Synthesis, cytotoxic evaluation, docking and in silico pharmacokinetic prediction of 4-arylideneamino/cycloalkylidineamino 1, 2-naphthoquinone thiosemicarbazones

Article abstract of DOI:10.3109/14756366.2012.721783

In an attempt to develop potent anticancer agents, a series of 4-arylideneamino/cycloalkylidineamino-1, 2-naphthoquinone thiosemicarbazones were synthesized and characterized using FT-IR, ¹H NMR, ¹³C NMR spectroscopy and elemental analysis. The compounds were screened for antiproliferative activity against three human cancer cell lines (Hep-G2, MG-63 and MCF-7) using the MTT assay. Significant anticancer activity was observed for several members of the series. The compounds 4-(3, 4, 5-trimethoxybenzylidene amino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS10) and 4-(4-hydroxy-3-methoxy benzylideneamino) 1, 2-naphthoquinone-2- thiosemicarbazone (TS13) were active cytotoxic agents in all three cancer cell lines, with IC50 values in the range of 3.5-6.4 μM. Further evaluation of some of these potent cytotoxic compounds demonstrated their good safety profile in a normal cell line (MCF-12A). Docking experiments showed a good correlation between the predicted glide scores and the IC50 values of these compounds. In silico ADME studies revealed that these compounds can be used for second generation development.

Full text of DOI:10.3109/14756366.2012.721783

Journal of Enzyme Inhibition and Medicinal Chemistry, 2013; 28(6): 1192–1198
© 2013 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2012.721783
RESEARCH ARTICLE
Synthesis, cytotoxic evaluation, docking and in silico
pharmacokinetic prediction of 4-arylideneamino/
cycloalkylidineamino 1, 2-naphthoquinone
thiosemicarbazones
Shubhanjali Shukla1, Radhey Shyam Srivastava1, Sushant Kumar Shrivastava1,
Ajit Sodhi2, and Pankaj Kumar3
1Department of Pharmaceutics, I.T., Banaras Hindu University, Varanasi, Uttar Pradesh, India, 2School of
Biotechnology, Faculty of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India, and 3School of
Pharmaceutical Science, Siksha ‘O’ Anusandhan University, Bhubaneswar, Orissa, India
Abstract
In an attempt to develop potent anticancer agents, a series of 4-arylideneamino/cycloalkylidineamino-1,
2-naphthoquinonethiosemicarbazonesweresynthesizedandcharacterizedusingFT-IR,1HNMR,13CNMRspectroscopy
and elemental analysis. The compounds were screened for antiproliferative activity against three human cancer cell
lines(Hep-G2,MG-63andMCF-7)usingtheMTTassay.Significantanticanceractivitywasobservedforseveralmembers
of the series. The compounds 4-(3, 4, 5-trimethoxybenzylidene amino) 1, 2-naphthoquinone-2-thiosemicarbazone
(TS10) and 4-(4-hydroxy-3-methoxy benzylideneamino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS13) were
active cytotoxic agents in all three cancer cell lines, with IC50 values in the range of 3.5–6.4 µM. Further evaluation of
some of these potent cytotoxic compounds demonstrated their good safety profile in a normal cell line (MCF-12A).
Docking experiments showed a good correlation between the predicted glide scores and the IC50 values of these
compounds. In silico ADME studies revealed that these compounds can be used for second generation development.
Keywords: Hep-G2, MG-63, MCF-7, MCF-12A, antiproliferative activity, docking
Introduction
and potent chemotherapeutic agents that selectively
Cancer is a severe human health problem worldwide
and the second most common cause of death after
cardiovascular diseases1. Despite of the significant
advancement in chemotherapy over recent decades
in the research and development of various antican-
cer drugs, current anticancer chemotherapy still suf-
fers from major drawbacks, such as lack of selectivity
of conventional chemotherapeutic agents for cancer
tissues, unwanted side effects and the acquisition of
multiple-drug resistance by cancer cells2. So, medici-
nal chemists are currently focusing on novel bio-
logical targets with the aim of providing new specific
destroy cancer cells while sparing their healthy
neighbours.
In 1974, the National Cancer Institute (NCI; Bethesda,
MD, USA) identified the quinone group as an important
pharmacophoric moiety which can exert an antiprolif-
erative effect in cancer cells3. Quinonoidal compounds
from natural or synthetic origins represent the second
largest class of clinically approved anticancer agents4.
