Synthesis and investigations into the anticancer and antibacterial activity studies of β-carboline chalcones and their bromide salts

Article abstract of DOI:10.1016/j.bmcl.2018.03.033

A series of sixteen β-carbolines, bearing chalcone moiety at C-1 position, were prepared from easily accessible 1-acetyl-β-carboline and various aldehydes under basic conditions followed by N²-alkylation using different alkyl bromides. The prepared compounds were evaluated for in vitro cytotoxicity against a panel of human tumor cell lines. N²-Alkylated-β-carboline chalcones 13a-i represented the interesting anticancer activities compared to N²-unsubstituted β-carboline chalcones 12a-g. Off the prepared β-carbolines, 13g exhibited broad spectrum of activity with IC₅₀ values lower than 22.5 μM against all the tested cancer cell lines. Further, the N²-alkylated-β-carboline chalcone 13g markedly induced cell death in MDA-MB-231 cells by AO/EB staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48. Additionally, the prepared β-carboline chalcones displayed moderate antibacterial activities against tested bacterial strains.

Full text of DOI:10.1016/j.bmcl.2018.03.033

Accepted Manuscript
Synthesis and Investigations into the Anticancer and Antibacterial Activity
Studies of β-Carboline Chalcones and their Bromide Salts
P.O. Venkataramana Reddy, M. Hridhay, Kumar Nikhil, Shahid Khan, P.N. Jha,
Kavita Shah, Dalip Kumar
PII:
S0960-894X(18)30222-1
https://doi.org/10.1016/j.bmcl.2018.03.033
BMCL 25687
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
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7 March 2018
12 March 2018
Please cite this article as: Venkataramana Reddy, P.O., Hridhay, M., Nikhil, K., Khan, S., Jha, P.N., Shah, K., Kumar,
D., Synthesis and Investigations into the Anticancer and Antibacterial Activity Studies of β-Carboline Chalcones
and their Bromide Salts, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.
2018.03.033
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Bioorganic & Medicinal Chemistry Letters
Synthesis and Investigations into the Anticancer and Antibacterial Activity
Studies of β-Carboline Chalcones and their Bromide Salts
Venkataramana Reddy P Oa, Hridhay Ma, Kumar Nikhilb, Shahid Khanc, P N Jhac, Kavita Shahb, and Dalip
Kumara,
a aDepartment of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India.
bPurdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
cDepartment of Biological Sciences, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of sixteen β-carbolines, bearing chalcone moiety at C-1 position, were prepared from
easily accessible 1-acetyl-β-carboline and various aldehydes under basic conditions followed by
N2-alkylation using different alkyl bromides. The prepared compounds were evaluated for in
vitro cytotoxicity against a panel of human tumor cell lines. N2-Alkylated-β-carboline chalcones
13a-i represented the interesting anticancer activities compared to N2-unsubstituted β-carboline
chalcones 12a-g. Off the prepared β-carbolines, 13g exhibited broad spectrum of activity with
IC50 values lower than 22.5 µM against all the tested cancer cell lines. Further, the N2-alkylated-
β-carboline chalcone 13g markedly induced apoptosis in MDA-MB-231 cells by AO/EB
staining assay. The most cytotoxic compound 13g possessed a relatively high drug score of 0.48.
Additionally, the prepared β-carboline chalcones displayed moderate antibacterial activity
against tested bacterial strains.
Keywords:
