Anti-HIV-1 screening of (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1- (aryl)prop-2-en-1-ones

Article abstract of DOI:10.1007/s00044-013-0652-y

Biological studies of two series of 38 quinolinyl chalcones (4a-s and 5a-s) were investigated for their in vitro anti-HIV-1 and cytotoxic activities. Out of 38 compounds, seventeen compounds were observed as good anti-HIV-1 agents with EC₅₀ values less than 20 μM. Compounds 4a, 4l, 4o, 5e, 5h, 5l, 5o, and 5r displayed potent anti-HIV-1 activity with EC₅₀ values less than 5 μM. Among these, compound 5h emerged as the best anti-HIV-1 agent (EC₅₀ = 1.1 μM). Compounds 4d, 4n, 4q, 4r, 4s, 5n, and 5r showed no toxicity in human lymphocytes. Bioassay results show that the type(s) and position(s) of the substituents seem to be critical for their cytotoxic and anti-HIV-1 activities. These results could be useful in the invention of new anti-HIV agents through structural modification.

Full text of DOI:10.1007/s00044-013-0652-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0652-y
ORIGINAL RESEARCH
Anti-HIV-1 screening of (2E)-3-(2-chloro-6-methyl/
methoxyquinolin-3-yl)-1-(aryl)prop-2-en-1-ones
•
•
Syed Umar Farooq Rizvi Matloob Ahmad Mujahid Hussain Bukhari
•
•
Catherine Montero Payel Chatterjee Mervi Detorio Raymond F. Schinazi
•
•
Received: 5 March 2013 / Accepted: 25 May 2013
Ó Springer Science+Business Media New York 2013
Abstract Biological studies of two series of 38 quinoli-
nyl chalcones (4a–s and 5a–s) were investigated for their
in vitro anti-HIV-1 and cytotoxic activities. Out of 38
compounds, seventeen compounds were observed as good
anti-HIV-1 agents with EC50 values less than 20 lM.
Compounds 4a, 4l, 4o, 5e, 5h, 5l, 5o, and 5r displayed
potent anti-HIV-1 activity with EC50 values less than
5 lM. Among these, compound 5h emerged as the best
anti-HIV-1 agent (EC50 = 1.1 lM). Compounds 4d, 4n,
4q, 4r, 4s, 5n, and 5r showed no toxicity in human lym-
phocytes. Bioassay results show that the type(s) and
position(s) of the substituents seem to be critical for their
cytotoxic and anti-HIV-1 activities. These results could be
useful in the invention of new anti-HIV agents through
structural modification.
Introduction
Human immunodeficiency virus has been a continuous
threat to human beings. It has resulted in the deaths of
millions of people across the globe. Currently, highly
active antiretroviral therapy (HAART) is being used for its
treatment, and it has turned HIV infection from fatal
infection to the chronic disease (Coffin et al., 1986;
De Clercq, 2006, 2007a, b). HAART uses a combination of
various antiviral drugs that inhibit the viral growth at dif-
ferent stages of its life cycle (Gallant et al., 2006; Pozniak
et al., 2006). There is continuous need for the development
of new drugs as the virus may develop resistance. In the
studies of inhibitory effects of chalcones against plant
viruses and human rhinoviruses, the antiviral property of
chalcones was exploited. The antiviral efficacy is known to
depend on the substitution patterns (Nowakowska, 2007).
Xanthohumol (Fig. 1) has been reported as an inhibitor of
HIV-1 with EC50 value of 0.50 lg/ml (Wang et al., 2004).
Similarly, chalcone extracted from the genus Desmos
Keywords Heterocyclic compounds ꢀ
Quinolyl chalcones ꢀ Arylketone ꢀ Cytotoxicity ꢀ
Anti-HIV-1 activity
(Fig. 1) exhibited potent anti-HIV activity with EC50
=
0.022 lg/ml (Wu et al., 2003).
This work is dedicated to the Late Professor Dr. Hamid Latif
Siddiqui, Institute of Chemistry, University of the Punjab, Lahore,
Pakistan.
Chalcones (1,3-diaryl-2-propen-1-ones) constitute an
important class of natural or synthetic compounds
belonging to the flavonoids family and are known to
exhibit a broad spectrum of various biological activities.
The presence of a,b-unsaturated carbonyl moiety as well as
of substituted aromatic rings renders the chalcones bio-
logically active. Some substituted chalcones and their
heterocyclic derivatives are reported to inhibit the growth
of microbes (Sato et al., 1997, Bukhari et al., 2012) and
malarial parasites (Henry, 1973). Many chalcones have
been claimed to be toxic to various animals (Jeney et al.,
1955) and have also shown inhibitory effects on sev-
eral enzymes (Hase et al., 1973) and herbaceous plants
S. U. F. Rizvi ꢀ M. H. Bukhari
Institute of Chemistry, University of the Punjab,
Lahore 54590, Pakistan
M. Ahmad (&)
Department of Chemistry, Government College University,
Faisalabad 38000, Pakistan
e-mail: matloob_123@yahoo.com
C. Montero ꢀ P. Chatterjee ꢀ M. Detorio ꢀ R. F. Schinazi
Department of Pediatrics, Center for AIDS Research,
The Veterans Affairs Medical Center, Emory University
School of Medicine, Decatur, GA 30033, USA
123

