Synthesis, X-ray crystal structures, and preliminary antiproliferative activities of new s-triazine-hydroxybenzylidene hydrazone derivatives

Article abstract of DOI:10.1155/2019/9403908

We herein report a new small library of Schiff-base compounds that encompasses s-triazine and (2 or 4)-hydroxylbenzylidene derivatives. These compounds were synthesized through a hydrazone linkage connecting both the s-triazine and hydroxybenzylidene deri

Full text of DOI:10.1155/2019/9403908

Hindawi
Journal of Chemistry
Volume 2019, Article ID 9403908, 10 pages
https://doi.org/10.1155/2019/9403908
Research Article
Synthesis, X-Ray Crystal Structures, and Preliminary
AntiproliferativeActivitiesofNews-Triazine-hydroxybenzylidene
Hydrazone Derivatives
1
,
2
3
1
1
AssemBarakat , FardousF. El-Senduny, ZainabAlmarhoon , HessaH. Al-Rasheed,
4
1
5
Farid A. Badria, Abdullah Mohammed Al-Majid , Hazem A. Ghabbour,
and Ayman El-Faham
1,2
1
Chemistry Department, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Alexandria 21321, Egypt
Department of Chemistry, Faculty of Science, Mansura University, Mansura 35516, Egypt
Department of Pharmacognosy, Faculty of Pharmacy, Mansura University, Mansura 35516, Egypt
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansura University, Mansoura 35516, Egypt
2
3
4
5
Correspondence should be addressed to Assem Barakat; ambarakat@ksu.edu.sa and
Ayman El-Faham; aymanel_faham@hotmail.com
Received 10 February 2019; Accepted 11 April 2019; Published 30 April 2019
Academic Editor: Maria F. Carvalho
Copyright © 2019 Assem Barakat et al. (is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
We herein report a new small library of Schiff-base compounds that encompasses s-triazine and ꢀ2 or 4)-hydroxylbenzylidene
derivatives. (ese compounds were synthesized through a hydrazone linkage connecting both the s-triazine and hydrox-
ybenzylidene derivatives. (e synthetic strategy adopted allowed the synthesis of the target compounds with excellent yields and
1
13
purities as observed from their NMR ꢀ H and C) and elemental analysis. Furthermore, 4f, 5b, and 5f were further confirmed by
X-ray single crystal diffraction technique. (e preliminary antiproliferative activities for the synthesized compounds were tested
against two different cancer cell lines including breast cancer ꢀMCF-7) and colon cancer ꢀHCT-116). From the eighteen
compounds, which have been examined, only two derivatives having piperidine moiety showed more selectivity against the two
cell lines MCF-7 and HCT-116, while the others showed very weak activity. (e position of the hydroxyl group in the benzylidine
ring and the substituent on the s-triazine moiety has great effect on the activity of the prepared compounds. (e IC50 values for the
two derivatives 4a and 5a evaluated against breast cancer cells, very close to those for the chemotherapeutic drug cisplatin, are
2
7 µM ꢀ13.3 µg/mL), 17 µM ꢀ8.4 µg/mL), and 20 µM ꢀ6 µg/mL) for 4a, 5a, and cisplatin, respectively. (ese results propose the
preliminary antiproliferative activity of these two derivatives may deserve further consideration for development of new de-
rivatives as potent anticancer agents.
hydrazone derivatives have shown to exhibit anti-
proliferative activities with the ability to prevent cell pro-
gression in cancerous cells through different mechanisms
[12]. Several hydrazone derivatives have been also shown
antitumoral [13], antifungal, antiplatelet, antitubercular,
antiviral, anticonvulsant, antimalarial, anti-inflammatory,
and antipyretic activities [9, 14–19].
Similarly, s-triazine derivatives represent important
class of compounds in medicinal chemistry [20–23].
Cyanuric chloride has been used as building blocks in the
1
. Introduction
Schiff bases have gained great importance in which these
compounds have been found to exhibit antimicrobial [1–4],
antiviral [1, 5], antioxidant [6], and antitumor [7, 8] ac-
tivities. (ese activities are largely attributed due to the
presence of the azomethine ꢀR-NH-N�C-R) group which is
important synthon for several transformations [9, 10]. In
addition, the hydrazone linkage provides an appropriate
system for pH-dependent of drugs release [11]. Several

2
Journal of Chemistry
synthesis of vast derivatives bearing the s-triazine moiety,
due to the low-cost, commercial availability, and ease of
displacement of the three chlorine atoms by various nu-
cleophiles under controlled temperature [24]. (ese ad-
vantages allowed for the preparation of mono-, di- and
trisubstituted s-triazines derivatives with a wide range of
biological activities [25–27], such as adenosine receptor
antagonist [28], antiamoebic [29], antileishmanial [31–33],
anticancer [32], antimalarial [34], antimicrobial [35–37],
antiviral [38], antitubercular [39], carbonic anhydrase
inhibitor [40], and cathepsin B inhibitor [41], Previously,
we reported new series of s-triazine Schiff-base derivatives
terms of ppm and J-coupling constants are given in Hz. Mass
spectra were recorded on a JEOL of JMS-600 H. Elemental
analysis was carried out on an Elmer 2400 elemental ana-
lyzer. All melting points were measured on a Gallenkamp
melting point apparatus in open glass capillaries and are
uncorrected. IR Spectra were measured as KBr pellets on a
Nicolet 6700 FT-IR spectrophotometer.
2
.1.2. 6-Chloro-4,6-disubstituted s-Triazine Derivatives ꢀ2a-
i). 6-Chloro-4,6-disubstituted s-triazine derivatives ꢀ2a-i)
were synthesized following the strategies and methods al-
ready reported by our group and others [47–51], as shown in
Scheme 1. 6-Hydrazine-4,6-disubstituted s-triazine de-
rivatives were synthesized following the published and re-
ported method by our group [47, 49]. All spectral data were
in good agreement with the reported data.
