Design, synthesis, anticancer, antibacterial, and antifungal evaluation of 4-aminoquinoline-1,3,5-triazine derivatives

Article abstract of DOI:10.1002/jhet.3791

A series of 4-aminoquinoline 1,3,5-triazine derivatives were synthesized and evaluated for anticancer activity against cancer cell lines HeLa, MCF-7, HL-60, HepG2 where these derivatives exert significant anticancer activity. The molecules found nontoxic against MCF-12A. The molecules also showed potent inhibition of EGFR-TK as compared to eroltinib in enzyme-based assay. The newly synthesized derivatives were screened for their in vitro antibacterial and antifungal activity against Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa and Candida albicans, Aspergillus niger, Aspergillus fumigatus using cefixime and fluconazole as standard. Antibacterial screening results suggest that compound 7c showed potent activity against S. aureus, P. aeruginosa, and P. vulgaris. In antifungal screening, compound 7b showed significant activity against A. niger, A. fumigatus and moderate activity against C. albicans.

Full text of DOI:10.1002/jhet.3791

Received: 20 August 2019
DOI: 10.1002/jhet.3791
Revised: 17 September 2019
Accepted: 5 October 2019
A R T I C L E
Design, synthesis, anticancer, antibacterial, and antifungal
evaluation of 4-aminoquinoline-1,3,5-triazine derivatives
1
2
1
1
Hans Raj Bhat
| Anup Masih | Anshul Shakya | Surajit Kumar Ghosh
|
2
Udaya Pratap Singh
1
Department of Pharmaceutical Sciences,
Dibrugarh University, Dibrugarh, Assam,
India
Abstract
A series of 4-aminoquinoline 1,3,5-triazine derivatives were synthesized and
evaluated for anticancer activity against cancer cell lines HeLa, MCF-7, HL-60,
HepG2 where these derivatives exert significant anticancer activity. The mole-
cules found nontoxic against MCF-12A. The molecules also showed potent
inhibition of EGFR-TK as compared to eroltinib in enzyme-based assay. The
newly synthesized derivatives were screened for their in vitro antibacterial and
antifungal activity against Bacillus subtilis, Bacillus cereus, Staphylococcus
aureus, Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa and Can-
dida albicans, Aspergillus niger, Aspergillus fumigatus using cefixime and flu-
conazole as standard. Antibacterial screening results suggest that compound
2
Drug Design and Discovery Laboratory,
Department of Pharmaceutical Sciences,
Sam Higginbottom University of
Agriculture Technology and Sciences,
Allahabad, India
Correspondence
Udaya Pratap Singh, Drug Design and
Discovery Laboratory, Department of
Pharmaceutical Sciences, Sam
Higginbottom University of Agriculture
Technology and Sciences, Allahabad
2
11007, India.
7c showed potent activity against S. aureus, P. aeruginosa, and P. vulgaris. In
E-mail: udaysingh98@gmail.com
antifungal screening, compound 7b showed significant activity against
A. niger, A. fumigatus and moderate activity against C. albicans.
1
| INTRODUCTION
have been approved and numerous agents are in various
[
10]
stages of clinical trial.
The epidermal growth factor
Cancer has a very devastating effect on human health
because of high morbidity and mortality. It was responsi-
ble for 9.6 million deaths across the world, the second
receptors (EGFRs) are a large family of receptor tyrosine
kinases (TK) over-expressed in several types of cancer,
including breast, lung, esophageal, and head and neck.
[11]
[1,2]
most reason of death after cardiovascular diseases.
The EGFR undergoes conformational changes after bind-
ing with the ligands (e.g., EGF) causing intermolecular
autophosphorylation, which plays important role for cellu-
lar survival, and proliferation via mitogen-activated pro-
Despite recent advances to treat cancer with personalized
therapy and novel immunotherapeutics, the overall sur-
[3,4]
vival rate is not significantly improved.
The generation
[
12,13]
of resistance against the drugs to treat cancer is the major
hurdle for the failure of the current therapeutic
tein kinase pathway.
The cancer patients are more
prone to microbial infection due to immuno-compromised
host defenses system, disruption in the barriers to infec-
[5–7]
regimes.
Various studies have shown that the impact
[
14]
of cancer is truly shocking in low- or middle-income coun-
tries because of fewer resources are available for diagnos-
tion, and shifts in the microbial flora.
Thus, novel
agents are urgently needed, which can simultaneously
able to control the cancer progression as well as anti-
microbial growth.
[8]
tics and therapeutic purpose. The role of kinases has
been widely implicated in propagation, survival, motility,
metabolism, angiogenesis, and evasion of antitumor
Heterocyclic molecules are well known for their impor-
tance in medicinal chemistry because of diverse pharmaco-
logical benefits and ease of derivatization for the generation
[9]
immune responses. Thus, inhibition of kinases is consid-
ered as a novel strategy to curb the menace of cancer, as a
result, more than 25 anticancer drugs that target kinases
[15]
of newer scaffolds. In this regard, 4-aminoquinoline and
J Heterocyclic Chem. 2019;1–10.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
BHAT ET AL.
