Synthesis of some new 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydrobenzo[h] quinoline-3-carbonitriles and their biological evaluation as cytotoxic and antiviral agents

Article abstract of DOI:10.1007/s12039-011-0184-2

A series of new 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydro-benzo[h] quinoline-3-carbonitriles supported with various pharmacophoric functionalities at position-1 is described. N-formyl, N-nitroso, Narylthiocarbamoyl, N-alkyl, N-sulfonyl, and N-acetyl deri

Full text of DOI:10.1007/s12039-011-0184-2

c
J. Chem. Sci. Vol. 124, No. 3, May 2012, pp. 625–631. ꢀ Indian Academy of Sciences.
Synthesis of some new 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydro-
benzo[h]quinoline-3-carbonitriles and their biological evaluation
as cytotoxic and antiviral agents
HASSAN M FAIDALLAH∗, KHALID A KHAN and ABDULLAH M ASIRI
Department of Chemistry, Faculty of Science, King Abdulaziz University,
P.O. Box 80203 Jeddah 21589, Saudi Arabia
e-mail: hfaidallahm@hotmail.com
MS received 28 February 2011; revised 26 August 2011; accepted 22 September 2011
Abstract. A series of new 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydro-benzo[h]quinoline-3-carbonitriles sup-
ported with various pharmacophoric functionalities at position-1 is described. N-formyl, N-nitroso, N-
arylthiocarbamoyl, N-alkyl, N-sulfonyl, and N-acetyl derivatives, 5–10 were prepared. A novel fused triazole
series was also prepared. The in vitro anticancer activity of twenty synthesized compounds, 4a, 4b, 7a2, 7b2
and 8b1 showed considerable cytotoxic activity against the three tested human tumor cell lines. Compounds
7a2 and 7b2 proved to be the most active with special effect against the human colon carcinoma HT29 and
human breast cancer MCF 7 cell lines. Compounds 7b2 and 7f2 also exhibited significant antivirus activity
against hepatitis-C virus.
Keywords. Synthesis; tetrahydrobenzo[h]quinolines; [1,2,4]triazolo[4,3-a]quinolines; cytotoxic agents;
antiviral agents.
1. Introduction
different electronic, lipophilic and steric environment.
Moreover, it was considered worthwhile to utilize the
N-acetyl derivatives as precursors for the synthesis
of the fused-ring system triazolo[3,4-a]pyridine as an
interesting structural variation, hoping to improve the
anticipated chemotherapeutic activity.
Motivated by these facts, and in continuation of our
interest in studying the synthesis and anticancer activ-
ities of 1,2,5,6-tetrahydrobenzo[h]quinoline analogs it
was also considered of interest to confirm the ability of
these synthesized compounds to inhibit the replication
of the Hepatitis C virus (HCV).
During our ongoing studies aimed at the discovery of
new structure leads endowed with diverse chemother-
apeutic activities,1–9 much concern has been given to
the antimicrobial and antitumor potentials of some
pyridines,10–12 particularly 3-cyano-4,6-disubstituted-
2(1H)-pyridinones. Some of these compounds were
selected by the NCI to be evaluated for their antitu-
mor potentials, where they exhibited promising broad-
spectrum antitumor activity against several subpanel
tumor cell lines. The results prompted further structure
modification of the disubstituted-2(1H)-pyridinone
scaffold by increasing compounds’ lipophilicity via the
synthesis of new 1,2,5,6-tetrahydrobenzo[h]quinoline
analogs. The target compounds were substituted with
formyl, acetyl, nitroso, benzenesulfonyl, thioureido and
alkyl groups at position-1 that are believed to be respon-
sible for the biological activity modulation in some
relevant anticancer agents. The substitution profile of
the main hexahydroquinoline ring was attempted to
comprise some biologically active counterparts such
as the thienyl and substituted phenyl rings, together
with other pharmacophoric groups that would confer
2. Experimental
2.1 General
Melting points were determined on a Gallenkamp melt-
ing point apparatus and were uncorrected. The infrared
(IR) spectra were recorded on Shimadzu FT-IR 8400S
infrared spectrophotometer using the KBr pellet tech-
1
nique. H and 13C NMR spectra were recorded on a
Bruker DPX-400 FT NMR spectrometer using tetram-
ethylsilane as an internal standard and DMSO-d6 as
a solvent (Chemical shifts in δ, ppm). Splitting pat-
terns were designated as follows: s: singlet; d: doublet;
∗For correspondence
625

626
Hassan M Faidallah et al.
