Multicomponent synthesis and anticancer activity studies of novel 6-(Trifluoromethyl)-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate derivatives

Article abstract of DOI:10.1080/00397911.2018.1490769

A series of novel 6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives were obtained in good yields from ethyl 4,4,4-trifluoro-3-oxobutanoate, urea, and aryl aldehyde via Biginelli multicomponent reaction. All the corresponding products 4a–4p were examined against four human cancer cell lines (A549, HepG2, COLO205 and DU145) and compounds 4e, 4i, and 4 m which showed promising anticancer activity have been identified.

Full text of DOI:10.1080/00397911.2018.1490769

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Multicomponent synthesis and anticancer activity
studies of novel 6-(Trifluoromethyl)-1, 2, 3, 4-
tetrahydropyrimidine-5-carboxylate derivatives
Anil Valeru, Zhi-Bin Luo, Imran Khan, Bin Liu, Bhavanarushi Sngepu,
Narender Reddy Godumagadda, Yin Xu & Jimin Xie
To cite this article: Anil Valeru, Zhi-Bin Luo, Imran Khan, Bin Liu, Bhavanarushi Sngepu, Narender
Reddy Godumagadda, Yin Xu & Jimin Xie (2018): Multicomponent synthesis and anticancer activity
studies of novel 6-(Trifluoromethyl)-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate derivatives,
Synthetic Communications, DOI: 10.1080/00397911.2018.1490769
To link to this article: https://doi.org/10.1080/00397911.2018.1490769
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https://doi.org/10.1080/00397911.2018.1490769
Multicomponent synthesis and anticancer activity studies
of novel 6-(Trifluoromethyl)-1, 2, 3, 4-tetrahydropyrimidine-
5-carboxylate derivatives
Anil Valerua, Zhi-Bin Luoa, Imran Khana, Bin Liua, Bhavanarushi Sngepua,
Narender Reddy Godumagaddab, Yin Xua and Jimin Xiea
b
aSchool of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang, P.R.China; Medicinal
Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 15 April 2018
A series of novel 6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-
carboxylate derivatives were obtained in good yields from ethyl
4,4,4-trifluoro-3-oxobutanoate, urea, and aryl aldehyde via Biginelli
multicomponent reaction. All the corresponding products 4a–4p
were examined against four human cancer cell lines (A549, HepG2,
COLO205 and DU145) and compounds 4e, 4i, and 4 m which
showed promising anticancer activity have been identified.
KEYWORDS
6-(trifluoromethyl)-1,2,3,4-
tetrahydropyrimidine-5-
carboxylate; anticancer
activity; Biginelli
condensationIntroduction
GRAPHICAL ABSTRACT
Multicomponent reactions (MCRs)[1] are proved effective protocols to build complex
molecules in a single step. Dihydropyrimidinones (DHPMs) are key building blocks in
N-containing heterocyclic compounds and play an important role in synthetic and
medicinal chemistry wherein exhibit wide range of applications such as antiviral,[2] anti-
cancer,[3] antibacterial and antifungal,[4] and calcium channel modulation.[5] 5-Fluoro
Uracil which has pyrimidine dione shows anticancer activity. Monastrol(I), with the
pyrimidine-2-thione motif, specifically inhibits the motility of the mitotic kinesin Eg5,[6]
meanwhile SQ 32926 (II),[7] and Mon-97 (III)[8] display antihypertensive and anticancer
activities (Fig. 1).
Biginelli[9–14] condensation is a simple, well-known, atom-economical, and direct
method for the construction of DHPMs by the three-component reaction of aldehyde,
1,3-dicarbonyl compound, and urea under acidic conditions. The available
CONTACT Jimin Xie
xiejm@ujs.edu.cn; Zhibin Luo
luozb@ujs.edu.cn
School of Chemistry and Chemical
Engineering, Jiangsu University, Zhenjiang, 212013, China.
Supplemental data for this article can be accessed on the publisher's website.
ß 2018 Taylor & Francis

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A. VALERU ET AL.
Figure 1. Biological activity compounds based on Dihydropyrimidinones (DHPMs).
methodologies for the Biginelli reaction in the literature employs catalysts such as Fe3O4
SBA-15(mesoporous nanocatalyst),[15] [Gmim]Cl-Cu(II) complex,[16] Mg/Ca–Al–CO3
hydrotalcite,[17] phosphoric acid,[18] poly(1-vinyl-3-(3-sulfopropyl) imidazolium hydrogen
sulfate) (poly(SIL)),[19] chiral organocatalyst,[20] ionic liquid ([Hmim]HSO4/TMSCl),[21]
perchloric acid doped silica (HClO4/SiO2),[22] bioglycerol-based sulfonic acid functional-
ized carbon catalyst,[23] and t-BuOK,[24] etc.[25,26] Considering that some of these methods
suffer from low yields and high cost of the catalysts, the development of new reaction
conditions capable of figuring out a solution to the formidable problems remains highly
desirable. Fluorine or trifluoro methyl group at appropriate position of an organic mol-
ecule dramatically alters the properties in terms of lipophilicity, lipid solubility, oxidative
thermal stability, permeability, oral bio availability thereby enhancement of transport
mechanism. In this work, we established a highly effective hydrofluoric acid promoted
Biginelli reaction for the preparation of structurally diverse pyrimidinone derivatives bear-
ing trifluoromethyl groups. The anticancer activities of pyrimidinone derivatives were
examined against four cancer cell lines such as A549, HepG2, COLO205, DU145 wherein
compounds 4e, 4i, and 4 m showed promising results.
Results and discussion
The initial investigation commenced with aryl aldehyde, trifluoromethyl 1,3-dicarbonyl
compound, and urea using commercially available aqueous HF (40%) as solvent
medium to prepare the desired 6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylate derivatives 4a–4p (Scheme 1). A mixture of aryl aldehyde, urea, and trifluoro-
methyl 1,3-dicarbonyl compound in aq HF (40%) were charged in polypropelene bottle
and stirred at ambient temperature to afford the desired products in high yields.
Different electron withdrawing or donating groups on the aryl aldehyde were examined
and the outcome showed satisfactory functional group tolerance (Table 1).
Cytotoxicity assay
The cytotoxicity of the compounds was determined on the basis of measurement of in
vitro growth inhibition of tumor cell lines in 96-well plates by cell-mediated reduction
of tetrazolium salt to water insoluble formazan crystals using 5-Fluorouracil as a stand-
ard. The cytotoxicity of compounds 4a–4p was assessed against a panel of four different
human tumor cell lines: A549 derived from human alveolar adenocarcinoma epithelial
cells (ATCC No. CCL-185), HepG2 derived from human hepatic carcinoma cells