1
,3,5-triazine have gained a lot of attention from the
The title hybrid derivatives were synthesized in 65%–
82% yield. Furthermore, the structure of title com-
pounds and intermediate were established by different
spectroscopic analysis. The FTIR spectra of title hybrid
researchers because of an extensive array of pharmacological
properties, such as antibacterial,
anti-inflammatory,
diabetic,
[
16,17]
[18,19]
antimalarial,
[20]
[21]
[22]
antifungal,
anti-HIV,
anti-
More recently,
[23]
[24]
−1
and against cystic fibrosis.
compounds 7(a-j) were found in 3408–3392 cm , which
these pharmacophores showed excellent anticancer activ-
ity. Thus, in the present study, we intended to synthesize
a single skeleton comprised of 4-aminoquinoline and
can be attributed to aromatic N Hstretch. The presence
[25]
−1
of C N group appeared at 1637–1623 cm . The peak
1
such as 1169–1165 was attributed to C S group. H
1
,3,5-triazine with subsequent screening against cancer, bac-
NMR spectra of the title compounds 7(a-j) showed pro-
ton of quinoline moiety as doublets with chemical shift
ranging from 8.63 to 6.76 ppm. The aliphatic proton of
the morpholine appeared as a multiplet in the range at
3.74–3.63 ppm. The methylene proton of cyclohexene
moiety appeared as a multiplet at 1.71–1.11 ppm. Fur-
thermore, the aromatic proton of para-nitroaniline
substituted 1,3,5-triazine derivative (7c) appeared as
doublets at 8.01–6.78 ppm. The methoxy of the com-
pound 7d appeared as a singlet at 3.74 ppm. The ali-
phatic protons of the methyl group of the ethylene
moiety were appeared as triplets at 1.23 ppm, while a
methylene group was observed at 3.26 ppm as quartet.
The N H proton appeared at 3.96–3.98 ppm as singlet.
The methyl proton appeared as a singlet at the chemical
shift range of 3.06 ppm (7g). The C NMR spectrum
of title compounds 7(a-j) showed the presence of nine
carbon of the quinoline ring in the region of 152.7–
113.1 ppm. The piperazine methylene carbons were
observed at 59.5 and 55.1 ppm. The two carbon of
the tri-substituted 1,3,5-triazine ring was observed at
176.4 and 171.1 ppm. Finally, the structure of the title
compounds was confirmed by Mass and elemental
analysis.
terial and fungal micro-organisms.
2
2
| RESULTS AND DISCUSSION
.1 | Chemistry
The synthesis of novel hybrid 4-aminoquinoline
,3,5-triazine derivatives 7a-j was accomplished in four steps.
1
Initially, the synthesis of 7-chloro-4-hydrazinylquinoline (3)
was achieved by reacting 4,7-dichloroquinoline with (1)
hydrazine hydrate (2) in the presence of ethanol. The second
step corresponds to the synthesis of di-substituted
1,3,5-triazines 5(a-j) by nucleophilic substitution of the Cl
1
3
atom of the 2,4,6-trichloro-1,3,5-triazine (4) with various ali-
phatic and aromatic amines (a-j), in presence of NaHCO as
3
a base. Whereas, synthesis of tri-substituted 1,3,5-triazine
derivatives 6(a-j) by the nucleophilic substitution of Cl atom
of di-substituted 1,3,5-triazine derivatives 5(a-j) with potas-
sium thiocyanate in presence of a few pieces of tin granules
as catalyst. The last step corresponds to the synthesis of title
compounds 7(a-j) upon reacting compound 3 with 6(a-j) in
the presence of dry acetone, as shown in Scheme 1.
ꢀ
SCHEME 1 Reagents and conditions: R-H (a-j) various amines (i) ethanol, reflux for 9 hours (ii) acetone, stir 6 hours at 40–45 C,
ꢀ
ꢀ
3 2 3
NaHCO (iii) KSCN, 1,4 dioxane, reflux at 105 C for 7–8 hours, K CO , tin granules (iv) dry acetone, reflux for 10–11 hours at 60–65 C

PHARMACOLOGICAL ACTIVITY OF 4-AMINOQUINOLINE 1,3,5-TRIAZINES DERIVATIVES
3
TABLE 1 Anticancer activity of
IC50 (in μM)
target compounds 7 (a-j)
Compounds
HeLa
MCF-7
HL-60
HepG2
MCF-12A
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
Nontoxic
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
51.2 ± 0.33
81.8 ± 0.34
44.5 ± 0.43
58.2 ± 0.27
32.4 ± 0.22
73.3 ± 0.45
78.2 ± 0.34
69.4 ± 0.34
41.2 ± 0.24
54.4 ± 0.34
31.3 ± 0.55
61.4 ± 0.34
76.5 ± 0.54
52.2 ± 0.33
64.5 ± 0.32
32.3 ± 0.43
79.5 ± 0.40
NA
47.6 ± 0.42
NA
63.3 ± 0.63
NA
40.3 ± 0.34
53.3 ± 0.22
26.3 ± 0.23
63.0 ± 0.34
69.3 ± 0.43
59.2 ± 0.45
34.3 ± 0.34
48.3 ± 0.31
14.3 ± 0.55
56.4 ± 0.30
68.3 ± 0.48
45.3 ± 0.33
74.2 ± 0.46
NA
g
h
i
72.2 ± 0.32
45.2 ± 0.22
61.0 ± 0.32
22.5 ± 0.86
71.2 ± 0.41
51.2 ± 0.35
63.4 ± 0.33
26.4 ± 0.38
j
Cisplatin
NA: Not active.
TABLE 2 EGFR tyrosine kinase inhibitory activity of selected
derivatives at 10 μM
along with replacing nitro with methyl cause a significant
reduction in the activity against the tested cell lines 7a. Com-
pound 7j causes further reduction of activity against HeLa
cells with a similar pattern of inhibition as compound 7a
against MCF-7, HL-60, and HepG2. Compound 7d, 7h, and
Compounds
Percent of inhibition
7
7
7
7
7
a
c
e
i
45.1
96.3
90.5
71.6
65.2
100
7f showed a further reduction in the inhibitory activity. The
least to no activity was reported in the case of the remaining
compound, that is, compounds 7g and 7b. The entire set of
compounds found nontoxic to MCF-12 A normal cells.
j
Erlotinib
2.3 | EGFR-TKs inhibitory activity
2.2 | Anticancer activity
The highly five potent derivative from the above study
viz., compounds 7a, 7c, 7e, 7i, and 7j were evaluated
in vitro for EGFR-TK enzyme inhibitory activity (at 10 μM)
and the results as presented in Table 2 are reported as
percent of inhibition in comparison to Erlotinib as a stan-
dard. The results suggested that compound 7c (96.3%)
showed the most potent inhibition of EGFR-TK followed
by 7e (90.5%). A significant decline in activity was
reported in the case of compound 7i (71.6%). The moder-
ate inhibition was reported in the case of compound 7j.
