New one-pot synthesis of 1,3,5-triazines: three-component condensation, dimroth rearrangement, and dehydrogenative aromatization

Article abstract of DOI:10.1021/acscombsci.9b00079

A new, effective one-pot synthesis of the 6,N²-diaryl-1,3,5-triazine-2,4-diamines under microwave irradiation was developed. The method involved an initial three-component condensation of cyanoguanidine, aromatic aldehydes, and arylamines in the presence of hydrochloric acid. Without isolation, the resulting 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-diamines were treated with a base to initiate Dimroth rearrangement and spontaneous dehydrogenative aromatization, affording the desired compounds. The developed method was found to be sufficiently general in scope, tolerating various aromatic aldehydes and amines; by using their combinations in the first step, a representative library of 110 compounds was successfully prepared and screened for anticancer properties.

Full text of DOI:10.1021/acscombsci.9b00079

Research Article
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Cite This: ACS Comb. Sci. XXXX, XXX, XXX−XXX
New One-Pot Synthesis of 1,3,5-Triazines: Three-Component
Condensation, Dimroth Rearrangement, and Dehydrogenative
Aromatization
Ahmad Junaid,† Felicia Phei Lin Lim,† Edward R. T. Tiekink,‡ and Anton V. Dolzhenko*,†,§
†School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia
‡Research Centre for Crystalline Materials, School of Science and Technology, Sunway University, 5 Jalan Universiti, Bandar
Sunway, Selangor Darul Ehsan 47500, Malaysia
§School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin
University, GPO Box U1987, Perth, Western Australia 6845, Australia
S
* Supporting Information
ABSTRACT: A new, effective one-pot synthesis of the 6,N2-diaryl-1,3,5-triazine-2,4-diamines under microwave irradiation was
developed. The method involved an initial three-component condensation of cyanoguanidine, aromatic aldehydes, and
arylamines in the presence of hydrochloric acid. Without isolation, the resulting 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-
diamines were treated with a base to initiate Dimroth rearrangement and spontaneous dehydrogenative aromatization, affording
the desired compounds. The developed method was found to be sufficiently general in scope, tolerating various aromatic
aldehydes and amines; by using their combinations in the first step, a representative library of 110 compounds was successfully
prepared and screened for anticancer properties.
KEYWORDS: triazines, multicomponent reactions, microwave-assisted synthesis, anticancer activity
The suitably substituted 6,N2-diaryl-1,3,5-triazine-2,4-dia-
mines of general structure 1 (Scheme 1) were also found to
INTRODUCTION
■
The 1,3,5-triazine ring has a long history of successful
implementation as a skeleton for the construction of bioactive
compounds, including several marketed drugs. This heterocyclic
ring became a privileged scaffold for drug development. The
exhibit antibacterial activity against Chlamydia pneumonia
without toxic effects toward human lung cells used as hosts14
and to inhibit the enzymes inosine monophosphate dehydro-
genase15 and Bruton’s tyrosine kinase.16
most significant results have been recently achieved in the devel-
Therefore, 6,N2-diaryl-1,3,5-triazine-2,4-diamines occupy a
therapeutically important place in chemical space. However,
chemical diversity around the 6,N2-diaryl-1,3,5-triazine-2,4-
diamine scaffold has not been sufficiently explored, resulting
in very fragmented data on the biological activity of this prom-
ising group of compounds.
opment of 1,3,5-triazine-based anticancer compounds.1
Interesting data supporting repurposing an anti-gastric-ulcer
medicine, irsogladine (Figure 1), as a potential anticancer thera-
peutic agent2 were obtained in in vivo models of breast cancer in
mice.3 Irsogladine was also found to suppress tumorigenesis in
mice.4 Several compounds similar to irsogladine in that they
had aromatic rings attached to one of their amino groups (e.g.,
CT-32228 and its analogues) were reported5−11 as potent inhib-
itors of lysophosphatidic acid acyltransferase β (LPAAT-β),
which has been identified as a valid target for the development of
new anticancer agents.12 The antiproliferative activity exhibited
by these compounds toward cancer cells was attributed to the
inhibition of LPAAT-β. However, structurally related 1,3,5-
triazines sharing the same 6,N2-diaryl-1,3,5-triazine-2,4-diamine
scaffold (i.e., SJ000516613 and SJ000517729) demonstrated
very potent anticancer activity with multiple cancer-related
kinases as their targets.13
No detailed studies aimed at understanding structural
requirements for the further design of new effective anticancer
agents have been performed because of the absence of suffi-
ciently diverse libraries of 6,N2-diaryl-1,3,5-triazine-2,4-dia-
mines. This situation originates from the limited number of
methods for the synthesis of such compounds and the draw-
backs of the existing synthetic approaches, which have narrow
Received: April 18, 2019
Revised: May 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acscombsci.9b00079
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Figure 1. Selected 6,N2-diaryl-1,3,5-triazine-2,4-diamines possessing anticancer properties.