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Table 1. Preparation of 6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 4a–4p.
No.
Product
R
Time(min)
Yield (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
C6H5
4-CH3C6H4
4-ClC6H4
30
40
20
25
20
20
25
30
20
20
40
30
40
35
40
60
90
87
91
92
86
86
89
85
82
82
85
80
88
79
81
80
4-BrC6H4
4-OCH3C6H4
2-CH3C6H4
4-FC6H4
4-NO2C6H4
3-CF3C6H4
4-CNC6H4
2-Furyl
2-Thienyl
2,4-diFC6H3
3-NO2C6H4
Styryl
9
10
11
12
13
14
15
16
Naphthalene
Table 2. Anticancer activities of compounds 4a–4p.
IC50 values in (mg/mL)
Test Compounds
A549
HepG2
COLO205
DU145
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
23.2 0.23
15.2 0.11
16.2 0.12
25.8 0.22
9.6 0.15
7.2 0.14
12.9 0.11
11.8 0.19
2.2 0.12
19.5 0.25
32.2 0.22
18.2 0.12
6.1 0.12
11.3 0.13
—
31.2 0.25
12.8 0.15
—
16.6 0.12
19.2 0.24
18.9 0.33
31.1 0.21
5.1 0.14
10.9 0.20
21.2 0.20
12.4 0.19
2.7 0.22
—
15.7 0.25
18.7 0.28
5.7 0.16
15.8 0.26
—
17.4 0.28
12.0 0.12
25.6 0.31
—
12.4 0.33
4.8 0.12
11.4 0.10
17.2 0.27
10.8 0.25
3.1 0.20
17.5 0.10
27.1 0.15
17.1 0.20
4.4 0.24
14.1 0.27
—
4.2 0.19
13.8 0.12
16.5 0.10
9.9 0.29
2.1 0.12
21.5 0.12
22.8 0.12
25.3 0.22
7.8 0.22
17.3 0.32
116.8 0.38
—
18.4 0.13
1.8 0.09
17.7 0.30
1.9 0.11
28.6 0.18
1.7 0.08
5-Fluoro uracil (Standard control)
1.7 0.07
—indicates IC50 value >116.8 mg/mL; A549: human alveolar adenocarcinoma epithelial cells (ATCC No. CCL-185);
HepG2: derived from human hepatic carcinoma cells (ATCC No. HB-8065); COLO205: derived from human colon cancer
cells (ATCC No. CCL-222) and DU145: derived from human prostate cancer cells (ATCC No. HTB-81).
(ATCC No. HB-8065), COLO205 derived from human colon cancer cells (ATCC No.
CCL-222), and DU145 derived from human prostate cancer cells (ATCC No. HTB-81)
using the MTT assay.[27] The IC50 values (50% inhibitory concentration) were calculated
from the plotted absorbance data for the dose-response curves. IC50 values (in lM) are
expressed as the average of three independent experiments. Among all the compounds

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A. VALERU ET AL.
examined, compounds 4e, 4i, and 4 m showed promising activity (IC50 concentration
<7.8 mg/mL on all cancer cell lines). The presence of CF3 group at appropriate position
of 6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylates, can enhance the prop-
erties of lipid solubility, oxidative thermal stability and thereby leading to a enhancement
of transport mechanism. Meanwhile compounds 4 b, 4f, 4 g, 4 h and 4n showed moderate
activity with IC50 concentration <21.2mg/mL on all cancer cell lines as shown in Table 2.
Conclusion
In conclusion, we have demonstrated a simple and efficient method for the preparation
of structurally diverse 6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate
derivatives under aq. HF (40%) medium. The anticancer activities of all the pyrimidi-
none derivatives were examined with promising bioactivities.
Experimental section
General procedure
A mixture of aryl aldehyde (0.1 mol), urea (0.1 mol) and trifluoromethyl 1,3-dicarbonyl
compound (0.1 mol) in aq HF (40%) were charged in polypropelene bottle and stirred
at ambient temperature for a period of 60 min. The reaction progress was monitored by
thin-layer chromatography (TLC). After completion of the reaction, the reaction mix-
ture was poured into crushed ice, and the resulted solid was filtered. The solid was
washed with water and then sodium bicarbonate solution and dried to afford the
product. Please see supporting information for further details (yield and data
characterization).
Funding
The authors acknowledge the financial support of National Natural Science Foundation of China
[No. 21676129], Jiangsu University scientific research funding [13JD062], and Jiangsu
Postdoctoral Foundation [1601034B].
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