Synthesis and characterization of novel 1,3-benzodioxole tagged noscapine based ionic liquids with in silico and in vitro cytotoxicity analysis on HeLa cells

Article abstract of DOI:10.1016/j.molliq.2020.112525

Ionic liquids (ILs) have proven themselves as a new class of anticancer compounds among the scientific community in the 21st century. With proven efficiency of ionic liquids here an attempt has been made on a legacy anticancer compound noscapine. In this study, a library of novel noscapine (Nos) based ionic liquids were synthesized and characterized using various techniques such as ¹H, ¹³C NMR spectroscopy and Mass spectrometry. These novel Nos-based ionic liquids were studied by in silico assays including molecular docking analysis, which showed the [Pip-Nos]OAc and [Pip-Nos]OTf derivatives of Nos-based ionic liquids have high molecular binding with docking score ?336.19 kJ/mol and ?326.71 kJ/mol, respectively, much higher than the parent compound noscapine (?267.06 kJ/mol). Also, pharmacokinetics and pharmacodynamics properties analyses showed the favorable results with high drug likeliness. The lead compounds were further well validated with in vitro anticancer cytotoxicity assay on HeLa cancer cell line. The in vitro cytotoxicity analysis depicted the high anticancer potency of lead compounds with lower IC₅₀ of acetate and triflate IL derivatives than the parent compound noscapine. In conclusion, the present study paves the way to elucidate the potential anticancer ionic liquids.

Full text of DOI:10.1016/j.molliq.2020.112525

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Synthesis and characterization of novel 1,3-benzodioxole tagged
noscapine based ionic liquids with in silico and in vitro
cytotoxicity analysis on HeLa cells
Hitesh Sehrawat, Neeraj Kumar, Ravi Tomar, Loveneesh Kumar,
Vartika Tomar, Jitender Madan, Sujata K. Dass, Ramesh Chandra
PII:
S0167-7322(19)36559-6
DOI:
https://doi.org/10.1016/j.molliq.2020.112525
MOLLIQ 112525
Reference:
To appear in:
Journal of Molecular Liquids
Received date:
Revised date:
Accepted date:
28 November 2019
14 January 2020
16 January 2020
Please cite this article as: H. Sehrawat, N. Kumar, R. Tomar, et al., Synthesis and
characterization of novel 1,3-benzodioxole tagged noscapine based ionic liquids with
in silico and in vitro cytotoxicity analysis on HeLa cells, Journal of Molecular
Liquids(2020), https://doi.org/10.1016/j.molliq.2020.112525
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Journal of Molecular Liquids
journal homepage: www.elsevier.com
Synthesis and characterization of novel 1,3-benzodioxole tagged noscapine based ionic liquids with in
silico and in vitro cytotoxicity analysis on HeLa cells
Hitesh Sehrawat,a Neeraj Kumar,a Ravi Tomar,a Loveneesh Kumar,a Vartika Tomar,a Jitender Madan,b*
Sujata K. Dass,c and Ramesh Chandraa,d*
a Drug Discovery & Development Laboratory, Department of Chemistry, University of Delhi, Delhi- 110007, India
b Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, India.
c Department of Neurology, BLK Super Speciality Hospital, Pusa Road, New Delhi-110005, India
d Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi- 110007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ionic Liquids (ILs) have proven themselves as a new class of anticancer compounds amongst the
scientific community in the 21st century. With proven efficiency of ionic liquids here an attempt
has been made on a legacy anticancer compound noscapine. In this study, a library of novel
Noscapine (Nos) based ionic liquids were synthesized and characterized using various
techniques such as 1H-, 13C- NMR spectroscopy and Mass spectrometry. These novel Nos-based
ionic liquids were studied by in silico assays including molecular docking analysis, which
showed the [Pip-Nos]OAc and [Pip-Nos]OTf derivatives of Nos-based ionic liquids have high
molecular binding with docking score -336.19 kJ/mol and -326.71 kJ/mol, respectively, much
higher than the parent compound noscapine (-267.06 kJ/mol). Also, pharmacokinetics and
pharmacodynamics properties analyses showed the favorable results with high drug likeliness.
The lead compounds were further well validated with in vitro anticancer cytotoxicity assay on
HeLa cancer cell line. The in vitro cytotoxicity analysis depicted the high anticancer potency of
lead compounds with lower IC50 of acetate and triflate IL derivatives than the parent compound
noscapine. In conclusion, the present study paves the way to elucidate the potential anticancer
ionic liquids.