Scheme 1. Reported Methods for the Synthesis of 6,N2-Diaryl-1,3,5-triazine-2,4-diamines (1)
Scheme 2. Proposed Method for the Synthesis of 6,N2-Diaryl-1,3,5-triazine-2,4-diamines (1{a,b})
scopes, suffer from low yields, are performed in numerous steps,
and require expensive reagents and catalysts.
One of these approaches relies on the sequential nucleophilic
substitution of cyanuric chloride with Grignard reagents,
ammonia, and amines15 (Route 1) or nucleophilic substitution
with amines followed by Suzuki coupling with arylboronic
acids17,18 (Route 2, Scheme 1).
Another approach for the synthesis of 1 utilizes the con-
densation of biguanides prepared from cyanoguanidine and
arylamines with esters or other carboxylic acid derivatives16
(Route 3) or the recently developed ruthenium-catalyzed
reaction of biguanides with benzylalcohols19 (Route 4).
6,N2-Diaryl-1,3,5-triazine-2,4-diamines (1) can also be pre-
pared by addition of sodium cyanamide to aryl isothiocyanates
B
DOI: 10.1021/acscombsci.9b00079
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Scheme 3. Model Reaction: Synthesis of 1,3,5-Triazine 1{4,10}
followed by triazine-ring formation in a reaction with
arylamidines20 (Route 5).
Table 1. Screening of Reaction Conditions for the
Microwave-Assisted Synthesis of 6-(4-Chlorophenyl)-N2-(2-
a
methoxyphenyl)-1,3,5-triazine-2,4-diamine 1{4,10}
Another approach for the synthesis of 1 involves triazine-ring
closure in the reaction of guanidine and 2-aroylimino-3-aryl-1,3-
thiazetidines, which can be prepared by the treatment of
N-aroyl-N′-arylthioureas with diiodomethane21 (Route 6).
The development of more general and practical methods for
the synthesis of a diverse library of 6,N2-diaryl-1,3,5-triazine-2,4-
diamines (1) is certainly needed to stimulate progress of drug-
discovery programs requiring this type of compounds. Herein
we report a new method for the efficient generation of 6,N2-
diaryl-1,3,5-triazine-2,4-diamines and illustrate it with the
preparation of 110 compounds, which were screened for their
antiproliferative activity against human prostate-cancer cells.
conditions
entry
1
(i)
(ii)
isolated yield (%)
61
140 °C, 15 min,
140 °C, 15 min,
5 N NaOH(aq)
EtOH
RESULTS AND DISCUSSION
■
2
3
4
5
6
7
8
9
140 °C, 15 min,
140 °C, 15 min,
52
55
63
72
80
61
45
62
63
67
15
63
55
64
67
It has been reported that the three-component reaction of
cyanoguanidine, anilines, and benzaldehydes in the presence of
acid produces salts of 1,6-diaryl-1,6-dihydro-1,3,5-triazine-2,4-
diamines (4),22 which undergo the Dimroth rearrangement23,24
upon treatment with bases to afford dihydrotriazines (5).25,26
We propose that the oxidative aromatization of 4 can be used as
a pathway for the synthesis of the desired 6,N2-diaryl-1,3,5-
triazine-2,4-diamines (1, Scheme 2).