[
42–44]; among of the reported compounds, only three
derivatives were able to inhibit the growth of lung ꢀA549)
and hepatocellular carcinoma ꢀHepG2) cancer cell lines.
(
e results showed that s-triazine with the two substituents
methoxy and piperidine in the target product made the
compound more selective to the hepatocyte carcinoma
HepG2 ꢀIC value of 1.5 µg/mL). On the contrary, the
(
e compounds of 4f, 5b, and 5f obtained as single
crystals by slow evaporation from ethanol solution to afford
the pure compounds at room temperature. Data were col-
lected on a Bruker APEX-II D8 Venture area diffractometer,
equipped with graphite monochromatic Mo Kα radiation,
5
0
combination between morpholine and piperdine motifs in
the final target made the compound more selective to the
lung carcinoma A549 ꢀIC value of 5.6 µg/ml) and with
5
0
˚
λ � 0.71073 A at 293 ꢀ2) and 296 ꢀ2) K. Cell refinement and
reasonable effect to the hepatocyte carcinoma HepG2 ꢀIC50
value 6.5 µg/ml) [44], Recently, Bai et al. [45] identified a
series of 1,3,5-triazine hydrazone derivatives as dual-
effective inhibitors against both epidermal growth factor
receptor ꢀWTEGFR) and mutant epidermal growth factor
receptor ꢀEGFR). Moreover, some of them exhibited
considerable antiproliferative activity against A549, A431,
and NCIH1975 cell lines.
data reduction were carried out by Bruker SAINT. SHELXT
was used to solve structures [52, 53]. (e final refinement
was carried out by full-matrix least-squares techniques with
anisotropic thermal data for nonhydrogen atoms on F.
CCDC No. 1567719 ꢀ4f), 1567728 ꢀ5b), and 1567725 ꢀ5f)
containng the supplementary crystallographic data for these
compounds wwhich can be obtained free of charge from the
Cambridge Crystallographic Data Centre via http://www.
ccdc.cam.ac.uk/data_request/cif.
Menwear et al. [46] reported 1,3,5-triazine hydrazone
based on 4-hydroxy-3,5-dimethoxyphenyl derivatives
ꢀ
Figure 1) as selective inhibitors of the mammalian target
of rapamycin ꢀmTOR). (ey claimed that the phenolic
hydroxyl group in the series is critical in the activity be-
cause it acts as a hydrogen donor, where when it was
substituted by a methoxy, a dramatic loss in the activity
was observed.
2.1.3. General Procedure for the Synthesis of Schiff Bases 4a-i
and 5a-h. A solution of hydroxybenzaldehyde derivatives
3a-b ꢀ6 mmol), drop of acetic acid, and s-triazine derivatives
2a-i ꢀ6 mmol) in EtOH ꢀ10 ml) were mixed and heated under
reflux for 3 h ꢀTLC 20% EtOAc/n-hexane). (e solvent was
evaporated slowly, to provide the corresponding product 4a-
i and 5a-h.
(
ese results encouraged us to develop small library
ꢀ
Figure 1) bearing of s-triazine derivatives with different
substituents and ꢀ2 or 4)-hydroxybenzylidene derivatives
through a hydrazone linkage. (e antiproliferative activities
of the target products will be discussed to fine-tune and get
more information related to the effect of both substituent in
the s-triazine moiety and the position of the hydroxyl group
in the benzylidene core attached to the s-triazine through the
hydrazone linkage.
(1) (E)-2,6-Di-tert-butyl-4-((2-(4,6-di(piperidin-1-yl)-1,3,5-
triazin 2-yl)hydrazono)methyl)phenol (4a). Yellow powder
−
1
°
in yield 93%; m.p: >250 C; IR ꢀKBr, cm ): 3637, 3423, 3197,
1
2960, 2935, 1583, 1570, 1510, 1462; H-NMR ꢀ400 MHz,
DMSO-d ): δ 8.34 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H, NH), 7.46 ꢀs,
6
1H, Ph), 7.19 ꢀs, 1H, Ph), 3.73 ꢀbrs, 8H, 4CH ), 1.55 ꢀm, 8H,
2
13
4
ꢀ
CH ), 1.38 ꢀs, 18H, 6CH ), 1.34 ꢀm, 4H, 2CH ); C-NMR
2 3 2
100 MHz, DMSO-d ): δ � 206.9, 156.6, 136.0, 128.9,124.4,
6
2
. Experimental Section
4
[
4.7, 34.3, 30.9, 30.1, 25.8, 24.6; LC/MS ꢀESI): 494.70
+
M + 1] ; Anal. for C H N O; Calcd: C, 68.12; H, 8.78; N,
2.1. Chemistry
28 43 7
1
9.86; Found: C, 68.13; H, 8.79; N, 19.89.
