Ultrasonic promoted synthesis of novel s-triazine-Schiff base derivatives; molecular structure, spectroscopic studies and their preliminary anti-proliferative activities

Article abstract of DOI:10.1016/j.molstruc.2016.06.061

Novel series of s-triazine-Schiff base derivatives were synthesized employing ultrasonic irradiation and characterized by NMR (¹H and ¹³C), FT-IR, and elemental analysis. The use of ultrasonic irradiation has allowed the preparation of the target products with better yields in shorter reaction time and excellent purities compared to the conventional heating. X-ray single crystal diffraction experiments verified the molecular structure of four from the new prepared s-triaizne-Schiff base derivatives. The molecular structures of the studied compounds are computerized using DFT/B3LYP method. The effects of substituent at the triazine and phenyl ring on the electronic and spectroscopic properties of the studied compounds were also investigated. The natural atomic charges showed that pipridino-s-triazine derivatives are richer in electrons than those having morpholino derivatives. The anti-proliferative effects for the prepared compounds were tested against three different cancer cell lines.

Full text of DOI:10.1016/j.molstruc.2016.06.061

Journal of Molecular Structure 1125 (2016) 121e135
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Ultrasonic promoted synthesis of novel s-triazine-Schiff base
derivatives; molecular structure, spectroscopic studies and their
preliminary anti-proliferative activities
,
c
,
,
c
,
, e
Ayman El-Faham a *, Saied M. Soliman b **, Hazem A. Ghabbour d
,
Yasser A. Elnakady f, Talal A. Mohaya g, Mohammed R.H. Siddiqui a,
Fernando Albericio a
, h, i, j
a Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia
b Department of Chemistry, Rabigh College of Science and Art, King Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia
c Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt
d Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
e Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
f Zoology Department, College of Science, King Saud University, P.O. Box 2455, 11451 Riyadh, Saudi Arabia
g King Abdelaziz City for Science and Technology, P.O. Box. 6086, 11442 Riyadh, Saudi Arabia
h School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa
i CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Barcelona 08028, Spain
j Department of Organic Chemistry, University of Barcelona, Barcelona 08028, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel series of s-triazine-Schiff base derivatives were synthesized employing ultrasonic irradiation and
characterized by NMR (1H and 13C), FT-IR, and elemental analysis. The use of ultrasonic irradiation has
allowed the preparation of the target products with better yields in shorter reaction time and excellent
purities compared to the conventional heating. X-ray single crystal diffraction experiments verified the
molecular structure of four from the new prepared s-triaizne-Schiff base derivatives. The molecular
structures of the studied compounds are computerized using DFT/B3LYP method. The effects of sub-
stituent at the triazine and phenyl ring on the electronic and spectroscopic properties of the studied
compounds were also investigated. The natural atomic charges showed that pipridino-s-triazine de-
rivatives are richer in electrons than those having morpholino derivatives. The anti-proliferative effects
for the prepared compounds were tested against three different cancer cell lines.
Received 12 March 2016
Received in revised form
21 June 2016
Accepted 22 June 2016
Available online 27 June 2016
Keywords:
Ultrasonic
s-triazine
Schiff-base
© 2016 Elsevier B.V. All rights reserved.
X-ray crystallography
DFTeNBO
Anti-proliferative activities
1. Introduction
Compounds containing s-triazine (1,3,5-triazine) moiety repre-
sent an interesting class of compounds in medicinal chemistry,
Ultrasonic irradiation is a powerful technique in chemical pro-
cesses, because it can be applied to many chemical reactions with
outstanding results [1e5]. Thus, huge number of organic synthesis
have been carried out in higher yield, shorter reaction time and
milder condition under ultrasonic irradiation [6e13].
because they display a broad range of biological activities such as
anti-cancer [14e18], antiviral [19,20], antibacterial [21e28], anti-
fungal [29,30], antimalarial [31e33], herbicidal [34] and antitu-
berculosis [35].
Hydrazone derivatives represent another class of compounds,
which have great interest with different biological activities
[36,37]. They have been used as an intermediate for the preparation
of heterocycles with useful activities [38,39]. Recently, hydrazones
incorporating triazine moiety have reported as anticonvulsant
agents [40].
* Corresponding author. Department of Chemistry, College of Science, King Saud
University, P. O. Box 2455, Riyadh 11451, Saudi Arabia.
** Corresponding author. Department of Chemistry, Rabigh College of Science and
Art, King Abdulaziz University, P.O. Box 344, Rabigh 21911, Saudi Arabia.
E-mail addresses: aelfaham@ksu.edu.sa, aymanel_faham@hotmail.com (A. El-
Faham), saied1soliman@yahoo.com (S.M. Soliman).
The vast range of pharmacological applications of these classes
of compounds [41e43] encouraged us to synthesize compounds
http://dx.doi.org/10.1016/j.molstruc.2016.06.061
0022-2860/© 2016 Elsevier B.V. All rights reserved.

122
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
incorporating hydrazone-s-triazine moiety based on acetophenone
derivatives. The molecular structure and spectroscopic aspects of
the studied molecules were also investigated using DFT method.
Additionally, the anti-proliferative effects of the prepared com-
pounds against three different cancer cellline including, the lung
carcinoma cell line A549, the hepatocellular carcinoma cell line
HepG2, and the Adenocarcinoma cell lineMCF7 were investigated.
2.2.2. Synthesis of 2-chloro-4-methoxy-6-piperidino-/or
morpholino-1,3,5-triazine (7a-b)
To a solution of 6 [47] (20 mmol) in acetone-water mixture 1:1
(100 mL), a solution of piperidine or morpholine in 30 mL acetone
and a solution of NaHCO3 (2.5 gm in 20 mL of water) were added
slowly at room temperature. The reaction mixture was kept under
stirring at room temperature overnight. Acetone was removed
under vacuum and the precipitate was collected by filtration, dried
and recrystallized from dichloromethane and hexane.
2. Experimental section
2.2.2.1. 2-Chloro-4-methoxy-6-(piperidin-1-yl)-1,3,5-triazine (7a).
White solid in 90% yield; m. p108e110 ꢁC; 1H NMR (CDCl3)
d:
2.1. Material and methods
1.49e1.60 (6H, m, 3CH2, piperidine); 3.70e3.73 (4H, m, 2 CH2N,
piperidine), 3.86 (3H, s, OCH3); 13C NMR (CDCl3)
d: 24.4, 25.5
The solvents used were of HPLC reagent grade. Melting points
were determined with a Mel-Temp apparatus. Ultrasonic bath was
purchased from Selecta (Barcelona, Spain). Nuclear magnetic
resonance spectra (1H NMR and 13C NMR spectra) were recorded on
a JEOL ECPe400 MHz spectrometer using CDCl3 or DMSO-d6 as
(CH2,piperidine), 44.5 (CH2N, pieridine), 54.5 (OCH3), 165.8, 170.7,
171.8 (C]N, triazine). Elemental Anal. Calcd for C9H13ClN4O: C,
47.27; H, 5.73; N, 24.50. Found C, 47.42; H, 5.89; N, 24.74.
solvent and reported in d-units (Figs. S1eS14, supporting infor-
2.2.2.2. 4-(4-Chloro-6-methoxy-1,3,5-triazin-2-yl)morpholine (7b).
White solid in 92% yield; m. p102e103 ꢁC; 1H NMR (CDCl3)
d:
mation). Fourier transform infrared spectroscopy (FTIR) spectra
were recorded on Nicolet 6700 spectrometer in the spectra range
500e4000 cmꢀ1. The sample was measured as powder sample in
KBr pellets. The spectral resolution was 4 cmꢀ1 and 32 scans were
used. Elemental analyses were performed on Perkin-Elmer 2400
elemental analyzer, and the values found were within 0.3% of the
theoretical values. The electronic spectra of the studied compounds
were measured in different solvents such as acetonitrile, methanol
and dichloromethane using UVeVis spectroscopy (Perkin Elmer
Lambda 35; Walthman, MA, USA). Follow-up of the reactions and
checks of the purity of the compounds was done by TLC on silica
gel-protected aluminum sheets (Type 60 GF254, Merck). The
compounds were named using ChemBioDraw Ultra version 14.0,
Cambridge Soft Corporation (Cambridge, MA, USA).
3.64e3.64 (4H, m, 2 CH2O, morpholine), 3.70e3.75 (4H, m, 2CH2N,
morpholine), 3.92 (3H, s, OCH3); 13C NMR (CDCl3)
d
: 43.8, (CH2O,
morpholine) 54.4(OCH3), 66.4 (CH2N, morpholine), 166.5, 172.1(C]
N, triazine). Elemental Anal. Calcd for C8H11ClN4O2: C, 41.66; H,
4.81; N, 24.29. Found C, 41.87; H, 4.67; N, 24.08.
2.2.3. General method for the synthesis of 2-hydrazino-4,6-
disubstituted-1,3,5-triazineusing ultrasonic irradiation (3, 5 and 8)
To
a
solution of 2-chloro-4,6-disubstituted-1,3,5-triazine
(20 mmol) in 50 mL ethanol, 10 mL of hydrazine hydrate (80%)
was added dropwise and then the reaction mixture was sonicated
for 60 min at 60 ꢁC. The solvent was removed under vacuum and
excess ether was added to afford the product as a white solid in
higher yield (>90%)than the reported yield for the synthesis of 2-
hydrazino-4,6-dipiperidino-1,3,5-triazine
(3a)
[48,49],
2-
2.2. Synthesis of 2-chloro-4,6-dipieridino/dimorpholino)1,3,5-
triazine (2a-c)
hydrazino-4,6-dimorpholino-1,3,5-triazine (3b) [46,50] and 2-
hydrazino-4,6-dimethoxy-1,3,5-triazine (5) [50,51]and used
directly in the next step.
The synthesis of (2-chloro-4,6-dipieridino/dimorpholino)-1,3,5-
triazine was prepared by modifying the reported method [44e46]
using one pot-reaction as follow:
2.2.3.1. 4-(4-Hydrazinyl-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)mor-
pholine (3c). White solid in 94% yield; m. p. 142e143 ꢁC; 1H NMR
To a solution of cyanuric chloride (5.52 g, 30 mmol) in acetone-
water mixture 1:1 (100 mL), a solution of piperidine or morpholine
(65 mmol; in case of preparation of 2c, 30 mmol of morpholine
were added slowly followed by addition of 30 mmol of piperidine
after 2 h) in 50 mL acetone and a solution of NaHCO3 (6 gm in 50 mL
of water) at a temperature 0e5 ꢁC. The reaction mixture was kept at
this temperature for 2 h and then the temperature was elevated to
room temperature and the stirring was continued overnight.
Acetone was removed under vacuum and the precipitate was
collected by filtration and recrystallized from dichloromethane-
hexane (1:2) to afford the desired product in good yield and pu-
rity. The spectral data of 2a and 2b were in good agreement with
the reported data [44e46].
(D2O- TFA) d: 1.49e1.60 (6H, m, 3CH2, piperidine), 3.60e3.74 (12H,
m, 2CH2O, morpholine, 4CH2N, piperidine and morpholine).
Elemental Anal. Calcd for C12H21N7O: C, 51.60; H, 7.58; N, 35.10.
Found: C, 51.83; H, 7.39; N, 34.92.
2.2.3.2. 2-Hydrazinyl-4-methoxy-6-(piperidin-1-yl)-1,3,5-triazine
(8a). White solid in 96% yield; m. p115e116 ꢁC; 1H NMR (D2O-TFA)
d: 1.49e1.60 (6H, m, 3CH2, piperidine); 3.70e3.73 (4H, m, 2 CH2N,
piperidine), 3.86 (3H, s, OCH3). Elemental Anal. Calcd for C9H16N6O:
C, 48.20; H, 7.19; N, 37.47. Found C, 48.00; H, 7.09; N, 37.62.
2.2.3.3. 4-(4-Hydrazinyl-6-methoxy-1,3,5-triazin-2-yl)morpholine
(8b). White solid in 94% yield; m. p158e160 ꢁC; 1H NMR (D2O-TFA)
d: 3.52e3.68 (4H, m, 2 CH2O, morpholine), 3.73e3.68 (4H, m, 2
2.2.1. 4-(4-Chloro-6-(piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine
(2c)
CH2N, morpholine), 3.90 (3H, s, OCH3). Elemental Anal. Calcd for
C8H14N6O2: C, 42.47; H, 6.24; N, 37.15. Found C, 42.62; H, 6.03; N,
36.90.
The product obtained as white solid in 94% yield; m. p.
125e126 ꢁC; 1H NMR (CDCl3)
d
: 1.52e1.64 (6H, m, 3CH2, piperi-
dine), 3.68e3.76 (12H, m, 2CH2O, morpholine, 4CH2N, piperidine
and morpholine);13C NMR (CDCl3)
: 24.6, 25.843.6 (CH2e-
2.2.4. General method for the synthesis s-triazine-Schiff base
derivatives
d
CH2eCH2, piperidine), 44.53 (CH2O, morpholine), 66.6 (CH2N,
piperidine), 66.9 (CH2N, morpholine), 163.9, 164.5, 169.5 (C]N,
triazine); Elemental Anal. Calcd forC12H18ClN5O: C, 50.79; H, 6.39;
N, 24.68. Found: C, 50.86; H, 6.50; N, 24.49.
2.2.4.1. Method A; conventional method. To a solution of 2-
substituted acetophenone 9(10 mmol) in ethanol (30 mL) con-
taining 2e3 drops of acetic acid, 2-hydrazino-4,6-disubstituted-
1,3,5-triazine 3,5, or 8(10 mmol) was added and the reaction