MeOH
5 N NaOH(aq)
140 °C, 15 min,
iPrOH
140 °C, 40 min,
EtOH
140 °C, 30 min,
EtOH
140 °C, 50 min,
EtOH
140 °C, 60 min,
EtOH
140 °C, 75 min,
EtOH
130 °C, 50 min,
EtOH
140 °C, 15 min,
5 N NaOH(aq)
140 °C, 15 min,
5 N NaOH(aq)
140 °C, 15 min,
5 N NaOH(aq)
140 °C, 15 min,
5 N NaOH(aq)
140 °C, 15 min,
5 N NaOH(aq)
140 °C, 15 min,
5 N NaOH(aq)
140 °C, 15 min,
5 N NaOH(aq)
For the optimization of the reaction conditions we utilized the
model reaction of cyanoguanidine with p-chlorobenzaldehyde
(2{4}) and o-anisidine (3{10}) (Scheme 3). Initially, salt
4{4,10} was prepared by heating the reagents in acetonitrile
under reflux in the presence of an equimolar quantity of con-
centrated hydrochloric acid. Then, we attempted to proceed
with the rearrangement step without isolation of the three-
component condensation product from the reaction mixture.
To make the reagents more compatible, the solvent for the
reaction was changed to ethanol, whereas the other parameters
were kept identical for the first step. Next, aqueous sodium
hydroxide (2 equiv) was added to the reaction mixture, and
heating was continued under reflux for another 4 h. Interestingly,
the main product of the reaction was the fully aromatic com-
pound 1{4,10} (∼60% yield) in a mixture with 6,N2-diaryl-1,6-
dihydro-1,3,5-triazine-2,4-diamine, 5{4,10}. It appeared that we
could achieve the preparation of 1 without the addition of any
oxidative agents.
10 150 °C, 50 min,
140 °C, 15 min,
5 N NaOH(aq)
EtOH
11 140 °C, 50 min,
140 °C, 15 min,
5 N KOH(aq)
EtOH
12 140 °C, 50 min,
140 °C, 15 min,
5 N Na2CO3(aq)
EtOH
13 140 °C, 50 min,
130 °C, 15 min,
5 N NaOH(aq)
EtOH
14 140 °C, 50 min,
150 °C, 15 min,
5 N NaOH(aq)
EtOH
15 140 °C, 50 min,
140 °C, 10 min,
5 N NaOH(aq)
EtOH
16 140 °C, 50 min,
140 °C, 20 min,
5 N NaOH(aq)
EtOH
a
The reactions were performed using a Discover SP CEM microwave
Inspired by these interesting observations and in order to
increase the throughput potential of our method, we decided to
continue the optimization under focused microwave irradiation,
performing all the steps in a one-pot manner. The three-
component microwave-assisted synthesis of 1-aryl-1,6-dihydro-
1,3,5-triazine-2,4-diamines (4) has been reported27,28 to be suc-
cessful, and we attempted to initiate the subsequent Dimroth
rearrangement of intermediate 4 without its isolation. Perform-
ing the model reaction under microwave irradiation in a
synthesizer with 2.5 mmol of 1{4,10}, 2.5 mmol of 2{4}, and
2.5 mmol of 3{10} in 2 mL of the specified solvent in the first step
and addition of 1 mL of the base in the second step.
Discover SP (CEM) reactor, we heated cyanoguanidine with
p-chlorobenzaldehyde (2{4}) and o-anisidine (3{10}) in
ethanol at 140 °C for 15 min; this was followed by addition of
an aqueous solution of sodium hydroxide to the reaction mixture
and heating at 140 °C for another 15 min (Table 1, entry 1).
C
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Figure 2. Building blocks for the library of 6,N2-diaryl-1,3,5-triazine-2,4-diamines (1).
To our satisfaction, 6-(4-chlorophenyl)-N2-(2-methoxyphenyl)-
1,3,5-triazine-2,4-diamine (1{4,10}) was isolated exclusively via
simple filtration in a 61% yield. Changing ethanol to other water-
miscible alcohols did not benefit the reaction outcome (entries 2
and 3). Improvements in the yield were achieved when the
reaction time in the first step was increased up to 50 min (entries
4−6). However, further extension of the reaction time for the
first step was detrimental to the yield (entries 7 and 8). The
manipulation of the reaction temperature in the first step did not
lead to any improvement in yields (entries 9 and 10). The
changes in the second-step parameters, such as the type of base,
reaction time, or temperature, also did not help increase the
yield (entries 11−16).
the benzene rings of anilines 3{1−13} were tolerated in the
reaction. The reaction was also successful with benzaldehydes
bearing the electron-donating or electron-withdrawing sub-
stituents on the ring (2{1−13}). However, the combinations of
a less electrophilic aldehyde with a strong electron-donor group
in the ring (e.g., 2{11}) and a less nucleophilic amine with an
electron-withdrawing group in close proximity to the reactive
amino group (e.g., 3{2}) resulted in the lower yield of product
1{11,2} (Table 2, entry 89). We also attempted to involve in the
reaction heterocyclic substrates 2{14} and 3{14}. Both the
substrates were well-tolerated, but the yields for the reactions
utilizing 3-aminopyridine (3{14}) were generally lower than
those with the majority of the amines used in the reaction
(Table 2, entries 9, 29, 40, 60, 71, 87, and 110).