Available online
Keywords:
Ionic Liquids
Noscapine
1,3-Benzodioxole
Anticancer
Pharmacology
1. Introduction
Ionic liquids (ILs) are generally synthesized from various
combination of organic cations (imidazolium, pyridinium,
Noscapine (phthalide isoquinoline alkaloid) known as
Narcotine, Nectodon, Nospen, Anarcontie, it was the first time
isolated from opium plant by a French chemist (Pierre Robiquet)
in 1817 as denomination of narcotine till the late of 1950s.[1,2]
The opium has contained various alkaloids such as thebaine,
papaverine, morphine, codeine, noscapine and narceine but
noscapine does not match structurally or chemically with other
alkaloids. In 1960, noscapine was considered as inactive drug but
later on it was used as an anti-tussive agent which further used
for decades in the world including India. The discovery of anti-
neoplastic properties of noscapine has attracted the researcher’s
attention towards its synthesis and biological application.
Noscapine was synthesized in 1994 and over the decades, various
methods were developed for the total synthesis of noscapine and
its derivatives.[3] Generally, noscapine was explored at four
positions i.e. 9th position hydrogen was replaced by bromine,
fluorine, chlorine, iodine, nitro, amino and others alkyl, carbonyl
reduced, 7`th methoxy convert into other ether groups and N-
methyl group was also replaced by other groups.[4–8] On the
literature survey, we found that there are many compounds
(podophyllotoxin, steganacin, noscapine and combretastatin A-2)
containing 1,3-benzodioxole motif reported as potential
antitumor drugs.[9]
piperidinium,
quinolinium,
pyrrolidinium,
quaternary
ammonium, so on) with a wide range of anions (halides,
tetrafluoroborate,
dicyanamide,
bis(trifluoromethanesulfonyl)amide, etc).[10–12] Ionic liquids
have attracted attention of the researchers due to their high
thermal & chemical stability, low volatility, low flammability,
high aqueous solubility and high ionic conductivity which
increases their applications in the various fields like
hexafluorophosphate,
nitrate, trifluoromethanesulphonate,
methylsulphate,
electrochemistry, fuel production
conversion, biotransformation, nanotechnology, catalysis,
organic synthesis, pharmaceutics and many other fields.[11–24]
& processing, biomass
Over the two decades, our laboratory has synthesized various
derivatives of noscapine with their in silico and in vivo studies.
To design and development of anticancer drug, molecular
docking analysis has been performed in a large number of reports
to assess the potency of natural drugs and their analogs.[9,25,26]
Molecular docking is a computational algorithm based technique
to study the binding potency of the target receptor with ligand
and helps in virtual screening of the drugs. Hence, we carried out
the in silico molecular docking analysis of noscapine and its
potential IL analogs. Furthermore, pharmacokinetics and
pharmacodynamics studies were performed employing the

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advanced pharmacological computational avenues, as also
performed in many research studies.[27–29] Pharmacological
parameters analysis helps in assessing drug impacts and further
validation to reach preclinical stages. Herein, we have reported
the synthesis of the noscapine based ionic liquids, in silico and in
vitro studies. Noscapine based ionic liquids were characterized
5-(Bromomethyl)-1,3-benzodioxole (2): It was obtained as
white solid in 70% yield; mp: 97-98 °C; H-NMR (CDCl3, 400
MHz): δ 6.88-6.81 (m, 2H), 6.74 (d, J = 7.8 Hz, 1H), 5.95 (s,
2H), 4.44 (s, 2H); 13C-NMR (CDCl3, 100 MHz): 147.851,
147.756, 131.456, 122.699, 109.4175, 108.273, 101.294, 34.199
1
[Pip-Nos]Br:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
1
by H-, 13C-NMR spectroscopy, mass spectrometry and melting
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
bromide (3): It was obtained as pale white solid in 90.1 % yield;
mp: 198-200 °C; 1H-NMR (400 MHz, CDCl3): δ 7.25 (d, J = 1.9
Hz, 1H), 6.99 (dd, J = 8.0, 1.8 Hz, 1H), 6.95 (d, J = 1.6 Hz, 1H),
6.82 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 6.28 (d, J = 5.5 Hz, 1H),
6.11-5.98 (m, 4H), 5.84 (d, J = 1.4 Hz, 1H), 5.78 (d, J = 1.2 Hz,
1H), 4.78 (d, J = 12.9 Hz, 1H), 4.67 (d, J = 12.9 Hz, 1H), 3.88 (t,
J = 4.9 Hz, 8H), 3.80 (s, 3H), 3.51 (s, 3H), 3.44-3.31 (m, 1H),
3.25-3.12 (m, 1H); 13C-NMR (100 MHz, CDCl3): 166.298,
153.025, 150.936, 149.987, 148.550, 147.582, 139.819, 137.241,
133.810, 127.984, 126.757, 120.892, 119.895, 119.138, 117.327,
112.727, 109.028, 108.012, 102.482, 102.013, 101.409, 75.648,
66.573, 64.992, 62.308, 59.069, 56.942, 53.827, 49.121, 24.367;
HRMS (ESI) m/z =548.2426 [M+]
point techniques. In our best knowledge, this is the first study in
which noscapine based ionic liquids has been synthesized and
explored for biological activity.