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
123
mixture was stirred with gentle reflux for 3 h. The solvent was
concentrated under vacuum and the precipitated product was
filtered off and dried at room temperature. The product was
collected and recrystallized from ethylacetateto afford the product
in pure state (Table S1, supporting information).
(Cf), 117.8 (Cd), 128.8 (Ce), 129.4 (Cc), 148.1 (Ca), 152.9 (C]N, Ch),
166.9 (N]CeO, C4 and C6 for triaizne moiety), 172.4(NeC]N, C2
for triazine moiety). Elemental Anal. Calc. for C13H16N6O2 (288.31);
C, 54.16; H, 5.59; N, 29.15. Found C, 54.31; H, 5.62; N, 29.00.
2.2.7. (E)-2-[1-(2-(4,6-di(piperidin-1-yl)-1,3,5-triazin-2-yl]
hydrazono)ethyl)aniline (10c)
2.2.4.2. Method B; ultrasound assisted method. A mixture 2-
hydrazino-4,6-disubstituted-1,3,5-triazine (10 mmol) and 2-
substituted acetophenone (10 mmol) in ethanol (30 mL) con-
tained 2e3 drops of acetic acid in Erlenmeyer flask was introduced
into a sonicator. Reactions were carried out at 40 ꢁC for 60 min.
After completion of reaction (as monitored by TLC using
ethylacetate-hexane; 4:6); the solvent was concentrated under
reduced pressure and the precipitated product was recrystallized
from ethylacetate to afford the product in pure state (Table S1,
supporting information).
Pale yellow solid in yield 69% (A), 93% (B); mp188e190 ꢁC;
lmax ¼ 335, 288, 283, 236 nm; IR (KBr): 3430 (NH), 3247 (NH), 1654
(C]N), 1613 (C]N), 1517,1487 (C]C)cmꢀ1;1H NMR (CDCl3)
d:
1.57e1.64 (12H, m, 2 ꢂ 3CH2, piperidine), 2.31 (3H, s, CH3),
3.71e3.76 (8H, m, 2 ꢂ 2CH2N, piperidine), 6.62 (2H, m, AreH), 7.06
(1H, t, J ¼ 8.4 Hz, AreH), 7.37 (1H, d, J ¼ 9.6 Hz, AreH),, 9.25 (1H, brs,
NH); 13C NMR (CDCl3)
d: 13.2 (CH3), 24.8, 25.8 (2CH2, piperidine),
44.6 (CH2N, piperidine), 115.9, 116.7, 119.5, 128.3, 129.1, 146.9 (5
phenyl carbons and CeNH2), 162.3, 164.5 (C]N). Elemental Anal.
Calc. for C21H30N8 (394.53); C, 63.93; H, 7.66; N, 28.40. Found C,
64.06; H, 7.78; N, 28.62.
2.2.5. (E)-2-[1-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)hydrazono)
ethyl]phenol (10a)
2.2.8. (E)-2-[1-(2-(4,6-di(piperidin-1-yl)-1,3,5-triazin-2-yl)
hydrazono)ethyl] phenol (10d)
White solid in yield 65% (A), 93% (B); mp194e196 ꢁC; lmax ¼ 318,
290, 281, 231 nm; IR (KBr): 3425 (NH), 3286 (OH), 1630 (C]N),
1589 (C]N), 1509 (C]C), 1444 (C]C)cmꢀ1 1H NMR (CDCl3)
; d:
1.60e1.65 (12H, m, 2 ꢂ 3CH2, piperidine), 2.34 (3H, s, CH3),
3.71e3.76 (8H, m, 2 ꢂ 2CH2N, piperidine), 6.82 (1H, t, J ¼ 9.2 Hz,
AreH), 6.97 (1H, d, J ¼ 8.0 Hz, AreH), 7.04 (1H, dd, J ¼ 13.6,13.2 Hz,
AreH), 7.40 (1H, d, J ¼ 7.6 Hz, AreH), 9.40 (1H, brs, NH), 13.13 (1H, s,
OH); 13C NMR (CDCl3)
d: 18.4 (CH3), 24.8, 25.8 (2CH2, piperidine),
44.6 (2CH2N, piperidine), 117.8, 118.2, 119.9, 126.9, 130.3, 159.1 (5
phenyl carbons and CeOH), 161.5, 163.5 (C]N, triazine). Elemental
Anal. Calc. for C21H29N7O (395.51): C, 63.77; H, 7.39; N, 24.79. Found
C, 63.98; H, 7.54; N, 24.58.
White solid in yield 72% (A) and 92% (B); mp170e172 ꢁC; IR (KBr)
3420e3313 (NH, OH), 1579 (C]N), 1438 (C]C)cmꢀ1 1H NMR
;
(DMSO-d6)
d
: 2.49 (3H, s, CH3), 3.99 (3H, s, OCH3), 4.04 (3H, s,
2.2.9. (E)-2-[1-(2-(4,6-dimorpholino-1,3,5-triazin-2-yl)hydrazono)
ethyl]aniline (10e)
OCH3), 6.94e6.98 (2H, m, Ar-Hb and He), 7.34 (1H, t, J ¼ 7.2 Hz, Ar-
Hd), 7.65 (1H, d, J ¼ 7.2 Hz, Ar-Hc), 11.49 (1H, s, NH), 13.26 (1H, s,
Pale yellow solid in yield 70% (A), 95% (B); mp199e201 ꢁC;
lmax ¼ 338, 292, 284, 234 nm; IR (KBr): 3433 (NH), 3384
OH); 13C NMR (DMSO-d6)
d: 13.5 (CH3, Cg), 54.7 (OCH3), 117.3 (Cb),
118.6 (Cf), 119.9 (Cd),128.1 (Ce), 130.9 (Cc),153.7 (C]CeO, Ca), 158.4
(C]N, Ch), 166.7 (N]CeO, C4 and C6 for triazine moiety) 172.3
(NeC]N, C2 for triazine moiety). Elemental Anal. Calc. for
(NH),1577(C]N), 1514 (C]N), 1439 (C]C)cmꢀ1; 1H NMR (CDCl3)
d:
2.29 (3H, s, CH3), 3.71e3.72 (8H, m, 2 ꢂ 2 CH2O, morpholine),
3.78e3.79 (8H, m, 2 ꢂ 2CH2N, morpholine), 6.66e6.71 (2H, m,
AreH), 7.09(1H, t, J ¼ 8.0 Hz, AreH), 7.38 (1H, d, J ¼ 8.0 Hz, AreH),
C
13H15N5O3 (289.30); C, 53.97; H, 5.23; N, 24.21. Found C, 54.09; H,
5.33; N, 24.01.
8.15 (1H, s, NH); 13C NMR (CDCl3)
d: 12.8(CH3), 43.8 (CH2O, mor-
pholine), 66.9 (CH2N, morpholine), 116.3, 116.9, 119.4, 128.4, 129.4,
146.9 (5 phenyl carbons and CeNH2),164.4,165.4 (C]N). Elemental
Anal. Calc. for C19H26N8O2 (398.47): C, 57.27; H, 6.58; N, 28.12.
Found C, 57.51; H, 6.66; N, 28.00.
2.2.6. (E)-2-[1-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)hydrazono)
ethyl]aniline (10b)
2.2.10. (E)-2-[1-(2-(4,6-dimorpholino-1,3,5-triazin-2-yl)
hydrazono)ethyl]phenol (10f)
White solid in yield 75% (A), 91% (B); mp225e228 ꢁC;
lmax ¼ 318, 290, 281, 231 nm; IR (KBr): 3445 (NH), 3320 (OH), 1578
(C]N),1517 (C]N),1448,1439 (C]C)cmꢀ1; 1H NMR (CDCl3)
d: 2.37
(3H, s, CH3), 3.74e3.82 (16H, m, 4CH2O and 4CH2N, morpholine),
6.85 (1H, t, J ¼ 7.2 Hz, AreH), 6.98(1H, d, J ¼ 8.0 Hz, AreH), 7.25 (1H,
d, J ¼ 7.2 Hz, AreH), 7.40 (1H, d, J ¼ 8.0 Hz, AreH), 8.56 (1H, brs,
NH), 13.06 (1H, s, OH); 13C NMR (CDCl3)
d: 11.9 (CH3), 43.9 (CH2O,
morpholine), 66.9 (CH2N, morpholine), 117.9, 118.1, 119.8, 127.1,
130.7, 159.1 (5 phenyl carbons and CeOH), 163.4, 164.4 (C]N).
Elemental Anal. Calc. For C19H25N7O3 (399.46): C, 57.13; H, 6.31; N,
24.55. Found C, 57.02; H, 6.21; N, 24.74.
Yellow solid in yield 71% (A), 90% (B), mp138e140 ꢁC; IR (KBr)
3437 (NH), 3323 (NH), 1579 (C]N), 1438 (C]C)cmꢀ1 1H NMR
;
(DMSO-d6) d: 2.32 (3H, s, CH3), 3.91 (6H, s, 2OCH3), 6.52 (1H, t,
J ¼ 8.0 Hz, AreHb), 6.71 (1H, d, J ¼ 8.0 Hz, AreHd), 7.04 (1H, t,
2.2.11. (E)-2-[1-(2-(4-morpholino-6-(piperidin-1-yl)-1,3,5-triazin-
2-yl) hydrazono)ethyl] aniline (10g)
J ¼ 6.4 Hz, AreHc), 7.39 (3H, brd, 2NH, AreHe), 10.96 (1H, s, NH);
13C NMR (DMSO-d6)
d: 14.4 (CH3, Cg), 54.6(OCH3), 114.4 (Cb), 116.2
Off white solid in yield 77% (A), 92% (B); mp198e200 ꢁC; IR

