Synthesis of new 1,3-thiazol derivatives of maleopimaric acid as anticancer, antibacterial and antifungal agents

Article abstract of DOI:10.1080/14786419.2019.1648459

A series of new 1,3-thiazole derivatives of maleopimaric acid 6a–f, 7a–f were synthesized and evaluated for anticancer, antibacterial and antifungal activities. Evaluation of cytotoxic activity against human embryonic kidney 293 cells (HEK293), human neuroblastoma cell line (SH-SY5Y), hepatocellular carcinoma cell line (HepG2) and human T-cell lymphoblast-like line (Jurkat), showed that introduction of the aminothiazole fragment at position 6 of the diterpenoid molecule leads to decrease of cell viability. Substance 3 was found to be the most active against all tested cell lines, inhibiting cell viability with IC₅₀ values in the range of 2–24 μM. The structure–activity relationship of these compounds was studied and the results show that the compounds 6c and 7e exhibited in vitro antifungal activity against Candida albicans and also possessed antibacterial profile against Enterobacter aerogenes, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Proteus vulgaris.

Full text of DOI:10.1080/14786419.2019.1648459

Natural Product Research
Formerly Natural Product Letters
ISSN: 1478-6419 (Print) 1478-6427 (Online) Journal homepage: https://www.tandfonline.com/loi/gnpl20
Synthesis of new 1,3-thiazol derivatives of
maleopimaric acid as anticancer, antibacterial and
antifungal agents
Rimma M. Sultanova, Alexander N. Lobov, Alina V. Shumadalova, Svetlana
A. Meshcheryakova, Zulfia R. Zileeva, Nailya S. Khusnutdinova, Vener A.
Vakhitov & Yulia V. Vakhitova
To cite this article: Rimma M. Sultanova, Alexander N. Lobov, Alina V. Shumadalova,
Svetlana A. Meshcheryakova, Zulfia R. Zileeva, Nailya S. Khusnutdinova, Vener A. Vakhitov
& Yulia V. Vakhitova (2019): Synthesis of new 1,3-thiazol derivatives of maleopimaric
acid as anticancer, antibacterial and antifungal agents, Natural Product Research, DOI:
10.1080/14786419.2019.1648459
To link to this article: https://doi.org/10.1080/14786419.2019.1648459
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NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1648459
Synthesis of new 1,3-thiazol derivatives of maleopimaric
acid as anticancer, antibacterial and antifungal agents
Rimma M. Sultanovaa , Alexander N. Lobova , Alina V. Shumadalovab,
Svetlana A. Meshcheryakovab, Zulfia R. Zileevac, Nailya S. Khusnutdinovac,
Vener A. Vakhitovc and Yulia V. Vakhitovac
aUfa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa,
b
c
Russian Federation; Bashkir State Medical University, Ufa, Russian Federation; Institute of
Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa,
Russian Federation
ABSTRACT
ARTICLE HISTORY
Received 12 April 2019
Accepted 20 July 2019
A series of new 1,3-thiazole derivatives of maleopimaric acid 6a–f,
7a–f were synthesized and evaluated for anticancer, antibacterial
and antifungal activities. Evaluation of cytotoxic activity against
human embryonic kidney 293 cells (HEK293), human neuroblast-
oma cell line (SH-SY5Y), hepatocellular carcinoma cell line
(HepG2) and human T-cell lymphoblast-like line (Jurkat), showed
that introduction of the aminothiazole fragment at position 6 of
the diterpenoid molecule leads to decrease of cell viability.
Substance 3 was found to be the most active against all tested
cell lines, inhibiting cell viability with IC50 values in the range of
2–24 lM. The structure–activity relationship of these compounds
was studied and the results show that the compounds 6c and 7e
exhibited in vitro antifungal activity against Candida albicans and
also possessed antibacterial profile against Enterobacter aerogenes,
Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pyo-
genes, Escherichia coli and Proteus vulgaris.
KEYWORDS
Maleopimaric acid;
a-bromoketones; a-diazoke-
tone; thiourea; Hantzsch
reaction; thiazoles;
cytotoxic activity;
antimicrobial activity
1. Introduction
Nitrogen and sulfur-containing significant heterocyclic compounds, such as thiazoles,
play an important role in modern synthetic and medicinal chemistry due to their C–N
and C–S bonds in the ring structure, which are found in many chemistry applications
(Frija et al. 2016). The 2-aminothiazole moiety is frequently found in biologically active
CONTACT Rimma M. Sultanova
sultanova_rm@anrb.ru
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1648459.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group