β-Carboline chalcones
β-Carbolinium chalcone bromides
Anticancer activity
Apoptosis
Antibacterial activity
2009 Elsevier Ltd. All rights reserved.
β-Carbolines are an important class of nitrogen containing
heterocycles due to their widespread biological and
pharmacological applications.1 Particularly, C-1 substituted β-
carbolines possess remarkable antimalarial, anti-HIV,
antimicrobial, antileishmania, and antitumoral properties.2-6
Recently, interest in β-carboline alkaloids was stimulated by their
potential antitumor and antibacterial activities.7-9 β-Carbolines
exhibit anticancer properties through DNA intercalation, tubulin
polymerization, topoisomerase and kinase inhibition.10,11 For
instance, natural β-carboline derivative Harmane 1, isolated from
cured tobacco and its smoke;12 exhibited moderate anticancer
activity through DNA intercalation in addition to anti-bacterial
activities.13,14 Kobayashi et al. reported isolation and cytotoxicity
of novel manzamine alkaloid Xestomanzamine A (2) from
Okinawan marine sponges of Xestospongia sp. and exhibited
weak cytotoxicity against KB cell lines.15 Cardellina group
isolated Eudistomin T (3) from Eudistoma olivaceum endowed
with antimicrobial and weak phototoxicity.16-18 In 2008, Cao
Fig. 1. Pharmacologically interesting C-1 substituted β-carbolines
On the other hand, compounds with enone system continue to be
of great interest because of their simple chemistry, easy synthesis
and biological importance and usefulness as building blocks in
synthetic chemistry.23 Particularly, wide variety of biological
activities associated with chalcones have encouraged organic and
medicinal chemists to undertake their structural modifications
and chemistry.24 Chalcones exhibit anti-cancer activities through
various mechanisms such as inhibition of multi-drug resistance
research group prepared
1-benzylidine-N2-benzylated-β-
carbolinium bromides 4 and 5 with interesting cytotoxic activities
(Fig.1 and Fig.2).19-21 From a series of novel β-carboline-based
chalcones Chauhan et al. identified compound 6 with high
cytotoxicity (IC50 =2.25 µM; MCF-7) against breast cancer cell
lines.22
———
 Corresponding author. Tel.: +91-1596-515238; fax: +91-1596-244183; e-mail: dalipk@pilani.bits-pilani.ac.in (Dalip Kumar)
 Corresponding author. Tel.: +001-7654969470; fax: +001-7654940239; e-mail: shah23@purdue.edu (Kavita Shah)

channels such as ABCG2, BCRP, p-glycoprotein and inhibition
of protein deacetylation.25 Also, many research groups either
isolated or synthesized natural chalcones with antibacterial as
well as anticancer activities. For example, Licochalcone A (7)
isolated from Glycyrrhiza inflate is known to exhibit potent
antibacterial activity especially towards Bacillus subtilis,
Staphylococcus aureus and Micrococcus luteus.26 In recent past,
Kumar et al. reported synthesis and antitumor activity of indole-
based chalcones 8 with IC50 values ranging 0.03-0.09 µM against
human pancreatic (PaCa-2) carcinoma cells.27
All the prepared chalcones 12a-g and their bromide salts 13a-i
were fully characterized using infra-red (IR), NMR (1H and 13C)
and mass spectral data. In IR spectra, two characteristic bands at
~3370 cm−1 (N-H) and ~1650 cm−1(C=O) were observed for all
1
compounds. The H NMR spectra for chalcones 12a-g showed
broad singlet at δ ~10.5–12.0 ppm (β-carboline N-H proton) and
two doublets at δ ~8.4 ppm and ~7.9 ppm (enone HC=CH
protons). 13C NMR spectra of 12a-g and 13a-i exhibited signals
for the carbonyl carbon at δ ~ 190 ppm. HPLC analysis (Column:
Waters-C18; 250×4.6 mm; condition: 0.01% TFA in acetonitrile;
flow rate = 1 mL/min; and UV detector) showed the purity of the
β-carbolines 12a-g and 13a-i greater than 97%.
In continuation of our efforts to develop potent anticancer
agents, recently we have identified indole analogues possessing
significant cytotoxicity.28-33 Inspired by the attractive anticancer
properties of β-carboline and chalcone units, herein, we have
designed a diverse series of β-carboline chalcones 12a-g and
their bromide salts 13a-i by incorporating amazing features of β-
carboline and chalcone in a single molecule (Fig. 2).
After synthesis and characterization, we studied the in vitro
anticancer activity of β-carboline chalcones 12a-g and their
bromide salts 13a-i against six different cancer cell lines by using
MTT assay. The tumor cell line panel consisted of pancreatic
cancer (BxPC-3), cervical cancer (HeLa), castration-resistant
prostate cancer (C4-2), human prostate cancer (PC-3), human
embryonic kidney 293 (HEK293T) and breast carcinoma (MDA-
MB-231) cells. Doxorubicin was used as the reference drug.