m: multiplet; q: quartet. Elemental analyses were per- 15 mmol) in water (5 mL) over a period of 2 h. Stirring
formed on a 2400 Perkin Elmer Series 2 analyzer and was maintained for further 2 h, and then the reaction
the found values were within 0.4% of the theoreti- mixture was left at room temperature overnight. The
cal values. Follow up of the reactions and checking the resulting solid product was filtered, washed with water,
homogeneity of the compounds were made by TLC on dried and recrystallized from ethanol as needles. IR
silica gel-protected aluminum sheets (Type 60 F254, (cm−1): 2226–2215 (CN), 1673–1666 (C=O pyridone).
Merck) and the spots were detected by exposure to
UV-lamp at λ 254. The chalcones 3a–g were prepared
according to a reported procedure.10 Physicochemical
and analytical data of all compounds are listed in a
table S1. 1H NMR and 13C NMR spectral data recorded
are given in tables S2 and S3, respectively as supple-
mentary data.
2.5 3-Cyano-2-oxo-1-(substituted-thiocarbamoyl)-4-
substituted-1,2,5,6-tertahydrobenzo[h] quinolines 7
A mixture of appropriate starting compound 4
(10 mmol) and the appropriate isothiocyanate
(11 mmol) in pyridine (10 ml) was heated under reflux
for 6–8 h. After being cooled to room temperature, the
reaction mixture was poured on ice cold water and
the separated solid product was filtered, washed with
water, dried and recrystallized from ethanol as nee-
dles. IR (cm−1): 2236–2222 (CN), 1675–1668 (C=O
pyridone), 1237–1219 (C=S).
2.2 3-Cyano-2-oxo-4-substituted-1,2,5,6-tetrahydro-
benzo[h]quinolines 4a–f
Method A: A mixture of the appropriate chalcone
3 (10 mmol), ethyl cyanoacetate (1.1 g, 10 mmol) and
ammonium acetate (6.2 g, 80 mmol) in absolute ethanol
(30 m) was heated under reflux for 8 h. After being
cooled to room temperature, the solid product formed
was filtered, washed with water, dried and recrystallized
from the DMF containing few drops of water.
2.6 3-Cyano-1,4-disubstituted-2-oxo-1,2,5,6-tetrahydro-
benzo[h]quinolines 8a–f
To a solution of the appropriate pyridone 4 (10 mmol) in
pyridine (10 ml), was added the appropriate alkyl halide
(10 mmol) and the mixture was heated under reflux for
3–4 h. The reaction mixture was allowed to attain room
temperature, poured on ice cold water and the separated
solid product was filtered, washed with water, dried
and recrystallized from ethanol. IR (cm−1): 2230–2224
(CN), 1678–1672 (C=O pyridone).
Method B: A one-pot mixture of the appropriate
aldehyde 2 (10 mmol), 3,4-dihydro-2H-naphthalene-1-
one 1 (1.46 g, 10 mmol), ethyl cyanoacetate (1.1 g,
10 mmol) and ammonium acetate (6.2 g, 80 mmol) in
absolute ethanol (50 ml) was refluxed for 6 h. The reac-
tion mixture was allowed to cool, and the formed pre-
cipitate was filtered, washed with water, dried and
recrystallized. IR (cm−1): 3388–3263 (NH), 2226–2218
(CN), 1678–1672 (C=O).