2
R. M. SULTANOVA ET AL.
molecules (Safari et al. 2016), (Abraham and Prakash 2017). They are useful for drug
design processes in medicinal chemistry due to their thiourea-like properties and ten-
dency to modulate biological targets (Baell and Holloway 2010). Therefore, in recent
times, increasing attention has been paid for the synthesis of this class of heterocycles.
The most straight forward synthesis of this heterocyclic compounds involves conden-
sation of a-bromoketone with thiourea (Kidwai et al. 2009), the reaction of a-thiocya-
nato carbonyl compounds with aromatic or aliphatic amine hydrochlorides (Aoyama
et al. 2006), treatment of styrene and thiourea with NBS (Donohoe et al. 2010) and
the condensation of aromatic ketone and thiourea with homogeneous and heteroge-
neous catalysts (Zhao et al. 2015).
Plant metabolites are widely used as structurally unique building blocks for the cre-
ation of new drugs (Tolstikov et al. 2011). Resin (diterpenoic) acids are the main com-
ponent of rosin and resinous resin of coniferous trees and serve as a source for
obtaining a variety of derivatives for both conjugated double bonds and the func-
tional carboxyl group. A convenient method for obtaining individual derivatives of
diterpenes is diene synthesis with active dienophiles, for example, maleic anhydride
(Halbrook et al. 1964).
Herein, we report the synthesis of new 1,3-thiazoles containing a diterpene frag-
ment via chemical modification of maleopimaric acid to the carboxyl function without
altering the diterpene scaffold with a target for enhancing or changing the biological
properties and investigation their anticancer, antibacterial, and antifungal activities.
2. Results and discussion
2.1. Chemistry
Maleopimaric acid (MPA) 1 – adduct of diene synthesis of pine sap Pinus Silvestris
containing ꢀ 30% levopimaric acid, with maleic anhydride (Rao et al. 2008) and N-
phenylimide maleopimaric acid 2 (Bei et al. 2015) was chosen for the modification.
Then, by treatment with excess thionyl chloride in dry benzene, the acids 1 and 2
were converted into the corresponding acid chlorides with a quantitative yield
(Koroleva et al. 2012). Subsequent interaction with diazomethane in anhydrous methy-
lene chloride led to the formation of a-diazoketones, which were converted to a-bro-
moketones 3 and 4 by the action of HBr (Figure 1). The obtained bromoketones 3, 4
were used to obtain a series of aminothiazoles 6a–f, 7a–f containing a diterpene frag-
ment by the Hantzsch reaction (Figure 1).
Reagents and conditions: (i) PhNH2, C6H5CH3, reflux, 8 h; (ii) SOCl2, C6H6, 20–23ꢁC,10 h;
(iii) CH2Cl2, CH2N2, ꢂ5 to 0 ꢁC, (iv) HBr, 20–23ꢁC, CH2Cl2, and (v) C6H6, reflux.
The structure of the obtained 1,3-thiazoles, containing a diterpene fragment
6a–f,7a–f, was confirmed by the methods of IR-spectroscopy, mass spectrometry and
1H, 13C NMR spectroscopy. In the IR spectrum, there is no absorption band of the
C ¼ O group (1717 cmꢂ1) and a characteristic absorption band of the C ¼ N group in
13
the 1610 cmꢂ1 region is observed. In the ‘ NMR spectrum, characteristic signals of
carbon atoms C (20) and C (40) and C (50) of the thiazole cycle appear in a weak field
at 161–170, 149–152 and 99–115 ppm, respectively.