2. Experimental
2.1 Materials
All the chemicals used were purchased from SRL, TCI,
Sigma-Aldrich, Merck, Alfa Aesar and LOBA Chemie. The
solvents used were of extra pure quality. Melting points were
1
recorded on Buchi M-560. The H NMR (400 MHz) and 13C
NMR (100 MHz) spectra were recorded on a Jeol Resonance
ASC 64 (400 MHz) spectrometer using CDCl3 and chemical
shifts were recorded in ppm with tetramethylsilane (TMS) as an
internal standard. High-resolution mass spectroscopy (HRMS)
were recorded on the Agilent 6530 Accurate-Mass Q-TOF
LC/MS.
[Pip-Nos]I
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
iodide (4) : It was obtained as pale yellow solid in 82.8 % yield;
2.2 General procedure
Synthesis procedure of 5-(Bromomethyl)-1,3-benzodioxole (2)
1
mp: 190-192 °C; H-NMR (400 MHz, CDCl3): δ 7.26-7.19 (m,
5-(Bromomethyl)-1,3-benzodioxole was prepared using
reported method.[30] Take a 250 mL round bottom flask A
charged with 1,3-Benzodioxole-5-methanol (5 g; 32.86 mmol) in
dry diethyl ether (50 mL). Take another 100 mL round bottom
flask B loaded with 3.1 mL (32.86 mmol; 1 equiv) of
phosphorous tribromide dissolved in 40 mL of diethyl ether. A
dropwise addition was carried out from Flask B to Flask A
maintaining the temperature at 0°C for and stirred for 15 minutes.
After the completion of the reaction, the reaction mixture was
worked up with water (3x100 mL) using a separating funnel
followed by washing with brine (1:1). After drying over sodium
sulphate and filtration, the solvent was evaporated on a vacuum
rotary evaporator. The crude was recrystallized in petroleum
ether to get the desired white solid product.
1H), 7.01-6.89 (m, 2H), 6.78 (d, J = 7.3 Hz, 1H), 6.37 (s, 1H),
6.23 (d, J = 10.1 Hz, 1H), 5.98 (s, 4H), 5.81 (s, 1H), 5.75 (s, 1H),
4.72 (d, J = 12.8 Hz, 1H), 4.60 (d, J = 12.8 Hz, 1H), 3.98-3.79
(m, 8H), 3.76 (s, 3H), 3.50 (d, J = 12.4 Hz, 3H), 3.43-3.29 (1H),
3.22-3.08 (1H); 13C-NMR (100 MHz, CDCl3): 166.250, 153.102,
151.032, 150.121, 148.626, 147.591, 139.953, 136.944, 133.849,
128.060, 126.527, 121.208, 119.675, 119.133, 117.289, 112.679,
109.133, 107.897, 102.434, 102.080, 101.447, 75.581, 66.707,
64.992, 62.327, 59.203, 56.942, 53.721, 49.054, 24.329; HRMS
(ESI) m/z =548.2427 [M+]
[Pip-Nos]BF4
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
tetrafluoroborate (5) : It was obtained as pale white solid in 85.9
Synthesis procedure of the 6-(benzo[d][1,3]dioxol-5-
ylmethyl)-5-(4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-
yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-
g]isoquinolin-6-ium bromide ionic liquid [Pip-Nos]Br (3)
1
% yield; mp: 197-199 °C; H-NMR (400 MHz, CDCl3): δ 7.22
(d, J = 8.2 Hz, 1H), 6.92 (t, J = 7.6 Hz, 2H), 6.78 (d, J = 8.2 Hz,
1H), 6.37 (s, 1H), 6.24-6.18 (1H), 6.04-5.95 (m, 3H), 5.89 (d, J =
5.0 Hz, 1H), 5.81 (d, J = 0.9 Hz, 1H), 5.75 (s, 1H), 4.67 (d, J =
12.8 Hz, 1H), 4.58 (d, J = 12.8 Hz, 1H), 3.84 (t, J = 4.6 Hz, 8H),
3.71 (s, 3H), 3.47 (s, 3H), 3.38 (s, 1H), 3.21-3.07 (1H); 13C-NMR
(100 MHz, CDCl3): 166.289, 153.044, 150.974, 150.045,
148.588, 147.582, 139.848, 137.165, 133.810, 127.965, 126.680,
120.902, 119.799, 119.148, 117.317, 112.698, 109.056, 107.993,
102.453, 102.032, 101.418, 75.639, 65.212, 62.308, 59.059,
56.932, 53.741, 49.006, 24.367; HRMS (ESI) m/z =548.2462
[M+]
1.1 equiv. of 5-(Bromomethyl)-1,3-benzodioxole, 1 equiv. of
noscapine were taken in 3 mL of toluene in a 25 mL round
bottom flask and at 60° C for 20 hours on a continuous stirring in
an oil bath. After the completion of reaction, toluene was
decanted and remaining solid residue was washed with ethyl
acetate to remove the unreacted part (3x10 mL). Chloroform was
added to dissolve the solid product followed by evaporation on a
vacuum rotary evaporator to obtain 3 as the solid ionic liquid
product.
