentally benign catalytic reactions as
many as possible. Here, we wish to report the use of a catalytic
agent, chlorotrimethylsilane in the Biginelli's reaction under
microwave-assisted solvent-free conditions. Table 1 summarizes
the results for reactions of terephthalic aldehyde with various
derivatives of 1 and 2. We initially examined the reaction of
acetylacetone (1a) with urea (2a) and terephthalic aldehyde (3)
in the presence of TMSCl under microwave irradiation conditions
at 100 ꢀC (Scheme 1). Experiments showed that 15 mol% quanti-
ties of catalyst are enough for the reaction to complete in
<6 min (as indicated by TLC). Alternatively, in the absence of
catalyst did not yield any product. The structure of product 4a
in 91% yield was elucidated by spectroscopy methods and its
purity was confirmed by elemental analysis. The optimized condi-
tions utilize a 1:2:3:0.3 ratio of dialdehyde, 1,3-dicarbonyl com-
pounds, thiourea, and TMSCl (Table 1).
Cytotoxic activity
Reagents and chemicals
RPMI 1640, fetal bovine serum (FBS), trypsin, and phosphate-
buffered saline (PBS) were purchased from Biosera (Ringmer, UK).
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
was obtained from Sigma (St Louis, MO, USA) and penicillin ⁄ strep-
tomycin were purchased from Invitrogen (San Diego, CA, USA).
Doxorubicin and dimethyl sulphoxide were obtained from EBEWE
Pharma (Unterach, Austria) and Merck (Darmstadt, Germany),
respectively.
Cell lines and cell culture
HeLa (human cervical adenocarcinoma), SKOV-3 (human ovarian
adenocarcinoma), LS-180 (human colon cancer), MCF7 (human
breast adenocarcinoma), and Raji (human B lymphoma) cells were
obtained from the National Cell Bank of Iran, Pasteur Institute, Teh-
ran, Iran. All cell lines were maintained in RPMI 1640 supple-
mented with 10% FBS, 100 units ⁄ mL penicillin-G, and 100 lg ⁄ mL
streptomycin. Cells were grown in monolayer cultures, except for
Raji cells, which were grown in suspension, at 37 ꢀC in humidified
air containing 5% CO2.
Cytotoxicity assay
Cell viability following exposure to synthetic compounds was esti-
mated by using the MTT reduction assay (23–25). SKOV-3, MCF7,
and Raji cells were plated in 96-well microplates at a density of
5 · 104 cells ⁄ mL (100 lL per well). LS-180 and HeLa cells were
plated at densities of 1 · 105 and 2.5 · 104 cells ⁄ mL, respec-
tively. Control wells contained no drugs and blank wells con-
tained only growth medium for background correction. After
overnight incubation at 37 ꢀC, half of the growth medium was
removed and 50 lL of medium supplemented with different con-
centrations of synthetic compounds dissolved in DMSO were
added in quadruplicate. Plates with Raji cells were centrifuged
before this procedure. Maximum concentration of DMSO in the
The procedure is shown to be equally efficient when thiourea is
replaced with urea or guanidine. In addition, it can be concluded
1
from both H NMR and 13C NMR spectra of the product that the
reaction is stereospecific loading to exclusive formation of one the
meso or dl diastereoproducts from which the meso product is
shown here for the simplicity.
Chem Biol Drug Des 2010; 75: 375–380
377

Azizian et al.
Table 1: TMSCl-catalyzed one- pot synthesis of compounds (4a–g) under microwave irradiation conditions
R2
X
O
H
N
NH
R1
HN
X
N
H
O
R2
Compounda
R1
R2
X
Time (min)
Yieldsb (%)
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
CF3
CF3
Me
Me
Me
OEt
Ph
O
S
NH
O
O
4
5
4
4
5
6
6
91
88
85
95
91
85
87
Me
2-thienyl
O
O
4g
aReaction conditions: dialdehyde (1 mmol), (thio)urea or guanidine (3 mmol), and 1,3- dicarbonylcompounds (2 mmol), TMSCl (0.3 mmol), under microwave irradi-
b
ation conditions, no solvent. Isolated yields.
cytotoxic effect of these compounds which can be a helpful hint
for future designs.