Therefore, for the preparation of a library of 6,N2-diaryl-1,3,5-
triazine-2,4-diamines (1) we used the microwave-assisted
reaction of cyanoguanidine with aldehydes 2 and arylamines 3
in ethanol at 140 °C for 50 min followed by the addition of an
aqueous solution of sodium hydroxide and heating at 140 °C
for another 15 min. The two points of diversity in the reac-
tion products were generated by various combinations of
arylaldehydes (chemset 1, Figure 2) and arylamines (chemset 2,
Figure 2).
We attempted to scale up the model reaction from 2.5 to
10 mmol under the same conditions. The isolated yield of
1{4,10} did not significantly change and was 79%.
The structures of the prepared compounds (1) were
confirmed by NMR-spectroscopic data. The three signals of
the carbon atoms in the aromatic triazine ring appeared in the
13C NMR spectra of 1 in the region 164.0−170.4 ppm. Together
with the absence of signals from the sp3-hydridized carbon atom
in the 13C NMR spectra and the corresponding proton in the 1H
NMR spectra, these observations suggest aromatization of the
dihydrotriazine ring. Other spectral evidence for such trans-
formation resulted from the high level of delocalization of
In general, the scope of the proposed method was found to be
broad, as illustrated by the synthesis of 110 representative
compounds (Table 2). The electron-donating and electron-
withdrawing groups in the ortho-, meta-, and para-positions of
D
DOI: 10.1021/acscombsci.9b00079
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Table 2. Prepared Library of 6,N2-Diaryl-1,3,5-triazine-2,4-diamines (1{a,b})
entry
product
yield (%)
entry
product
yield (%)
1
2
3
4
5
6
7
8
1{1,1}
1{1,6}
1{1,7}
1{1,9}
1{1,10}
1{1,11}
1{1,12}
1{1,13}
1{1,14}
1{2,1}
1{2,3}
1{2,6}
1{2,7}
1{2,9}
1{2,11}
1{2,12}
1{2,13}
1{3,1}
1{3,2}
1{3,3}
1{3,4}
1{3,5}
1{3,6}
1{3,7}
1{3,9}
1{3,10}
1{3,12}
1{3,13}
1{3,14}
1{4,2}
1{4,3}
1{4,4}
1{4,5}
1{4,6}
1{4,7}
1{4,10}
1{4,11}
1{4,12}
1{4,13}
1{4,14}
1{5,2}
1{5,3}
1{5,4}
1{5,6}
1{5,9}
1{5,10}
1{5,11}
1{6,6}
1{6,7}
1{6,9}
1{6,12}
1{7,1}
1{7,2}
1{7,3}
1{7,7}
55
54
40
57
40
60
41
66
32
32
35
57
57
40
40
42
57
50
48
48
41
61
61
67
61
53
52
69
33
45
50
43
57
50
50
80
58
51
53
35
55
58
45
55
48
76
58
27
32
48
45
45
52
39
48
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
1{7,9}
65
43
48
71
28
45
62
37
37
43
56
46
44
66
66
29
60
52
40
50
69
47
58
50
42
61
65
81
48
59
49
27
48
18
55
33
61
70
58
49
48
62
78
50
65
47
48
50
20
53
76
54
51
57
31
1{7,10}
1{7,12}
1{7,13}
1{7,14}
1{8,2}
1{8,3}
1{8,4}
1{8,5}
1{8,6}
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
1{8,7}
1{8,8}
1{8,10}
1{8,12}
1{8,13}
1{8,14}
1{9,1}
1{9,2}
1{9,6}
1{9,9}
1{9,10}
1{9,11}
1{10,1}
1{10,2}
1{10,4}
1{10,7}
1{10,9}
1{10,10}
1{10,11}
1{10,12}
1{10,13}
1{10,14}
1{11,1}
1{11,2}
1{11,3}
1{11,10}
1{11,13}
1{12,1}
1{12,3}
1{12,6}
1{12,7}
1{12,11}
1{13,1}
1{13,7}
1{13,9}
1{13,12}
1{14,1}
1{14,3}
1{14,4}
1{14,6}
1{14,7}
1{14,9}
1{14,12}
1{14,13}
1{14,14}
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
π-electrons on the atoms and groups directly attached to the
electron-deficient 1,3,5-triazine ring. They include chemical
shifts of signals of the primary amino group protons and those
protons of the aryl group in position 6 of the triazine ring, which
are located in close proximity to the triazine and positioned in its
plane as a result of extended conjugation. These signals are
shifted significantly downfield because of the anisotropic effect
from the π-electron cloud of the triazine ring.