124
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
(KBr): 3426 (NH), 3293 (NH), 1589 (C]N), 1514 (C]N), 1438 (C]C)
cmꢀ1; 1H NMR (CDCl3)
: 1.53e1.60 (6H, m, 3CH2, piperidine), 2.25
3. Crystal structures determination and refinement
d
(3H, s, CH3), 3.65e3.75 (12H, m, 2 CH2N, piperidine, 2 CH2O and 2
CH2N, morpholine), 6.82e6.87(2H, m, AreH), 7.22 (1H,t, J ¼ 7.2 Hz,
AreH), 7.32 (1H, d, J ¼ 8.0 Hz, AreH), 8.30 (1H, brs, NH);13C NMR
The compounds 10c, 10d, 10e and 10f were obtained as single
crystals by slow evaporation from their solutions at room temper-
ature. Data were collected on a Bruker APEX-II D8 Venture area
(CDCl3)
d
: 11.9 (CH3), 24.7, 25.7 (CH2, piperidine), 43.8 (CH2O,
diffractometer, equipped with graphite monochromatic Cu Ka ra-
morpholine), 44.6 (CH2, piperidine), 66.7 (CH2N, morpholine),116.1,
116.8, 119.2, 128.3, 129.3, 146.9 (5 phenyl carbons and CeNH2),
159.1, 163.4, 164.4 (C]N). Elemental Anal. Calc. for C20H28N8O
(396.50): C, 60.59; H, 7.12; N, 28.26. Found C, 60.87; H, 7.32; N,
28.51.
diation at 100 (2) K. Cell refinement and data reduction were car-
ried out by Bruker SAINT, SHELXS-97 [52,53] was used to solve
structure. The final refinement was carried out by full-matrix least-
squares techniques with anisotropic thermal data for non-
hydrogen atoms on f. CCDC numbers 1431262, 1431201, 1430929
and 1431178 contain the supplementary crystallographic data for
these compounds can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2.2.12. (E)-2-[1-(2-(4-morpholino-6-(piperidin-1-yl)-1,3,5-triazin-
2-yl)hydrazono] ethyl)phenol (10h)
White solid in yield 72% (A), 94% (B); mp164e165 ꢁC; IR (KBr):
3432 (NH), 3298 (OH), 1591 (C]N), 1534(C]N), 1438 (C]C)cmꢀ1
;
1H NMR (CDCl3)
d: 1.53e1.60 (6H, m, 3CH2, piperidine), 2.27 (3H, s,
4. Computational details
CH3), 3.62e3.79 (12H, m, 2CH2N, piperidine, 2 CH2O and 2CH2N,
morpholine), 6.79(1H, t, J ¼ 6.4 Hz, AreH), 6.91 (1H, d, J ¼ 8.0 Hz,
AreH), 7.17(1H, m, AreH), 7.36 (1H, d, J ¼ 6.8 Hz, AreH), 10.20 (1H,
All calculations for the studied compounds were carried out
using Gaussian 03 software [54]. Without any symmetry re-
strictions and starting with the X-ray structures as input files, ge-
ometry optimization followed by frequency calculations were
performed by DFT/B3LYP method using 6e311G(d,p) basis set. No
negative vibrational modes were obtained. The optimized geome-
tries, frontier molecular orbitals (FMOs) and molecular electrostatic
potential (MEP) maps were drawn using GaussView4.1 [55]. The
charge distribution on the atomic sites was deduced using natural
bond orbital (NBO) method [56] at the DFT/B3LYP level. The nuclear
magnetic resonance (NMR) chemical shifts calculations were per-
formed using GIAO method [57,58] while the origin of the elec-
tronic spectra was deduced using time dependent density TD-DFT
method.
brs, NH), 12.89 (1H, s, OH); 13C NMR (CDCl3)
d: 12.9 (CH3), 24.5, 25.7
(CH2, piperidine), 44.3(CH2O, morpholine), 66.6 (CH2N, piperidine),
66.9 (CH2N, morpholine),117.9, 118.5,119.6,127.4,128.9,130.9,159.1
(5 phenyl carbons and CeOH), 163.4, 164.4 (C]N). Elemental Anal.
Calc. for C20H27N7O2 (397.22): C, 60.44; H, 6.85; N, 24.67. Found C,
60.71; H, 7.01; N, 24.89.
2.2.13. (E)-2-[1-(2-(4-methoxy-6-morpholino-1,3,5-triazin-2-yl)
hydrazono)ethyl] aniline (10i)
Yellow solid in yield 72% (A), 94% (B); mp168e171 ꢁC; IR (KBr):
3427 (NH), 3268 (NH), 1650 (C]N), 1519 (C]N), 1438 (C]C)cmꢀ1
;
1H NMR (CDCl3)
d: 2.29 (3H, s, CH3), 3.68 (4H, brs, 2 CH2O, mor-
pholine), 3.83 (4H, brs, 2 CH2N, morpholine), 3.92 (3H, s, OCH3),
6.41(2H, brs, 2NH), 6.65e6.71 (2H, m, AreH), 7.09(1H, t, J ¼ 7.6 Hz,
AreH), 7.36 (1H, d, J ¼ 8.4 Hz, AreH), 8.11 (1H, brs, NH); 13C NMR
5. Biological screening (MTT-ASSAY)
(CDCl3)
d
: 12.8 (CH3), 43.9 (CH2, morpholine), 54.3 (OCH3), 66.7
The anti-proliferative activities of the compounds against cancer
cell lines had been demonstrated using MTT-Assay [59] (supporting
information). The metabolic activities of three cancer cell lines,
including the lung carcinoma cell line A549, the hepatocellular
carcinoma HepG2 cell line, and the breast carcinoma cell line MCF-
7 (Table S2, supporting information), were measured in absence
and presence of the compounds. Growth inhibitions were
(CH2N, morpholine), 116.25, 116.9, 118.9, 128.4, 129.6, 130.4, 146.9,
147.7 (5 phenyl carbons and CeNH2), 159.1, 161.9, 165.8 (C]N).
Elemental Anal. Calc. for C16H21N7O2 (343.39): C, 55.96; H, 6.16; N,
28.55. Found C, 56.16; H, 6.09; N, 28.79.
2.2.14. (E)-2-[1-(2-(4-methoxy-6-(piperidin-1-yl)-1,3,5-triazin-2-
yl)hydrazono)ethyl] phenol (10j)
measured in 96-well plates. Aliquots of 120 mL of the suspended
Pale solid in yield 70% (A), 95% (B); mp 150e152 ꢁC; IR (KBr,):
cells (50,000 mLꢀ1) were seeded into wells of 96-well plate und
cultivated at 37 ꢁC, 5% CO2, and high humidity atmosphere. After
3430 (NH), 3284 (OH), 1650 (C]N), 1597 (C]N), 1498 (C]C) cmꢀ1
;
1H NMR (DMSO-d6)
d: 1.54e1.68 (6H, m, 3CH2, piperidine), 2.31
24 h 60
mL of a serial dilution of the inhibitor(S) had been given to
(3H, s, CH3), 3.82e3.95 (4H, m, 2 CH2N, piperidine), 3.91(3H, s,
OCH3), 6.90 (1H, t, J ¼ 7.5 Hz, AreH), 7.24 (1H,t, J ¼ 8.0 Hz, AreH),
7.63 (1H, d, J ¼ 6.4 Hz, AreH), 10.38 (1H, s, NH), 13.40 (1H, brs,OH).
Elemental Anal. Calc. for C17H22N6O2 (342.40): C, 59.63; H, 6.48; N,
24.54. Found C, 59.85; H, 6.27; N, 24.81.
each well. After 3 days of incubations, growth were determined the
MTT assay. Briefly, 20 ml MTT (5 mg/mL in PBS) were added to each
well, and the plates were incubated for 2 h at 37 ꢁC, and 5% CO2-
atmosphere in the cell incubator. The supernatants were then
discarded and 200 ml of isopropanol/HCl were added to each well
and mixed to dissolve the formazan crystals. The absorbance was
then read at 560 nm using a plate reader (Thermo Scientific, USA).
The viability of the cells was calculated by dividing the absorbance
average of the treated cells by the absorbance average of the control
cells multiply 100%. The IC50 values were defined as sample con-
centration inhibiting 50% of cell growth. The activities of the cells
were plotted against the concentration of the drugs, and the IC50
values were calculated from the regression curve.
2.2.15. (E)-2-[1-(2-(4-methoxy-6-(piperidin-1-yl)-1,3,5-triazin-2-
yl)hydrazono)ethyl]aniline (10k)
Pale yellow solid in yield71% (A), 93% (B); mp140e141 ꢁC; IR
(KBr): 3428 (NH), 3292 (NH), 1646 (C]N), 1617 (C]N), 1554 (C]
N), 1482 (C]C) cmꢀ1 1H NMR (CDCl3)
; d: 1.54e1.66 (6H, m, 3CH2,
piperidine), 2.27 (3H, s, CH3), 3.78 (4H, brs, 2 CH2N, piperidine),
3.91 (3H, s, OCH3), 6.64e6.70 (2H, m, AreH), 7.10 (1H, t, J ¼ 6.8 Hz,
AreH), 7.36 (1H, d, J ¼ 9.6 Hz, AreH), 8.19 (1H, s, NH); 13C NMR
(CDCl3)
d: 12.4 (CH3), 24.5, 25.7 (CH2, piperidine), 44.4 (CH2N,
6. Results and discussion
piperidine), 53.9 (OCH3), 115.9, 116.7, 118.9, 128.1, 129.4146.9 (5
phenyl carbons and CeNH2), 159.1, 163.4, 164.4 (C]N). Elemental
Anal. Calc. for C17H23N7O (341.42): C, 59.81; H, 6.79; N, 28.72. Found
C, 60.01; H, 6.93; N, 28.58.
6.1. Synthesis
The first and second chlorine atoms of 2,4,6-trichloro-1,3,5-