2.7 3-Cyano-2-oxo-1-(substituted-sulfonyl)-4-substituted-
1,2,5,6-tetrahydrobenzo[h]quinolines 10 a–f
2.3 3-Cyano-1-formyl-2-oxo-4-substituted-1,2,5,6-tetra-
hydrobenzo[h]quinolines 5a–f
A mixture of the appropriate start 4 (10 mmol) and
appropriate sulfonyl chloride (10 mmol) in pyridine
(10 ml) was heated under reflux for 4–6 h. After cooling
to room temperature, the reaction mixture was poured
on crushed ice and the separated solid product was
filtered, washed with water, dried and recrystallized
from ethanol. IR (cm−1): 2236–2224 (CN), 1676–1668
(C=O pyridone), 1378–1372 and 1198–1172(SO2).
A solution of the appropriate pyridinone 4 (3 mmol)
in formic acid (5 ml) was heated under reflux for 3 h.
The reaction mixture was poured on crushed ice (10 g)
and the separated solid product was filtered, washed
with water, dried and recrystallized from ethanol as nee-
dles. IR (cm−1): 2214–2208 (CN), 1676–1672 (C=O
pyridone), 1665–1660 (C=O aldehyde).
2.8 1-Acetyl-3-cyano-2-oxo-4-substituted-1,2,5,6-tetra-
2.4 3-Cyano-1-nitroso-2-oxo-4-substituted-1,2,5,6-tetra- hydrobenzo[h]quinolines 11a–f
hydrobenzo[h]quinolines 6a–f
To a solution of the appropriate 4 (10 mmol) in
To an ice-cooled stirred solution of the appropriate acetic anhydride (10 ml), was added anhydrous sodium
starting material 4 (10 mmol) in acetic acid (15 ml), was acetate (1.2 g, 15 mmol). The reaction mixture was
added drop-wise, a solution of sodium nitrite (1.05 g, refluxed for 4 h, cooled, and then poured on crushed

Biological evaluation as cytotoxic and antiviral agents
627
ice with vigorous stirring. The resulting solid prod- statistical significance was tested between samples and
uct was filtered, thoroughly washed with water, dried negative control (cells with vehicle) using independent
and recrystallized from aqueous ethanol. IR (cm−1): t-test by SPSS 11 program. The percentage change in
2231–2218 (CN), 1727–1722 (C=O acetyl), 1674– viability was calculated according to the formula:
1666 (C=O pyridone).
[Reading of the sample/(Reading of the negative
control − 1)] × 100
2.9 4-Cyano-1-methyl-5-Substituted-6,7-diydro[1,2,4]
triazolo[4,3-a]benzo[h]quinolines 12a–f
A probit analysis was carried for LC50 determinations
using SPSS 11 program.
A mixture of the appropriate 1-acetylpyridinone 11
(10 mmol) and hydrazine hydrate (0.9 g, 15 mmol) in
ethanol (15 ml) was heated under reflux for 6–8 h. The
reaction mixture was allowed to attain room tempera-
ture, poured on crushed ice and the precipitated solid
product was filtered, washed with water, dried and rec-
rystallized from DMF/water. IR (cm−1): 2226–2218 (CN).
3.2 In vitro effect on the replication of hepatitis-C virus
in HCV-infected HepG2 hepatocellular carcinoma cell
line
Fifteen compounds were selected and tested by the
Genetic Engineering and Biotechnology Research Insti-
tute (GEBRI), Mubarak City for Science and Technol-
ogy Applications, Alexandria, Egypt.