Table 1 summaries the cytotoxicity results in terms of IC50
values. It is evident that most of the derivatives exhibited
moderate to good cytotoxicity against the tested cancer cell lines.
The structural changes by varying substituents on β-carboline (R)
and aryl (Ar) moieties on enone part produced the sixteen
compounds with a wide ranging anticancer activity with IC50
values ranging from 15.9 µM to >100 µM. Compound 12a
without any substituents on β-carboline and enone moieties
displayed moderate anticancer activity against a panel of cancer
cell lines (IC50 = 65.5-93.0 µM). Replacement of phenyl group of
enone moiety with tolyl, p-methoxyphenyl and 3,4-
dimethoxyphenyl led to inactive compounds 12b-d (IC50 = >100
µM). Introduction of 3,4,5-trimethoxyphenyl moiety resulted in
compound 12e with improved activity. Cytotoxicity of
compounds 12f-g could not be tested due to solubility problem.
Fig. 2. Rational design of β-carboline chalcones and their bromide salts
To improve the cytotoxic activity, N2-alkylated derivatives of
β-carbolines 13a-i were prepared. Interestingly, as shown in
Table 1, compared with parent β-carboline chalcones 12c-e (12c:
IC50 >100 µM, 12d: IC50>100 µM, 12e: IC50 = 70-100 µM), the
N2-alkylated-β-carbolines 13a-i showed enhanced cytotoxic
activity (IC50 = 15-100 µM). Incorporation of benzyl at N2 of β-
carbolines 12c-e yielded compounds 13a, 13d and 13g shown
good to moderate activity (IC50 = 15-88 µM). Notably, compound
13g found to be the most potent analogue of the series with broad
cytotoxicity against all the tested cell lines (IC50 = 15.9-22.1
µM). Introduction of propargyl moiety in β-carbolines 12c-e also
resulted with similar activity (13c, 13f and 13i, IC50 = 19.1->100
µM). However, butylated derivatives 13b, 13e and 13h were
inferior in the activity (IC50 25.1->100 µM) when compared to
N2-benzylated analogues 13g. The activity results suggested that
N2-alkylation of β-carboline moiety is beneficial for the
anticancer activity.
Synthesis of novel β-carboline chalcone analogues 12a-g and
13a-i is depicted in Scheme 1.22,34-36 Initially the 1-acetyl-β-
carboline 10 was prepared by the Pictet–Spengler reaction of
tryptamine with pyruvaldehyde under acidic conditions followed
by in situ aromatization with 10% palladium on carbon. Later the
N-H protection of 1-acetyl-β-carboline with di-tert-butyl
dicarbonate in the presence of DMAP produced N-boc-1-acetyl-
β-carboline 11. Further, reaction of 11 with respective aldehydes
in the presence of NaOH solution (20%) in aqueous ethanol for
16 h afforded β-carboline chalcone analogues 12a-g in good to
excellent yields. Finally, the N2-alkylation of three β-carboline
chalcones 12c-e with various alkylbromides led to the
corresponding bromide salts 13a-i with more than 80% yields.
We also investigated potential toxicity of compounds 12a-g
and 13a-i against murine fibroblast NIH3T3 cell line. The results
indicate that all the tested compounds 12a-g and 13a-i exhibit
lower toxicity than the standard drug, Doxorubicin.
Next to determine the preliminary mechanism of cell death,
we performed acridine orange/ethidium bromide assay.37-39
Acridine orange is a vital dye and stains both live and dead cells.
Ethidium bromide stains cells that have lost membrane integrity
and tinge the nucleus red. Thus, live cells appear uniformly green
in acridine orange/ethidium bromide assay. Fig 3 shows that
control cells possess normal healthy morphology with intact
nuclear architecture and are green in colour.
Scheme 1. Synthesis of β-carboline chalcones 12a-g and their bromide salts
13a-i. Reagents and conditions: a) Pyruvaldehyde, TFA, DCM, 30 °C, 48 h,
N2; b) 10% Pd/C, Xylene, reflux, 24 h; c) Di-tert-butyldicarbonate, DMAP,
THF, 24 h; d) ArCHO, 20% NaOH, ethanol:water (1:1), 0 °C - 25 °C, 16 h; e)
RBr, DMF, 50 °C, 12h.