The least activity was reported in the case of compound
7a against EGFR-TK, which was found less than 50%, as
compared to eroltinib.
The MTT assay was used to evaluate the in vitro cytotoxic
activity synthesized derivatives against various cell lines
such as HeLa (cervical cancer), MCF-7 (breast cancer),
HL-60 (Human promyelocytic leukemia), and HepG2
(Hepatocellular carcinoma) along with MCF 12A (normal
epithelial cell) in reference to cisplatin as reference drug.
The relationship between surviving fraction and drug
concentration was plotted to obtain the survival curve of
all the cell lines HeLa, MCF-7, HL-60, HepG2, and MCF
1
2A. The response parameter calculated was the IC50
values, which responds to the concentration required for
0% inhibition of cell viability, and results are presented
in Table 1.
The results as presented in Table 1, compound 7e was
5
revealed as the most potent compound among all the deriva-
tives as comparable to cisplatin against HeLa cells. In the
next instance, the activity was significantly reduced on
replacing chloro with fluoro (7i) against all cell lines. The
replacement of fluoro by nitro leads to further decline in the
activity, 7c. The insertion of di-nitro in the aromatic group
2.4 | Antibacterial activity
The synthesized hybrid derivatives were tested for their
in vitro antibacterial activity against Gram-positive bacteria
(Staphylococcus aureus, Bacillus subtilis, and Bacillus cereus),
and Gram-negative bacteria (Pseudomonas aeruginosa,

4
BHAT ET AL.
TABLE 3 Antibacterial activity of target hybrid derivatives 7(a-j)
Minimum inhibitory concentration (μg mL−
1
)
Compounds
S. aureus
12.5
25
B. subtilis
B. cereus
P. aeruginosa
E. coli
25
P. vulgaris
7
7
7
7
7
7
7
7
7
7
a
b
c
d
e
f
25
12.5
25
12.5
12.5
3.12
25
25
50
25
25
3.12
50
25
12.5
25
12.5
50
3.12
3.12
25
25
50
50
25
25
25
3.12
50
25
50
25
25
50
g
h
i
25
25
25
25
50
25
25
25
25
25
50
25
25
25
25
50
50
j
50
12.5
3.12
50
25
25
50
Cefixime
3.12
3.12
3.12
6.25
3.12
Escherichia coli, and Proteus vulgaris) by the broth dilution
technique in terms of MIC using Cefixime as reference as
presented in Table 3. The term higher, equipotent, and mod-
erate activity were considered for the concentration range of
TABLE 4 Antifungal activity of target hybrid derivatives 7(a-j)
Minimum inhibitory
concentration (μg mL−
1
)
−1
3.125, 6.25–25, and 50–100 μg mL , respectively. Compound
Compounds C. albicans
A. niger
16
A. fumigatus
7a bearing with N-methyl piperazine showed moderate
7
7
7
a
b
c
16
08
16
08
16
08
16
08
16
08
04
16
08
16
16
16
16
16
08
16
16
08
activity against all the three Gram-positive (S. aureus,
B. subtilis, and B. cereus) and three Gram-negative strains
08
32
(
P. aeruginosa E. coli, and P. vulgaris). Whereas the com-
pound 7b showed mild to moderate activity against all the
bacterial strains, expect B. subtilis. The insertion of p-NO on
7d
7e
08
2
32
1,3,5-triazine (7c) showed improved activity against
7
7
7
7
f
32
S. aureus, P. aeruginosa, and P. vulgaris and moderate inhibi-
tory effect against B. subtilis, B. cereus, and E. coli. However,
g
h
i
16
16
the replacement of para-NO with 4-methoxyaniline 7d
2
32
showed improved activity against P. vulgaris and found mod-
erate activity against B. subtilis, B. cereus, and P. aeruginosa
with mild activity against S. aureus and E. coli. The com-
pound 7e, (p-Cl) showed significant activity against B. cereus,
P. aeruginosa, E. coli, and P. vulgaris and found moderate
activity against S. aureus and B. subtilis. Whereas, the intro-
duction of diethylamine on the 1,3,5-triazine (7f) showed
potent activity against S. aureus, with mild to moderate activ-
ity against the rest of the strains. Moreover, replacing
diethylamine with dimethylamine (7g) render compound
moderately active against B. subtilis, B. cereus, P. aeruginosa,
and E. coli with mild activity against S. aureus and P. vulgaris.
Compound 7h having cyclohexamine on 1,3,5-triazine
showed moderate activity against all the three Gram-positive
7j
08
Fluconazole
08
inhibitory activity against B. subtilis, P. aeruginosa, and E. coli
and mild activity against S. aureus, B. cereus, and P. vulgaris.
Based on these antibacterial screening results, it has
been suggested that electron-withdrawing groups such as
nitro and methoxy on the fourth position of the
phenylamine are necessary for the potential antimicro-
bial compounds development.
(S. aureus, B. subtilis, and B. cereus) and two Gram-negative
2.5 | Antifungal activity
bacterial strains (P. aeruginosa and E. coli) with mild activity
against P. vulgaris. Compound 7i containing p-fluoro showed
considerable inhibitory activity against entire Gram-positive
and Gram-negative strains, except E. coli and P. vulgaris.