2
.1.1. General. All reagents and solvents were purchased
from commercial suppliers and were used without further
(2) (E)-2,6-Di-tert-butyl-4-((2-(4,6-dimorpholino-1,3,5-triazin-
1
13
purification; NMR spectra ꢀ H-NMR and C-NMR) were
recorded on a JEOL 400 MHz spectrometer. H-NMR
2-yl)hydrazono)methyl)phenol (4b). Yellow powder in yield
1
−1
°
91%; m.p: 180 C; IR ꢀKBr, cm ): 3086, 3053, 2953,
1
3
1
ꢀ
400 MHz) and C-NMR ꢀ100 MHz) were run in either
2885,1598, 1560, 1516, 1463, 1371; H-NMR ꢀ400 MHz,
deuterated dimethylsulphoxide ꢀDMSO-d ) or deuterated
DMSO-d ): δ 8.25 ꢀs, 1H, CH �), 8.10 ꢀbrs, 1H, NH), 7.38 ꢀs,
6
6
chloroform ꢀCDCl ). Chemical shifts ꢀδ) are referred in
1H, Ph), 7.12 ꢀs, 1H, Ph), 3.70 ꢀbrs, 8H, 4CH ), 1.50 ꢀm, 8H,
3
2

Journal of Chemistry
3
OMe
R2
N
HO
N
N
N
MeO
N
H
R1
Kinase inhibitors of mTOR [46]
R = R = piperidine
1
2
R = R = morpholine
1
2
R = morpholine, R = piperidine
1
2
R1
R2
N
N
N
HN
NH2
t
R2
N
t
Bu
Bu
R2
HO
N
N
N
N
N
N
t
t
Bu
N
H
R1
Bu
N
H
N
R1
OH
Figure 1: Rational design for the target products.
(
i) R H, R H, Na CO
1 2 2 3
acetone-water r.t.
(ii) Hydrazine
ethanol, reflux
R1
N
R2
Cl
N
Cl
N
N
N
N
t
Bu
HN
t
NH2
Cl
1
Bu
2
a-i
HO
O
t
Bu
O
R2
N
t
Bu
Ethanol, reflux
drops AcOH
OH 3b
3
a
t
t
Bu
Bu
R2
N
HO
N
N
N
N
N
N
t
t
Bu
Bu
N
H
R1
N
H
R1
OH
4
a-i
5
a-h
R = R = piperidine, 4a or 5a
1
2
R = R = morpholine, 4b or 5b
1
2
R = diethylamine; R = morpholine, 4c or 5c
1
2
R = methoxy; R = morpholine, 4d or 5d
1
2
R = piperidine; R = morpholine, 4e or 5e
1
2
R = benzylamine; R = morpholine, 4f or 5f
1
2
R = aniline; R = morpholine, 4g or 5g
1
2
R = methoxy; R = piperidine, 4h or 5h
1
2
R = diethyamine; R = piperidine, 4i
1
2
Scheme 1: Synthetic route for preparation of s-triazine Schi™-base derivatives.
1
3
1
4
CH ), 1.35 (s, 18H, 6CH ); C-NMR (100 MHz, DMSO-d ):
2908, 2870, 1624, 1591, 1456; H-NMR (400 MHz, DMSO-d ):
2
3
6
6
δ ꢀ 198.9, 155.3, 135.1, 129.0, 125.1, 65.9, 44.6, 34.2, 30.9,
δ 8.60 (s, 1H, CH ꢀ), 7.80 (brs, 1H, NH), 7.66 (s, 1H, Ph), 7.50
+
3
0.1LC/MS (ESI): 498.31 [M + 1] ; Anal. for C H N O ;
(s, 1H, Ph), 3.82 (brs, 4H, 2CH ), 3.72 (t, 4H, J ꢀ 22.3 Hz,
26
39
7
3
2
Calcd: C, 62.75; H, 7.90; N, 19.70; Found: C, 62.71; H, 7.91 N,
9.72.
2CH ), 3.60 (brs, 4H, 2CH ), 1.49 (s, 9H, 3CH ), 1.44 (s, 9H,
2
2
3
13
1
3CH ), 1.18 (m, 6H, 2CH ); C-NMR (100 MHz, DMSO-d ):
3 3 6
δ ꢀ 198.4, 176.5156.6, 143.9, 136.0, 125.3, 124.4, 67.5, 47.9, 44.7,
+
(
1
3) (E)-2,6-Di-tert-butyl-4-((2-(4-(diethylamino)-6-morpholino-
34.3, 31.1, 12.3; LC/MS (ESI): 484.33 [M + 1] ; Anal. for
,3,5-triazin-2-yl)hydrazono)methyl)phenol (4c). Yellow pow-
C H N O ; Calcd: C, 64.57; H, 8.54; N, 20.27; Found: C,
26 41 7 2
−
1
°
der in yield 89%; m.p: 195 C; IR (KBr, cm ): 3420, 2999, 2960,
64.57; H, 8.53; N, 20.25.

4
Journal of Chemistry
+
(
4)
(E)-2,6-Di-tert-butyl-4-((2-(4-methoxy-6-morpholino-
67.5, 53.9, 47.9, 34.3, 31.0; LC/MS ꢀESI): 441.29 [M + 1] ;
1
,3,5-triazin-2-yl)hydrazono)methyl)phenol (4d). Yellow
Anal. for C H N O ; Calcd: C, 65.43; H, 8.24; N, 19.07;
24 36 6 2
−
1
°
powder in yield 80%; m.p: 114 C; IR ꢀKBr, cm ): 3215, 3045,
Found: C, 65.44; H, 8.23; N, 19.10.