3. Biological evaluation
3.1 In vitro MTT cytotoxicity assay
3.2a Cell Culture and RNA Extraction: HepG2
cells were washed twice in EMEM media supple-
mented with 200 μM L-Glutamine, 100U Penicillin,
100 μg streptomycin and 25 μM HEPES buffer; N-
[2-hydroxyethyl]piperazine-Nꢁ-[2-ethanesulfonic acid]
(Bio Whittaker, USA). The cells were suspended in
EMEM Culture media and then were left to adhere on
polystyrene 6-well plates for 24 h in 37◦C, 5% CO2,
95% humidity incubator. The cells were washed twice
from debris and dead cells using EMEM media and then
infected with 2% HCV-infected serum in EMEM cul-
ture medium with 8% FBS. Each of the tested com-
pounds was added at concentrations of 10, 25, 50, and
100 μg/mL. Positive and negative control cultures were
included. After 96 h incubation another dose of the test
compound was added and the cells were further incu-
bated for another 96 h. The RNA was extracted follow-
ing a method reported by El-Awady et al.15 The
positive strand and its replicating form (negative strand)
of HCV were detected by RT-PCR using specific
primers to the 5ꢁ-untranslated region of the virus.
All the procedures were done in a sterile area using
a Laminar flow cabinet biosafety class II level (Baker,
SG403INT, Stanford, ME, USA). Cells were batch cul-
tured for 10 days, then seeded at concentration of
10 × 103 cells/well in fresh complete growth medium
in 96-well microtiter plastic plates at 37◦C for 24 h
under 5% CO2 using a water jacketed carbon diox-
ide incubator (Sheldon, TC2323, Cornelius, OR, USA).
Media was aspirated, fresh medium (without serum)
was added and cells were incubated either alone (neg-
ative control) or with different concentrations of the
test compounds to give a final concentration of (100,
50, 25, 12.5, 3.125, 1.56, 0.78 μg/mL). DMSO was
employed as a vehicle for dissolution of the tested com-
pounds and its final concentration on the cells was
less than 0.2%. Cells were suspended in RPMI 1640
medium (for HePG2 and HT29 cell lines) and DMEM
(for MCF 7 cell line), 1% antibiotic-antimycotic mix-
ture (10,000 IU/mL penicillin potassium, 10,000 μg/mL
streptomycin sulphate and 25 μg/mL amphotericin B),
and 1% L-glutamine in 96-well flat bottom microplate
at 37◦C under 5% CO2.
After 48 h of incubation, the medium was aspirated,
40 μL of MTT salt (2.5 μg/mL) were added to each
well and incubated for further 4 h at 37◦C under 5%
4. Results and discussion
CO2. To stop the reaction and dissolve the formed crys- 4.1 Chemistry
tals, 200 μL of 10% sodium dodecyl sulphate (SDS) in
The synthetic strategies adopted for the preparation
deionized water was added to each well and incubated
overnight at 37◦C. The absorbance was then measured
using a microplate multi-well reader (Bio-Rad Labora-
tories Inc., model 3350, Hercules, California, USA) at
of the intermediate and target compounds are described
in schemes 1 and 2. In scheme 1, TWO synthetic
pathways were adopted to synthesize the target tetra-
hydrobenzo[h]quinolines 4 according to a reported
595 nm and a reference wavelength of 620 nm.13,14
A

628
Hassan M Faidallah et al.
procedure.10 The first method involved the forma- the synthesis of the target compounds in the second
tion of the 2-arylidene-3,4-dihydro-2H-naphthalen-1- part (scheme 2). In this respect, heating 4 with formic
one 3 (chalcones) via Claisen–Schmidt condensation acid resulted in the formation of the N-formyl deriva-
of the appropriate aryl or heteroaryl aldehydes 2 tives 5. Whereas, reacting 4 with sodium nitrite in
with 3,4-dihydro-2H-naphthalene-1-one 1. These chal- the presence of cold acetic acid yielded the N-nitroso
cones 3a–d, in their turn, were allowed to react with derivatives 6.