Compound 7j bearing morpholine showed significant
All the synthesized compounds 7(a-j) have been evaluated
for antifungal activity against Candida albicans, Aspergil-
lus niger, and Aspergillus fumigatus using fluconazole as a
standard drug as shown in Table 4. The term higher,

PHARMACOLOGICAL ACTIVITY OF 4-AMINOQUINOLINE 1,3,5-TRIAZINES DERIVATIVES
5
equipotent, and moderate activity were considered for the
quinoline), 7.34 (d, 1H J = 2.3 Hz, quinoline), 6.42 (d, 1H
J = 5.4 Hz, quinoline), 3.89 (br,s, 1H, NH), 1.95 (s, 2H,
−
1
concentration range of 4.0, 8.0–16, and 32 μg mL , respec-
tively. The compound 7b bearing 1,3-diaminopropane on
s-triazine showed moderate activity against A. niger,
A. fumigates and mild activity against C. albicans. On
replacing, 1,3-diaminopropane with 4-methoxy (7d), no
activity was found against fungal strains, except consider-
able inhibitory activity improved against A. niger. The
compound 7h having cyclohexamine on 1,3,5-triazine
showed significant activity against A. niger and found
moderate active against C. albicans and A. fumigates.
Other compounds, such as 7a, 7c, 7e, 7f, 7g, 7i, and 7j,
bearing N-methyl piperazine, para-nitroaniline, para-
chloroaniline, diethylamine, dimethylamine, and mor-
pholine, respectively, showed mild to moderate activity
against entire tested fungal strains.
13
NH2); C NMR (100 MHz, CDCl ) δ ppm: 152.8, 149.6,
3
149.2, 134.9, 129.5, 124.8, 121.5, 119.6, 113.2; electron
+
spray mass spectroscopy (ES-MS) m/z: 194.78 (M + H) ;
Elemental analysis for C H ClN : Calculated: C, 55.83; H,
9
8
3
4.16; N, 21.70. Found: C, 55.89; H, 4.13; N, 21.74.
3.2.2 | General procedure for the
synthesis of di-substituted 1,3,5-triazine
derivatives 5a–j
2,4,6-Trichloro-1,3,5-triazine (4) (0.1 mol) was dissolved
in 25 mL acetone and various distinguished amines (a–j)
(0.2 mol) were added constantly in the above solution at
ꢀ
4
0–45 C and stirred for 6 hours followed by drop-wise
addition of NaHCO solution (0.1 mol), taking care that
3
3
3
| MATERIAL AND METHODS
.1 | Chemistry
reaction mixture does not become acidic. The reaction
was monitored by TLC using benzene:ethyl acetate (9:1)
as a mobile phase. The product was filtered, washed with
cold water, and recrystallized with ethanol to afford pure
[
16]
All commercially available solvents and reagents were of
analytical grade and used without further purification.
Melting points were determined on a Veego, MPI melting
compounds 5a–j.
−
1
point apparatus and FTIR (2.0 cm , flat, smooth, abex)
were recorded on Perkin Elmer RX-I Spectrophotometer.
3.2.3 | General procedure for the
synthesis of tri-substituted 1,3,5-triazine
derivatives 6a-j
1
H NMR spectra were recorded in DMSO using Bruker
13
Avance II 400 NMR and C NMR spectra on Bruker
Avance II 100 NMR spectrometer in CDCl using TMS as
Di-substituted 1,3,5-triazine derivatives 5a-j (0.01 mol),
3
internal standard. Mass spectra were obtained on VG-
AUTOSPEC spectrometer equipped with electrospray
ionization sources. Elemental analysis was carried out on
Vario EL-III CHNOS elemental analyzer.
potassium thiocyanate (0.01 mol), and K CO (0.01 mol)
2
3
were dissolved in 1,4-dioxane. The resulting mixture was
refluxed for 7–8 hours in presence of tin granules that act
as a catalyst. The reaction was monitored by TLC using
benzene:ethyl acetate (9:1) as a mobile phase. The reac-
tion mixture was filtered and concentrated under reduced
pressure. The resulting residue was purified by ethanol to
3.2 | Synthesis
[
18]
afford the desired product 6a-j.
3.2.1 | 7-chloro-4-hydrazinylquinoline (3)
A mixture of 4,7-dichloroquinoline (1) (0.10 mol), hydra-
zine hydrate (2) (0.15 mol) in 80 mL absolute ethanol
was refluxed for 9 hours. The resulting reaction mixture
was cooled and dried after filtration. The final product
was recrystallized from ethanol to give compound 3. The
reaction was monitored by TLC using ethanol:acetone
3.2.4 | General procedure for the
synthesis of titled compounds 7a-j
A solution of compound 3 (0.01 mol.) and desired tri-
substituted 1,3,5-triazine derivatives 6a-j (0.01 mol.) in
ꢀ
dry acetone was refluxed at 60–65 C for 10–11 hours. The
[26]
(
1:1) as mobile phase.
reaction was monitored by TLC using ethanol:acetone
(1:1) as a mobile phase. The reaction mixture was filtered
and concentrated under reduced pressure. The resulting
residue was dissolved in dichloromethane, washed with
brine, and dried over anhydrous Na SO . The dried solu-
ꢀ
Yellow crystals; Yield: 84%; M.p.: 225–226 C;
−1
MW:193.63; R : 0.68; FTIR (νmax; cm KBr): 3267 (N H
f
secondary), 3272 (NH2 primary), 3053 (C H broad), 1618
1
(
(
C C), 1549–1448 (aromatic C N), 1263 (C N); H NMR
400 MHz, DMSO, TMS) δ ppm: 8.38 (d, 1H J = 5.4 Hz,
2
4
tion was concentrated under reduced pressure to obtain
quinoline), 8.25(d, 1H J = 2.5 Hz, quinoline), 7.87 (s, 1H,
the title compounds 7a-j.

6
BHAT ET AL.