1
2
958, 2908, 2866, 1614, 1598, 1544,1463; H-NMR ꢀ400 MHz,
DMSO-d ): δ 7.94 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H, NH), 7.70 ꢀs,
(9) (E)-2,6-Di-tert-butyl-4-((2-(4-(diethylamino)-6-(piperidin-
6
1
2
3
1
H, Ph), 7.52 ꢀs, 1H, Ph), 3.93 ꢀs, 3H, OCH ), 3.83 ꢀbrs, 4H,
1-yl)-1,3,5-triazin-2-yl)hydrazono)methyl)phenol (4i). Yellow
3
−
1
°
CH ), 3.70 ꢀbrs, 4H, 2CH ), 1.45 ꢀs, 9H, 3CH ), 1.43 ꢀs, 9H,
powder in yield 94%; m.p: 169 C; IR ꢀKBr, cm ): 3423, 3197,
2
2
3
1
3
1
CH ); C-NMR ꢀ100 MHz, DMSO-d ): δ �194.6, 173.5,
2960, 2908, 2858, 1583, 1570, 1510, 1435; H-NMR ꢀ400 MHz,
3
6
56.6, 143.9, 136.0, 125.3, 124.4, 67.5, 53.9, 47.9, 34.3, 31.0;
DMSO-d ): δ 8.44 ꢀs, 1H, CH �), 7.95 ꢀbrs, 1H, NH), 7.55
6
+
LC/MS ꢀESI): 443.27 [M + 1] ; Anal. for C H N O ; Calcd:
ꢀs, 1H, Ph), 7.47 ꢀs, 1H, Ph), 3.76 ꢀbrs, 4H, 2CH ), 3.72 ꢀt, 4H,
23
34
6
3
2
C, 62.42; H, 7.74; N, 18.99; Found: C, 62.43; H, 7.75; N, 19.01.
J � 22.3 Hz, 2CH ), 3.60 ꢀbrs, 4H, 2CH ), 1.49 ꢀs, 9H, 3CH ),
2
2
3
1
.44 ꢀs, 9H, 3CH ), 128 ꢀm, 2H, CH ), 1.22 ꢀm, 6H, 2CH );
3 2 3
13
(
5) (E)-2,6-Di-tert-butyl-4-((2-(4-morpholino-6-(piperidin-1-
C-NMR ꢀ100 MHz, DMSO-d ): δ �199.3, 176.1, 156.2,
6
yl)-1,3,5-triazin-2-yl)hydrazono)methyl)phenol (4e). Yellow
142.8, 136.0, 125.3, 124.4, 67.5, 47.9, 44.7, 34.3, 31.0, 12.2;
−
1
+
°
powder in yield 90%, m.p: >250 C; IR ꢀKBr, cm ):
LC/MS ꢀESI): 482.35 [M + 1] ; Anal. for C H N O;
2
7
43
7
3
215,3157, 3045, 2958, 2908, 2866, 1614, 1598, 1544, 1463;
Calcd: C, 67.32; H, 9.00; N, 20.36; Found: C, 67.31; H, 9.00;
N, 20.35.
1
H-NMR ꢀ400 MHz, DMSO-d ): δ 8.34 ꢀs, 1H, CH �), 7.80
6
ꢀ
brs, 1H, NH), 7.46 ꢀs, 1H, Ph), 7.19 ꢀs, 1H, Ph), 3.73 ꢀbrs,
8
H, 4CH ), 1.50 ꢀm, 4H, 2CH ), 1.45 ꢀm, 4H, 2CH ), 1.38 ꢀs,
(10) (E)-2,4-Di-tert-butyl-6-((2-(4,6-di(piperidin-1-yl)-1,3,5-
2
2
2
13
1
8H, 6CH ), 1.34 ꢀm, 2H, CH ); C-NMR ꢀ100 MHz,
triazin-2-yl)hydrazono)methyl)phenol (5a). Yellow powder
3
2
−
1
°
DMSO-d ): δ �198.7, 156.6, 136.0, 128.9, 124.4, 44.7, 34.3,
in yield 90%; m.p: 217 C; IR ꢀKBr, cm ): 3637, 3423, 3197,
6
+
1
3
0.9, 30.1, 25.8, 24.6; LC/MS ꢀESI): 496.33 [M + 1] ; Anal. for
2960, 2935, 1583, 1570, 1510, 1462; H-NMR ꢀ400 MHz,
C H N O ; Calcd: C, 65.43; H, 8.34; N, 19.78; Found: C,
DMSO-d ): δ 8.03 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H, NH), 7.32 ꢀs,
2
7
41
7
2
6
6
5.43; H, 8.35; N, 19.76.
1H, Ph), 7.01 ꢀs, 1H, Ph), 3.79 ꢀbrs, 8H, 4CH ), 1.51 ꢀm, 8H,
2
13
4
CH ), 1.38 ꢀs, 18H, 6CH ), 1.27 ꢀm, 4H, 2CH ); C-NMR
2 3 2
(
6) (E)-4-((2-(4-(Benzylamino)-6-morpholino-1,3,5-triazin-
ꢀ100 MHz, DMSO-d ): δ � 206.9, 156.6, 136.0, 128.9, 124.4,
6
2
-yl)hydrazono)methyl)-2,6-di-tert-butylphenol (4f). Yellow
44.7, 34.3, 30.9, 30.1, 25.8, 24.6; LC/MS ꢀESI): 494.35
−
1
+
°
powder in yield 88%, m.p: 169 C; IR ꢀKBr, cm ): 3421, 3116,
[M + 1] ; Anal. for C H N O; Calcd: C, 68.12; H, 8.78; N,
28
43 7
1
2
958, 2860, 1618, 1591, 1508, 1440; H-NMR ꢀ400 MHz,
19.86; Found: C, 68.11; H, 8.78; N, 19.83.