Med Chem Res
Fig. 1 Structures of anti-HIV
chalcones: xanthohumol (1),
and the one extracted from the
genus Desmos (2)
OH
O
HO
OH
O
O
OH
O
O
OH
OH
(1)
(2)
Fig. 2 Structures of potent
antiviral drugs, AZT, and
aplaviroc
O
N
NH
HOOC
N
O
O
H
O
N
O
O
N
H
O
N3
AZT, Zidovudine (I)
OH
Aplaviroc (II)
(Cross, 1975). Major biological activities which have been
reported to be associated with chalcones include anti-
inflammatory (Ballesteros et al., 1995), antifungal (Go
et al., 2005), antioxidant (Arty et al., 2000), antimalarial
(Narender et al., 2005), antileishmanial (Boeck et al.,
2006), antituberculosis (Sivakumar et al., 2005), analgesic
(Viana et al., 2003), anti-HIV (Tiwari et al., 1989), anti-
tumor (Tiwari et al., 1989; Xia et al., 2000), and cytotoxic
(Champelovier et al., 2011).
Materials and methods
General synthesis of compounds (4a–s and 5a–s) was
carried out from substituted anilines using Vilsmeier–
Haack reaction conditions as depicted in Fig. 3 and have
been reported previously by our group (Rizvi et al., 2010).
The synthesized compounds were screened for their
in vitro antiviral effects in human peripheral blood mono-
nuclear (PBM) cells according to our standardized assay
(Schinazi et al., 1990). Cells obtained from LifeSouth
Community Blood Centers (Atlanta, GA) were isolated by
Histopaque (Sigma-Aldrich, St. Louis, MO) and discon-
tinuous gradient centrifugation from healthy seronegative
donors. The median effective concentration (EC50) was
determined using a reported method (Belen’kii and
Schinazi 1994). Assays were conducted using at least two
different donor cells in duplicate or triplicate. The results
are presented in Table 2.
Our previous studies have exhibited that quinoline-
based chalcones display antimicrobial (Rizvi et al., 2010),
antileishmanial (Rizvi et al., 2010, 2012a), anti HIV-1
cytotoxic (Rizvi et al., 2012b), and anti-angiogenic activ-
ities (Rizvi et al., 2012c). The present study was designed
to further investigate the in vitro anti-HIV-1 and cytotox-
icity in two series (4a–s and 5a–s) of quinolyl chalcones.
Heterocyclic skeleton plays a key role in the antiviral
activity as is depicted by the structures of various antiviral
drugs, e.g., Zidovudine (I) and Aplaviroc (II) (Fig. 2).
Keeping in view the potential of heterocyclic ring sys-
tem and chalcones in the antiviral activity, we planned to
synthesize the titled chalcones having diversified structural
features. The chalcones thus prepared are based on quin-
oline ring system, and they bear a range of substituted
thiophene and furan moieties. The hypothesis of this
research was based on the assumption that quinoline- and
thiophene-synergized molecules bearing chalcone func-
tionalities are expected to be potent HIV inhibitors. This
study resulted in the discovery of 20 new anti-HIV agents
(Table 1).
All the titled compounds were also evaluated for cyto-
toxicity in human PBM, CEM, and Vero cells, to determine
their spectrum of toxicity. CEM cells are a line of lym-
phoblastic cells originally derived from a child with acute
lymphoblastic leukemia whereas; Vero cells are derived
from African Green monkey kidney cells. These cells (i.e.,
PBM, CEM, and Vero cells) were cultured in 96-well
plates (5 9 104 cells per well) along with increasing con-
centrations of the test compound (Stuyver et al., 2002).
Cell viability was measured after 5-day incubation period
using the Cell Titer 96 Aqueous One Solution cell prolif-
eration assay (Promega, Madison, Wis.) by incubating in
123