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
125
triazine (cyanuric chloride, 1) were replaced by secondary amine or
6.2. X-ray crystallography
methoxy group, while the third chlorine atom had been replaced by
hydrazine using ultrasonic irradiation. Accordingly, 2-hydrazine-
4,6-disubstituted-1,3,5-triazine derivatives were prepared by sub-
sequent replacement of chlorine atoms. Finally, the hydrazine de-
rivatives were condensed with 2- amino-/or 2-hydroxy-
acetophenone using ultrasonic irradiation to afford the target
product in high yield and purity.
The products 2aec were obtained using one pot synthesis;
where cyanuric chloride 1 was reacted with morpholine or
piperidine in acetone-water media in the presence of NaHCO3
as hydrogen chloride scavenger at 0 ꢁC for 2 h and the second
nucleophile (piperidine or morpholine) was added in the
presence of NaHCO3 at room temperature (Scheme 1). After
removing the acetone under vacuum the product was obtained
in good yield and purity as indicated from their spectral data.
The products7aeb were obtained from the reaction of the
dichloromethoxy derivative 6 with piperidine or morpholine in the
presence of NaHCO3 to afford the products7aeb (Scheme 1) in good
yield and purity as observed from their spectral data.
The crystallographic data and refinement information of the
tested compounds 10c, 10d, 10e and 10f, are summarized in
Table S3 (supporting information). The selected bond lengths and
bond angles are listed in Tables S4eS7 (supporting information)
and the asymmetric units containing one independent molecule as
shown in Fig. 1. The 1,3,5 triazine rings in the four compounds (C1/
N1/C2/N2/C3/N3) have planar structure, while the piperidine ring
in compounds 10c and 10d and morpholine ring in compounds 10e
and 10f have a chair conformation. All CeC, CeN, CeO bonds and
angles was in the normal range without exceptions [60]. These
molecules were found in the trans (E) conformation around the C]
N. The bond lengths in the triazine ring are slightly distorted and
reached to 1.359 Å (N1eC1) in compound 10d and 1.364 Å (N2eC2)
in compound 10e, which is somewhat different from the bond
lengths in non-substituted s-triazines (1.337 Å) [61e62].
The crystal packing of compound 10c, molecules are linked via
one strong classical intermolecular hydrogen bond between
N6eH1N6/N8 along b axis with H … A 2.572(19) Å and 150.5 (16)ꢁ
angle. In compound 10d, molecules are linked together by one
classical hydrogen interaction between N6eH1N6/O1 and one
non-classical between C21eH21C/N4 along b axis. Molecules of
compound 10e were arranged along the c axis by three intermo-
lecular interactions between N8eH1N8/O2, C10eH10A$$$O2 and
C19eH19B/N1. On the other hand, compound 10f showed a
network structure through four hydrogen bond interactions be-
tween N6eH1N6/O2, C4eH4A$$$N1, C9eH9A$$$O3 and
C10eH10A$$$N3. Data are summarized in Table S8 and showed in
Fig. S15 (Supporting information).
The hydrazine derivatives 3, 5, and 8 were obtained by treat-
ment of 2, 4, or 7 with hydrazine hydrate 80% in ethanol for
60 min at 60 ꢁC employing ultrasonic irradiation (Scheme 1) to
afford the products in excellent yields and purities (>90%). The
hydrazine derivatives 3, 5or 8 were condensed with 2-amino-/or 2-
hydroxy-acetophenone 9in the presence of drops of glacial acetic
acid and ethanol as solvent using ultrasonic irradiation for 60 min
(Scheme 2) to afford the target products10aek in excellent yields
and purities. Ultrasonic reaction gave the product in higher yield
and purity in shorter reaction time (Table S1, supporting
information).
All the assigned 1H NMR and 13C NMR peaks for the target
products 10aek are in good agreement with those reported data for
similar compounds [40e46].
6.3. DFT studies
6.3.1. Optimized geometrical structures
The DFT calculated structures and geometric parameters (bond
Scheme 1. Synthesis of 2-hydrazino-4,6-disubstituted-1,3,5-triazine.

126
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
Scheme 2. Synthesis of 4,6-disubstituted-s-triazine Schiff base derivatives.
Fig. 1. ORTEPs diagram of the titled compounds 10c, 10d, 10e and 10f Displacement ellipsoids are plotted at the 40% probability level for non-H atoms.
lengths and bond angles) are given in Fig. 2 and Table 1, respec-
tively. All optimized structures have C1 point group. Statistical pa-
rameters such as root mean square deviation (RMSD) and
correlation coefficient (R2) were computed (Table 1). The small
RMSD values as well as the high correlation coefficients (R2) indi-
cated a good agreement between the calculated and experimental
geometric parameters.
The N9/H53, N10/H53, N8/H57 and N8/H56 intra-
molecular distances were found to be 1.917 Å (exp. 1.944 Å), 1.700
(exp. 1.875 Å), 1.699 (exp. 1.825 Å) and 1.908 (exp. 2.034 Å) for 10c,
10d, 10e, and 10f, respectively. These results indicated that 10c and
10e showed longer NeH/N intramolecular H-bonding interactions
than the OeH/N interaction occurred in 10d and 10f, respectively
which agree with our reported X-ray structure. The morpholine and
piperidine rings have the chair form configuration for all the
studied compounds. The calculated dihedral angles of the triazine
ring indicated deviation from the planarity upto 2.323, 0.911, 0.167
and 1.590ꢁ for 10c, 10d,10e, and 10f, respectively. It is the minimum
for 10d which have the shortest OeH/N H-bonding interaction
and is the maximum for those having the weaker NeH/N intra-
molecular H-bonding interaction (10c and 10e). These results
indicated that the deviation of the triazine ring from planarity

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
127
Fig. 2. The optimized molecular structure and atom numbering of the studied compounds.
decreased with increasing the strength of the intramolecular H-
bond as the steric effect of the groups surrounding the triazine
moiety which is almost the same for all compounds.
that the conformers (10d and 10f) with NeH/O H-bond are more
stable than 10da and 10fa by 13.57 and 13.34 kcal/mol, respectively.
The analysis of thermodynamic parameters showed that 10da and
10fa have zero population and could not exist. We could conclude
that the intramolecular H-bonding interactions stabilized the
structure of the studied compounds.
In order to assess the effect of intramolecular H-bonding inter-
action on the stability of the studied structures, the C44eO1eH57
and C40eO3eH53 bond angles of 10d and 10f, respectively, were
rotated by 180ꢁ. These leading to one more conformer for each
compound have no intramolecular H-bonding interactions (Fig. 2).
For simplicity, the two new conformers are abbreviated 10da and
10fa (Fig. 2). The structures of these suggested conformers were
also optimized and their relative stabilities were predicted using
the total energy difference and thermodynamic parameter data
shown in Table S9 (supporting information). The results showed
6.3.2. Atomic charge distribution
Once the calculated geometries fitted well with the experi-
mental X-ray structure, the electronic and spectroscopic properties
of the studied systems could be obtained with good accuracy. The
atomic charges obtained using NBO calculations were collected in
Table S10 (supporting information). All hydrogen atoms have