NATURAL PRODUCT RESEARCH
3
Figure 1. Synthesis of new 1,3-thiazoles 6a–f, 7a–f.
2.2. Cytotoxicity assay
The chemically modified MPA derivatives containing a thiazole fragment were eval-
uated for in vitro cytotoxic activity towards the HEK293, SH-SY5Y, Jurkat, and HepG2
cell lines. Cell line panel consisting of cancerous cells of different tissue origin (lymph-
oid, neuronal-like and hepatic cells) and the conditionally-normal cells (e.g. HEK293)
was used to explore the selective cytotoxicity of compounds toward tumor or normal
cells. Previously, we showed that maleopimaric acid 1 demonstrates very weak cyto-
toxic properties against conditionally normal and cancer cell lines (Sakhautdinov et al.
2018). Analysis of the data obtained (Table 1) shows that the introduction of the N-
phenylimide group into the molecule of bromoketone derived from maleopimaric acid
is accompanied, generally, by a decrease of the cytotoxic ability of the evaluated com-
pounds, with the exception of the 6a/7a pair. Comparison of compounds that do not
contain the N-phenylimide cycle, revealed that substance 3 is the most active against
all cell lines tested, inhibiting cell viability with IC50 values in a range of 2–24 lM,
depending on the cell line tested. It can be assumed that the relatively high cytotoxic
activity of this compound is due to the presence of a halogen atom. Introduction of
the pharmacophoric aminothiazole fragment at position 6 of the diterpenoid molecule,
via chemical modification of maleopimaric acid to the carboxyl function (6a com-
pound), leads to a certain decrease of cell viability.
Compounds 6d and 6e containing phenyl or o-tolyl substituents at the 2 position
of the thiazole ring, respectively, have pronounced cytotoxic properties, especially
towards the HEK293 and Jurkat cell lines. Compounds containing 2-methyl- (6f),
2-allyl- (6c) and 2-acetyl- (6b) aminothiazoles exhibit moderate cytotoxic activity.
2.3. Antimicrobial activity
According to the literature, abiethan diterpenes are active against gram-positive and
gram-negative bacteria and various types of fungi (Moujir et al. 1993; Savluchinske-
Feio et al. 2006). The diene adduct of levopimaric acid with acrylic acid and a number
of Schiff bases synthesized on its basis are active against strains of S. aureus and