Table 1. In vitro cytotoxicity of β-carboline chalcones 12a-g and their bromides 13a-i against a panel of cancer cells and a non-
cancerous cell line (IC50 in μM)
Compd
12a
12b
12c
12d
12e
12f
Ar
C6H5
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CF3C6H4
R
BxPC-3
72.02±2.75
> 100
> 100
> 100
HeLa
82.36±3.43
> 100
> 100
> 100
C4-2
80.25±5.46
> 100
> 100
> 100
PC-3
HEK293T
MDA-MB-231
71.11±4.12
> 100
> 100
> 100
NIH3T3
> 100
> 100
> 100
> 100
93.02±3.54 65.58±2.84
> 100
> 100
> 100
> 100
ND
> 100
> 100
> 100
82.1±5.09
ND
70.78±4.98
ND
75.2±3.6
ND
71.6±4.87
ND
71.54±4.3
ND
> 100
ND
4-(CH3)2NC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
Doxorubicin
ND
ND
ND
ND
ND
ND
ND
12g
13a
13b
13c
13d
13e
13f
13g
13h
13i
Benzyl
50.25±4.91
50.79±4.91
> 100
55.3±3.48
> 100
30.14±3.41
20±2.1
25.1±3.65
72.02±5.3
13.56±2.21
60.14±4.65
44.99±4.32
> 100
45.25±4.41
> 100
25.32±2.79
22.1±3.23
35.56±2.2
70.1±4.9
5.23±1.92
65.5±5.58
38.79±4.91
> 100
42.05±4.35
> 100
24.4±2.64
16.13±4.2
39.65±2.98
65.5±5.74
3.2±1.1
88.3±7.1
64.99±5.5
> 100
78.95±6.4
> 100
29.6±3.1
22.02±3.25 17.18±2.98
40.13±3.5
60.98±6.1
10.2±0.98
41.4±3.6
35.18±4.1
> 100
55.14±5.8
> 100
52.2±4.95
40.9±3.96
> 100
48.23±4.69
> 100
21.2±3.1
15.95±3.41
32.05±4.0
59.61±4.81
7.85±1.59
85.3±5.1
74.6±2.50
> 100
82.25±3.33
> 100
72.1±4.12
55.23±5.8
68.6±6.54
88±3.85
21.32 ±2.56
n-Butyl
Propargyl
Benzyl
n-Butyl
Propargyl
Benzyl
19.14±2.78
n-Butyl
Propargyl
34.4±3.89
55.07±4.4
3.59±1.1
*The activity data represent mean values  SD of experiments conducted in triplicates at three independent times
Fluorescence microscopic image of MDA-MB-231 cells treated
with 13g and reference drug-Doxorubicin clearly demonstrate
morphological changes characteristic of apoptotic cells
formation. This suggest that 13g induced apoptosis in MDA-MB-
231 cancer cell line.
against Gram-positive bacterial stain (S. aureus) with 15 mm of
ZOI and MIC value of 440 µg/mL
For predicting the adsorption, distribution, metabolism and
excretion (ADME) properties, computational studies for the
compounds 12a-g, and 13a-i were performed. Lipinski’s rule of
five and drug likeness score were used for predicting the
physiochemical properties of the molecules.41-43 The newly
prepared β-carboline derivatives 12a-g and 13a-i were evaluated
for percentage absorption (% ABS) and drug-likeness score
(Table 3). β-Carboline chalcones 12a-g and their bromide salts
13a-i possess lower logP values suggesting them to be better
candidates for bioavailability. This was in accordance with the
better cytotoxicity of β-carboline chalcones 12a-g and 13a-i. All
the β-carbolines, 12a-g and 13a-i showed topological polar
surface area (TPSA) less than 160 Å2 but greater than 40 Å2,
which indicates good intestinal absorption property of these
molecules than their Blood-Brain Barrier (BBB) penetration
ability. Drug-likeness model score (a combined outcome of
physicochemical
properties,
pharmacokinetics
and
pharmacodynamics of a compound is represented by a numerical
value) was computed by MolSoft software for the synthesized
compounds. Computed drug-likeness scores are presented in
Table 3. β-carboline chalcones, 12c-e, 13a and 13d-i possessed a
positive score in the range of 0.06-0.48, which implies them to be
Fig. 3. Morphological assessment of 13g-treated MDA-MB-231 cells
good drug candidates. The most cytotoxic compound 13g [IC50
15.9 µM against MDA-MB-231 cell line] possessed a relatively
high drug score of 0.48.