128
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
Table 1
Comparative experimental and calculated data of the bond distances and bond angles for the studied compounds.
10c
10d
10e
10f
Parameter
Calc.
Exp.
Parameter
Calc.
Exp.
Parameter
Calc.
Exp.
Parameter
Calc.
Exp.
R(1e43)
R(2e10)
R(2e12)
R(3e11)
R(3e12)
R(4e10)
R(4e11)
R(5e10)
R(5e13)
R(5e25)
R(6e11)
R(6e28)
R(6e40)
R(7e8)
R(7e12)
R(8e43)
R(9e53)
R(13e15)
R(13e16)
R(16e19)
R(19e22)
R(22e25)
R(28e30)
R(28e31)
R(31e34)
R(37e40)
R(43e44)
R(44e45)
R(44e53)
R(45e47)
R(47e49)
R(49e51)
1.515
1.347
1.337
1.350
1.328
1.344
1.343
1.364
1.461
1.462
1.363
1.462
1.463
1.353
1.377
1.294
1.370
1.086
1.534
1.535
1.535
1.534
1.086
1.533
1.534
1.534
1.476
1.409
1.433
1.386
1.396
1.382
1.411
1.505
1.352
1.342
1.354
1.333
1.345
1.340
1.359
1.465
1.458
1.359
1.462
1.457
1.380
1.375
1.293
1.392
0.990
1.519
1.523
1.532
1.520
0.991
1.524
1.531
1.519
1.488
1.409
1.421
1.386
1.384
1.376
1.406
R(1e44)
R(2e9)
R(2e12)
R(2e24)
R(3e9)
1.342
1.364
1.462
1.462
1.343
1.344
1.349
1.335
1.352
1.325
1.360
1.462
1.465
1.347
1.382
1.294
1.533
1.534
1.535
1.534
1.533
1.534
1.534
1.534
1.475
1.511
1.427
1.408
1.401
1.385
1.396
1.386
1.699
1.362
1.359
1.461
1.457
1.343
1.341
1.354
1.337
1.350
1.329
1.359
1.458
1.463
1.383
1.389
1.292
1.532
1.523
1.521
1.525
1.523
1.536
1.524
1.523
1.477
1.499
1.418
1.407
1.393
1.388
1.382
1.378
1.825
R(1e17)
R(1e20)
R(2e29)
R(2e32)
R(3e11)
R(3e13)
R(4e12)
R(4e13)
R(5e11)
R(5e12)
R(6e11)
R(6e14)
R(6e23)
R(7e12)
R(7e26)
R(7e35)
R(8e9)
R(8e13)
R(9e38)
R(10e40)
R(14e17)
R(20e23)
R(26e29)
R(32e35)
R(38e39)
R(38e49)
R(39e40)
R(39e47)
R(40e41)
R(41e43)
R(43e45)
R(45e47)
R(9e53)
1.423
1.423
1.422
1.423
1.345
1.338
1.348
1.330
1.344
1.343
1.365
1.461
1.460
1.363
1.460
1.462
1.351
1.374
1.294
1.367
1.527
1.527
1.527
1.527
1.475
1.515
1.434
1.409
1.412
1.382
1.397
1.385
1.917
1.431
1.425
1.430
1.440
1.357
1.338
1.363
1.330
1.351
1.341
1.359
1.459
1.467
1.356
1.466
1.467
1.361
1.376
1.295
1.372
1.514
1.519
1.510
1.503
1.483
1.516
1.424
1.405
1.411
1.370
1.389
1.388
1.944
R(1e17)
R(1e20)
R(2e29)
R(2e32)
R(3e40)
R(4e11)
R(4e12)
R(5e12)
R(5e13)
R(6e11)
R(6e13)
R(7e11)
R(7e14)
R(7e23)
R(8e12)
R(8e26)
R(8e35)
R(9e10)
R(9e13)
R(10e38)
R(14e17)
R(20e23)
R(26e29)
R(32e35)
R(38e39)
R(38e49)
R(39e40)
R(39e47)
R(40e41)
R(41e43)
R(43e45)
R(45e47)
R(10e53)
1.423
1.423
1.421
1.424
1.343
1.342
1.344
1.349
1.326
1.347
1.336
1.364
1.461
1.461
1.361
1.461
1.464
1.348
1.379
1.294
1.527
1.527
1.528
1.526
1.475
1.511
1.427
1.408
1.401
1.385
1.396
1.386
1.700
1.429
1.428
1.442
1.440
1.355
1.345
1.340
1.353
1.330
1.344
1.338
1.361
1.470
1.462
1.356
1.470
1.466
1.366
1.374
1.293
1.498
1.506
1.495
1.487
1.475
1.504
1.412
1.401
1.391
1.382
1.379
1.380
1.875
R(3e10)
R(4e9)
R(4e11)
R(5e10)
R(5e11)
R(6e10)
R(6e27)
R(6e39)
R(7e8)
R(7e11)
R(8e42)
R(12e15)
R(15e18)
R(18e21)
R(21e24)
R(27e30)
R(30e33)
R(33e36)
R(36e39)
R(42e43)
R(42e53)
R(43e44)
R(43e51)
R(44e45)
R(45e47)
R(47e49)
R(49e51)
R(8e57)
R(51e53)
RAMD,R2
0.026, 0.987
123.3
0.010, 0.993
122.9
0.009, 0.991
109.4
0.014, 0.981
109.2
A(1e43e8)
A(1e43e44)
A(10e2e12)
A(2e10e4)
A(2e10e5)
A(2e12e3)
A(2e12e7)
A(11e3e12)
A(3e11e4)
A(3e11e6)
A(3e12e7)
A(10e4e11)
A(4e10e5)
A(4e11e6)
A(10e5e13)
A(10e5e25)
A(13e5e25)
A(5e13e16)
A(5e25e22)
A(11e6e28)
A(11e6e40)
A(28e6e40)
A(6e28e31)
A(6e40e37)
A(8e7e12)
A(7e8e43)
A(8e43e44)
A(9e53e44)
A(9e53e51)
A(14e13 16)
A(15e13e16)
A(13e16e19)
A(16e19e22)
A(19e22e25)
A(28e31e34)
A(31e34e37)
A(34e37e40)
A(43e44e45)
A(43e44e53)
122.0
120.3
113.9
124.7
117.5
127.4
114.0
113.7
125.0
117.1
118.6
115.4
117.8
117.9
122.4
122.3
115.1
110.8
110.7
122.4
122.3
115.3
111.0
110.8
121.1
120.6
117.8
122.9
118.6
109.5
111.6
111.3
110.7
111.2
111.2
110.6
111.5
119.6
122.9
A(1e44e43)
A(1e44e45)
A(9e2e12)
A(9e2e24)
A(2e9e3)
123.5
116.9
122.3
122.3
117.9
117.5
115.1
110.7
110.8
115.6
124.6
124.7
118.1
113.6
127.8
113.8
113.6
117.3
118.3
122.3
122.5
115.0
110.9
110.7
121.0
122.6
121.8
116.4
121.9
111.3
110.7
111.3
111.2
110.7
111.4
121.7
121.4
121.1
117.5
A(17e1e20)
A(1e17e14)
A(1e20e23)
A(29e2e32)
A(2e29e26)
A(2e32e35)
A(11e3e13)
A(3e11e5)
A(3e11e6)
A(3e13e4)
A(3e13e8)
A(12e4e13)
A(4e12e5)
A(4e12e7)
A(4e13e8)
A(11e5e12)
A(5e11e6)
A(5e12e7)
A(11e6e14)
A(11e6e23)
A(14e6e23)
A(6e14e17)
A(6e23e20)
A(12e7e26)
A(12e7e35)
A(26e7e35)
A(7e26e29)
A(7e35e32)
A(9e8e13)
A(8e9e38)
A(9e38e39)
A(9e38e49)
A(10e40e39)
A(10e40e41)
A(39e38e49)
A(38e39e40)
A(38e39e47)
A(40e39e47)
A(39e40e41)
111.0
111.5
111.6
110.9
111.5
111.7
113.9
125.0
117.4
127.1
114.0
113.7
125.3
117.0
118.8
115.0
117.7
117.8
122.2
122.3
114.4
109.5
109.5
122.6
122.3
114.5
109.7
109.5
121.3
120.5
117.7
121.5
123.1
118.5
120.8
122.7
119.8
117.5
118.4
A(17e1e20)
A(1e17e14)
A(1e20e23)
A(29e2e32)
A(2e29e26)
A(2e32e35)
A(3e40e39)
A(3e40e41)
A(11e4e12)
A(4e11e6)
A(4e11e7)
A(4e12e5)
A(4e12e8)
A(12e5e13)
A(5e12e8)
111.0
111.5
111.6
111.0
111.6
111.7
123.5
116.9
115.2
125.0
117.7
124.9
118.0
113.7
117.1
127.6
118.3
113.6
117.3
114.1
122.3
122.3
114.4
109.5
109.5
122.4
122.4
114.4
109.6
109.5
120.8
121.9
116.3
122.0
121.7
121.4
121.1
117.5
119.6
120.3
113.0
125.6
117.5
127.8
115.1
113.3
125.5
116.7
117.1
114.8
116.9
117.8
122.9
122.6
114.4
110.2
110.3
122.4
121.8
114.7
110.0
109.9
117.6
118.5
116.4
123.4
117.8
109.6
109.6
111.0
110.6
110.8
110.8
110.0
111.8
118.8
123.4
116.8
122.4
122.9
117.1
117.1
114.3
109.8
110.2
114.6
125.8
125.7
117.7
112.4
128.5
114.6
113.0
116.6
116.8
122.5
122.2
114.4
110.3
110.0
116.0
116.0
119.9
115.4
123.6
111.1
110.6
110.8
110.8
109.9
111.7
121.0
121.8
120.5
117.7
111.1
111.7
109.0
111.4
110.5
112.8
125.4
117.2
128.5
113.9
112.6
125.9
116.3
117.6
114.4
117.3
117.8
121.2
121.2
114.2
110.3
109.4
120.8
120.6
115.1
110.6
109.7
118.8
119.9
116.7
122.9
123.0
118.2
120.3
122.8
119.7
117.5
118.8
111.9
111.6
108.2
111.1
111.7
123.1
116.7
114.1
125.9
117.0
126.1
117.1
112.8
116.8
127.8
117.9
113.1
117.1
114.3
120.3
120.4
113.7
109.7
109.5
120.8
120.6
114.6
110.9
110.5
117.8
121.0
115.2
124.2
120.6
122.1
120.9
117.0
120.1
A(2e9e4)
A(12e2e24)
A(2e12e15)
A(2e24e21)
A(9e3e10)
A(3e9e4)
A(3e10e5)
A(3e10e6)
A(9e4e11)
A(4e11e5)
A(4e11e7)
A(10e5e11)
A(5e10e6)
A(5e11e7)
A(10e6e27)
A(10e6e39)
A(27e6e39)
A(6e27e30)
A(6e39e36)
A(8e7e11)
A(8e7e58)
A(7e8e42)
A(8e42e43)
A(8e42e53)
A(12e15e18)
A(15e18e21)
A(18e21e24)
A(27e30e33)
A(30e33e36)
A(33e36e39)
A(43e42e53)
A(42e43e44)
A(42e43e51)
A(44e43e51)
A(5e13e6)
A(5e13e9)
A(11e6e13)
A(6e11e7)
A(6e13e9)
A(11e7e14)
A(11e7e23)
A(14e7e23)
A(7e14e17)
A(7e23e20)
A(12e8e26)
A(12e8e35)
A(26e8e35)
A(8e26e29)
A(8e35e32)
A(10e9e13)
A(9e10e38)
A(10e38e39)
A(10e38e49)
A(39e38e49)
A(38e39e40)
A(38e39e47)
A(40e39e47)
A(39e40e41)