4
R. M. SULTANOVA ET AL.
Table 1. In vitro cytotoxic activity of synthesized compounds in human cell lines (HEK293,
SH-SY5Y, Jurkat and HepG2).
IC50 (mM)a
Compounds
1c
3
HEK293
Jurkat
HepG2
SH-SY5Y
b
b
195.5 9.8
14.17 1.04
80.5 6.7
–
–
2.18 0.44 (p¼0.00001)d
23.85 0.01
(p¼0.00001)d
>100
6.21 1.27
(p¼0.001)d
52.54 1.43
(p¼0.00009)d
17.77 1.94
(p¼0.003)d
18.12 0.57
4
72.46 2.67
25.14 0.72
17.8 2.07
17.53 5.30
(p¼0.00001)d
27.65 1.47
6a
6b
6c
6d
6e
6f
47.19 2.63
(p¼0.00002)d
47.16 3.55
(p¼0.00006)d
37.97 1.00
(p¼0.00003)d
57,04 1.40
(p¼0.00001)d
41.20 5.93
(p¼0.00002)d
76.37 1.63
(p¼0.00001)d
>100
31.77 3.78
(p¼0.03)d
20.30 0.08
15.13 3.15
5.36 2.10
25.26 2.49
(p¼0.01)d
23.29 5.61
9.73 1.55
11.67 0.10
26.75 3.49
22.21 5.61
9.60 0.52
22.76 7.61
23.70 0.25
89.29 21.75
26.83 3.21
25.98 1.50
14.65 1.76
(p¼0.05)d
7a
7b
7c
7d
20.47 2.86
67.61 11.73
(p¼0.0007)d
>100
36.60 4.52
(p¼0.004)d
59.18 16.68
(p¼0.01)d
65.73 4.58
(p¼0.00001)d
>100
>100
>100
>100
>100
>100
7e
7f
>100
>100
>100
>100
>100
>100
>100
Doxorubicin
1.90 0.04
5.42 0.38
7.21 0.16
0.22 0.005
aIC50 (lM) values obtained from MTT assays. Cells were incubated with compounds for 48 h. Values were the
mean SD from two independent experiments, performed in triplicate;.
bnot measured;
c(Sakhautdinov et al. 2018);
dCorresponding cell line versus HEK293 cells. IC50 values differences for certain cell lines proved by one-way ANOVA
with Dunnett’s Post Hoc test.
E. coli (Li et al. 2013). Quaternary ammonium salts of maleopimaric acid exhibit pro-
nounced antimicrobial activity against P. aeruginosa, E.coli, K. pneumoniae, P. vulgaris,
E. agglomerans, S. typhimurium, A. faecalis, S. aureus, B. cereus, S. pyogenes, M. luteus,
M. smegmatis, C. xerosis (Wang et al. 2012).
In this regard, it was of interest to study the effect of new derivatives of maleopi-
maric acid and maleopimarilimide containing a 2-aminothiazole fragment on the
growth of strains of gram-negative and gram-positive bacteria, lower fungi C. albicans.
The investigation of antibacterial screening data revealed that the compound 1
(MPA) and its derivatives showed good inhibition towards all tested gram-positive and
gram-negative bacteria and lower fungi C. albicans at 50 mg/ml concentrations
(Table 2).
Derivative of MPA 6c and 2-phenylmaleopimarilimide 7e, containing, respectively,
2-N-allylamine- and 2-N-(o-tolyl)aminothiazole moiety at position 6 (Table 2) showed
good antibacterial (MIC 0.39–12.5 mg/ml) and antifungal (MIC 0.195–0.78 mg/ml) activ-
ities. However, 6c showed weak antimicrobial activity (MIC 50 mg/ml) against
Pseudomonas aeruginosa.

NATURAL PRODUCT RESEARCH
5
Table 2. Antibacterial and antifungal activities of synthesized compounds.
Minimum inhibitory concentrations (MIC), mg/ml
Compounds
S. aureus S. pyogenes E. coli P. vulgaris K. pneumoniae Ent. aerogenes P. aeruginosa E. cloacae C. albicans
1
2
3
6a
6c
6d
6e
7a
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
12.5
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
3.12
3.12
6.25
6.25
1.56
6.25
0.78
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
7d
7b
7e
0.39
–
–
–
–
0.78
0.39
0.78
1.56
0.39
1.56
0.39
1.56
0.195
25
7.8
1.0
0.39
miconazole
nystatin
fluconazole
Amphoterecin B
gentamycin
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0.39
32
0.78
>128
Kanamycin (MIC90) 2.0
16
Based on the data obtained it was possible to investigate some structure-activity
relationships: replacement a carboxyl group with a 2-aminothiazole fragment in the
MPA molecule or the presence of an N-phenylimide fragment due to modification of
the anhydride cycle does not lead to an increase in antimicrobial and antifungal activ-
ities. Among the MPA derivatives with N-substituted 2-aminothiazole fragments at
position 6, the compound with the N-allyl radical is the most active, and in the case
of maleopimarilimide, the presence of an o-toluidine substituent leads to pronounced
antimicrobial and antifungal activities against studied test cultures.
It should be noted that the obtained results are not enough to establish a strict
pattern between the chemical structure of the synthesized compounds and their anti-
microbial activity, however, they correlate with the available literature that the intro-
duction of aromatic groups into Schiff bases improves their antibacterial activity
(Faizul et al. 2007; Salimon et al. 2010).
According to the results obtained it is important to continue research for new anti-
microbial and antifungal drugs in a series of maleopimaric acid and maleopimarilimide
derivatives, the structure of which is fundamentally different from the known antibac-
terial drugs.
3. Experimental
3.1. General
All reagents and starting materials were obtained from commercial sources and used
as received. All solvents were dried according to standard literature procedures. All
reactions were performed under an atmosphere of argon unless indicated otherwise.
1H NMR, 13C NMR, and 15N NMR spectra were recorded on a Bruker Avance-III 500 MHz
spectrometer with chemical shift values in parts per million (ppm) relative to TMS (dH
0.00 and dC 0.0) or residual chloroform (dH 7.28 and dC 77.2) as standard. Proton,