[Pip-Nos]OAc
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
General procedure for the synthesis of 4-10
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
acetate (6) : It was obtained as white solid in 85.2 % yield; mp:
Compound 3 was used as precursor for the metathesis
reactions. An equal amount of 3 and the salt of desired anion X-
were taken in a 10 mL round bottom flask containing 2 mL of
dichloromethane for 8 hours at room temperature. After the
completion of reaction time, chloroform was added to dissolve
the ionic liquid and filtered to remove the solid residue through
the chloroform solution followed by the evaporation on a vacuum
rotary evaporator to obtain the desired ionic liquid product.
1
192-194 °C; H-NMR (400 MHz, CDCl3): δ 7.26-7.19 (m, 1H),
6.96 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.78 (d, J = 8.2 Hz, 1H),
6.37 (s, 1H), 6.29-6.20 (1H), 6.07-5.91 (m, 4H), 5.81 (d, J = 1.4
Hz, 1H), 5.75 (d, J = 0.9 Hz, 1H), 4.73 (s, 1H), 4.64 (s, 1H), 3.85
(t, J = 5.0 Hz, 8H), 3.78 (d, J = 10.5 Hz, 3H), 3.47 (s, 3H), 3.41-
3.31 (1H), 3.15 (t, J = 9.4 Hz, 1H), 1.18 (s, 3H); 13C-NMR (100

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MHz, CDCl3): 166.514, 166.303, 153.021, 150.942, 149.984,
1H), 3.92 (t, J = 4.6 Hz, 8H), 3.85 (s, 3H), 3.54 (s, 3H), 3.47-3.37
(m, 1H), 3.28-3.15 (m, 1H); 13C-NMR (100 MHz, CDCl3):
166.322, 152.993, 150.927, 149.964, 148.517, 147.540, 139.720,
137.277, 133.750, 127.962, 126.836, 120.814, 119.875, 119.122,
117.335, 112.716, 109.008, 107.968, 102.492, 102.003, 101.409,
75.641, 66.566, 65.004, 62.302, 59.048, 56.935, 53.993, 49.231,
24.354; HRMS (ESI) m/z =550.2012 [M+]
148.537, 147.569, 139.807, 137.239, 133.808, 127.982, 126.769,
120.890, 119.884, 119.137, 117.330, 112.716, 109.022, 108.002,
102.482, 102.012, 101.409, 75.641, 65.004, 62.302, 59.149,
59.063, 56.935, 53.830, 49.106, 29.768, 24.363; HRMS (ESI)
m/z =548.2435 [M+]
[Pip-Nos]DCA
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
dicyanamide (7) : It was obtained as zurich white solid in 86.9 %
yield; mp: 191-193 °C; 1H-NMR (400 MHz, CDCl3): δ 7.27-7.19
(m, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.92 (s, 1H), 6.79 (d, J = 7.8
Hz, 1H), 6.39-6.34 (1H), 6.24 (d, J = 11.0 Hz, 1H), 5.99 (t, J =
4.4 Hz, 4H), 5.81 (s, 1H), 5.75 (s, 1H), 4.73 (d, J = 12.8 Hz, 1H),
4.63 (d, J = 12.8 Hz, 1H), 3.85 (t, J = 5.0 Hz, 8H), 3.76 (s, 3H),
3.52-3.43 (3H), 3.38 (s, 1H), 3.21-3.07 (m, 1H); 13C-NMR (100
MHz, CDCl3): 166.284, 153.031, 150.942, 149.988, 148.546,
147.597, 139.831, 137.258, 133.817, 127.982, 126.765, 122.816,
121.331, 120.890, 119.894, 119.170, 117.330, 112.716, 109.027,
108.030, 102.472, 102.003, 101.409, 75.645, 66.642, 65.033,
62.292, 59.072, 56.945, 53.830, 49.125, 24.363; HRMS (ESI)
m/z =548.2516 [M+]
Biological target of Noscapine retrieval and its evaluation
Among the various chemotherapeutic drugs, noscapine is
reported to be the potential anticancer compound targeting the
tubulin protein. Noscapine targets the tubulin protein, by its high
potency towards the binding groove and further induces the
conformational changes to the tubulin protein.[5] Noscapine via
targeting the tubulin regulates its polymerization into the
microtubules and combat the mitotis in cancer cells. Also,
mechanistic studies demonstrated the binding of noscapine with
tubulin protein; in estimation of one noscapine compound per
tubulin dimer.[31,32] Hence, we have retrieved the tubulin
protein with PDB ID 1TUB from the protein data bank. The 3D
structure was evaluated by employing a multistep process using
the preparation wizard module of Maestro version 9.7. 3D
structure energy minimized and optimized for its stable
conformations. Protein chains and bound ligand consisted of the
structure were analyzed. Furthermore, the 3D crystal structure
was assessed for its stereochemical properties by Ramachandran
plot and its stability using the various computational algorithms,
including Swiss-Model, Verify-3D, Saves Server. [33–35]
[Pip-Nos]NO3
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