3
1
2
.2.5 | N-(4,6-bis((4-methylpiperazin-
-yl)amino)-1,3,5-triazin-2-yl)-
-(7-chloroquinolin-4-yl)
DMSO, TMS) δ ppm: 8.67 (d, 1H, J = 5.6 Hz, Quinoline-
H), 8.07 (d, 1H, J = 8.2 Hz, Quinoline-H), 8.01–6.78 (m,
8H, 8CH, Ar H), 7.79 (d, 1H, J = 1.8 Hz, Quinoline-H),
7.35 (d, 1H, J = 7.2 Hz, Quinoline-H), 6.79 (d, 1H,
hydrazinecarbothioamide 7a
J = 5.4 Hz, Quinoline-H), 3.98 (s, 4H, 4 N H),1.97 (s,
ꢀ
13
Yield: 82%; MP: 236–237 C; MW: 558.11; Rf: 0.69; FTIR
1H, N H N H);
C-NMR (100 MHz, CDCl ) δ
3
−1
(
νmax; cm KBr): 3392 (N H), 3064 (Ar C H str), 1638,
ppm:182.2, 171.8, 164.2, 152.8, 149.5, 149.4, 145.1, 137.8,
134.9, 129.5, 124.9, 124.6, 121.7, 119.8, 119.2, 113.1; ES-
MS m/z: 605.0 (M + 1); Elemental analysis for
C H ClN O S: Calculated: C, 49.71; H, 3.00; N, 25.51;
1
8
623 (C N str),), 1538 (N H bend), 1165, 982 (C N str),
31 (C Cl str), 828 cm ; H-NMR (400 MHz, DMSO,
−1 1
TMS) δ ppm: 8.64 (d, 1H, J = 5.6 Hz, Quinoline-H), 8.04
d, 1H, J = 8.2 Hz, Quinoline-H), 7.79 (d, 1H, J = 2.6 Hz,
Quinoline-H), 7.35 (d, 1H, J = 7.2 Hz, Quinoline-H), 6.78
d, 1H, J = 5.2 Hz, Quinoline-H), 3.98 (s, 4H, 4NH),
25
18
11 4
(
Found: C, 49.73; H, 3.04; N, 25.54.
(
2
1
.67–2.36 (m, 16H, 8CH , piperazine), 2.28 (s, 6H, 2CH ),
3.2.8 | N-(4,6-bis((4-methoxyphenyl)
amino)-1,3,5-triazin-2-yl)-
2-(7-chloroquinolin-4-yl)
2
3
13
.97 (s, 1H, N H N H); C-NMR (100 MHz, CDCl ) δ
3
ppm:182.1, 176.5, 172.3, 152.8, 149.6, 149.2, 34.9, 129.5,
1
5
24.9, 121.7, 119.8, 113.1, 59.2, 55.2, 46.8; ES-MS m/z:
59.18 (M + 1); Elemental analysis for C H ClN S:
hydrazinecarbothioamide 7d
23
32
13
ꢀ
Calculated: C, 49.50; H, 5.78; N, 32.63; Found: C,
9.54; H, 5.81; N, 32.61.
Yield: 76%; MP: 268–269 C; MW: 574.06; Rf: 0.72; FTIR
−
1
4
(νmax; cm KBr): 3395 (N H), 3079 (Ar C H str), 2985,
634, 1628 (C N str), 1539 (N–H bend), 1167, 985 (C N
1
−1 1
str), 834 (C Cl str) cm ; H-NMR (400 MHz, DMSO,
TMS) δ ppm: 8.64 (d, 1H, J = 5.4 Hz, Quinoline-H), 8.02
(d, 1H, J = 8.1 Hz, Quinoline-H), 7.78 (d, 1H, J = 1.9 Hz,
Quinoline-H), 7.58–6.98 (m, 8H, 8CH, Ar H), 7.32 (d,
1H, J = 7.5 Hz, Quinoline-H), 6.76 (d, 1H, J = 5.6 Hz,
3
.2.6 | N-(4,6-bis((3-aminopropyl)
amino)-1,3,5-triazin-2-yl)-
-(7-chloroquinolin-4-yl)
2
hydrazinecarbothioamide 7b
Quinoline-H), 3.97 (s, 4H, 4 N H), 3.74 (s, 6H, 2OCH ),
3
ꢀ
13
Yield: 75%; MP: 211–212 C; MW: 476; Rf: 0.73; FTIR
1.98 (s, 1H, N H N H); C-NMR (100 MHz, CDCl ) δ
3
−1
(
νmax; cm KBr): 3394 (N H), 3068 (Ar C H str), 1634,
ppm:182.2, 171.8, 164.2, 153.4, 152.8, 149.6, 149.4, 134.8,
131.2, 129.5, 124.8 121.8, 121.6, 119.8, 115.1, 113.1, 55.8;
ES-MS m/z: 575.08 (M + 1); Elemental analysis for
C H ClN O S: Calculated: C, 56.49; H, 4.21; N, 21.96;
1
627 (C N str),), 1539 (N H bend), 1168, 987 (C N str),
−1 1
8
32 (C Cl str), 832 cm ; H-NMR (400 MHz, DMSO,
TMS) δ ppm: 8.63 (d, 1H, J = 5.4 Hz, Quinoline-H), 8.01
d, 1H, J = 8.1 Hz, Quinoline-H), 7.78 (d, 1H, J = 1.9 Hz,
Quinoline-H), 7.33 (d, 1H, J = 7.1 Hz, Quinoline-H), 6.76
27
24
9 2
(
Found: C, 56.53; H, 4.19; N, 21.99.
(
(
d, 1H, J = 5.3 Hz, Quinoline-H), 5.08 (s, 4H, 2NH ), 3.97
2
s, 4H, 4N H), 3.37–1.86 (m, 12H, 6CH ), 1.98 (s, 1H,
3.2.9 | N-(4,6-bis((4-chlorophenyl)
amino)-1,3,5-triazin-2-yl)-
2-(7-chloroquinolin-4-yl)
2
13
N H N H); C-NMR (100 MHz, CDCl ) δ ppm:182.2,
1
1
mental analysis for C H ClN S: Calculated: C,
4
5
3
65.4, 164.1, 152.8, 149.5, 149.2, 134.8, 129.5, 124.9, 121.8,
19.7, 113.1, 39.6, 31.5; ES-MS m/z: 477.04 (M + 1); Ele-
hydrazinecarbothioamide 7e
19
26
11
ꢀ
7.94; H, 5.51; N, 32.37; Found: C, 47.93; H,
.53; N, 32.39.