Numerous studies have demonstrated the anticancer
effect of naturally occurring 1, 2-naphthoquinones, such
as rhinacanthone5, beta-lapachone6 and mansonones7
(Figure 1a–1c) as well as synthetic 1, 2-naphthoquinones
Address for Correspondence: Dr. Radhey Shyam Srivastava, Pharmaceutical Chemistry, Department of Pharmaceutics, Institute of
Technology, Banaras Hindu University, Varanasi, Uttar Pradesh, India. Tel.: +91542-26702749. Fax: +915422368428.
E-mail: rssriitbhu@yahoo.com; shubpharma@rediffmail.com
(Received 15 May 2012; revised 08 August 2012; accepted 09 August 2012)
1192

1, 2-naphthoquinone thiosemicarbazones as anticancer agents 1193
Materials and methods
Reagents, instruments and cell lines
All the chemicals and solvents of analytical grade used
in the present studies were procured from Merck, Genei
(Bangalore), Himedia (Mumbai) and Aldrich. e syn-
1
thesized compounds were characterized by MP, IR, H
and 13C NMR spectral analysis. Melting points were
determined by Electrothermal Stuart-SMP10, open cap-
illary melting point apparatus and are were uncorrected.
e IR spectra of the compounds were recorded on FT-IR
spectrometer (SHIMADZU Infrared-spectrophotometer,
FTIR-8400S) using KBr pellet technique. e 1H-NMR
and 13C NMR spectra were recorded on JEOL AL300,
FT-NMR spectrophotometer with Operating frequency,
300 MHz at temperature 25°C using DMSO-d6 as solvent
and TMS as internal standard. Chemical shifts (δ) were
reported in ppm. Elemental analysis was performed with
CE-440 elemental analyzer (Exeter Analytical Inc., USA).
e cell lines MCF-7 (human breast cancer), Hep-G2
(liver sarcoma), MG-63 (Osteosarcoma) and MCF-12A
(normal breast epithelial cells) were procured from
National Centre for Cell Sciences Repository, Pune,
India. ese cells were maintained in Dulbecco’s mini-
mum essential medium (DMEM) supplemented with
10% heat-inactivated foetal calf serum and 0.1% antibi-
otic solution (complete medium-CM) at 37°C in humidi-
fied air containing 5% CO2.
Figure 1. Structures of some potent natural and synthetic
anticancer 1, 2-naphthoquinone derivatives.
including 4-hydroxy-3-methyl-1, 2-naphthoquinone
thiosemicarbazone (HM-NQTS)8, 1, 2-furano naph-
thoquinones, 1, 2-pyranonaphthoquinones9, 3-methyl
phenylazolawsone derivatives and their copper com-
plexes (HMPAL)10 (Figure 1d–1f).
An extensive literature survey revealed that the pres-
ence of a 1, 2-dione group embedded in a six membered
ring scaffold was essential for the anticancer activity of
this class of compounds. Changes in the oxygen-oxygen
donor atom system of quinonoidal compounds can have
pronounced effects on their coordination propensities
and biological activities11. e anticancer activity of thi-
osemicarbazones has also received a great deal of atten-
tion and the combination of 1, 2-naphthoquinone with
the potent cytotoxic thiosemicarbazone pharmacophore
has been shown to synergistically increase the antican-
cer effects of parent 1, 2-naphthoquinone derivatives12.
In our previous research paper, we reported the synthesis
of 1, 2-naphthoquinone analogues which can exert anti-
proliferative activity13.
e cytotoxicities of quinonoidal compounds can
be explained by a number of mechanisms including
intercalation, DNA strand breakage, free radical medi-
ated alkylation and inhibition of DNA repair enzymes14.
Frydman et al15. reported that several 1, 2-naphthoqui-
none derivatives can induce DNA-TOPO II-mediated
DNA cleavage, which is crucial for the cytotoxicity of
these compounds.
ese findings pave a way for research to be carried
out in this area and attracted our interest towards the
synthesis of 4-arylideneamino/cycloalkylidineamino
1, 2-naphthoquinone thiosemicarbazones as new anti-
cancer compounds. A hypothetical binding model also
proposed by docking studies to understand the binding
preference of synthesized compounds with the active site
of target enzyme (ATPase domain of Topoisomerase-II).
Further, to get an insight about the drug likeliness of
synthesized compounds, they were subjected to in silico
ADME prediction studies.