nitrate (8) : It was obtained as pale white solid in 84.2 % yield;
1
mp: 188-190 °C; H-NMR (400 MHz, CDCl3): δ 7.23-7.21 (m,
Preparation of tubulin protein for molecular docking
analyses
1H), 6.97-6.91 (m, 2H), 6.78 (q, J = 4.0 Hz, 1H), 6.37 (s, 1H),
6.24 (s, 1H), 5.98-5.92 (m, 4H), 5.81 (s, 1H), 5.75 (s, 1H), 4.72-
4.64 (m, 2H), 3.84 (dd, J = 9.4, 3.4 Hz, 8H), 3.76 (s, 3H), 3.47 (d,
J = 6.0 Hz, 3H), 3.38-3.33 (m, 1H), 3.19-3.10 (m, 1H); 13C-NMR
(100 MHz, CDCl3): 166.332, 153.026, 150.951, 150.003,
148.556, 147.559, 139.802, 137.215, 133.798, 127.982, 126.755,
120.890, 119.855, 119.132, 117.326, 112.721, 109.041, 107.982,
102.482, 102.022, 101.418, 75.655, 66.623, 65.081, 62.316,
59.067, 56.935, 53.816, 49.125, 24.363; HRMS (ESI) m/z
=548.2437 [M+]
Prior to molecular docking, the tubulin protein was prepared.
The 3D crystal structure was checked, and unwanted ligands
were removed by using the protein preparation module of the
Whatif server (https://swift.cmbi.umcn.nl/servers). After that,
water molecules were removed from the crystal structure of
tubulin; to avail to dry trajectories and hydrogen atoms were
added to stabilize the protein structure.
Preparation of Noscapine and its IL analogs for molecular
docking analyses
[Pip-Nos]OTf
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
trifluoromethanesulfonate (9) : It was obtained as origami white
Noscapine and its IL analogs were drawn using the Marvin
sketch and Chemdraw software. Compounds were saved in the
required format (.mol/mol2) for molecular docking. Prepared
compounds were assessed for energy minimization through
Pymol molecular modeling suites.
1
solid in 87.4 % yield; mp: 186-188 °C; H-NMR (400 MHz,
CDCl3): δ 7.28 (d, J = 8.3 Hz, 1H), 6.96-6.81 (4H), 6.40 (s, 1H),
6.16 (s, 1H), 6.03 (d, J = 3.2 Hz, 2H), 5.85 (s, 1H), 5.79 (s, 1H),
5.68 (s, 1H), 4.53 (d, J = 13.1 Hz, 1H), 4.32 (d, J = 13.1 Hz, 1H),
3.95-3.84 (m, 8H), 3.53 (s, 6H), 3.47 (s, 1H), 3.17 (q, J = 9.3 Hz,
1H); 13C-NMR (100 MHz, CDCl3): 166.230, 153.061, 151.067,
150.166, 148.700, 147.569, 139.776, 136.968, 133.604, 127.824,
126.597, 121.048, 120.770, 119.486, 119.121, 117.272, 112.565,
109.125, 107.773, 102.330, 102.080, 101.390, 75.645, 67.010,
66.080, 62.294, 58.824, 56.907, 53.601, 48.895, 24.367; HRMS
(ESI) m/z =548.2400 [M+]
Molecular docking analyses
Molecular docking is a computer-aided drug design approach
to screen the list of compounds and to define the binding
conformation of compounds to the target protein. We have
performed the molecular docking through the HEX 8.0. It is the
computational approaches to define the interaction geometries of
potential drugs with target biological targets. HEX 8.0 works
based on Fast Fourier Transformation algorithms to derive the
minimal binding energy conformations of the ligand-protein
complex using the steric shapes and electrostatic potentials.
[Pip-Nos]Cl
:
6-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(4,5-
dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-
methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium
chloride (10) : It was obtained as pale white in 90.2 % yield; mp:
The output of molecular docking, a complex system was
studied to analyze the involved molecular interaction using the
Ligplot server. Ligplot identifies the hydrogen bonds and
hydrophobic interactions of the docked complex. Moreover,
binding conformations and molecular interactions were analyzed
using the Chimera modeling suite.[36]
1
191-193 °C; H-NMR (400 MHz, CDCl3): δ 7.29 (t, J = 4.1 Hz,
1H), 7.03 (d, J = 8.2 Hz, 1H), 6.99 (s, 1H), 6.85 (d, J = 8.2 Hz,
1H), 6.44 (s, 1H), 6.32 (s, 1H), 6.05 (d, J = 3.2 Hz, 4H), 5.88 (s,
1H), 5.82 (s, 1H), 4.80 (d, J = 12.8 Hz, 1H), 4.72 (d, J = 13.3 Hz,

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Pharmacological analyses of Noscapine and lead
compounds
color, which were then dissolved by solubilizing buffer (100 μl)
to each well. At reference wavelength of 630 nm, the absorbance
value obtained is 560 nm in a plate reader (Tecan, Switzerland).