Med Chem Res
Table 1 Aryl moiety (Ar) of aromatic ketones (4a–s and 5a–s)
O
R
Ar
N
Cl
(4a-s) and (5a-s) 4: R = Me 5: R = OMe
Chalcones
a
Ar
Chalcones
g
Ar
Chalcones
m
Ar
S
O
S
Cl
Cl
CH3
S
Cl
H3C
CH3
S
O
b
h
n
H3C
S
S
O
c
d
e
i
o
p
q
CH3
Br
O
O
S
S
CH3
Br
j
H3C
CH3
S
S
I
k
S
H
N
f
l
r
s
Cl
an incubator at 37 °C with 5 % CO2 for human PBM cells.
The results are also summarized in Table 2.
the series 4a–s, it is observed that incorporation of elec-
tron-donating substituents (by mesomeric effect) to the
thiophenyl ring shows activity comparable to 4a. For
example, compounds 4b, 4c, 4d, and 4e that have methyl
substitutions at various positions show comparable potency
to unsubstituted compound 4a against HIV-1. However, a
substitution that is electron withdrawing by inductive effect
at ortho position reduces the anti-HIV-1 activity drasti-
cally, as is the case with 4f (bearing ortho chloro substi-
tution) EC50 value [100 lM. Our analogy for loss of
potency is that halogens are electron withdrawing by
inductive effect and are electron donating by resonance
Results and discussion
The results (Table 2) indicated that the chalcones derived
from unsubstituted thienyl derivatives (4a and 5a) were
shown to demonstrate good anti HIV-1 activity
(EC50 = 5.3 and 9.5 lM, respectively). Thus, introduction
of diversified substitution pattern resulted in the estab-
lishment of interesting structure–activity relationship. In
123

Med Chem Res
Fig. 3 Schematic lay-out for
the synthesis of chalcone
compounds (4a–s and 5a–s)
R
R
R
(i)
(ii)
O
NH2
N
O
N
Cl
O
H
(1a-b)
(3a-b)
(2a-b)
(iii)
a
=
H
C
R
;
3
=
b R OCH3
;
R
r
A
N
l
C
4a-s; R = CH3
5a-s; R = OCH3
Reagents; (i) glacial acetic acid, o-
H P
ArCOCH3/NaOH(aq), EtOH
O4
(ii) DMF/POCl3 (iii)
3
Table 2 Anti-HIV-1 activity in human PBM cells (EC50) and cyto-
toxic activities in PBM, CEM, and vero cells (IC50) of the series
4a–s and 5a–s
Table 2 continued
Anti-HIV-1 activity in human PBM cells
Cytotoxicity
(IC50, lM) in
Anti-HIV-1 activity in human PBM cells
Cytotoxicity
(IC50, lM) in
Code
EC50 (lM)
EC90 (lM)
PBM CEM Vero
5i
8.1
[10
[10
3.8
[10
[10
[10
20.0
26.4
[100
12.0
[10
38.7
20.8
53.8
2.5
8.3
9.5
Code
EC50 (lM)
EC90 (lM)
PBM CEM Vero
5j
17.3
23.7
1.7
31.6
71.6
4.7
13.2
17.6
16.4
22.9
AZT
4a
4b
4c
4d
4e
4f
0.0033 0.022
5.3
0.030 0.015 [100 14.3
56.0
4.8
5k
5l
35.0
22.7
[10
[100
18.7
[100
13.0
29.1
[10
[10
[10
11.5
16.3
[100
5.5
10.7
25.3
42.9
55.4
13.0
15.8
25.7
10.6
16.1
16.3
32.0
19.9
10.8
3.2
8.3
82.1
66.5
5m
5n
5o
5p
5q
5r
5s
5.4
4.5
15.7
[10
24.4
7.3
C100 64.2
[100
2.7
[100 [100 [100
4.4
69.1
2.4
3.4
10.8
31.6
31.6
13.7
12.1
14.9
11.6
31.6
31.6
11.9
31.6
31.6
61.1
4.9
[10
5.7
14.2
23.2
[100
5.7
95.4
48.2
16.9
87.9
15.5
9.8
4g
4h
4i
3.8
[100 [100 52.0
10.2 9.8 15.6
9.8
8.0
[10
[10
[10
4.9
4j
4k
4l
effect. Therefore, halogens at the ortho position dominate
the inductive effect, and as a result, the net effect of the
substituents is electron withdrawing, reducing the potency
against HIV-1. However, halogen substitution at meta and
para positions exhibited activity comparable with 4a, e.g.,
4g and 4h. Similarly, the unsubstituted pyrrole ring dem-
onstrated antiviral activity comparable with 4a with EC50
value of 4.9 lM. Interestingly, the similar behavior is
observed for compound 4o (containing unsubstituted ben-
zofuran ring) which displayed EC50 value of 3.2 lM
(Fig. 4).
11.6
13.3
4m
4n
4o
4p
4q
4r
4s
6.6
14.0
50.6
3.2
[100 [100 [100
4.8
5.5
17.3
15.5
13.0
35.8
20.9
9.1
[10
[100
37.4
10.5
9.5
[10
[100
100
43.7
16.5
[100 16.7
[100 22.6
33.3
44.5
[10
[10
[10
4.5
83.0
14.0
47.8
15.5
13.0
3.9
2.9
5a
5b
5c
5d
5e
5f
1.8
[10
[10
[10
1.4
10.6
15.0
14.7
1.6
82.9
31.6
45.9
8.9
For quinolinyl chalcones 5a–s bearing methoxy substi-
tution at the quinoline ring system, very interesting and
encouraging results were obtained. Compounds 5a, 5l, and
5o having no substituent on ring B, i.e., thiophene, pyrrole,
and benzofuran ring displayed good biological activity
with EC50 values of 9.5, 3.8, and 2.7 lM, respectively.
7.9
[10
[10
6.2
14.6
20.8
2.7
2.3
14.2
11.6
4.6
5g
5h
[10
1.1
31.6
6.5
123