ethyl cyanoacetate and ammonium acetate to yield
Condensation of 4 with the appropriate aryl isoth-
the target 2-oxo-1,4-disubstituted-1,2,5,6-tetrahydro- iocyanate in alkaline medium afforded the correspond-
benzo[h]quinoline-3-carbonitriles 4a–d. On the other ing N-arylthiocarbamoyl analogs 7. The IR spectra of
hand, the same compounds 4 could be directly pre- these compounds showed C=S absorption at 1240–
pared via one-pot multicomponent reaction (MCR) of 1222 cm−1 as well as a C=O and CN absorptions
the 3,4-dihydro-2H-naphthalene-1-one 1, the aldehydes in the regions of 1672–1667 and 2236–2218 cm−1.
1
2, an excess of ammonium acetate and ethyl cyanoac- The structures were further supported by H NMR
etate in boiling ethanol. Such type of reactions has data. Furthermore, when compounds 4 were alkylated
received considerable interest since it is easier to per- with the appropriate alkyl halide in the presence
form, gives higher yields and less time consuming. of sodium hydroxide, the targeted N-alkyl tetrahy-
Therefore, a comparison of the data obtained from the drobenzo[h]quinolines 8 were formed, but in low
above-mentioned synthetic methods revealed that the yields. However, better yields were obtained when the
one-pot reaction was better in terms of yield percent- reaction was carried out in pyridine as a basic solvent.
age. The IR spectra of the tetrahydrobenzo[h]quinolines
At this stage, it was thought of interest to study
4a–d exhibited absorption bands at 2248–2218 cm−1 the effect of applying different alkylating conditions
and 1678–1665 cm−1 for the CN and CO groups, on such type of compounds. In this respect, com-
respectively. Their structure was further confirmed from pounds 4 were treated with the same alkyl halides in
1
their H NMR which showed beside the aromatic pro- the presence of ethanolic silver nitrate16 or sodium
tons two multiplets at δ2.26–2.88 and 2.54–2.90 ppm ethoxide17,18 as basic catalysts in an attempt to obtain
corresponding to the H-5 and H-6 respectively.
the O-alkyl derivatives 9, nevertheless, such method
The tetrahydrobenzo[h]quinolines 4a–d obtained failed to produce the targeted compounds. On the other
from scheme 1 were utilized as key intermediates for hand, reacting compounds 4 with substituted sulfonyl
O
O
+
H
R
2a-d
CNCH COOC H ,
2
2 5
1
CH COONH
3
4
EtOH, reflux,
3-6h (one pot)
KOH, EtOH
r.t., 6-8h
R
O
CN
CNCH COOC H , CH COONH
4
2
2
5
3
R
EtOH, reflux, 6-8h
N
H
O
3a-d
4a-d
2, 3 and 4: R = a: C H ; b: 4-BrC H ; c: 4-CH OC H d: 3,4-(CH O) C H ;
6
5
6
4
3
6
4;
3
2 6 3
e: 3,4-(OCH O)C H f: 2-thienyl
2
6 3;
Scheme 1. Synthesis of 3-Cyano-2-oxo-4-substituted-1,2,5,6-tetrahydrobenzo[h]quinolines.