=
In the view of interesting antibacterial activities of chalcones,
the newly prepared β-carboline derivatives 12a-g and 13a-i were
screened for their antibacterial activity.23,24,40 In vitro antibacterial
activity of sixteen β-carboline chalcones 12a-g and their bromide
salts 13a-i was evaluated against two Gram-positive bacterial
strains including Staphylococcus aureus (MTCC 96), Bacillus
subtilis (MTCC 121) and three Gram-negative bacterial strains
including Escherichia coli (MTCC 1652), Pseudomonas
aeruginosa (MTCC 424) and Enterobacter cloacae (NAIMCC-
B-02025) with respect to Chloramphenicol, a standard drug. The
Zone of Inhibition (ZOI) and Minimum Inhibitory
Concentrations (MICs) for compounds 12a-g and 13a-i were
determined by the modified broth micro-dilution values method
as given in Table 2. The activity results described that β-
carboline chalcones exerted moderate antibacterial activity
against tested bacterial strains. Among all the compounds,
carboline derivative 13a was found to be most potent analogue
In conclusion, a library of sixteen simple β-carboline chalcones
12a-g and bromide salts 13a-i was prepared in good yields. In
vitro antitumor activity of newly synthesized β-carbolines 12a-g
and 13a-i was performed against a panel of cancer cell lines and
compound 13g displayed fairly good anticancer activity against
all the tested cancer cells with IC50 value ranges 15.9 to 22.1 µM.
Activity of N2-benzylated-β-carboline chalcones were found to be
better than that of N2-unsubstituted-β-carboline chalcones
Preliminary mechanism of action studies suggests that 13g
induces apoptosis in breast cancer cells and possess a relatively
good drug score of 0.48. Additionally, β-carboline chalcones
12a-g and 13a-i demonstrate moderate antibacterial activity
against the tested bacterial strains.

Table 2. In vitro antibacterial activity of β-carboline chalcones 12a-g and their bromides 13a-i against a panel of bacterial strains
Compd Ar
R
Gram positive
Gram negative
E. coli
B. subtilis
S. aureus
E. cloacae
P. aeruginosa
ZOI (mm) MIC (µM) ZOI (mm) MIC (µM) ZOI (mm) MIC (µM) ZOI (mm) ZOI (mm)
C6H5
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CF3C6H4
4-(CH3)2NC6H4
4-CH3OC6H4
9
12
8
ND
-
-
8
8
-
-
6
7
7
7
-
-
22
838
720
885
ND
-
-
870
875
-
-
-
-
-
-
-
-
-
10
9
ND
10
11
8
8
-
6
8
-
-
-
-
-
-
12a
12b
12c
12d
12e
12f
12g
13a
13b
13c
13d
13e
13f
13g
13h
13i
10
12
ND
7
11
11
15
9
9
7
9
9
820
733
ND
>900
710
715
440
-
-
-
-
-
828
846
ND
834
726
880
874
-
-
-
-
-
8
ND
-
-
-
-
-
7
-
-
7
-
12
9
21
ND
-
10
8
8
-
-
-
-
-
Benzyl
4-CH3OC6H4
4-CH3OC6H4
n-Butyl
Propargyl
Benzyl
n-Butyl
Propargyl
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2 Benzyl
3,4,5-(CH3O)3C6H2 n-Butyl
3,4,5-(CH3O)3C6H2 Propargyl
Chloramphenicol
6
9
10
9
-
12
10
13
20
726
806
590
24
-
8
-
-
-
32
812
-
17
22
22
*ZOI (in mm) and MIC (in µg/mL) values. Assay experiments were performed in duplicates at two independent times