X-ray crystallography for a representative compound, 1{12,11}
(Figure 3), allowed unambiguous structure assignment and
E
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Table 3. Antiproliferative Activity of the Most Potent
Compounds Identified in the Screening against DU145
Prostate-Cancer Cells
entry
compound
GI50 (μM)
1
2
3
4
5
1{8,8}
1{8,5}
1{8,2}
1{11,2}
nilotinib
3.43
4.01
2.38
0.67
6.35
Figure 3. Molecular structure of 1{12,11} showing atom labeling and
70% displacement ellipsoids.
CONCLUSIONS
■
We developed a new, efficient approach for the synthesis of 6,N2-
diaryl-1,3,5-triazine-2,4-diamines. This method combines sev-
eral processes, which are performed in two steps in a one-pot
manner: three-component condensation, the Dimroth rear-
rangement, and dehydrogenative aromatization. The application
of microwave irradiation for the synthesis allows shortening of
the reaction time and automation of library synthesis. The
developed method can be applied for the synthesis of diverse
libraries of bioactive 6,N2-diaryl-1,3,5-triazine-2,4-diamines (1)
as exemplified by the preparation of a library of 110 compounds,
some of which demonstrated good antiproliferative activity
against prostate-cancer cells.
confirmed structural features proposed on the basis of the NMR
spectroscopic data.
Even though the exact mechanism of the observed sequence
of transformations in the one-pot synthesis of 6,N2-diaryl-1,3,5-
triazine-2,4-diamines (1) is still to be investigated, we propose
that initially an aniline undergoes addition to the acid-activated
triple bond of cyanoguanidine and condensation of the
intermediate biguanide (I) with an aldehyde (Scheme 4). The
resulting 1-aryl-1,6-dihydro-1,3,5-triazine-2,4-diamines (4) can
undergo triazine-ring opening producing II, the key inter-
mediate for the Dimroth rearrangement (pathway a). The role
of sodium hydroxide in the aromatization process can be
rationalized via its participation in the nucleophilic attack of the
hydroxide ion toward II, producing intermediate III (pathway
b). The dehydrogenation of III leads to the formation of
amidobiguanide (IV), which undergoes intermolecular cycliza-
tion to afford the final product, 1.
The prepared compounds were screened for antiproliferative
activity against a human prostate-cancer cell line, DU145, at a
10 μM concentration with the MTT assay.29 Out of 110 com-
pounds tested, 4 compounds, 1{8,2}, 1{8,5}, 1{8,8}, and
1{11,2}, inhibited cell growth more than 45% at this concen-
tration (see the Supporting Information, Table S1). These com-
pounds were further tested in the same assay in the concen-
tration range 0.02−10 μM to determine their GI50 values, and
were found to be more potent than the reference anticancer drug
nilotinib (Table 3). In general, the derivatives of p-anisaldehyde
(2{8}) possessed more potent anticancer properties than
triazines obtained from other aldehydes in this library. However,
compound 1{11,2}, with the isosteric N,N-dimethylamino
group instead of the methoxy group, retained good activity
even at very low concentrations. Compared with nilotinib in
terms of GI50 values, 1{11,2} was nearly 10 times more potent
than the reference drug.