Yield: 79%; MP: 276–277 C; MW: 582.89; Rf: 0.81; FTIR
−
1
(νmax; cm KBr): 3394 (N H), 3078 (Ar C H str), 1637,
1
8
629 (C N str),), 1537 (N H bend), 1169, 989 (C N str),
35 (C Cl str) cm ; H-NMR (400 MHz, DMSO, TMS) δ
−1 1
3
1
.2.7 | N-(4,6-bis((4-nitrophenyl)amino)-
,3,5-triazin-2-yl)-2-(7-chloroquinolin-4-yl)
ppm: 8.63 (d, 1H, J = 5.6 Hz, Quinoline-H), 8.01 (d, 1H,
J = 8.2 Hz, Quinoline-H), 7.79 (d, 1H, J = 1.8 Hz,
Quinoline-H), 7.67–7.24 (m, 8H, 8CH, Ar H), 7.34 (d,
hydrazinecarbothioamide 7c
1H, J = 7.8 Hz, Quinoline-H), 6.77 (d, 1H, J = 5.4 Hz,
ꢀ
Yield: 67%; MP: 289–290 C; MW: 604; Rf: 0.76; FTIR
Quinoline-H), 3.98 (s, 4H, 4 N H), 1.97 (s, 1H,
−1
13
(
νmax; cm KBr): 3397 (N H), 3072 (Ar C H str), 1637,
N H N H); C-NMR (100 MHz, CDCl ) δ ppm:182.2,
3
1
9
624 (C N str),), 1538 (N H bend), 1526 (NO str), 1163,
89 (C N str), 834 (C Cl str) cm ; H-NMR (400 MHz,
171.8, 164.2, 152.8, 149.6, 149.4, 137.2, 134.8, 129.7, 129.5,
127.8, 124.9, 122.1, 121.6, 119.8, 113.1; ES-MS m/z: 582.89
2
−
1 1

PHARMACOLOGICAL ACTIVITY OF 4-AMINOQUINOLINE 1,3,5-TRIAZINES DERIVATIVES
7
−
1 1
(
M + 1); Elemental analysis for C H Cl N S: Cal-
982 (C N str), 836 (C Cl str) cm ; H-NMR (400 MHz,
DMSO, TMS) δ ppm: 8.64 (d, 1H, J = 5.9 Hz, Quinoline-
H), 8.03 (d, 1H, J = 8.1 Hz, Quinoline-H), 7.79 (d, 1H,
J = 1.8 Hz, Quinoline-H), 7.32 (d, 1H, J = 7.8 Hz,
Quinoline-H), 6.76 (d, 1H, J = 5.3 Hz, Quinoline-H), 3.97
(s, 4H, 4N H), 2.58 (s, 2H, 2CH) 1.71–1.11 (m, 20H,
25
18
3 9
culated: C, 51.51; H, 3.11; N, 21.63; Found: C, 51.54; H,
.12; N, 21.58.
3
3
1
.2.10 | N-(4,6-bis (diethylamino)-
,3,5-triazin-2-yl)-2-(7-chloroquinolin-4-yl)
13
10CH ), 1.97 (s, 1H, N H N H); C-NMR (100 MHz,
2
hydrazinecarbothioamide 7f
CDCl ) δ ppm:182.2, 171.8, 160.8, 152.9, 149.5, 149.4,
3
134.8, 129.5, 124.8, 121.6, 119.8, 113.1, 54.8, 25.7, 25.1,
ꢀ
Yield: 69%; MP: 249–251 C; MW: 474.03; Rf: 0.75; FT-IR
32.8; ES-MS m/z: 527.12 (M + 1); Elemental analysis for
−1
(
νmax; cm KBr): 3399 (N H), 3072 (Ar C H str), 2986,
C H ClN S: Calculated: C, 57.07; H, 6.13; N, 23.96;
25
32
9
1
9
639, 1624 (C N str),), 1539 (N H bend), 1165,
86 (C N str), 839 (C Cl str) cm ; H-NMR (400 MHz,
Found: C, 57.04; H, 6.11; N, 23.97.
−
1 1
DMSO, TMS) δ ppm: 8.64 (d, 1H, J = 5.7 Hz, Quinoline-
H), 8.02 (d, 1H, J = 8.1 Hz, Quinoline-H), 7.79 (d, 1H,
J = 1.9 Hz, Quinoline-H), 7.33 (d, 1H, J = 7.7 Hz,
Quinoline-H), 6.76 (d, 1H, J = 5.4 Hz, Quinoline-H), 3.97
3.2.13 | N-(4,6-bis((4-fluorophenyl)
amino)-1,3,5-triazin-2-yl)-
2-(7-chloroquinolin-4-yl)
(
s, 2H, 2 N H), 3.26 (q, 8H, 4CH ), 1.97 (s, 1H,
hydrazinecarbothioamide 7i
2
13
N H N H), 1.23 (t, 12H, 4CH3); C-NMR (100 MHz,
ꢀ
CDCl ) δ ppm:182.1, 177.8, 171.8, 152.8, 149.6, 149.4,
Yield: 65%; MP: 279–280 C; MW: 549.99; Rf: 0.81; FTIR
3
−1
1
34.9, 129.5, 124.8, 121.6, 119.8, 113.2, 44.6, 12.8; ES-MS
(νmax; cm KBr): 3396 (N H), 3078 (Ar C H str), 1632,
m/z: 475.06 (M + 1); Elemental analysis for C H ClN S:
1634 (C N str), 1539 (N H bend), 1208 (Ar F), 1165,
987 (C N str), 839 (C Cl str) cm ; H-NMR (400 MHz,
DMSO, TMS) δ ppm: 8.62 (d, 1H, J = 5.8 Hz, Quinoline-H),
21
28
9
−1 1
Calculated: C, 53.21; H, 5.95; N, 26.59; Found: C,
3.23; H, 5.97; N, 26.57.