Table 3. Calculated drug-like properties of β-carboline chalcones 12a-g and β-carbolinium chalcone bromides 13a-i
Lipinski’s parameters
Drug-
No. of
violations
nHBA
(N&O)
3
nHBD
LogPa
Molecular
Compd
nRB
TPSAb
% ABSc
likeness
Scored
(NH&OH)
weight
298.35
312.37
328.37
358.40
388.42
366.34
341.41
419.50
385.49
367.43
449.53
415.51
397.45
479.56
445.54
427.48
1
4.49
4.93
4.54
4.13
4.12
5.38
4.59
1.72
1.56
0.28
1.31
1.15
-0.13
1.29
1.13
-0.14
3
45.75
45.75
54.99
64.22
73.46
45.75
48.99
45.98
45.98
45.98
55.22
55.22
55.22
64.45
64.45
64.45
93.22
93.22
90.03
86.84
83.65
93.22
92.10
93.13
93.13
93.13
89.95
89.95
89.95
86.76
86.76
86.76
0
-0.28
-0.15
0.06
0.40
0.29
-0.27
-0.32
0.14
-0.05
0.00
0.33
0.16
0.21
0.48
0.13
0.16
12a
12b
12c
12d
12e
12f
12g
13a
13b
13c
13d
13e
13f
3
4
5
6
3
4
4
4
4
5
5
5
6
6
6
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
4
5
6
4
4
6
7
5
7
8
6
8
9
7
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
13g
13h
13i
a LogP = Lipophilicity calculated using molinspiration cheminformatics software
b TPSA = Topological polar surface area calculated using molinspiration cheminformatics software
c % ABS = Percentage absorption calculated using the formula %ABS = 109 - (0.345 x TPSA).
d Drug-likeness Score = calculated online using Molsoft.
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Authors are thankful to Council of Scientific & Industrial
Research (CSIR, No. 02(0239)/17/EMR-II), New Delhi, India
and National Institute of Health (R03 CA 166912 to KS) for
providing financial support to carry out this work. Also, we
would like to acknowledge BITS Pilani, Rajasthan and DST-
FIST, New Delhi for NMR and HRMS facility.
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Figures
Fig. 1. Pharmacologically interesting C-1 substituted β-carbolines
Fig. 2: Rational design of β-carboline chalcones and their bromide salts

Fig. 3. Morphological assessment of 13g-treated MDA-MB-231 cells

Tables
Table 1. In vitro cytotoxicity of β-carboline chalcones 12a-g and their bromides 13a-i against a panel of cancer cells and a non-
cancerous cell line (IC50 in μM)
Compd
12a
12b
12c
12d
12e
12f
Ar
C6H5
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CF3C6H4
R
BxPC-3
72.02±2.75
> 100
> 100
> 100
HeLa
82.36±3.43
> 100
> 100
> 100
C4-2
80.25±5.46
> 100
> 100
> 100
PC-3
HEK293T
MDA-MB-231
71.11±4.12
> 100
> 100
> 100
NIH3T3
> 100
> 100
> 100
> 100
93.02±3.54 65.58±2.84
> 100
> 100
> 100
> 100
ND
> 100
> 100
> 100
82.1±5.09
ND
70.78±4.98
ND
75.2±3.6
ND
71.6±4.87
ND
71.54±4.3
ND
> 100
ND
4-(CH3)2NC6H4
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
3,4,5-(CH3O)3C6H2
Doxorubicin
ND
ND
ND
ND
ND
ND
ND
12g
13a
13b
13c
13d
13e
13f
13g
13h
13i
Benzyl
50.25±4.91
50.79±4.91
> 100
55.3±3.48
> 100
30.14±3.41
20±2.1
25.1±3.65
72.02±5.3
13.56±2.21
60.14±4.65
44.99±4.32
> 100
45.25±4.41
> 100
25.32±2.79
22.1±3.23
35.56±2.2
70.1±4.9
5.23±1.92
65.5±5.58
38.79±4.91
> 100
42.05±4.35
> 100
24.4±2.64