Biological evaluation as cytotoxic and antiviral agents
629
R
N
R
R
N
CN
CN
O
CN
O
O
H
N
NO
S
N
H
O
1
R
6
5
7
2
R NCS,
NaNO ,
2
pyridine,
AcOH,
HCOOH,
reflux, 3h
o
reflux,
6-8h
zero C,
2h
R
N
R
R
2
R X, EtOH,
CN
O
CN
CN
2
AgNO or NaOC H ,
reflux, 3-10h
3
2 5
R X, pyridine,
reflux, 3-4h
2
R
N
9
O
N
H
O
2
R
8
4
acetic anhydride,
anhyd. sod. acetate,
reflux, 4h
benzenesulfonyl chloride,
pyridine, reflux, 4-6h
R
R
N
R
CN
CN
CN
hydrazine hydrate
N
O
EtOH, reflux,
6-8h
O
N
N
O S
2
3
R
N
O
10
11
12
4-6,11 and 12: R = a: C6H5; b: 4-BrC6H4; c: 4-CH3OC6H4; d: 3,4-CH3O)2C6H3;e: 3,4-(OCH2O)C6H3;
f: 2-thienyl
7,8 and 10: R = a1- a3: C6H5; b1- b3: 4-BrC6H4; c1- c3: 4-CH3OC6H4; d1- d3: 3,4-(CH3O)2C6H3;
e1- e3: 3,4-(OCH2O)C6H3; f1- f3: 2-thienyl
7a1-f1, R1 = C6H5; 7a2-f2, R1 = 4-ClC6H4
8a1-f1, R2 = CH3; 8a2-f2, R2 = C2H5
10a1-f1, R3 = CH3; 10a2-f2, R3 = C6H5; 10a3-f3, R3 = 4-CH3C6H4
Scheme 2. Synthesis of 3-Cyano-1,4-disubstituted-2-oxo-1,2,5,6-tetrahydrobenzo[h]quinolines.
chlorides in the presence of pyridine resulted in 2,5-diphenyltetrazolium bromide) method13,14 against a
the introduction of a substituted sulfonyl moiety at panel of three human tumor cell lines namely; Cau-
position-1 to yield compounds 10. Warming the starting casian breast adenocarcinoma MCF7, hepatocellular
compounds 4 with acetic anhydride in the presence of carcinoma HePG2 and colon carcinoma HT29. The
anhydrous sodium acetate afforded the N-acetyl deriva- results are presented in table 1 as LC50 (μM) which is
tives 11. In their turn, when compounds 10 were reacted the lethal concentration of the compound which cause
with hydrazine hydrate, the targeted 5,6-dihydro- death of 50% of the cells in 24 h.
benzo[h][1,2,4]triazolo[3,4-a]quinolines 12 were suc-
cessfully obtained.
The obtained data revealed that, the three tested
human tumor cell lines exhibited variable degree of
sensitivity profiles towards twelve of the tested com-
pounds namely; 4a–b, d, 5a–b, 7a2–b2, 8a1–b1, f1,
10b2 and 11a. Among these, the human colon car-
cinoma HT29 cell line showed pronounced sensitiv-
ity against compounds 7a2 and 7b2 with LC50 values
of 9.2 and 8.3 μM, respectively. Moreover, a remark-
able cytotoxic potential was displayed by compound
8b1 against the same cell line (13.1 μM). Meanwhile,
4.2 In vitro MTT cytotoxicity assay
Twenty analogs namely; 4a–f, 5a–b, 6a–b, 7a1–a2, b2,
8a1–b1, f1, 10a1–b2, 11a–b, and 12a were selected
to be evaluated for their in vitro cytotoxic effect
via the standard MTT (3-(4,5-dimethylthiazol-2-yl)-

630
Hassan M Faidallah et al.
Table 1. Cytotoxic effects (LC50; μM)a of the active compounds on some human
tumor cell lines using the MTT assay.
Compd
no.
Human colon
carcinoma HT29
Human hepatocellular
carcinoma HePG2
Human breast
cancer MCF 7
4a
4b
4d
5a
5b
7a2
7b2
8a1
20.7
18.4
76.8
40.9
34.7
9.2
37.8
25.4
–
40.3
46.8
22.9
21.5
48.5
31.6
–
47.6
33.8
–
b
–
52.8
3.1
2.2
63.4
10.1
–
–
–
2.14
8.3
55.5
13.1
83.2
64.4
76.2
12.1
8b1
8f1
10b2
46.8
–
1.69
11a
Doxorubicinc
aLC50: Lethal concentration of the compound which causes death of 50% of cells in
24 h (μM).
bTotally inactive against this cell line.