Med Chem Res
Fig. 4 Anti-HIV-1 activity of
quinolinyl chalcones having
unsubstituted ring B (thiophene,
pyrrole, and benzofuran,
respectively)
O
O
S
N
Cl
HN
N
Cl
4a; EC50 = 5.3µM
= 4.9µM
4l; EC50
O
O
N
Cl
4o; EC50 = 3.2µM
Fig. 5 Structure of the most
potent anti-HIV-1 agents 5e and
5h, among the titled chalcones
Cl
O
O
S
S
N
Cl
Cl
N
Cl
5e; EC50 = 1.4µM
= 1.1µM
5h; EC50
Compounds 5e and 5h having 2,5-dimethyl and 2,5-di-
chlorothiophenyl moieties demonstrated the most potent
biological activity with EC50 values of 1.4 and 1.1 lM,
respectively (Fig. 5).
potent against HIV-1 at EC50 less than 10 lM and signifi-
cant cytotoxicity at active concentrations, especially at or
less than the antiviral concentrations. Compounds 4o, 5e,
5h, and 5o demonstrated the most potent anti-HIV-1
activity (EC50 = 1.1, 1.4, 2.7, and 3.2 lM, respectively),
however, with high toxicity less than 5 lM in human PBM
cells. This compounds may serve as a lead for further anti-
HIV drug development.
Among the compounds under investigation, the unsub-
stituted thiophene derivatives (4a and 5a) showed cyto-
toxicity in all three types of cells (i.e., PBM, CEM, and
Vero cells). Methyl- and halo-substituted derivatives at
position 3 (4b, 4f, 4i, 5b, 5f, and 5i) and position 5 (4d, 4g,
4j–k, 5d, 5g, and 5j–k), and the chalcone 4d proved to be
nontoxic in human PBM cells, while 4b, 4k, and 5k
showed no toxicity in CEM cells and 4b, 4d, 4f, 4i, and 5b
exhibited no cytotoxicity in Vero cells. The disubstituted
thiophene derivatives (4e, 4h, 5e, and 5h) were found to be
toxic in all three types of cells. Similarly, pyrrole-,
5-methyl furan-, benzofuran-, and benzodioxane deriva-
tives (4l/5l, 4m/5m, 4o/5o, and 4p/5p, respectively) were
cytotoxic to all three types of cells used. In case of naph-
thalene derivatives, compound (5q) proved to be cytotoxic,
while 5r was nontoxic against all three types of cells.
Finally, in case of anthracene derivatives of chalcones,
compound (4s) was proven to be nontoxic in human PBM
cells.
Acknowledgments The authors (SUFR, MA, and MHB) are
grateful to the Higher Education Commission, Pakistan and the
Institute of Chemistry, University of the Punjab, Lahore, for their
financial assistance. The authors are also thankful to the International
Centre for Chemical and Biological Sciences, HEJ Research Institute
of Chemistry, University of Karachi, Karachi, for spectral measure-
ments. This study was also supported in part by the NIH Grant 2P30-
AI-050409 and the Department of Veterans Affairs (to RFS).
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