16.13±4.2
39.65±2.98
65.5±5.74
3.2±1.1
88.3±7.1
64.99±5.5
> 100
78.95±6.4
> 100
29.6±3.1
22.02±3.25 17.18±2.98
40.13±3.5
60.98±6.1
10.2±0.98
41.4±3.6
35.18±4.1
> 100
55.14±5.8
> 100
52.2±4.95
40.9±3.96
> 100
48.23±4.69
> 100
21.2±3.1
15.95±3.41
32.05±4.0
59.61±4.81
7.85±1.59
85.3±5.1
74.6±2.50
> 100
82.25±3.33
> 100
72.1±4.12
55.23±5.8
68.6±6.54
88±3.85
21.32 ±2.56
n-Butyl
Propargyl
Benzyl
n-Butyl
Propargyl
Benzyl
19.14±2.78
n-Butyl
Propargyl
34.4±3.89
55.07±4.4
3.59±1.1
*The activity data represent mean values  SD of experiments conducted in triplicates at three independent times
Table 2. In vitro antibacterial activity of β-carboline chalcones 12a-g and their bromides 13a-i against a panel of bacterial strains
Compd Ar
R
Gram positive
Gram negative
E. coli
B. subtilis
S. aureus
E. cloacae
P. aeruginosa
ZOI (mm) MIC (µM) ZOI (mm) MIC (µM) ZOI (mm) MIC (µM) ZOI (mm) ZOI (mm)
C6H5
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CF3C6H4
4-(CH3)2NC6H4
4-CH3OC6H4
9
12
8
ND
-
-
8
8
-
-
6
7
7
7
-
-
22
838
720
885
ND
-
-
870
875
-
-
-
-
-
-
-
-
-
10
9
ND
10
11
8
8
-
6
8
-
-
-
-
-
-
12a
12b
12c
12d
12e
12f
12g
13a
13b
13c
13d
13e
13f
13g
13h
13i
10
12
ND
7
11
11
15
9
9
7
9
9
820
733
ND
>900
710
715
440
-
-
-
-
-
828
846
ND
834
726
880
874
-
-
-
-
-
8
ND
-
-
-
-
-
7
-
-
7
-
12
9
21
ND
-
10
8
8
-
-
-
-
-
Benzyl
4-CH3OC6H4
4-CH3OC6H4
n-Butyl
Propargyl
Benzyl
n-Butyl
Propargyl
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2 Benzyl
3,4,5-(CH3O)3C6H2 n-Butyl
3,4,5-(CH3O)3C6H2 Propargyl
Chloramphenicol
6
9
10
9
-
12
10
13
20
726
806
590
24
-
8
-
-
-
32
812
-
17
22
22

*ZOI (in mm) and MIC (in µg/mL) values. Assay experiments were performed in duplicates at two independent times
Table 3. Calculated drug-like properties of β-carboline chalcones 12a-g and β-carbolinium chalcone bromides 13a-i
Lipinski’s parameters
Drug-
No. of
violations
nHBA
(N&O)
3
nHBD
LogPa
Molecular
Compd
nRB
TPSAb
% ABSc
likeness
Scored
(NH&OH)
weight
298.35
312.37
328.37
358.40
388.42
366.34
341.41
419.50
385.49
367.43
449.53
415.51
397.45
479.56
445.54
427.48
1
4.49
4.93
4.54
4.13
4.12
5.38
4.59
1.72
1.56
0.28
1.31
1.15
-0.13
1.29
1.13
-0.14
3
45.75
45.75
54.99
64.22
73.46
45.75
48.99
45.98
45.98
45.98
55.22
55.22
55.22
64.45
64.45
64.45
93.22
93.22
90.03
86.84
83.65
93.22
92.10
93.13
93.13
93.13
89.95
89.95
89.95
86.76
86.76
86.76
0
-0.28
-0.15
0.06
0.40
0.29
-0.27
-0.32
0.14
-0.05
0.00
0.33
0.16
0.21
0.48
0.13
0.16
12a
12b
12c
12d
12e
12f
12g
13a
13b
13c
13d
13e
13f
3
4
5
6
3
4
4
4
4
5
5
5
6
6
6
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
4
5
6
4
4
6
7
5
7
8
6
8
9
7
0
0
0
0
1
0
0
0
0
0
0
0
0
0
0
13g
13h
13i
a LogP = Lipophilicity calculated using molinspiration cheminformatics software
b TPSA = Topological polar surface area calculated using molinspiration cheminformatics software
c % ABS = Percentage absorption calculated using the formula %ABS = 109 - (0.345 x TPSA).
d Drug-likeness Score = calculated using Molsoft.