DMSO-d ): δ 8.22 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H, NH), 7.55 ꢀs,
6
1
H, Ph), 7.37-7.28 ꢀm, 5H, Ph), 7.19 ꢀs, 1H, Ph), 4.23 ꢀs, 2H,
(11) (E)-2,4-Di-tert-butyl-6-((2-(4,6-dimorpholino-1,3,5-triazin-
CH Ph), 3.73 ꢀbrs, 4H, 2CH ), 1.50 ꢀm, 4H, 2CH ), 1.40 ꢀs,
2-yl)hydrazono)methyl)phenol (5b). Yellow powder in yield
2
2
2
1
3
−1
°
1
1
2
8H, 6CH ); C-NMR ꢀ100 MHz, DMSO-d ):δ �198.7,
95%; m.p: 188 C; IR ꢀKBr, cm ): 3086, 3053, 2953, 2885,1598,
3
6
1
56.6, 136.0, 129.5, 128.9, 124.4, 123.2, 65.9, 44.7, 31.2, 30.0,
1560, 1516, 1463, 1371; H-NMR ꢀ400 MHz, DMSO-d ): δ 8.25
6
+
5.6, 24.5; LC/MS ꢀESI): 518.32 [M + 1] ; Anal. for
ꢀs, 1H, CH �), 8.10 ꢀbrs, 1H, NH), 7.38 ꢀs, 1H, Ph), 7.12 ꢀs, 1H,
C H N O ; Calcd: C, 67.28; H, 7.59; N, 18.94; Found: C,
Ph), 3.70 ꢀbrs, 8H, 4CH ), 1.50 ꢀm, 8H, 4CH ), 1.35 ꢀs, 18H,
2
7
41
7
2
2
2
13
6
7.30; H, 7.60; N, 18.95.
6CH ); C-NMR ꢀ100 MHz, DMSO-d ): δ �198.9, 155.3,
3
6
1
35.1, 129.0, 125.1, 65.9, 44.6, 34.2, 30.9, 30.1; LC/MS ꢀESI):
+
(
7) (E)-2,6-Di-tert-butyl-4-((2-(4-morpholino-6-(phenylamino)-
498.31 [M + 1] ; Anal. for C H N O ; Calcd: C, 62.75; H,
26 39 7 3
1
,3,5-triazin-2-yl)hydrazono)methyl)phenol (4g). Yellow pow-
7.90; N, 19.70; Found: C, 62.75; H, 7.89; N, 19.72.
−
1
°
der in yield 87%; m.p: 151 C; IR ꢀKBr, cm ): 3448, 3215, 3169,
1
2
953, 2866, 1595, 1570, 1554, 1476, 1435, 1440; H-NMR
(12) (E)-2,4-Di-tert-butyl-6-((2-(4-(diethylamino)-6-morpholino-
ꢀ
400 MHz, DMSO-d ): δ 8.35 ꢀs, 1H, CH �), 8.02 ꢀbrs, 1H,
1,3,5-triazin-2-yl)hydrazono)methyl)phenol (5c). Yellow powder
6
−
1
°
NH), 7.50 ꢀs, 1H, Ph), 7.30-7.26 ꢀm, 5H, Ph), 7.20 ꢀs, 1H, Ph),
in yield 87%; m.p: 203 C; IR ꢀKBr, cm ): 3421, 3116, 2966,
1
3
.70 ꢀbrs, 4H, 2CH ), 1.56 ꢀm, 4H, 2CH ), 1.35 ꢀs, 18H, 6CH );
2980, 1647, 1618, 1591, 1508,1499, 1440; H-NMR ꢀ400 MHz,
2
2
3
1
3
C-NMR ꢀ100 MHz, DMSO-d ): δ �198.7, 156.6, 136.0, 129.5,
DMSO-d ): δ 8.82 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H, NH), 7.53 ꢀs,
6
6
1
5
7
28.9, 124.4, 123.2, 66.0, 31.2, 30.0, 25.6, 24.5; LC/MS ꢀESI):
1H, Ph), 7.54 ꢀs, 1H, Ph), 3.82 ꢀbrs, 4H, 2CH ), 3.72 ꢀt, 4H,
2
+
04.30 [M + 1] ; Anal. for C H N O ; Calcd: C, 66.77; H,
J � 22.3 Hz, 2CH ), 3.60 ꢀbrs, 4H, 2CH ), 1.57 ꢀs, 9H, 3CH ),
28
37
7
2
2
2
3
13
.41; N, 19.47; Found: C, 66.76; H, 7.40; N, 19.49.
1.40 ꢀs, 9H, 3CH ), 1.18 ꢀm, 6H, 2CH ); C-NMR ꢀ100 MHz,
3 3
DMSO-d ): δ �198.4, 176.5, 156.6, 143.9, 136.0, 125.3, 124.4,
6
13
(
8) (E)-2,6-Di-tert-butyl-4-((2-(4-methoxy-6-(piperidin-1-yl)-
67.5, 47.9, 44.7, 34.3, 31.1, 12.3; C-NMR ꢀ100 MHz, DMSO-
+
1
,3,5-triazin-2-yl)hydrazono)methyl)phenol (4h). Yellow
d ): δ � ; LC/MS ꢀESI): 484.33 [M + 1] ; Anal. for
6
−
1
°
powder in yield 93%; m.p: 124 C; IR ꢀKBr, cm ): 3302, 2958,
C H N O ; Calcd: C, 64.57; H, 8.54; N, 20.27; Found: C,
26 41 7 2
1
2
908, 2866, 1614, 1587, 1545, 1504, 1438, 1409; H-NMR
64.56; H, 8.53; N, 20.24.