5
8.02 (d, 1H, J = 8.2 Hz, Quinoline-H), 7.78 (d, 1H, J = 1.9 Hz,
Quinoline-H), 7.41–7.31 (m, 8H, 8CH, Ar H), 7.34 (d, 1H,
J = 7.7 Hz, Quinoline-H), 6.78 (d, 1H, J = 5.2 Hz, Quinoline-
H), 3.97 (s, 4H, 4N H), 1.98 (s, 1H, N H N H); C-NMR
3
1
.2.11 | N-(4,6-bis (dimethylamino)-
,3,5-triazin-2-yl)-2-(7-chloroquinolin-4-yl)
13
hydrazinecarbothioamide 7g
(100 MHz, CDCl ) δ ppm:182.1, 171.8, 164.2, 157.4, 152.8,
3
149.5, 149.4, 134.8, 134.4, 129.5, 124.9, 121.6, 120.6, 119.8,
ꢀ
Yield: 76%; MP: 197–198 C; MW: 417.92; Rf: 0.79; FTIR
116.4, 113.1; ES-MS m/z: 550.97 (M + 1); Elemental analysis
−1
(
νmax; cm KBr): 3393 (N H), 3071 (Ar C H str), 2987,
for C H ClF N S: Calculated: C, 54.60; H, 3.30; N, 22.92;
25
18
2 9
1
9
636, 1628 (C N str),), 1534 (N H bend), 1168,
83 (C N str), 838 (C Cl str) cm ; H-NMR (400 MHz,
Found: C, 54.62; H, 3.28; N, 22.95.
−
1 1
DMSO, TMS) δ ppm: 8.62 (d, 1H, J = 5.8 Hz, Quinoline-
H), 8.01 (d, 1H, J = 8.2 Hz, Quinoline-H), 7.78 (d, 1H,
J = 1.9 Hz, Quinoline-H), 7.34 (d, 1H, J = 7.9 Hz,
Quinoline-H), 6.78 (d, 1H, J = 5.4 Hz, Quinoline-H), 3.98
3.2.14 | 2-(7-chloroquinolin-4-yl)-N-
(4,6-dimorpholino-1,3,5-triazin-2-yl)
hydrazinecarbothioamide7j
(
s, 2H, 2 N H), 3.06 (s, 12H, 4CH ), 1.97 (s, 1H,
3
13
ꢀ
N H N H); C-NMR (100 MHz, CDCl ) δ ppm:182.2,
Yield: 77%; MP: 265–266 C; MW: 501.99; Rf: 0.83; FTIR
3
−1
1
77.8, 171.8, 152.8, 149.6, 149.4, 134.8, 129.5, 124.9, 121.6,
(νmax; cm KBr): 3398 (N H), 3079 (Ar C H str), 1641,
1
19.8, 113.2, 38.4; ES-MS m/z: 418.96 (M + 1); Elemental
1637 (C N str),), 1535 (N H bend), 1168, 985 (C N str),
−1 1
analysis for C H ClN S: Calculated: C, 48.86; H,
4
838 (C Cl str) cm ; H-NMR (400 MHz, DMSO, TMS) δ
ppm: 8.63 (d, 1H, J = 5.8 Hz, Quinoline-H), 8.02 (d, 1H,
J = 8.2 Hz, Quinoline-H), 7.79 (d, 1H, J = 1.8 Hz,
Quinoline-H), 7.32 (d, 1H, J = 7.6 Hz, Quinoline-H), 6.78
(d, 1H, J = 5.3 Hz, Quinoline-H), 3.98 (s, 2H, 2 N H),
17
20
9
.82; N, 30.16; Found: C, 48.83; H, 4.81; N, 30.18.
3
1
.2.12 | N-(4,6-bis (cyclohexylamino)-
,3,5-triazin-2-yl)-2-(7-chloroquinolin-4-yl)
3.74–3.63 (m, 16H, 8CH , Morpholine), 1.98 (s, 1H,
2
13
hydrazinecarbothioamide 7h
N H N H); C-NMR (100 MHz, CDCl ) δ ppm:182.2,
3
177.8, 171.7, 152.8, 149.5, 149.4, 134.8, 129.5, 124.8, 121.6,
ꢀ
Yield: 79%; MP: 285–287 C; MW: 526.10; Rf: 0.87; FTIR
119.8, 113.1, 66.4, 48.7; ES-MS m/z: 503.02 (M + 1); Elemen-
−1
(
νmax; cm KBr): 3408 (N H), 3072 (Ar C H str), 2985,
tal analysis for C H ClN O S: Calculated: C, 50.24; H,
21
24
9 2
1
638, 1629 (C N str),), 1537 (N H bend), 1167,
4.82; N, 25.11; Found: C, 50.27; H, 4.82; N, 25.12.

8
BHAT ET AL.
3
.3 | Anticancer evaluation
the ADP-Glo Luminescence reader. All the assay com-
ponents were added to the blank control except the sub-
strate. By removing the blank control value, you can
obtain the corrected activity for each protein kinase
target.
In vitro cytotoxicity was determined using a standard
MTT assay with protocol appropriate for the individual
test system. The four human cancer cell lines HeLa,
MCF-7, HL-60, and HepG2 were cultured in the MEM
medium supplemented with 10% FBS, 1% glutamine,
and 50 mM/ml gentamicin sulfate in a CO incubator in
3.5 | Antibacterial screening
2
a humidified atmosphere of 5% CO and 95% air. The
2
3
cells were seeded in 96-well plates at a density of 5 × 10
All synthesized compounds were screened for determination
of their minimum inhibitory concentration (MIC, μg/mL)
against selected Gram-positive organisms viz., B. subtilis
(NCIM-2063), B. cereus (NCIM-2156), S. aureus (NCIM-
2079) and Gram-negative organism viz., P. aeruginosa
(NCIM-2036), E. coli (NCIM-2065), P. vulgaris (NCIM-2027)
by the broth dilution method as recommended by the
National Committee for Clinical Laboratory Standards with
cells per well and incubated until confluency 90%–95%.