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
129
Table 1 (continued )
10c
10d
10e
10f
Parameter
Calc.
Exp.
Parameter
Calc.
Exp.
Parameter
Calc.
Exp.
Parameter
Calc.
Exp.
A(45e44e53)
A(44e45e47)
A(44e53e51)
A(45e47e49)
A(47e49e51)
A(49e51e53)
RMSD,R2
117.5
123.1
118.4
118.9
120.0
122.1
117.8
122.2
118.8
119.1
120.4
121.6
A(43e44e45)
A(43e51e49)
A(44e45e47)
A(45e47e49)
A(47e49e51)
119.6
122.4
121.1
120.1
119.3
120.3
121.5
120.0
120.7
119.8
A(39e47e45)
A(40e41e43)
A(42e41e43)
A(41e43e45)
A(44e43e45)
A(43e45e47)
123.1
122.0
119.9
120.1
120.4
118.8
122.7
121.8
119.1
120.3
119.8
119.0
A(39e47e45)
A(39e47e48)
A(40e41e43)
A(41e43e45)
A(43e45e47)
122.3
119.4
121.1
120.1
119.3
122.4
118.8
120.9
119.9
119.5
0.935, 0.986
1.468, 0.961
0.908, 0.986
1.100, 0.978
positive charge densities where the NH and OH protons are the
most electropositive H-atoms. The NH proton of the hydrazone
group has natural charge of 0.3797, 0.3834, 0.3826 and 0.3792 for
10c, 10d, 10e, and 10f, respectively. Compounds having OH sub-
stituent at the phenyl ring such as 10d and 10f have more positive
charge at this NH proton compared to those having amino group as
substituent (10c and 10e). For compounds 10e and 10c, the natural
charge values at the NH-protons of the amino group have natural
charges in the range 0.3632e0.4313. The H53 of 10e and H56 of 10c
have higher positive charge compared to the H55 and H57,
respectively.
The high positive charge at H53 and H56 is mainly due to the
involvement of these H-sites in the intramolecular H-bonding
interaction with the N9 and N8 of 10e and 10c, respectively. The N9,
N10, N8 and N8 of 10c, 10d, 10e, and 10f have natural charge of
ꢀ0.3158, ꢀ0.3243, ꢀ0.3224 and 0.3164, respectively. We noted that
the compounds 10d and 10f, those having the strong intra-
molecular OeH/N H-bonds, have higher negative charge density
at the N-atoms of the hydrazone moiety than those having weaker
NeH/N H-bond (10e and 10c)
The studied compounds have large number of strong electro-
negative atoms such as nitrogen and oxygen atoms. The N- and O-
atoms of the NH2 and OH groups, respectively, have the highest
negative natural charge. In addition, the N-atoms of the triazine
moiety have high negative natural charges. It is clear from the
charge analysis that compounds having OH-substituent (10f and
10d) have triazine ring with N-atoms less electron rich than those
having amino group as substituent (10e and 10c). Moreover, com-
pounds with piperidine rings attached to the triazine ring have N-
atoms richer in electrons than those having morpholine substitu-
ent. The morpholine has one more O-atom over the piperidine,
which withdraw more electron density from the triazine ring N-
atoms. In general, the O- and N-atoms possess the highest negative
natural charge values. As a result, all C-atoms attached to them are
highly electropositive. For example, the C11, C12 and C13 in case of
10e have the highest positive charge values (0.6503e0.6670). All
are located between three strongly negative N-atoms.
The calculated dipole moment is one of the electronic properties
related to the atomic charge distribution and plays an important
role in the chemical reactivity of compound. The calculated dipole
moment values of 10c, 10d, 10e, and 10f are 1.2552, 3.1771, 3.3103
and 2.4348 Debye, respectively. The order of polarity is
10d > 10f > 10c > 10e. In comparison, the most polar compounds
are those having OH group (10f and 10d) while the least polar
compounds are those with NH2 substituent (10e and 10c). In all
compounds, the dipole moment vector is oriented towards the
phenylhydrazone moiety, which indicates the importance of the
substituent at the phenyl group on the polarity of the molecule.
One of the most interesting tools used to visualize the size,
shape, charge density and the sites of chemical reactivity of mole-
cules is the molecular electrostatic potential (MEP). The molecular
electrostatic potential (MEP) maps shown in Fig. 3 were used to
visualize the atomic charge density distribution of the studied
Fig. 3. The molecular electrostatic potential (MEP) map of the studied compounds.
compounds.
MEP
values
increase
in
the
order
red < orange < yellow < green < blue where the red represents the
most negative regions while blue is for the most positive regions.
The negative red regions are located around the N- and O-atoms as
well as the phenylhydrazone moiety while the blue positive regions
are mainly related to the NeH protons. In one regard, the NeH
protons represent the most favored H-sites for making the intra and
intermolecular H-bonding interactions while the N and O-atoms
are the most H-acceptor sites. Moreover, the MEP regions with red
are the most suitable ones for electrophilic attack. In contrast, the
blue spaces represent the regions of the highest reactivity towards
the nucleophilic attack [63].
The orbital energy level analysis of the studied compounds
showed EHOMO values of e(ꢀ5.1990, ꢀ5.6714, ꢀ5.5308 and
ꢀ5.1008 eV) and ELUMO values of ꢀ1.1002, ꢀ1.3603, ꢀ1.2158 and
ꢀ0.9753, for compounds 10c, 10d, 10e and 10f, respectively (Fig. 4).
As a result, 10f has the highest electrophilic behavior (electron
acceptor) while 10c is the most nucleophilic one (electron donor).
In addition, the negative values of the HOMO and LUMO energies
indicate the stability of the studied systems [64].
One of the significant results that could be obtained from the
FMO analysis is the determination of the molecule ability to elec-
tronic transition. The high HOMO-LUMO energy gap indicates a

130
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
transition.
In order to assign the experimental electronic spectra of the
studied compounds, TD-DFT calculations were performed. The
experimentally observed and theoretically computed electronic
spectra are shown in Fig. S16 (supporting information) and Fig. 5,
respectively. The complete description of the calculated spectro-
scopic states obtained from the TD-DFT results were collected in
Table S11(supporting information) while the most important
spectral bands are given in Table 2. The common feature of the
electronic spectra of the studied compounds is three intense bands.
In addition, 10e and 10f have an extra shoulder. For all bands, the
effect of changing the substituent at the triazine ring on the elec-
tronic spectra (lmax) is very small. In contrast, the changing of the
substituent at the phenyl ring significantly changed the locations of
the highest lmax band. The longest wavelength band in the amino
substituted compounds (10e and 10c) is shifted to higher energy in
the corresponding hydroxy derivatives (10f and 10d), respectively.
This band is assigned mainly to HOMO/LUMO (81e85%) excita-
tion. These results agreed well with the FMO analysis discussed
above.
The experimental UVeVis spectra of the studied compounds are
shown in Fig. S20 (supporting information). It is clear that the three
short wavelength bands have almost the same lmax for all the
studied compounds. In contrast the longest wavelength band in
case of 10e and 10c (335e338 nm) has higher lmax compared to
that for 10f and 10d (318 nm). In agreement with our calculations,
changing the substituent at the phenylhydrazone moiety affected
the position of this band where the amino derivatives have longer
lmax than the hydroxy ones. Since these bands are assigned mainly
to HOMO-LUMO excitation, these results are consistent with the
higher FMO energy gap of 10f and 10d compared to 10e and 10c,
respectively. On the other hand, changing the substituent at the
triazine ring almost showed slight effect on the electronic spectra.
6.3.3. Reactivity studies
The reactant compounds were optimized using the same level of
theory and their optimized structures are given in Fig. S17 (sup-
porting information). Several reactivity descriptors such as ioni-
zation potential (I), electron affinity (A), chemical potential (
m),
hardness ( ) as well as electrophilicity index ( ) were proposed for
h
u
understanding various aspects of reactivity associated to chemical
reactions [65e70]. The definition of these parameters is given by
Equations (1)e(5).
I ¼ ꢀEHOMO
A ¼ ꢀELUMO
(1)
(2)
(3)
(4)
(5)
Fig. 4. The FMOs plots of the studied compounds.
h
m
¼ (IꢀA)/2
more difficult electronic transition to occur and hence more stable
molecule. The HOMO-LUMO energy gap is calculated to be 4.0989,
4.3111, 4.3149 and 4.1256 eV for 10c, 10d, 10e and 10f, respectively.
From these data, we could observe the high stability of the hydroxy
derivatives toward the electron transfer compared to the amino
substituted compounds.
The electron densities and shapes of the frontier molecular
orbital HOMO and LUMO of the studied compounds are shown in
Fig. 4. Neither the substituent at the triazine ring nor the substit-
uent at the phenyl moiety has any effect on the HOMO and LUMO
patterns. In all the studied systems, both the HOMO and LUMO
levels are mainly localized over the triazine ring and the phenyl-
hydrazone moieties. Since the distribution of the HOMO and LUMO
¼ ꢀ(I þ A)/2
u
¼
m h
2/2
The results of electronic parameters are listed in Table 3. It could
be seen that the reactants R3 and R4 have higher chemical potential
than that for the reactants R1 and R2. As a result, the flow of
electrons will takes place from the former reactants to the latter. In
addition, the electrophilicity index showed that the reactants R3
and R4 have lower values than R1 and R2. Hence, the R3 and R4 are
considered as nucleophiles while R1 and R2 are electrophiles. The
reaction could be described at nucleophilic attack of R3 and R4 as
nucleophile on the reactants R1 and R2 as electrophiles. On the
basis of the hard and soft acid base principle, the reactions between
R1þR3 as well as R2þR4 are more favored than the R1þR4 and
levels are mainly delocalized over the
p-system of the molecules so
the lowest energy electronic transition belongs mainly to
p/p*

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
131
Fig. 5. The calculated electronic spectra of the studied compounds.
Table 2
The most important electronic transitions obtained from the TD-DFT calculation.
No.
lmax
fosc
Assignment
Exp.
10c
1
2
3
4
10d
1
2
3
10e
1
2
3
4
10f
1
341.3
282.4
234.9
214.9
0.3113
0.4874
0.2736
0.4554
H / L (84%)
H-1 / L (79%)
335
283
H / Lþ3 (69%)
He7 / L (11%), H-3 / Lþ1 (27%), H-2 / Lþ1 (17%)
236
321.6
277.6
215.1
0.4300
0.4963
0.6835
H / L (81%)
H-3 / L (77%)
H-1 / Lþ1 (53%)
318
281
231
343.8
279.0
235.3
217.9
0.3124
0.5506
0.3186
0.2424
H / L (85%)
H-1 / L (77%)
338
284
e
H / Lþ3 (69%)
H-2 / Lþ1 (44%), H-1 / Lþ2 (10%)
234
322.7
277.9
217.0
0.4029
0.2998
0.3933
H / L (82%)
H-3 / L (39%), H-2/L (49%)
H-2 / Lþ1 (16%), H-1 / Lþ1 (12%), H-1 / Lþ2 (28%), H-1 / Lþ3 (20%)
318
281
231
2
3
Table 3
The quantum chemical reactivity parameters of compounds 10c, 10d, 10e, and 10f.
Parameter
R1
R2
R3
R4
10c
10d
10e
10f
I
6.5893
1.7421
2.4236
ꢀ4.1657
4.1657
3.5800
0.4126
5.7079
1.4868
2.1105
ꢀ3.5974
3.5974
3.0658
0.4738
5.8973
ꢀ0.3031
3.1002
ꢀ2.7971
2.7971
1.2618
0.3226
6.1087
ꢀ0.0629
3.0858
ꢀ3.0229
3.0229
1.4807
0.3241
5.1008
0.9753
2.0628
ꢀ3.0380
3.0380
2.2372
0.4848
5.5308
1.2158
2.1575
ꢀ3.3733
3.3733
2.6371
0.4635
5.1990
1.1002
2.0494
ꢀ3.1496
3.1496
2.4202
0.4879
5.6714
1.3603
2.1556
ꢀ3.5159
3.5159
2.8673
0.4639
A
h
m
c
u
S
R2þR3 reactions.
takes place from molecule with the highest chemical potential.
From this point of view, the ability of the studied compounds to
electron flow from it will be the highest for 10c. Moreover, the
electrophilicity index of the studied compounds are in the order
10f > 10d > 10e > 10c. From this point of view, 10f has the highest
electrophilicity index so it has higher electrophilic behavior
compared to the others [71], in agreement with the large number of
strong electronegative atoms in this compound compared to the
others.
Moreover, these chemical reactivity descriptors could be used
for describing the different pharmacological and biological reac-
tivity of compounds. Based on the molecular orbital calculations of
the synthesized compounds, these reactivity descriptors are sum-
marized and listed in Table 3. The results showed the hydroxy de-
rivatives are harder than the amino compounds as a consequence of
the higher electronegativity of the former compared to the latter, in
agreement with the higher electronegativity of O-atom compared
to nitrogen.
The negative chemical potential values indicated the stability of
the studied system. It is well known that the flow of electrons could
6.3.4. Natural bond orbital (NBO) analysis
One of the interesting features of the NBO analysis is examining