ꢀ
400 MHz, DMSO-d ): δ 7.94 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H,
6
NH), 7.70 ꢀs, 1H, Ph), 7.52 ꢀs, 1H, Ph), 3.93 ꢀs, 3H, OCH ),
(13) (E)-2,4-Di-tert-butyl-6-((2-(4-methoxy-6-morpholino-
3
3
1
.83 ꢀbrs, 4H, 2CH ), 3.70 ꢀbrs, 4H, 2CH ), 1.45 ꢀs, 9H, 3CH ),
.43 ꢀs, 9H, 3CH ), 1.35 ꢀm, 2H, CH ); C-NMR ꢀ100 MHz,
1,3,5-triazin-2-yl)hydrazono)methyl)phenol (5d). Yellow
2
2
3
1
3
−1
°
powder in yield 83%; m.p:195 C; IR ꢀKBr, cm ): 3215, 3045,
3
2
1
DMSO-d ): δ �194.6, 173.5, 156.6, 143.9, 136.0, 125.3, 124.4,
2958, 2908, 2866, 1614, 1598, 1544,1463; H-NMR ꢀ400 MHz,
6

Journal of Chemistry
5
DMSO-d ): δ 7.95 ꢀs, 1H, CH �), 7.78 ꢀbrs, 1H, NH), 7.65 ꢀs,
2.2. Anticancer Activity. (e cytotoxic activity of 18 newly
synthesized compounds was tested against two mammalian
cancer cell lines, colon cancer cells ꢀHCT-116), and breast
cancer cells ꢀMCF-7). (e cell lines were obtained from
VACSERA, holding company for biological products and
6
1
2
3
1
H, Ph), 7.50 ꢀs, 1H, Ph), 3.92 ꢀs, 3H, OCH ), 3.83 ꢀbrs, 4H,
3
CH ), 3.70 ꢀbrs, 4H, 2CH ), 1.45 ꢀs, 9H, 3CH ), 1.43 ꢀs, 9H,
2
2
3
1
3
CH ); C-NMR ꢀ100 MHz, DMSO-d ): δ �194.6, 173.5
3
6
56.6, 143.9, 136.0, 125.3, 124.4, 67.5, 53.9, 47.9, 34.3, 31.0;
+
°
LC/MS ꢀESI): 443.27 [M + 1] ; Anal. for C H N O ; Calcd:
vaccines, Cairo, Egypt. (e cells were grown at 37 C and 10%
23
34 6 3
C, 62.42; H, 7.74; N, 18.99; Found: C, 62.42; H, 7.75; N, 19.22.
CO in DMEM ꢀLonza, 12-604F) medium supplemented
2
with 10% fetal bovine serum ꢀFBS, Lonza, Cat. No.14-801E),
100 IU/mL penicillin, and 100 µg/mL streptomycin ꢀLonza,
17-602E). (e viability of the cells were quantified by using
MTT reagent ꢀ3-ꢀ4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide), which measures the activity of mi-
tochondrial dehydrogenase in the viable cells [54].
(
14) (E)-2,4-Di-tert-butyl-6-((2-(4-morpholino-6-(piperidin-
1-yl)-1,3,5-triazin-2-yl)hydrazono)methyl)phenol (5e). Yel-
−
1
°
low powder in yield 86%; m.p: 171 C; IR ꢀKBr, cm ) 3134,
1
3
ꢀ
045, 2958, 2908, 2866, 1614, 1598, 1544, 1463; H-NMR
400 MHz, DMSO-d ): δ 8.34 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H,
6
4
NH), 7.46 ꢀs, 1H, Ph), 7.19 ꢀs, 1H, Ph), 3.73 ꢀbrs, 8H, 4CH ),
(e cells were seeded in 96-well plates as 5 ×10 cells/mL
2
1
6
.50 ꢀm, 4H, 2CH ), 1.45 ꢀm, 4H, 2CH ), 1.38 ꢀs, 18H,
ꢀ100 µl/well). Six serial dilutions of tested compounds were
2
2
13
°
CH ), 1.34 ꢀm, 2H, CH ); C-NMR ꢀ100 MHz, DMSO-d ):
added after overnight incubation of the cells at 37 C and 5%
3
2
6
δ � 198.7, 156.6, 136.0, 128.9, 124.4, 44.7, 34.3, 30.9, 30.1,
CO . DMSO was used as a negative control ꢀ0.5 %). (e cells
2
+
2
5.8, 24.6; LC/MS ꢀESI): 496.33 [M + 1] ; Anal. for
were incubated for 48 hrs. After that, 10 µl of MTT ꢀ5 mg/ml
PBS) was added to each well and incubated for another
4 hours. (e formazan crystals were solubilized by 100 µl
C H N O ; Calcd: C, 65.43; H, 8.34; N, 19.78; Found: C,
2
7
41 7 2
6
5.44; H, 8.35; N, 19.97.
acidified SDS solution ꢀ10% SDS/0.01 M HCl). Biotek plate
®
(
15) (E)-2-((2-(4-(Benzylamino)-6-morpholino-1,3,5-triazin-
reader measured the absorbance after 14 hours of incubation
°
2
-yl)hydrazono)methyl)-4,6-di-tert-butylphenol (5f). Yellow
at 37 C and 5% CO at 570 nm. Each experiment was re-
2
−
1
°
powder in yield 85%; m.p: 152 C; IR ꢀKBr, cm ): 3421,
3
ꢀ
peated three times, and standard deviation was calculated
1
116, 2958, 2860, 1618, 1591, 1508, 1440; H-NMR
ꢀ±). IC was calculated as the concentrations that cause 50%
50
400 MHz, DMSO-d ): δ 8.22 ꢀs, 1H, CH �), 7.80 ꢀbrs,
inhibition for cell growth.