6
R. M. SULTANOVA ET AL.
carbon and nitrogen assignments are based on two-dimensional HSQC, HMBC, COSY,
and DEPT experiments. Mass spectra were obtained using a Thermo Finnigan MAT 95
XP spectrometer. Infrared spectra were obtained neat using a Shimadzu IR-Prestige-21
spectrometer. Melting points were measured on a micro melting point apparatus.
Synthesis of Maleopimaric acid 1 (Gonis et al. 1973), the acid chloride MPC
(Koroleva et al. 2012), Maleopimaric acid N-phenylamide 2 (Bei et al. 2015) is described
in the literature. All starting thiourea, N-acyl-, N-allyl-, N-phenyl-, N-o-tolylthiourea, thio-
acetamide are commercially available.
3.2. General synthesis of a-diazoketones
To a 180 ml ether solution of diazomethane (from 18 g of N-nitroso-N-methyl urea)
was added dropwise over 1 h a solution of 3.925 g (0.06 mol) of MPC chloride in 20 ml
of methylene chloride, with constant stirring and at ꢂ5ꢁ C. Then the reaction mixture
was heated to room temperature and stirred for another 2 h. The solvent was removed
under reduced pressure. The resulting diazoketone was recrystallized from petrol-
eum ether.
3.3. General synthesis of a-bromoketones 3,4
With a stirring, 1 ml of a 48% aqueous solution of HBr was added to a solution of
1 mmol of a diazoketone in 10 ml of CH2Cl2. After the end of gas evolution, the solu-
tion was stirred for 1 h, then the organic layer was separated, washed with 5% soda
solution and dried over MgSO4. After distilling off the solvent, the crude product was
washed with diethyl ether.
3.4. General synthesis of 1,3-thiazols 6a–f,7a–f
The thio compound 5a–f 1 mmol was dissolved by heating in 10 ml of MeOH, 0.477 g
of 1 mmol of bromoketone 3 in 10 ml of benzene or 0.552 g of 1 mmol of bromoke-
tone 4 in 10 ml of CH2Cl2 was added. The solution was boiled for 1 h and cooled. The
solvent was removed in a water jet vacuum. The crude product was washed and crys-
tallized from petroleum ether.
3.5. Cell culture and cell viability assay
Compounds were assessed for their cytotoxic activity against human embryonic kidney
293 cells (HEK293), human neuroblastoma cell line (SH-SY5Y), hepatocellular carcinoma
cell line (HepG2) and human T-cell lymphoblast-like line (Jurkat) using the 3-(4,5-dime-
thylthiazol2-yl)2,5-diphenyltetrazolium bromide (MTT) assay (Mosmann 1983). HEK293,
SH-SY5Y, and HepG2 cells were maintained in DMEM (Biolot, Russia) supplemented
with 2 mM L-glutamine (Biolot, Russia), 50 mg/mL gentamicin sulfate (Invitrogen, USA)
and 10% fetal bovine serum (FBS, Invitrogen, USA). Jurkat cells were maintained in
RPMI (Invitrogen, USA) supplemented with 1% L-glutamine, 50 mg/mL gentamicin sul-
fate and 10% FBS. All cells were cultured at 37 ꢁC and 5% CO2. Cells were seeded on