General procedure for synthesis of
4-arylideneamino/cycloalkylidineamino 1,
2-naphthoquinone
An equimolar mixture of substituted aryl aldehydes/
cyclic ketones (0.01 M) and 4-amino-1, 2-naphthoqui-
none (0.01 M) in 20 mL ethanol/methanol was refluxed
on a water bath for 6–10 h in the presence of few drops
of glacial acetic acid/concentrated H2SO4 as catalyst. e
progress of the reaction was monitored using thin layer
chromatography (TLC) at appropriate time points. After
completion of the reaction, the solution was cooled and
the separated solid was filtered, washed with ice-cold
water and dried. Finally, the product thus obtained was
recrystallized from ethyl acetate and ethanol in different
proportions.
General procedure for synthesis of 4-arylideneamino
1, 2-naphthoquinone-2-thiosemicarbazones
iosemicarbazide hydrochloride (1.0 mM) dissolved
in 5 mL hot distilled water was added to a suspension
of 4-arylideneamino-1, 2-naphthoquinone (1.0 mM)
in 50.0 mL ethanol. e reaction mixture was refluxed
on a water bath for 4–8 h. e progress of the reaction
was monitored using TLC at appropriate time intervals.
After completion of the reaction, the precipitate formed
was filtered, washed several times with warm ethanol
and dried. Compounds were purified by recrystalliza-
tion or column chromatography whichever was desired.
© 2013 Informa UK, Ltd.

1194 S. Shukla et al.
Spectral data of compound TS01 and TS02 are given
below whereas spectroscopic data of remaining com-
pounds are documented in Supplementary file.
concentration of compounds was added in triplicate to
every well having monolayer of cells and incubated at
37°C in a CO2 incubator for 48 h. After incubation, 30 µL
of 5 mg/mL solution of 3-(4, 5-dimethylthiazol-2-yl)-2,
5-diphenyltetrazolium bromide (MTT) was added to
each well, and the plate was incubated for another 4h.
Incubation at 37°C for 4 h allowed the reduction of MTT
by viable cells to an insoluble formazan product, which
was dissolved by addition of 0.04 N HCl in isopropanol,
and the absorbance of each well was measured by using
ELISA plate reader at 540 nm. Statistical analysis was
performed using Graph Pad prism software, version 5
(Graph Pad software) by nonlinear regression analysis.
IC50 values were calculated for each set of triplicate wells.
4-benzylideneamino 1, 2-naphthoquinone-2-
thiosemicarbazone (TS01)
Yield: 61.4%. M.P. 184–185°C; IR (KBr, υmax·cm−1): 3458.84
(–NH2 str.), 3053.19 (Ar.–C–H str.), 1683.49 (C=O str. of qui-
none), 1626.57 (–CH=N str.), 1576.59 (C=N str.), 1239.75
1
(C=S str.); H NMR (DMSO-d6, 300 MHz) δ (ppm): 13.89
(s, 1H, NH), 9.26, 8.86 (2s, 2H, NH2), 8.31 (s,1H, –CH=N),
6.89–7.79 (m, 9H, Ar–H); 13C NMR (DMSO–d6) δ (ppm):
118.29–140.06 (Aromatic–C, C5-C10, C1’-C6’), 154.29 (–C=N),
157.42 (–CH=N), 177.78 (C=O of quinone), 180.17 (C=S);
anal. calcd. For C18H14N4OS (%): C, 64.65; H, 4.22; N, 16.75;
S, 9.59. Found (%): C, 64.69; H, 4.26; N, 16.73; S, 9.63.
Molecular docking
Molecular docking studies were conducted in order
to validate the obtained pharmacological data and to
provide understandable evidence for the observed anti-
cancer activity of the compounds. e computation was
carried out using the Schrödinger 2011 molecular model-
ling software package. Docking was performed by using
the Glide 5.7 integrated with Maestro 9.2 (Schrödinger,
LLC, 2011) interface on the Linux operating system.
4-(4-nitrobenzylideneamino) 1, 2-naphthoquinone-2-
thiosemicarbazone (TS02)
Yield: 53.2%. M.P. 198–199°C; IR (KBr, υmax·cm−1): 3443.31
(–NH2 str.), 3219.02 (–NH str.) 3078.14 (Ar.–C–H str.),
1678.12 (C=O str. of quinone), 1623.49 (–CH=N str.),
1571.19 (C=N str.), 1367.26, 1520.28 (–N=O str.), 1219.10
1
(C=S str.); H NMR (DMSO–d6, 300 MHz) δ (ppm): 14.08
(s, 1H, NH), 9.42, 8.97 (2s, 2H, NH2), 8.57 (s,1H,–CH=N),
7.48–8.27 (m, 8H, Ar–H); 13C NMR (DMSO–d6) δ (ppm):
127.29–142.53 (Aromatic–C, C5–C10 C1’–C6’), 155.71 (–C=N),
159.33 (–CH=N), 178.67 (C=O of quinone),181.31 (C=S);
anal. calcd. For C18H13N5O3S (%): C, 56.98; H, 3.45; N, 18.46;
S, 8.45. Found (%): C, 57.01; H, 3.42; N, 18.50; S, 8.41.