6
1
1
4
H, NH), 7.55 ꢀs, 1H, Ph), 7.37-7.28 ꢀm, 5H, Ph), 7.19 ꢀs,
H, Ph), 4.23 ꢀs, 2H, CH Ph), 3.73 ꢀbrs, 4H, 2CH ), 1.50 ꢀm,
H, 2CH ), 1.40 ꢀs, 18H, 6CH ); C-NMR ꢀ100 MHz,
2
2
3. Results and Discussion
1
3
2
3
DMSO-d ): δ �198.7, 156.6, 136.0, 129.5, 128.9, 124.4,
3.1. Chemistry. (e s-triazine Schiff-base derivatives 4a-i and
5a-h were synthesized in three steps: ꢀi) one pot-reaction of
cyanuric chloride with the first amine in acetone-water media
6
1
3
1
23.2, 65.9, 44.7, 31.2, 30.0, 25.6, 24.5; C-NMR ꢀ100 MHz,
+
DMSO-d ): δ � ; LC/MS ꢀESI): 518.32 [M + 1] ; Anal. For
6
°
C H N O ; Calcd: C, 67.28; H, 7.59; N, 18.94; Found:
and in the presence of Na CO at 0–5 C for 2 h. (e second
2
7
41
7
2
2
3
C, 67.29; H, 7.60; N, 19.06.
amine was added to the reaction mixture followed by addition
of equivalent amount of Na CO at 5 C and then let the
°
2
3
(
16) (E)-2,4-di-tert-butyl-6-((2-(4-morpholino-6-(phenylamino)-
reaction mixture reach the room temperature under stirring
for 18 h to afford 6-chloro-2,4-disubstituted-s-triazine de-
rivatives in good yields and purities; the spectral data were in
good agreement with the reported in the literature [44]. ꢀii) 6-
chloro-2,4-disubstituted-s-triazine derivatives reacted with
hydrazine hydrate in ethanol according to the reported
method [47, 49], to afford the hydrazino derivatives 2a-i as
white solid in good yields and purities which have been used
directly in the next step without further purification. ꢀiii) 6-
hydrazino-2,4-disubstituted-s-triazine 2a-i were reacted with
substituted aldehydes 3a,b in ethanol under reflux in the
presence of catalytic amount of AcOH to give the target
products 4a-i and 5a-i in high yields ꢀScheme 1).
(e final products were separated by simple filtration
after the precipitation. (e molecular structure were de-
duced by different set of physical spectrophotometric tools
including H-NMR, C-NMR, LC-MS, IR, and CHN ele-
mental analysis. Of these, the molecular structure of three
compounds, namely, 4f, 5b, and 5f, has been further con-
firmed by X-ray single crystal diffraction technique
ꢀFigure 2).
1
,3,5-triazin-2-yl)hydrazono)methyl)phenol (5g). Yellow pow-
−
1
°
der in yield 88%; m.p: 242 C; IR ꢀKBr, cm ): 3448, 3215, 3169,
1
2
953, 2866, 1595, 1570, 1554, 1476, 1435, 1440; H-NMR
ꢀ
400 MHz, DMSO-d ): δ 8.35 ꢀs, 1H, CH �), 8.02 ꢀbrs, 1H,
6
NH), 7.50 ꢀs, 1H, Ph), 7.30-7.26 ꢀm, 5H, Ph), 7.20 ꢀs, 1H, Ph),
3
.70 ꢀbrs, 4H, 2CH ), 1.56 ꢀm, 4H, 2CH ), 1.35 ꢀs, 18H, 6CH );
2 2 3
1
3
C-NMR ꢀ100 MHz, DMSO-d ): δ �198.7, 156.6, 136.0, 129.5,
6
1
5
28.9, 124.4, 123.2, 66.0, 31.2, 30.0, 25.6, 24.5; LC/MS ꢀESI):
+
04.30 [M + 1] ; Anal. for C H N O ; Calcd: C, 66.77; H, 7.41;
2
8 37 7 2
N, 19.47; Found: C, 66.77; H, 7.41; N, 19.48.
(
17) (E)-2,4-Di-tert-butyl-4-((2-(4-methoxy-6-(piperidin-1-
yl)-1,3,5-triazin-2-yl)hydrazono)methyl)phenol (5h). Yellow
−
1
°
powder in yield 81%; m.p:155 C; IR ꢀKBr, cm ): 3302, 2958,
1
2
ꢀ
908, 2866, 1614, 1587, 1545, 1504, 1438, 1409; H-NMR
400 MHz, DMSO-d ): δ 7.94 ꢀs, 1H, CH �), 7.80 ꢀbrs, 1H,
6
NH), 7.70 ꢀs, 1H, Ph), 7.52 ꢀs, 1H, Ph), 3.93 ꢀs, 3H, OCH ),
3
3
3
.83 ꢀbrs, 4H, 2CH ), 3.70 ꢀbrs, 4H, 2CH ), 1.45 ꢀs, 9H,
2 2
13
CH ), 1.43 ꢀs, 9H, 3CH ), 1.35 ꢀm, 2H, CH ); C-NMR
3
3
2
ꢀ
100 MHz, DMSO-d ): δ �194.6, 173.5 156.6, 143.9, 136.0,
6
1
25.3, 124.4, 67.5, 53.9, 47.9, 34.3, 31.0; LC/MS ꢀESI): 441.29
In the title compounds, the crystallographic data and
refinement information are summarized in Figures S1–S6 and
Tables S1–S9 ꢀSupplementary Materials). (e asymmetric
+
[
M + 1] ; Anal. for C H N O ; Calcd: C, 65.43; H, 8.24; N,
24
36 6 2
1
9.07; Found: C, 65.42; H, 8.25; N, 19.20.

6
Journal of Chemistry
ꢀ
a)
ꢀb)
ꢀ
c)
Figure 2: ORTEP diagram of the titled compounds 4f ꢀa), 5b ꢀb), and 5f ꢀc). Displacement ellipsoids are plotted at the 40% probability level
for non-H atoms.
unit of the three containing is shown in Figure 2, where
compound 4f contains an additional lattice water molecule.
All the bond lengths and angles are in normal ranges [55].