132
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
all possible interactions between “filled” (donor) Lewis-type NBOs
and “empty” (acceptor) non-Lewis NBOs [72,73]. The intensity of
the charge transfer among these NBOs could be quantitatively
compared using the stabilization energy estimated by the second
order perturbation theory. The stabilization energies (E(2)) due to
derivatives stabilized the system further upto 8.51 kcal/mol than
the corresponding ICT from the LP O-atom NBO of the hydroxyl
derivative probably due to the higher electronegativity of the O-
atom which weaken its corresponding ICT interaction.
Interestingly, compounds 10e and 10c have the LP(1)
the most important
p/p*, n/p* and n/s* intramolecular
N9/BD*(1)N10eH53(8.49
kcal/mol)
andLP(1)N8/BD*(1)
charge transfer (ICT) interactions for the studied molecules are
given in Table S12 (supporting information).
N9eH56 (9.34 kcal/mol) indicate the presence of intramolecular
H/O interaction between one of the amino group H-atoms and the
adjacent N-atom of the hydrazone moiety. Also, compounds, 10f
and 10d, have the ICT LP(1)N10/BD*(1)O3eH53 (25.62 kcal/mol)
and LP(1)N8/BD*(1)O1eH57 (25.84 kcal/mol), respectively be-
tween the OH H-atom and the adjacent N-atom of the hydrazone
moiety. It is clear from these results that the intramolecular
OeH/N H-bonding interactions are stronger by 16.50e17.13 kcal/
mol than the NeH/N ones.
The effects of the substituent at the triazine and phenyl rings on
the extent of the ICT interactions are given in Table 4. The first
column showed the ICT number (No.) while the next two columns
showed the effect of the substituent at the triazine ring and the last
two columns showed the effect of the substituent at the phenyl ring
on the degree of the ICT. 10e and 10c have the same substituent at
the phenyl ring but differ in the substituent on the triazine ring. The
former has two morpholine moieties as substituents, while the
latter with two piperidine moieties attached to the triazine ring.
The same is true for the 10f and 10d molecules. These substituent
6.3.5. NMR spectra
The GIAO NMR calculated chemical shifts (C.S) of the studied
compounds compared to the experimental results were collected in
Table S13 (supporting information). The correlation coefficients
(R2) showed that the agreement between the experimental and
calculated data is good. The correlation graphs of 10e as example
are shown in Fig. 6. The high chemical shifts of the 13C-chemical
shifts of the triazine ring compared to the carbon atoms of the ar-
omatic structure because all are bonded to two strong electroneg-
ative N-atoms. Moreover, the aliphatic C-atoms have lower
chemical shift values than the aromatic ones where C-atoms of the
morpholine rings are predicted to have higher C.S than those for the
piperidine ring structure. As is well known, the electronegative
atoms tend to deshield the 13C signals. Most of the proton signal
agreed well with the experimental data (Table S13, supporting
information).
changes very slightly affected the triazine ring
p/p* and n/s*
ICT interactions. ICT numbers 17e21 and 17e19 showed the most
significant variations due to changing the substituent for the amino
and hydroxyl derivatives, respectively. The maximum change in the
stabilization energy of these ICT interactions due to changing the
nature of the substituent at the triazine ring did not exceed
3.00 kcal/mol for the LP(1)N6 /BD*(2)N3eC11 in case of 10e
compared to the LP(1)N5 / BD*(2)N2eC10 of 10c. It is noted that
the ICT from the Lp(N) of the piperidine ring to the adjacent
p*-
antibond of the triazine ring is more intense than that from the
Lp(N) of the morpholine ring. The presence of the strong electro-
negative O-atom tends to weak these ICT interactions.
The effect of changing the substituent at the phenyl ring showed
some variations in the
p/p* and n/p* ICT interactions. Most of
the * ICT interactions are stabilized by changing the substit-
p/p
uent from the amino derivative to the hydroxy one whatever the
nature of the substituent at the triazine ring. The maximum sta-
6.4. Anti-proliferative effects
bilization of the
p
/
p
* ICT occurred for 10d compared to 10f (ICT
Three cancer cell lines were incubated with serial dilution of
each compound (from 616 pg MLꢀ1 to 1 mg MLꢀ1) in 96-well plate
for 3days, and then tested for growth inhibition by MTT-Test
(Mosmann, 1983 #6), as described in the method section. The re-
sults showed that three derivatives (10a, 10i and 10j) were able to
inhibit the growth of two of the three tested cancer cell lines
(Table S14). The adenocarcinoma cell line MCF7 was resistant to all
tested derivatives. However the other two cell lines, the lung car-
cinoma A549 and the hepatocyte carcinoma HepG2, were sensitive
to three of the tested derivatives (10a, 10i and 10j). HepG2 were the
No. 7). The LP(2)O3/BD*(2)C40eC41 (35.36 kcal/mol) ICT of 10fis
lower than the LP(1)N10/BD*(2)C39eC40 (43.87 kcal/mol) of 10e.
Also, the LP(2) O1/BD*(2)C44eC45 (35.62 kcal/mol) of 10dis
lower than the LP(1)N9 /BD*(2)C44eC53 (41.07 kcal/mol) of 10c.
The ICT from the lone pair NBO of the N-atom in case of the amino
Table 4
Effect of the substituent on the ICT interactions for the studied compounds.
most sensitive cell line to compound 10j with IC50 value of1.5 mg/
No.
10ce10e
10de10f
10fe10e
10de10c
mL. Furthermore, the two other derivatives (10a and 10i) affect the
growth of the two cancer cell lines (A549and HepG2) with similar
activity IC50, 19.9 ( 2.1), 15.5 ( 1.7) for 10a and 5.6 ( 1.1), 6.5 ( 1.1
for 10i), respectively (Table S14).
1
2
3
4
0.75
0.63
0.99
0.87
ꢀ0.72
ꢀ0.17
0.05
ꢀ0.75
ꢀ0.07
ꢀ0.09
0.04
ꢀ1.26
ꢀ1.29
0.55
0.65
2.18
1.96
2.04
1.88
5
0.12
In general, different substituent on the triazine moiety showed
better growth inhibition effects than similar groups as shown in
10d, 10f and 10i (Table S14). The hydroxyl derivatives showed
better strongest growth inhibition effects than the amino group
(10ivs10k) this might be due to the effect of the electronegativity of
the oxygen and the type of hydrogen bond. The methoxy has some
effect on the growth inhibition effects as shown in compounds 10a,
10i and 10k. The combination between OCH3 and piperidine (10j)
makes the compounds more selective to the hepatocyte carcinoma
6
7
8
9
0.17
0.07
0.04
0.06
0.07
0.07
ꢀ0.03
ꢀ3.30
ꢀ3.50
1.05
3.25
4.23
ꢀ0.92
0.83
2.26
2.39
3.65
0.09
1.30
3.16
2.46
0.07
10
11
12
13
14
15
16
17
18
19
20
21
22
ꢀ1.12
0.05
ꢀ0.14
ꢀ0.14
0.07
ꢀ0.16
ꢀ0.16
0.08
0.20
0.19
ꢀ0.14
0.01
0.03
3.00
1.85
ꢀ2.91
ꢀ2.35
ꢀ2.80
0.85
ꢀ0.13
ꢀ0.18
0.13
ꢀ0.17
0.14
0.00
0.51
1.98
0.02
0.04
2.60
2.27
ꢀ0.01
HepG2with IC50 value of1.5
morpholine and piperdine (10i) makes the compounds more se-
lective to the lung carcinoma A549 with IC50 value of 5.6 g/mL and
reasonable effectto the hepatocyte carcinoma HepG2with IC50
value 6.5 g/mL. Further investigations are running in our lab to get
insights into the mode of action of the active compounds.
mg/mL, while the combination between
0.91
1.56
m
ꢀ1.34
ꢀ3.10
ꢀ1.53
0.08
1.00
3.43
0.26
0.22
ꢀ8.51
17.13
ꢀ5.45
16.50
m

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
133
Fig. 6. The correlation graphs of the experimental and calculated 1H and 13C NMR chemical shifts.
7. Conclusions
chemical reactivity parameters of the compounds were predicted.
Anti-proliferative effects showed that three derivatives 10a, 10i,
and 10j were able to inhibit the growth of two cancer cell lines
(A549 and HepG2). The combination between OCH3 and piperidine
(10j) makes the compounds more selective to the hepatocyte car-
Ultrasonic irradiation assisted the synthesis of a novel series of
4,6-disubstituted-s-triazine-Schiff base derivatives. Ultrasonication
affords the product in higher yield and purity than the conventional
heating. The structure of the studied compounds were calculated
and found to agree with the X-ray structure. The calculations
showed that the studied compounds are stabilized by NeH/N (10e
and 10c) and NeH/O (10f and 10d) H-bonds. The spectral char-
acteristics such as NMR and UVeVis spectra were discussed both
experimentally and theoretically. The NBO analysis revealed the
presence of intramolecular stronger H-bonding interaction in case
of 10f and 10d than 10e and 10c, which stabilized the former by
16.50e17.13 kcal/mol compared to the latter. In addition, the
cinoma HepG2with IC50 value of1.5
between morpholine and piperdine (10i) makes the compounds
more selective to the lung carcinoma A549 with IC50 value of 5.6 g/
mL and reasonable effectto the hepatocyte carcinoma HepG2with
IC50 value 6.5 g/mL. These results back the development of a
mg/mL, while the combination
m
m
medicinal chemistry program to fine-tune the anti-proliferative of
this new family of compounds and further studies are running in
our lab to get insights into the structure-reactivity relationship of
the compounds.