In silico ADME predictions of the best fit molecules
e ultimate goal of drug discovery is the identification
of innovative small molecular scaffolds exhibiting high
binding affinity and selectivity for the target enzyme
together with a reasonable absorption, distribution,
metabolism and excretion (ADME) profile. Such chemi-
cal entities are likely to carve a niche in the horizon of
drug development process. e best fit ligands were neu-
tralized and checked for their ADME properties using
Qikprop17.
Since quinones are good electrophiles so they can eas-
ily be attacked by Glutathione (GSH) in the liver, resulting
in the formation of GSH-quinone conjugates, which is the
natural defence exerted by our body to reduce toxicity of
electrophillic drugs like quinone18,19. Hence possibility
of most active compound (TS10) to form glutathione
conjugate was predicted by using software Pallas v3.1.1.2
which generated a pool of possible metabolites of TS1020.
General procedure for synthesis
of 4-cycloalkylidineamino 1,
2-naphthoquinone-2-thiosemicarbazones
To the boiling solution of 4-cycloalkylidineamino 1,
2-naphthoquinone (0.01 M) in 50 mL of ethanol, few
drops of glacial acetic acid were added. ereafter, thi-
osemicarbazide hydrochloride (0.01 M) dissolved in
15 mL of water was added drop wise with stirring. e
reaction mixture was refluxed for 10–12 h. On cooling the
precipitate formed was filtered and recrystallized with
methanol.
In vitro antiproliferative activity
e cytotoxicity of compounds TS01-TS18 was evaluated
against MCF-7 (human breast cancer), Hep-G2 (liver
sarcoma) and MG-63 (Osteosarcoma) cell lines using the
standard MTT assay16. Doxorubicin, a quinone derivative
and a clinical antitumor drug, was used as a marker to
evaluate the relative cytotoxic efficiency of synthesized
compounds. Compounds TS09, TS10, TS11 and TS13
were further evaluated against MCF-12A, a normal epi-
thelial cell line.
e cells were seeded in a 96-well plate at the density of
approximately 20,000 cells per well and allowed to attach
for 24 h. Various concentrations (1–25 µM) of the test
compounds were prepared by dissolving them in DMSO
and then by serially diluting with culture medium. Each
Results and discussion
Synthesis of 4-arylideneamino/cycloalkylidineamino
1, 2-naphthoquinone thiosemicarba-zones
e synthetic route of the target compounds TS01–TS18 is
illustrated in Scheme 1. According to previously reported
method, synthesis of starting materials 1, 2-naphtho-
quinone was accomplished from water soluble dye
β-naphthol orange13. 4-amino 1, 2-naphthoquinone
(ANQ), the key intermediate for the synthesis of target
compounds was obtained through nucleophilic sub-
stitution of 1, 2-naphthoquinone with sodium azide in
acetic acid. Condensation of ANQ with appropriate aryl
aldehydes/cyclic ketones in presence of glacial acetic
Journal of Enzyme Inhibition and Medicinal Chemistry

1, 2-naphthoquinone thiosemicarbazones as anticancer agents 1195
Scheme 1. General pathway for the synthesis of 4-arylideneamino/cycloalkylidineamino 1, 2-naphthoquinone-2-thiosemicarbazones,
reagents & conditions (i) Na2S2O4, stirring at 40–50°C; (ii) FeCl3 in conc. HCl with crushed ice, add with stirring; (iii) sodium azide in
water and glacial acetic acid, heated to 40°C; (iv) a. aromatic aldehydes, glacial acetic acid, ethanol/methanol, reflux 6–10h (iv) b.
cyclic ketones, concentrated H2SO4, ethanol/methanol, reflux 8–10 h and (v) a. thiosemicarbazide hydrochloride, ethanol, reflux 4–8 h,
(v) b. thiosemicarbazide hydrochloride, ethanol, reflux 10–12 h.
acid/conc. H2SO4 as catalyst afforded the formation of
4-arylideneamino/cycloalkylidineamino 1, 2-naphtho-
quinones. Derivatization of one of the carbonyl group
of 4-arylideneamino/cycloalkylidineamino 1, 2-naph-
thoquinones with thiosemicarbazide side chain led to
synthesis of proposed compounds [TS01-TS18].
peak was observed in the range of 182–180 ppm due
to presence of C=S group of compounds. Presence of
a characteristic singlet peak in H NMR in the range of
8.11–8.68 δ ppm confirmed the presence of azomethine
proton (–CH=N–).