EXPERIMENTAL PROCEDURES
■
General Procedure for the Preparation of 6,N2-Diaryl-
1,3,5-triazine-2,4-diamines, 1{a,b}, Represented by the
Synthesis of 1{4,10}. To a solution of cyanoguanidine (0.21 g,
2.5 mmol), p-chlorobenzaldehyde (0.35 g, 2.5 mmol), and
o-anisidine (0.28 mL, 2.5 mmol) in EtOH (2 mL) in a 10 mL
seamless pressure vial, concentrated HCl (0.21 mL, 2.5 mmol)
was added. The reaction mixture was irradiated in a Discover SP
(CEM) microwave reactor operating at maximal microwave
power up to 150 W at 140 °C for 50 min. Then, an aqueous
solution of NaOH (5 N, 1 mL) was added to the reaction
mixture, and irradiation continued for another 15 min at 140 °C.
After cooling, the precipitated product was filtered, washed with
water, and recrystallized from EtOH to give the product as a
yellowish solid. Yield: 0.65 g, 80%; mp: 185−187 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): δ 3.87 (3H, s, OCH3), 6.95−
7.10 (3H, m, H-3′′, H-4′′, and H-5′′), 7.20 (2H, brs, NH2), 7.57
(2H, d, J = 8.6 Hz, H-3′ and H-5′), 8.07 (1H, s, NH), 8.18 (1H,
d, J = 7.4 Hz, H-6′′), 8.30 (2H, d, J = 8.6 Hz, H-2′ and H-6′); 13C
NMR (75 MHz, DMSO-d6): δ 55.7 (OCH3), 110.9 (C-3′′),
120.3 (C-5′′), 122.0 (C-6′′), 123.6 (C-4′′), 127.6 (C-1′′), 128.4
(C-3′ and C-5′), 129.5 (C-2′ and C-6′), 135.4 (C-1′), 136.1
(C-4′), 149.7 (C-2′′), 164.6 (C-4), 167.2 (C-6), 169.2 (C-2).
Scheme 4. Proposed Mechanism for the Synthesis of 6,N2-Diaryl-1,3,5-triazine-2,4-diamines (1{a,b})
F
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Anal. calcd for C16H14ClN5O: C, 58.63; H, 4.31; N, 21.37.
Found: C, 58.48; H, 4.43; N, 21.52.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Informationisavailablefree ofcharge on the ACS
Publications website at DOI: 10.1021/acscombsci.9b00079.
■
S
Synthesis and biological-evaluation details, character-
ization data for the prepared compounds, and copies of
1H and 13C NMR spectra for all products (PDF)
Crystallographic data for compound 1{12,11} (CIF)
AUTHOR INFORMATION
Corresponding Author
*Tel.: +60 3 5514 5867. Fax: +60 3 5514 6364. E-mail: anton.
dolzhenko@monash.edu.
■
ORCID
Anton V. Dolzhenko: 0000-0001-5059-2276
Author Contributions
A.V.D. conceptualized the topic and developed the method-
ology; A.J. optimized the method, performed the library
synthesis and characterization and biological evaluation; A.J.
and A.V.D. prepared the original draft; A.D edited the
manuscript; A.J. and F.P.L.L. prepared the supporting
information preparation; E.R.T.T. performed the X-ray
diffraction study; A.J. and F.P.L.L. completed the NMR
spectroscopic analysis; and A.V.D provided the resources,
supervision, and project administration. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The Research Centre for Crystalline Materials (Sunway
University) is thanked for the X-ray-intensity data.
■
ABBREVIATIONS
■
GI50, 50% growth inhibition; LPAAT-β, lysophosphatidic acid
acyltransferase β; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-
nyltetrazolium bromide
(15) Pitts, W. J.; Guo, J.; Dhar, T. G. M.; Shen, Z.; Gu, H. H.;
Watterson, S. H.; Bednarz, M. S.; Chen, B.-C.; Barrish, J. C.; Bassolino,
D.; Cheney, D.; Fleener, C. A.; Rouleau, K. A.; Hollenbaugh, D. L.;
Iwanowicz, E. J. Rapid Synthesis of Triazine Inhibitors of Inosine
Monophosphate Dehydrogenase. Bioorg. Med. Chem. Lett. 2002, 12,
2137−2140.
(16) Kawahata, W.; Asami, T.; Kiyoi, T.; Irie, T.; Taniguchi, H.;
Asamitsu, Y.; Inoue, T.; Miyake, T.; Sawa, M. Design and Synthesis of
Novel Amino-triazine Analogues as Selective Bruton’s Tyrosine Kinase
Inhibitors for Treatment of Rheumatoid Arthritis. J. Med. Chem. 2018,
61, 8917−8933.
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