Noscapine and lead noscapine based IL derivatives ([Pip-
Nos]OAc and [Pip-Nos]OTf) were studied for their
pharmacokinetic and pharmacodynamic properties using multiple
servers though SwissADME, pkCSM, ACD/I-Lab, and
Molinspiration. It involves many pharmacological parameters,
including the Lipinski rule of five, drug-likeliness and ADMET
(Absorption, metabolism, excretion, toxicity).
3.
Result and discussion
3.1. Chemistry
In our laboratory, we are focused to design and develop the
methodologies for the synthesis of new analogs of noscapine
from the last few decades. In continuation of our research, we
have developed methodology for the synthesis of 1,3-
benzodioxole tagged noscapine ionic liquids. In the present work,
5-(Bromomethyl)-1,3-benzodioxole was synthesized by using
1,3-Benzodioxole-5-methanol (Supporting information Scheme-
1) followed by quaternization reaction on noscapine to get the
desired ionic liquid, which was then reacted with various anion
metathesis reactions at room temperature to replace bromide
anion with the desired anion. All the salts used for the anion
metathesis were KI, NaBF4, CH3COONa, NaN(CN)2, NaNO3,
NaOTf, and NaCl. Scheme 1 shown below summarizes the
quaternization and metathesis reaction routes for the synthesis of
1,3-benzodioxole tagged noscapine based ionic liquids. All the
synthesized ionic liquids were obtained in excellent yield. These
ionic liquids were obtained pure which were characterized by 1H-
Standard Cell Proliferation Assay against Human Cervical
Cancer Cells
The anti-proliferative effect was assessed by employing
Standard Cell Proliferation Assay i.e. MTT [3-(4,5-
dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] cell
assay. Human cervical cancer cells, HeLa were employed to
evaluate the cytotoxic effect of synthesized compounds using 96-
wells microtitre plate. Briefly, 5x103 HeLa cells well were plated
in 200μl of DMEM medium and incubated for 24 h. After a
predetermined incubation period, serum DMEM was replaced
with serum-free DMEM. The next day, cells were treated with a
gradient concentration (10-70μM) of noscapine, [Pip-Nos]OAc
and [Pip-Nos]OTf for 72 h. At the end of treatment, 5 mg/ml of
MTT dye was added to each well and the plate was incubated at
37°C in dark for 4 h. The formazan crystals were formed of pink
,
13C-NMR spectroscopy, and mass spectrometry (see supporting
information).
Scheme 1: Synthesis of Noscapine based ionic liquids
Table 1. Pharmacological properties analysis of [Pip-Nos] OTf and [Pip-Nos] OAc
Drug
Water solubility
Caco-2
Intestinal
Skin
P-
VDss(h Fraction
Total
Clearan
ce (Log
ml/min/
kg)
(Log mol/L)
permeability
(Log Papp in (human)
absorption
Permeability
Log Kp
glycoprot
ein
substrate
uman)
(Log
L/kg)
unbound
(human)
(Fu)
10-6 cm/s)
0.077
% Absorbed
[Pip-Nos]
OTf
[Pip-Nos]
-2.972
-3.202
79.62
-2.735
-2.735
No
No
-0.818
-0.717
0.391
0.347
0.759
0.921
85.839
0.656

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OAc
Table 2. Toxicity profile of [Pip-Nos] OTf and [Pip-Nos] OAc
Drug
AMES toxicity
Max. tolerated hERG
I
Oral
Rat Oral Rat Skin
T.Pyrifor
Minnow
toxicity
(Log mM)
dose (human)
(Log
inhibitor
Acute Toxicity Chronic
(LD50)
(mol/kg)
Sensitiz mis
Toxicity
(LOAEL)
Log
ation
Toxicity
(Log
ug/L)
mg/kg/day)
mg/kg_bw
/day)
[Pip-Nos]
OTf
[Pip-Nos]
OAc
No
No
0.409
0.273
No
No
3.007
3.125
0.289
No
No
0.285
0.285
-3.973
-3.607
1.07
3.2. Biology
Molecular docking analyses
Biological target of Noscapine retrieval and its evaluation
Molecular docking was performed to assess the interaction of
noscapine and its potential IL analogs with target tubulin protein.