1
Derivatizing one of the quinone carbonyl oxygen in
4-arylideneamino/cycloalkylidineamino 1, 2-naph-
thoquinone with thiosemicarbazide side chain gave
rise to additional bands in the range of 3219–3381 and
3411–3491 cm−1 in the IR spectrum of synthesized com-
pounds which revealed the asymmetric and symmetric
stretches of the amino group. Strong imine absorption at
1562–1593 cm−1 due to C=N linkage also confirmed the
successful derivatization.
1H NMR spectrum of thiosemicarbazone derivatives
showed a singlet in the range of 13.78-14.11 ppm due
to NH proton of thiosemicarbazone and 2 singlet were
observed at 9.17–9.45 and 8.79–8.98 ppm which showed
that2protonsofNH2 grouparemagneticallyinequivalent.
In 13C NMR spectrum of thiosemicarbazone derivatives,
Antiproliferative activity
e synthesized compounds were evaluated for antip-
roliferative activity against a panel of three cancer cell
lines MCF-7, Hep-G2 and MG-63 using MTT assay with
doxorubicin as the positive control and the results are
expressed as IC50 in Supplementary Table S1.
Majority of the compounds exhibited promising anti-
cancer potency against MCF-7 and Hep-G2 cell lines but
were found to be less active against MG-63. Compounds
TS10 & TS13 displayed remarkable cytotoxicity against
the MCF-7 cell line with IC50 values 3.5, 3.81 µM respec-
tively which is very close to standard drug doxorubicin.
Microscopic images of morphological changes in cells
after treatment with compound TS10 are shown in
Figure 2. Compounds TS01, TS06, TS07, TS08, TS12, TS15
© 2013 Informa UK, Ltd.

1196 S. Shukla et al.
and TS16 were significantly active against MCF-7 and
Hep-G2 but nonsignificant for MG-63. Compounds TS02
and TS03 were found to be least active in the series (IC50
12.17–20.07 µM).
7.55–12.41 µM) in all tested cell lines. e cytotoxic activ-
ity gets enhanced by the replacement of the phenyl ring
with the cyclopentyl or cyclohexyl ring.
e major challenging aspect of synthesizing new
chemotherapeutic agents is selectivity towards cancer-
ous cells compared to the normal cells. erefore, we
have studied the cytotoxic efficacy of some of the potent
compounds TS09, TS10, TS11 & TS13 on MCF-12A, a
normal epithelial cell line. Compounds showed only
25–35% cell death in the MCF-12A cell line (Figure 3);
thus the compounds are selective toward cancerous cells
with high margin of safety.
On the basis of cytotoxicity screening, the prelimi-
nary structure activity relationship study suggested that
compounds with electron donating groups on phenyl
ring were generally more potent than compounds having
phenyl ring with electron withdrawing substituents. e
pharmacological data indicated that 3, 4, 5-trimethoxy-
phenyl analogue (TS10) showed approximate 3–4 fold
improvement in cytotoxicity against all the cell lines (IC50
3.5–6.14 µM) compared with phenyl analogue having
electron withdrawing nitro group at 4th position (TS02,
IC50 13.98–20.07 µM).
Inspection of cytotoxicity data of compounds TS04
and TS14 showed that migration of hydroxyl group from
2nd position of phenyl ring (TS14, IC50 7.24–9.04 µM)
to 4th position of phenyl ring (TS04, IC50 5.42–9.08 µM)
enhanced the activity. In nitro-substituted analogues,
presence of electron withdrawing group on the 4th posi-
tion (TS02, IC50 13.98–20.07 µM) led to decreased activity
as compared to nitro group at 2nd position (TS12, IC50
Molecular docking
estructureofthehumanTopoisomerase-IIATPase(TP-
II) co-crystallized with AMP-PNP complex [PDB:1ZXM]
was retrieved from the Protein Data Bank [www.rcsb.org
(DOI: 10.2210/pdb1zxm/pdb)] and further modified for
docking calculations by deleting the substrate cofactor
as well as the crystallographically observed water mol-
ecules. e active site of the protein was defined for gen-
erating the grid. Glide calculations were carried out with
Impact version v57111 and the Glide scores are shown in
Supplementary Table S1.