NATURAL PRODUCT RESEARCH
7
96-well plates at a density of 2 ꢃ 104 cells/well for HEK293, 3 ꢃ 104 cells/well for SH-
SY5Y, 2 ꢃ 104 cell/well for HepG2 and 1 ꢃ 105 cells/well for Jurkat cells. Studied com-
pounds were previously dissolved in 100% DMSO (Sigma-Aldrich, UK) to 100 mM stock
solutions and diluted in completed DMEM or RPMI immediately before adding them
to the assay plates. After 24 h of culturing cells were treated with compounds at final
concentrations of 1, 10, 100 mM for 48 h. A final concentration of DMSO in samples
and controls on the plate was 0.1%. Cell viability was determined by conventional
R
V
MTT assay according to the manufacturer’s instruction using «2300 EnSpire
Multimode Plate Reader» (Perkin Elmer, USA) at 540 nm. The dose of the compound
that inhibited 50% cell the viability (IC50 value) was calculated using nonlinear regres-
sion analysis (GraphPad Prism v.5.02; GraphPad Software Inc., USA). The viability of
control group was set at 100%, and viability of treated groups was determined
through the comparison of its optical density with control. Data were expressed as
mean SD calculated from two independent experiments, performed in triplicate.
Differences between experimental groups were analyzed by one-way ANOVA followed
by Dunnett’s Post Hoc test.
3.6. Antimicrobial activity
Antibacterial and antifungal activities of the compounds 1–11 were assayed using the
agar diffusion and the twofold broth (pH 7.2–7.4) dilution methods (Mironov 2012).
Microbial strains of the Department of Microbiology and Virology, Bashkir State
Medical University deposited at L.A. Tarasevich State Institute of Standardization and
Control of Biomedical Preparations, the Ministry of Health of the Russian Federation
were used as test organisms: E. coli, E. cloacae, E. aerogenes, P. vulgaris, K. pneumoniae,
Ps. aeruginosa, St. aureus, Str. pyogenes and lower fungi C. albicans. Test compounds
(10 mg) were weighed and dissolved in 1 ml DMSO. These solutions were then diluted
in beef extract broth to achieve a final concentration of 0.1 mg/ml (stock solution).
The nutrient broth, which contained a logarithmic serially twofold diluted amount of
test compound inoculated with 2.0 ꢃ 106 c.f.u/ml was used. The cultures were incu-
bated for 24 h at 37 ꢁC and the growth was monitored visually. The lowest concentra-
tion (highest dilution) required to arrest the growth of bacteria was regarded as
minimum inhibitory concentration (MIC). Minimum inhibitory concentration values are
given in Table 2.
4. Conclusion
Twelve new thiazole-containing derivatives of maleopimaric acid have been success-
fully obtained and tested as potential anti-cancer, anti-microbial and antifungal agents.
All compounds showed moderate cytotoxic activity with respect to the HEK293, SH-
SY5Y, Jurkat and HepG2 cell lines compared to the parent maleopimaric acid (IC50
195.5 mM). Among the studied compounds, a-bromoketone 3 was the most active,
which suppressed cell viability in the range of IC50 values from 2 to 24 lM, depending
on the cell line. This study offers the possibility of using derivatives of natural products

8
R. M. SULTANOVA ET AL.
(diterpenic acids) as a reactive scaffold for obtaining new potential chemotherapeutic
agents for the treatment of certain forms of cancer.
At the same time, compounds 6c and 7e show a particularly attractive combination
of high antifungal and antibacterial activities with low cytotoxicity.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by State assignments @ AAAA-A17-117011910025-6, @ AAAA-A17-
117011910027-0 and @ AAAA-A16-116020350033-8. Experiments were carried out using the
equipment of Collective Use Service Centers «Chemistry» and «Biomics».
ORCID
Rimma M. Sultanova
Alexander N. Lobov
http://orcid.org/0000-0001-6719-2359
http://orcid.org/0000-0002-9223-508X
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