Hex 8.0 was set to shape and 3D conformations mode to identify
the binding mode in fast Fourier transformation mode, with
whole protein sampling algorithms. Grid dimension for tubulin
protein made to 0.6 Å (as per docking manual), translation steps,
protein flip and twist range of 360° and output of 25 interacting
conformations. Out of these 25 complex systems, a top-scored
docked complex with minimum binding free energy score was
opted. In results, among all the synthesized ionic liquid products
compound 6 and compound 9 has shown the best binding score
(supplementary table-S1). [Pip-Nos]OAc and [Pip-Nos]OTf
scored best -336.19 kJ/mol and -326.71 kJ/mol, respectively,
much higher than Noscapine (-267.06 kJ/mol) (Figure-3). [Pip-
Nos]OAc was found possess the potential interaction to tubulin
protein with two hydrogen bonds; one at 166th amino acid of
chain B of bond length 3.18 Å with donor angle 152.99° and
second at 407th amino acid of chain A of bond length 3.51 Å with
donor angle 111.58°. Also, hydrophobic interactions with 165th
amino acid of chain B and 407th amino acid of chain A of tubulin
protein.
The 3D structure of the tubulin protein of human origin was
retrieved from the protein data bank with PDB ID 1TUB.
Tubulin structure was consisted of two chains (alpha and beta
chains), chain A of length 440 amino acids and chain B of chain
length 427 amino acids; along with conjugated co-crystal ligands
Guanosine-5'-Diphosphate,
Taxotere
and
Guanosine-5'-
Triphosphate (Figure-1). Stereochemical and structural properties
of tubulin protein were analyzed through the Ramachandran plot
evaluation. It defines the dihedral angels and existence of amino
acid residues in allowed/disallowed regions. Ramachandran plot
showed that the 88.5% amino acids lie in favorable to allowed
region, 6.2% amino acids in the generously allowed region and
only 5.3 % amino acids lies in the disallowed region (Figure-1).
Local quality assessment plot depicted the tubulin structure has
high similarity (~0.1 Å to 0.8 Å deviations) with native structure
reported to have high quality. Also, the Verify3D server
confirmed the good qualities of the structure by demonstrating
more than 80% of residues have optimal 3D/1D profiles (Figure-
2). These outputs concluded the good quality of the tubulin
crystal structure for further studies.

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Figure-1: (A) Three-dimensional crystal structure of Tubulin protein; retrieved from protein databank with PDB ID:1TUB, (B)
Ramachandran plot assessment of tubulin protein, 88.5% amino acids lie in favorable to allowed region, 6.2% amino acids in the
generously allowed region and only 5.3 % amino acids lies in the disallowed region.
Figure-2: (A) Local quality estimation of tubulin protein residues. (B) Structural validation of tubulin protein structure by Verify3D
servers. Both servers showed a good quality of protein structure.
Noscapinebinding Tubulin Protein
[Pip-Nos] OAc binding Tubulin Protein
[Pip-Nos] OTf binding Tubulin Protein
A
B
C
Figure-3: (A) Binding of Noscapine (encircled in yellow) to the binding groove of tubulin protein (sky blue ribbon style depiction), (B)
Binding of [Pip-Nos]OAc (encircled in pink) to the binding groove of tubulin protein, (C) Binding of [Pip-Nos]OTf (encircled in
purple) to the binding groove of tubulin protein.

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A
Molecular Interactions (Hydrogen Bonding) of
Noscapine with Tubulin
B
Molecular Interactions (Hydrogen Bonding) of
[Pip-Nos] OAc with Tubulin
C
Molecular Interactions (Hydrogen Bonding) of
[Pip-Nos] OTf with Tubulin
Figure-4: Depiction of Molecular interactions of; (A) Noscapine with tubulin protein, (B) [Pip-Nos]OAc with tubulin protein, (C)
[Pip-Nos]OTf with tubulin protein.
[Pip-Nos]OTf compound found to possess the strong
interaction majorly at chain B with five hydrogen bonds; one at
166th amino acid of chain B of bond length 2.57 Å with donor
angle 159.65° and second at 195th amino acid of chain B of bond
length 3.05 Å with donor angle 158.93°, third and fourth at 197th
amino acids of chain B of bond lengths 3.11 Å and 3.39 Å and
fifth at 407th amino acid of chain B of bond length 3.10 Å with
donor angle 102.10°. Also, hydrophobic interaction with residues
165th of chain B and 407th amino acid of chain A of tubulin
protein. Noscapine resulted in a docking score of -267.06 kJ/mol
and three hydrogen bonds with 166 and 119 residues of chain B
and 407 residues of chain A and hydrophobic interaction with
407 residues of chain A of tubulin protein (Figure-4). On
comparative study with parent compound (noscapine), both [Pip-
Nos]OAc and [Pip-Nos]OTf have shown the higher binding
energy score and large molecular interactions. These results
elucidated the potency of designed IL analogs of noscapine.
pkCSM server. In results, we found that [Pip-Nos]OTf has high
tolerated daily dose with 0.409 log mg/kg/day, and [Pip-
Nos]OAc has a 0.273 log mg/kg/day.