It was observed that the most active compounds of the
series, TS10 and TS13 were predicted to be most active
in silico. Some other compounds like TS04, TS05, TS06,
TS09, TS11, TS15 having significant biological activity are
also found to have good glide scores. e afore findings
confirms that the experimental results of wet lab are in
good agreement with the predicted ones as observed
from the glide score. Standard drug doxorubicin was
used to probe the hydrophilic and hydrophobic interac-
tions between synthesized ligands and topoisomerase-II.
Glide predicted binding interactions of doxorubicin and
compound TS13 were shown in Supplementary Figures
S1 and S2, respectively.
However, some compounds like TS17 and TS18 having
cycloalkylidene group did not exhibit good glide scores
Figure 2. Morphological changes in MCF-7 cells incubated
for 48 h, (A) negative control (B) with 5 µM concentration
of compound TS10, morphological changes in Hep-G2
cells incubated for 48 h, (C) negative control (D) with 5 µM
concentration of compound TS10, morphological changes in
MG-63 cells incubated for 48 h, (E) negative control (F) with 5
µM concentration of compound TS10. e cells were observed
under phase contrast microscope 100×.
Figure 3. Percentage cytotoxicity of MCF-12 A, a normal epithelial
cell line at various concentration (1–25 µM) of compounds TS09,
TS10, TS11 and TS13.
Journal of Enzyme Inhibition and Medicinal Chemistry

1, 2-naphthoquinone thiosemicarbazones as anticancer agents 1197
but were found to have significant activity. It is possible
that these compounds may act through a different mech-
anism, and further studies are required to elucidate their
mechanism of action.
Lal Nehru Memorial Fund, New Delhi for the grant of fel-
lowship to Mrs. Shubhanjali Shukla.
Declaration of interest
In silico ADME predictions of the best fit molecules
Qikprop helps in analysing the pharmacokinetics and
pharmacodynamics of the ligand by accessing the drug
like properties. As revealed in Supplementary Tables S2
and S3, all the best-fit compounds were found to be non
toxic for CNS, value of permeability less than 500 through
MDCK Cells indicated the non permeability of com-
pounds through blood-brain barrier, a desirable aspect.
Apart from this, majority of compounds were predicted
to possess significant oral absorption. None of the best
fit compounds violated the Lipinski rule of five as well as
log P, donor HB and acceptor HB were within the range
indicated the drug like behaviour of compounds.
e possible metabolites prediction of most active
compound with software Pallas v 3.1.1.2 indicated
that the compound can form GSH conjugate so the
toxic metabolites of electrophillic quinone compound
can be scavenged by natural defence biomarker GSH
(Supplementary Figure S3).
e authors report no conflicts of interest.
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Conclusion
In summary, we have successfully synthesized and
characterized a library of 4-arylideneamino/ cycloal-
kylidineamino 1, 2-naphthoquinone thiosemicarbazone
derivatives of biological interest. ese compounds
exhibited promising anticancer activity against selected
human cancer cell lines (MCF-7, Hep-G2 and MG-63).
Some of the potent compounds were further evaluated
for cytotoxicity against one normal cell line (MCF-12A)
and exhibited selective killing of cancer cells as com-
pared to normal cell line. e results of in vitro antipro-
liferative screening of synthesized compounds revealed
that the compounds TS09, TS10, TS11, TS13, TS14, TS17
and TS18 showed significant cytotoxicity against all the
cancer cell lines. e wet lab findings are also supported
by molecular docking studies. Along with that, results of
in silico pharmacokinetic predictions revealed the drug
likeliness of synthesized compounds, so they are more
likely to move on to higher phases of the drug develop-
ment process and provide useful insights about the struc-
tural requirements necessary for carrying out rationally
based pharmacophoric modifications in order to obtain
promising compounds with anticancer effects.
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Acknowledgments
e authors express their sincere thanks to the Head,
Department of Chemistry, Faculty of Science, Banaras
Hindu University, Varanasi, India for providing the facili-
ties of 1H NMR and 13C NMR spectroscopy. We gratefully
acknowledge the financial assistance given by Jawahar
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Journal of Enzyme Inhibition and Medicinal Chemistry