cPositive control cytotoxic agent
compounds 4a and 4b revealed an obvious cytotoxicity member in this study with a broad spectrum of activity
profile against colon carcinoma HT29 with LC50 values against the tested cell lines, with special effectiveness
20.7and 18.4 μM, respectively.
against the human colon carcinoma HT29 and human
Moreover, compounds 5a, 5b, 8a1 and 10b2 were breast cancer MCF 7 cell lines (LC50 values 8.3 and
able to exhibit moderate activity against the same cell 2.2 μM, respectively) (table 1). A close examination of
line with LC50 values range of 34.7–64.4 μM. Whereas, the structure of the active compounds showed that the
mild activity was displayed by compounds 4d, 8f1 and 4-bromophenyl counterpart at position-4 of the tetrahy-
11a at LC50 range of 76.2–83.2 μM. Furthermore, the drobenzo[h]quinoline skeleton is the most favourable
growth of the human hepatocellular carcinoma HePG2 substituent when compared with other analogs. More-
cell line was found to be moderately inhibited by nine over, the thiocarbamoyl substituent at position-1 (as
of the active compounds namely; 4a–b, 5a–b, 7a2, b2, in compounds 7a2 and 7b2) was responsible for the
8a1, b1 and10b2, with LC50 values range of 21.5– high activity displayed by these analogs. Substitution
48.5 μM. Among these, the highest cytotoxic activ- at position-1 with an aldehyde, alkyl, alkylsulfonyl or
ity was displayed by compounds 4b, 7a2 and 7b2 acetyl functionalities resulted in moderate to weakly
which were almost equipotent (LC50 values 25.4, 22.9 active compounds (5, 8, 10 and 11), whereas cycliza-
and 21.5 μM, respectively). On the other hand, human tion of the acetyl compounds 11 to the bicyclic 6,7-
breast cancer MCF 7 was proved to be the least sensitive dihydro[1,2,4]triazolo[3,4-a]benzo[h]quinolines 12 led
among the cell lines tested as it was affected by only to complete abolishment of activity.
seven of the test compounds. However, an outstanding
growth inhibition potential was shown by compounds
7a2, 7b2 and 8b1 as evidenced from their LC50 val-
ues (3.1, 2.2 and 10.1 μM, respectively). The rest four
active compounds namely 4a, 4b, 5b and 8a1 showed
moderate to mild activity against the same cell line with
LC50 values of 47.6, 33.8, 52.8 and 63.4 μM, respec-
tively (table 1). Further interpretation of the results
revealed that, compounds 4a, 4b, 7a2, 7b2 and 8b1
showed considerable broad spectrum of cytotoxic activ-
ity against the three tested human tumor cell lines. In
particular, compound 7b2 proved to be the most active
4.3 Antiviral activity
Compounds 4a,b,d,f, 5d, 6b,d, 7b2,d2,f2, 8b1,d1,f1,
11a and 12d were investigated for their in vitro effect
on the replication of hepatitis-C virus in HepG2 hep-
atocellular carcinoma cell line infected with the virus.
Out of these compounds only two derivatives 7b2 and
7f2 were able to inhibit the hepatitis-C virus RNA (+)
and (−) strands at 10–100 μg/mL concentration range.

Biological evaluation as cytotoxic and antiviral agents
631
The rest of the series were either inactive or exhibited Research Center (NRC), Cairo, Egypt, for their efforts
insignificant activity.
in performing the MTT cytotoxicity assay.
References
5. Conclusion
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The present paper describes the synthesis of new 2-oxo-
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found to increase the activity and on the other hand,
N-arylthiocarbamoyl group on position-1 depicted
a significant enhancement in the anticancer activ-
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to complete abolishment of activity. Out of 15 com-
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Acknowledgements
The authors are thankful to the authorities of the
Bioassay-Cell Culture laboratory, in vitro bioassays on
human tumor cell lines for drug discovery unit, National