In the crystal packing, the molecules of compound 5b are
linked together by one hydrogen bond between
N6—H1N6· · ·O1. Compound 5f molecules are connected
with each other via three hydrogen bonds O2—H2A···O1,
N5—H5A···N3, and N6—H6C· · ·N1. Finally, molecules of
structure 5f arranged in the crystal structure using only one
hydrogen bond between N4—H1N4· · ·O2.
donor, also has more inductive on the benzylidene ring,
which usually preferred in most of the cases as previously
reported [46, 49]. In the meantime, the substituents in the
s-triazine ring have affected the activity of the prepared
compounds. (e substituent with two piperidine ring always
showed higher reactivity than the same with two morpholine
ring as shown in cases 4a and 5a vs. 4b and 5b. (e same
effect of piperidine was noticed in the cases of 5e vs. 5b and
4c vs. 4i ꢀwhich they have weak activity). On the contrary,
the presence of two morpholine rings showed better activity
than derivatives with only one as in the cases 4b vs. 5c, 5d, 5f,
5g, and 5h. (ese observations agreed with our previously
3
.2. Biological Activity. Antiproliferative activity for the new
reported data [44].
synthesized s-triazine Schiff-base derivatives was tested
against two cancer cell lines for breast cancer ꢀMCF-7) and
colon cancer ꢀHCT-116). An initial screening for the pos-
sible antiproliferative activity was carried out at 10 µM for
As noticed from Figure 5, the concentration that kills
5
0% of breast cancer cells was evaluated for the two most
active compounds 4a and 5a. Compound 4a showed IC of
5
0
2
1
7 µM ꢀ13.3 µg/mL), while 5a was more active at IC of
50
4
8 hours, and then the viability was determined by MTT
7 µM ꢀ8.4 µg/mL) which was very close to the chemo-
assay. Among 18 tested compounds, only compounds 4a
and 5a showed cytotoxic activity against breast cancer cells
at 10 µM ꢀFigure 3). On the contrary, very weak activity was
observed for the tested compounds against colon cancer cells
therapeutic drug cisplatin which killed 50% of the cells at
concentration of 20 µM ꢀ6 µg/mL).
4
. Conclusions
ꢀ
Figure 4).
Based on the results obtained and showed in Figures 3
(e new series of s-triazine Schiff-base derivatives were
synthesized using the mild and conventional method. (e
chemical structures of the prepared compounds have been
confirmed by different sets of spectroscopic techniques. (e
newly compounds examined against antiproliferative ac-
tivity showed that two derivatives have piperidine moiety
more selective against the two cell lines ꢀMCF-7) and ꢀHCT-
116).
and 4, we can concluded that 2-hydroxybenzylidene de-
rivatives showed better activity than the analogous 4-
hydroxybenzylidene 5a-h derivatives vs. 4a-h derivatives
even in the weak activity. (is might be due to in the 4-
position the hydroxyl group is more sterically hindered,
while when the hydroxyl group in the 3- position, it become
less sterically hindered and more available for hydrogen

Journal of Chemistry
7
100
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
DMSO 4a 4b 4c 4d 4e 4f 4g 4h 4i 5a 5b 5c 5d 5e 5f 5g 5h
Label of the compound at 10µM
Figure 3: Cytotoxic activity for 4a-i and 5a-h against breast cancer cells (MCF-7).
100
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
DMSO 4a 4b 4c 4d 4e 4f 4g 4h 4i 5a 5b 5c 5d 5e 5f 5g 5h
Label of the compound at 10 µM
Figure 4: Anticancer activity 4a-i and 5a-h against colon cancer cells (HCT-116).
1
20
00
1
8
6
4
2
0
0
0
0
0
–
20
0
.1
1
10
100
1000
Concentration (µM)
4
5
a
a
Cisplatin
DMSO
Figure 5: Cytotoxicity of 4a and 5a against MCF-7 cells. Cells were treated with DMSO, 4a, and 5a or cisplatin for 48 hours and then the
viability was determined by MTT assay.
Based on the results obtained, we can conclude that both
the substituent on the triazine ring and the position of the
hydroxy group in the benzylidene moiety have critical e™ect
on the biological activity of the prepared compounds, where
2-hydroxybenzylidene derivatives showed better activity
than the analogous 4-hydroxybenzylidene 5a-h derivatives
vs. 4a-h derivatives even in the weak activity cases. ¡e
substituents in the s-triazine ring have a™ected the activity

8
Journal of Chemistry
where s-triazine with two piperidine ring always showed
higher reactivity than analogous one two morpholine ring as
shown in case 4a and 5a vs. 4b and 5b. (e concentration
that kills 50% of breast cancer cells was evaluated for the two
most active compounds 4a and 5a. Compound 5a showed
higher activity ꢀIC �17 µM ꢀ8.4 µg/mL)) than 4a
Journal of Medicinal Chemistry, vol. 43, no. 11, pp. 2592–2596,
2008.
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0
ꢀ
IC � 27 µM ꢀ13.3 µg/mL)). (ese values, especially those of
5
0
5
a, are very close to that of the chemotherapeutic drug
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0
propose that the antiproliferative activity of these two
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Data Availability
[
9] S. Rollas and S. K u¨ ç u¨ kg u¨ zel, “Biological activities of hydra-
Crystallographic data for the structures reported in this
manuscript have been deposited in the Cambridge Crys-
tallographic Data Centre under the following CCDC
numbers: 1567719 ꢀ4b), 1567728 ꢀ5b), and 1567725 ꢀ5f).
Copies of these data can be obtained free of charge from
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Conflicts of Interest
[
(
e authors declare no conflicts of interest.
Acknowledgments
[
(
e authors would like to extend their sincere appreciation
to the Deanship of Scientific Research at King Saud Uni-
versity, Saudi Arabia, for providing funding ꢀno. RGP-234).
[
Supplementary Materials
Figures S1–S6: ORTEP diagram and molecular packing of
compounds 4b, 5b, and 5f; Tables S1–S9: summary of the
crystallographic data and refinement information of com-
pounds 4b, 5b, and 5f. ꢀSupplementary Materials)
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