Cytotoxicity activity
The data of cytotoxicity are present in Table 2. IC16 and IC50 were
calculated for each compound. The most cytotoxic effect was seen
on HeLa cell line; in this manner, all compounds except compound
4e had IC16 lower than 100 lM (because of low solubility, the max-
imum concentration tested for compound 4e was 25 lM). The low-
est activity was observed in Raji, because only one compound had
IC50 lower than 100 lM.
Conclusion
In conclusion, we have presented the first synthesis of novel deriva-
tives of bis(dihydropyrimidinone)benzenes using the efficient, easily
available, and low quantities of an inexpensive catalyst under
microwave irradiation conditions. This method not only preserved
the simplicity of Biginelli's one-pot condensation but also remark-
ably improved the yields (>85%) of dihydropyrimidinones in shorter
reaction times (4–6 min) as against the longer reaction times
required for other catalysts after the addition of a low catalyst con-
centration. The procedure gives the products in good yields and
avoids problems associated with solvent use (cost, handling, safety
and pollution), and easy experimental work-up procedure, hence, it
As seen in Table 2, compound 4b showed the best activity among
the synthesized compounds against the different cell lines. For
instance, this compound was the only compound having IC50 of
lower than 100 lM in Raji and MCF7 cell lines. Furthermore, in
all cell lines, its IC16 and IC50 were the lowest compared to other
ones. A structural analysis indicated that the key point was pres-
ence of sulfur instead of oxygen or nitrogen in C2 position of pyri-
midinone ring. This implies that this position might play a role in
Table 2: Cytotoxic activity of compounds assessed by the MTT reduction assay
HeLa cells
SKOV-3 cells
LS-180 cells
MCF7 cells
Raji cells
a
a
Compound IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
IC16 (lM)
IC50 (lM)
4a
4b
4c
4d
4e
4f
55.0 € 43.3
5.0 € 5.3
15.0 € 5.2
12.5 € 1.6
>25
>100
26.4 € 9.2
68.9 € 0.9
40.1 € 1.2
>25
37.5 € 10.7
7.2 € 1.9
>100
>100
>25
>100
23.9 € 1.8
>100
>100
>25
>100
4.0 € 1.4
>100
>100
>25
>100
29.2 € 4.5
>100
>100
>25
24.1 € 12.9
17.2 € 6.8
28.3 € 19.0
35.0 € 11.4
>25
>100
45.3 € 12.6
>100
>100
>25
>100
>100
32.9 € 1.6
>100
>100
>25
15.1 € 0.8
28.6 € 9.6
32.8 € 6.5
19.9 € 2.4
>100
21.7 € 3.6
42.4 € 16.5
61.5 € 3.9
>100
14.9 € 5.1
41.6 € 10.8
66.0 € 5.9
>100
7.9 € 2.6
>100
92.6 € 17.9
>100
19.8 € 3.7
>100
>100
>100
>100
>100
4g
>100
Doxorubicin 0.023 € 0.001 0.055 € 0.004 0.062 € 0.016 0.233 € 0.118 0.024 € 0.007 0.135 € 0.038 0.009 € 0.006 0.063 € 0.020 0.016 € 0.004 0.050 € 0.008
Values represent the mean € SD of at least three different experiments. The maximum concentration of the compound tested for cytotoxicity was 100 lM,
except for G, which because of lower solubility, were tested at the maximum concentrations of 25 lM.
aIC16 and IC50 values are defined as the concentration of the compound necessary to inhibit cell growth by 16 and 50%, respectively.
378
Chem Biol Drug Des 2010; 75: 375–380

Synthesis of Bis(dihydropyrimidinone)benzenes
is a useful addition to the existing methods. Development of the
method to one-pot synthesis of products containing two different
dihydropyrimidinone units and determination of the stereochemistry
of the products by X-ray crystallography are currently under investi-
gation in our laboratories.
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J.D., Gougoutas J., Hedberg A. et al. (1995) Calcium entry block-
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On the other hand, the cytotoxic assays of these derivatives in par-
ticular compound 4b revealed that these compounds can be
assumed as good scaffold for future design as cytotoxic agents
because the results showed that the presence of special group in
specific position can cause a great improvement in cytotoxic
effects.
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Acknowledgments
We gratefully acknowledge financial support from the Islamic Azad
University-South Tehran and also research council of Shiraz Univer-
sity of Medical Sciences.
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