For drug design and development, one of the important
aspects is side effects and toxicity. We have assessed the toxicity
profiles of the drugs, which showed both compounds are non-
carcinogenic with negative results to the Ames test. The relative
toxicity of compounds was measured to determine the acute
toxicity lethal dosage value (LD50). LD50 illustrates the dosage
concentration of the drug, which may lead to the death of 50% of
animals under study. We found the LD50 values of 3.007 and
3.125 (mol/kg), and Oral Rat Chronic Toxicity value 0.289 log
mg/kg_bw/day and 1.07 log mg/kg_bw/day for [Pip-Nos]OTf
and [Pip-Nos]OAc respectively and no skin sensitivity to humans
for both the drugs (Table-2).
Cytotoxicity Assay for Noscapine and lead compounds in
HeLa cancer cells
Pharmacological analyses of [Pip-Nos]OTf and [Pip-
Nos]OAc
By molecular docking analysis, we found [Pip-Nos]OAc and
[Pip-Nos]OTf as potential compounds to bind strongly with
tubulin protein. These compounds were studied for cytotoxicity
and compared with parent compound (Noscapine) on HeLa cells.
The cytotoxicity induced by noscapine, [Pip-Nos]OAc and [Pip-
Nos]OTf in HeLa cells was measured by standard cell
proliferation assay in terms of IC50 value. The IC50 of [Pip-
Nos]OTf was estimated to be 17.2-μM significantly lower than
(One way ANOVA test, P<0.05) 23.5-μM of noscapine acetate
and 47.2-μM of noscapine (see supporting information, Table
S2). The high therapeutic efficacy of [Pip-Nos]OTf as compared
to [Pip-Nos]OAc and noscapine may be contributed to
augmented permeation that further disrupted the cell organelles
and triggered death mechanism in a lower concentration.
After the evaluation of lead compounds ([Pip-Nos]OAc and
[Pip-Nos]OTf) with in vitro and in silico assays, pharmacological
properties were analyzed based on Lipinski rule of five, which
includes these assumptions: Molecular mass less than 500
Dalton, High lipophilicity (expressed as LogP less than 5), Less
than 5 hydrogen bond donors, Less than 10 hydrogen bond
acceptors and Molar refractivity should be between 40-130. Our
results showed both compounds do not violet the Lipinski rule of
five for drug development. One primary consideration for drug
development is its absorption, as the intestine is the primary site
of the absorption during oral administration of the drug. We
studied the percentage of intestinal absorption of drugs for
humans. We found [Pip-Nos]OTf and [Pip-Nos]OAc compounds
have high oral absorption values 79.62% and 85.83%
respectively, with same skin permeability value (log Kp) of -
2.735 Compounds with less than 30% absorption considered to
be poorly absorbed.[37] P-glycoprotein substrate properties
analysis was studied with its important role during the
glycoprotein mediated transport, which may be either exploited.
Another important parameter is to assess the plasma
concentration of the drug; determined by the volume of
distribution (VDss). We found both the compounds are very
lesser absorbed with a score of -0.818 and -0.717 and fraction
unbound values of 0.391 fraction unit and 0.347 fraction unit
respectively for [Pip-Nos]OTf and [Pip-Nos]OAc (Table-1).[38]
Besides, maximum recommended daily dose of drugs for human
were determined using the local weighed methods using the
100
Series1
Noscapine
[PipNos]Acetate
Series2
75
50
25
0
[PipNos] OTf
Series3
0
10
20
30
40
50
60
70
Concentration(micromolar)

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Dhiman, A. Verma, R. Chandra, D. Panda, H.C. Joshi, Synthesis of
Figure-5: Depiction of cytotoxicity analysis of Noscapine,
[Pip-Nos]OAc and [Pip-Nos]OTf on HeLa cells
microtubule-interfering halogenated noscapine analogs that perturb
mitosis in cancer cells followed by cell death, Biochem. Pharmacol.
72 (2006) 415–426. https://doi.org/10.1016/j.bcp.2006.05.004.
3. Conclusion
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CRediT author statement
D. Sood, N. Kumar, A. Singh, M.K. Sakharkar, V. Tomar, R.
Chandra, Antibacterial and Pharmacological Evaluation of
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
The corresponding author is responsible for
ensuring that the descriptions are accurate
and agreed by all authors.
The role(s) of all authors should be listed,
using the relevant above categories.
Authors may have contributed in multiple
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Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
The authors have no conflict of interest

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Highlights
 Design and synthesis of 1,3-benzodioxole
tagged Noscapine based ionic liquids
 Pharmacological analyses of Noscapine
ionic liquids
 In vitro cytotoxicity assay for Noscapine
and lead compounds in HeLa cancer cells
 Noscapine based ionic liquids as potential
cancer curing drug