Then, each well was treated with 100 μL medium con-
taining the desired concentrations of test derivatives
(
1–100 μM) and incubated for 48 hours. Cells in the con-
trol wells received the same volume of medium con-
taining 0.1% DMSO. About 20 μL MTT working solution
(
5 mg/mL) was then added to each well and incubated
[27]
for another 4 hours. At the end of incubation, the
medium was carefully removed and 200 μL DMSO was
added. By using ELISA reader, the optical density was
measured at 540 nm. The experiment was performed in
triplicate. Cell survival was calculated as the percentage
of MTT inhibition as %growth inhibition = 100 − (mean
OD of individual test Group/Mean OD of each Control
Group) × 100.
minor modifications.
Cefixime was used as a standard
antibacterial agent. Solutions of the test compounds and ref-
erence drugs were prepared in dimethyl sulfoxide (DMSO) at
concentrations of 100, 50, 25, 12.5, 6.25, and 3.125 μg/mL.
Eight tubes were prepared in duplicate with the second set
being used as MIC reference controls (16–24 hours visual).
ꢀ
After sample preparation, the controls were placed in a 37 C
incubator and read for macroscopic growth (clear or turbid)
the next day. Into each tube, 0.8 mL of nutrient broth was
pipetted (tubes 2–7), tube 1 (negative control) received
1.0 mL of nutrient broth and tube 8 (positive control)
received 0.9 mL of nutrient. Tube 1, the negative control, did
not contain bacteria or antibiotics. The positive control,
tube 8, received 0.9 mL of nutrient broth because it con-
tained bacteria but not antibiotics. The test compound
was dissolved in DMSO (100 μg/mL), 0.1 mL of increas-
ing concentration of the prepared test compounds that
are serially diluted from tube 2 to tube 7 from highest
(100 μg/mL) to lowest (3.125 μg/mL) concentration
(tubes 2–7 containing 100, 50, 25, 12.5, 6.25, and
3.125 μg/mL). After this process, each tube was inocu-
lated with 0.1 mL of the bacterial suspension whose con-
3.4 | EGFR TK inhibitory activity
Kinase activity was determined using Kinase-Glo Plus
luminescence kinase assay kit, by quantitating the
amount of ATP remaining in the solution of kinase
[
15]
reaction.
The luminescent signal is correlated with
the residual amount present and it was inversely related
to kinase activity. The tested compounds were diluted
to 100 mM in 10% DMSO, and then 5 mL of the dilution
was added to a 50 mL reaction. All of the enzymatic
ꢀ
reactions were performed at 30 C for 40 minutes, 50 mL
of reaction mixture contains 10 mM MgCl , 40 mM Tris,
2
8
pH 7.4, 0.1 mg/mL BSA, 0.2 mg/mL Poly (Glu, Tyr) sub-
strate, 10 mM ATP and EGFR. Incubate the plate for
centration corresponded to 0.5 McFarland scale (9 × 10
cells/mL) and each bacterium was incubated at 37 C for
ꢀ
5
minutes at room temperature and then add 50 mL of
24 hours at 150 rpm. The final volume in each tube was
1.0 mL. The incubation chamber was kept humid. At the
end of the incubation period, MIC values were recorded
as the lowest concentration of the substance that gave no
visible turbidity, that is, no growth of inoculated bacteria.
Kinase-GloPlus Luminescence kinase assay to each
reaction. ADP-Glo assay kit is the protein kinase assays
used to determine IC50 values in which ADP generation
was measured as it leads to an increase in luminescence
signal. The reaction mixture was incubated in a 96-well
ꢀ
plate at 30 C for 30 minutes; after the incubation period
add 25 mL of ADP-Glo reagent to terminate the assay.
Shake the 96-well plate for 30 minutes at ambient
temperature and incubate it, then add 50 mL of
kinase detection reagent. Read the 96-well plate using
3.6 | Antifungal screening
All synthesized compounds were screened for determina-
tion of their MIC (μg/mL) against selected fungal strain

PHARMACOLOGICAL ACTIVITY OF 4-AMINOQUINOLINE 1,3,5-TRIAZINES DERIVATIVES
9
viz., C. albicans, A. niger, and A. fumigates by the broth
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4
| CONCLUSIONS
In the present study, a novel series of 4-aminoquinoline-
,3,5-triazines were developed as broad-spectrum antip-
[
[
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1
roliferative, anti-bacterial, and anti-fungal agent. The
results suggest the utility of these molecules against can-
cer and their co-infections, which is the major cause of
mortality during the course of cancer treatment. How-
ever, more studies are needed to optimize these mole-
cules to get potent inhibitor, and our study is in progress
toward the development of new hybrid derivatives of this
skeleton and will be reported in due course.
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ACKNOWLEDGMENT
2
Authors are gratified to SAIF, Panjab University Chandi-
garh, India for providing spectral data of compounds syn-
thesized herein and SHUATS for providing basic facilities
to carry out the project.
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CONFLICT OF INTEREST
The authors declare no conflict of interest.
[24] Srivastava, J. K.; Awatade, N. T.; Bhat, H. R.; Kmit, A.;
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Hans Raj Bhat https://orcid.org/0000-0002-9643-4916

10
BHAT ET AL.
[
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Siqueira, G. M.; Lund, R. G.; Cunico, W. Sci. World J. 2011, 11,
How to cite this article: Bhat HR, Masih A,
1
489.
Shakya A, Ghosh SK, Singh UP. Design, synthesis,
anticancer, antibacterial, and antifungal evaluation
of 4-aminoquinoline-1,3,5-triazine derivatives.
J Heterocyclic Chem. 2019;1–10. https://doi.org/10.
[
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