134
A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
[25] A. Solankee, J. Patel, Synthesis of chalcones, pyrazolines, amino pyrimidines
Acknowledgements
and pyrimidinethiones as antibacterial agents, Indian J. Chem. 43B (2004)
1580e1584.
The authors thank the Deanship of Scientific Research at King
Saud University for funding this work through Prolific Research
Group Program (PRG-1437-33; Saudi Arabia).
[26] G.S. Gadaginamath, R.S. Kavali, S.R. Pujar, Synthesis and antibacterial activity
of some new 1-n-butyl-3-acetyl-5-(2,4-diamino-1,3,5-triazin-6-yl)methoxy-
2-methyl inodole derivatives, Indian J. Chem. 38B (1999) 1226e1228.
[27] A.R. Shelar, S.A. Adure, M.A. Shelar, Synthesis and antibacterial activity mono
aryloxy-s-triazine derivatives of penicillin, cephalosporin, ampicillin and
cephalexin, Indian J. Chem. 37B (1998) 358e364.
Appendix A. Supplementary data
[28] D.K. Basedia, B. Shrivastava, B.K. Dubey, P. Sharma, Synthesis, characterization
and antimicrobial activity of novel 2,5-substituted aryl-7 phenyl-1,3,4-
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.06.061.
oxadiazolo-[3,2-a]-1,3,5-triazine derivatives, Int. J. Biomed. Res.
5 (2014)
13e18.
[29] R.K. Khare, A.K. Srivastava, H. Singh, Synthesis and fungicidal activity of some
6-aryl-2-(B-D-glucopyranosyl)-3-oxo-2,3-dihydro-1,3,4-oxadiazolo[3,2-b]-
1,2,4,6-thiatriazine-1,1-dioxides, Indian J. Chem. 44B (2005) 163e166.
[30] D. Indorkar, O.P. Chourasia, S.N. Limaye, Synthesis, characterization, antimi-
crobial, antifungal activity of some s-triazine derivatives of Isoxazoline, Pyr-
azoline and PC model computational studies, Res. J. Pharm. Sci. 1 (2012)
10e16.
[31] K.S. Parikh, S.P. Vyas, Synthesis and antimicrobial screening of some new s-
Triazine based Piperazine and Piperidine derivatives, Der Chem. 3 (2012)
430e434.
[32] A.K. Srivastava, S.K. Raja, S.K. Puri, M.S. Chauhan, Synthesis and bioevaluation
of hybrid 4-aminoquinoline triazines as a new class of antimalarial agents,
Bioorg. Med. Chem. 18 (2008) 6530e6533.
[33] A. Agarwal, K. Srivastava, S.K. Puri, M.S. Prem, Synthesis of 2,4,6-trisubstituted
triazines as antimalarial agents, Bioorg. Med. Chem. 15 (2005) 531e535.
[34] A.K. Srivastava, S.R. Raja, M.I. Siddiqi, S.K. Puri, J.K. Sexana, M.S. Chauhan, 4-
Anilinoquinoline triazines: a novel class of hybrid antimalarial agents, Eur. J.
Med. Chem. 46 (2011) 676e690.
[35] A.S. Gajare, S.B. Bhawsar, D.B. Shinde, M.S. Shingare, Synthesis of 2,4-diaryl
amino-6-(3,5,6-trichloropyridin-2-yl)oxy triazine and its herbicidal activity,
Indian J. Chem. 37B (1998) 510e513.
[36] M. Rafat, D.H. Fleita, O.K. Sakka, Novel Synthesis of hydrazide-hydrazone
derivatives and their utilization in the synthesis of coumarin, pyridine, thia-
zole and thiophene derivatives with antitumor activity, Molecules 16 (2011)
16e27.
[37] K. Padmini, P. Jaya Preethi, M. Divya, P. Rohini, M. Lohita, K. Swetha,
P. Kaladar, A Review on biological importance of hydrazones, J. Pharma Res.
Rev. 2 (2013) 43e58.
[38] P. Vicini, F. Zani, P. Cozzini, I. Doytchinova, Hydrazones of 1,2-benzisothiazole
hydrazides: synthesis, antimicrobial activity and QSAR investigations, Eur. J.
Med. Chem. 37 (2002) 553e564.
[39] M.N. Arshad, A. Bibi, T. Mahmood, A.M. Asiri, K. Ayub, Synthesis, crystal
structures and spectroscopic properties of Ttriazine-based hydrazone de-
rivatives; a comparative experimental-theoretical study, Molecules 20 (2015)
5851e5874.
[40] M. Amir, I. Ali, M.Z. Hassan, N. Mulakayala, Design, synthesis, and biological
evaluation of hydrazone incorporated 1,2,4-triazines as anticonvulsant
agents, Arch. Pharm. 347 (2014) 958e968.
[41] K. Ji, C. Lee, B.G. Janesko, E.E. Simanek, Triazine-substituted and acyl hydra-
zones: experiment and computation reveal a stability inversion at low pH,
Mol. Pharm. 12 (2015) 2924e2927.
[42] J.A. Chaudhari, Novel piperazinylo bisaryl hydrazino-s-triazine derivatives
and their application as epoxy resin curing agents, Int. J. Polym. Mater. Polym.
Biomater. 58 (2009) 401e408.
[43] J.A. Chaudhari, R.P. Patel, Novel s-triazineeepoxy resin curing system and
their material applications, J. Chem. Biol. Phys. Sci. 2 (2012) 1234e1240.
[44] V.V. Bakharev, A.A. Gidaspov, V.E. Parenov, I.V. Ulyankina, A.V. Zavodskaya,
E.V. Selezneva, K.Y. Suponitskii, A.B. Sheremetev, Synthesis of 4amino-6-
chloro1,3,5triazin2(1H)ones, Russ. Chem. Bull. Int. Ed. 61 (2012) 99e112.
[45] T. Peppel, M. Kockerling, Large 1,3,5-triazine-based ligands coordinating
transition metal ions: syntheses and structures of the ligands and the ball
References
[1] R. Cella, H.A. Stefani, Ultrasound in heterocycles chemistry, Tetrahedron 65
(2009) 2619e2641.
[2] Y. Jiang, X. Chen, L. Qu, J. Wang, J. Yuan, S. Chen, X. Li, An efficient ultrasound-
assisted method for the synthesis of 1,4-disubstituted triazoles, Z. Naturforsch
66b (2011) 77e82.
[3] A.K. Singh, S.K. Shukla, M.A. Quraishi, Ultrasound mediated green synthesis of
hexahydro triazines, J. Mater. Environ. Sci. 2 (2011) 403e406.
[4] K. Srinivas, P.K. Dubey, A simple, rapid and environmentally benign synthesis
of N-alkyl/aryalkyl benzimidazoles promoted by ultrasound irradiation, Adv.
Appl. Sci. Res. 5 (2014) 336e341.
[5] A.K. Singh, S.K. Shukla, I. Ahamad, M.A. Quraishi, Solvent free microwave
assisted synthesis of 1H-Indole-2,3-dione derivatives, J. Heterocycl. Chem. 46
(2009) 571e574.
[6] J.T. Li, W.Z. Yang, S.X. Wang, S.H. Li, T.S. Li, Improved synthesis of chalcones
under ultrasound irradiation, Ultrason. Sonochem 9 (2002) 237e239.
[7] J.T. Li, G.F. Chen, W.Z. Yang, T.S. Li, Ultrasound promoted synthesis of 2-aroyl-
1,3,5-triaryl-4-carbethoxy-4- cyanocyclohexenols, Ultrason. Sonochem 10
(2003) 123e126.
[8] L. Ding, W. Wang, A. Zhang, Synthesis of 1,5-dinitroaryl-1,4-pentadien-3-ones
under ultrasound irradiation, Ultrason. Sonochem 14 (2007), 563e267.
[9] G. Cravotto, P. Cintas, Power ultrasound in organic synthesis: moving cav-
itational chemistry from academia to innovative and large-scale applications,
Chem. Soc. Rev. 35 (2006) 180e196.
[10] J.T. Li, G.F. Chen, W.Z. Xu, T.S. Li, The Michael reaction catalyzed by KF/basic
alumina under ultrasound irradiation, Ultrason. Sonochem 10 (2003)
115e118.
[11] P.N.K. Babu, B.R. Devi, P.K. Dubey, Ultrasound assisted convenient, rapid and
environmentally benign synthesis of N-alkylbenzimidazoles, Der Chem. Sin. 4
(2013) 105e111.
[12] H. Feng, Y. Li, S. Lin, E.V.V. der Eycken, G. Song, Nano Cu-catalyzed efficient
and selective reduction of nitroarenes under combined microwave and ul-
trasound irradiation, Sustain. Chem. Pro 2 (2014) 1e6.
[13] M.F. Mady, A.A. El-Kateb, I.F. Zeid, K.B. Jørgensen, Comparative studies on
conventional and ultrasound-assisted synthesis of novel homoallylic alcohol
derivatives linked to sulfonyl dibenzene moiety in aqueous media, J. Chem.
2013 (2013) 1e9.
[14] F. Sa˛czewski, A. Bułakowska, P. Bednarski, Synthesis and anticancer activity of
novel 2,4-diamino-1,3,5-triazine derivatives, Eur. J. Med. Chem. 41 (2006)
219e225.
[15] F. Sa˛czewski, A. Bułakowska, Synthesis and anticancer activity of novel
alkenyl-1,3,5-triazine derivatives, Eur. J. Med. Chem. 41 (2006) 611e615.
[16] R. Patel, K. Premlata, P.R. Dhanji, K. Chikhalia, Synthesis and studies of novel
2-(4-cyano-3-trifluoro methyl phenyl amino) -4 -(quinoline-4-yloxy)-6-
(piperazinyl/piperidinyl)-s-triazines as potential antimicrobial, anti-
mycobacterial and anticancer agents, Eur. J. Med. Chem. 46 (2011)
4354e4365.
[17] Y.W. Mohmmad, R.B. Abdul, A. Amir, A. Fareeda, Probing the antiamoebic and
cytotoxicity potency of novel tetrazole and triazine derivatives, Eur. J. Med.
Chem. 48 (2012) 313e320.
[18] K. Arya, A. Dandia, Synthesis and cytotoxic activity of trisubstituted-1,3,5-
triazines, Bioorg. Med. Chem. 17 (2007) 3298e3304.
[19] V.K. Pandey, Z. Tusi, M. Tandon, Synthesis of thiadiazolo-s-triazines for their
antiviral activity based on QSAR studies, Indian J. Chem. 42B (2003)
2583e2588.
[20] Y.-Z. Xiong, F.C. J-Balzarini, E. De Clercq, Structural modulation of diary-
ltriazine with potent anti-HIV activity, Eur. J. Med. Chem. 43 (2008)
1230e1236.
shaped
nanometer-scaled
Co
complex
[Co(2,4-R-6-R’-1,3,5-
triazine)2](Br1.7(OH)0.3)
$
4.8H2O {R
¼
bis(2-diphenylmethylene) hydra-
zinyl; R’ ¼ piperidin-1-yl}, J. Coord. Chem. 62 (2009) 1902e1913.
[46] S.T. Asundaria, S.A. Patel, K.M. Mehta, K.C. Patel, Synthesis, characterization
and antimicrobial studies of some novel 1,3,4-thiadiazolium-2-thiolate de-
rivatives, S. Afr. J. Chem. 63 (2010) 141e144.
[47] M.M. Naseer, De Wang, L. Zhao, Z.-T. Huang, M.-X. Wang, Synthesis and
functionalization of heteroatom-bridged bicyclocalixaromatics, large molec-
ular triangular prisms with electron-rich and -deficient aromatic interiors,
J. Org. Chem. 76 (2011) 1804e1813. The product 4 was obtained as white
solid from CH2Cl2/hexane in yield 92%; mp 79e81 ꢁC (Lit.[47] yield 89 %; mp
[21] K. Srinivas, U. Srinivas, K. Bhanuprakash, K. Harakishore, U.S.N. Murthy,
V. Jayathirtha, Synthesis and antibacterial activity of various substituted s-
triazines, Eur. J. Med. Chem. 41 (2006) 1240e1246.
[22] N. Sunduru, A. Agarwal, S.B. Katiyar, Synthesis of 2,4,6-trisubstituted pyrim-
idine and triazine heterocycles as antileishmanial agents, Bioorg. Med. Chem.
14 (2006) 7706e7715.
[23] A.M. Geoffrey, R. Reddy, A. Francis, A. Belley, D. Lehoux, G. Moeck, Tri-
aminotriazine DNA helicase inhibitors with antibacterial activity, Bioorg. Med.
Chem. 16 (2006) 1286e1290.
[24] P. Pradip, B.N. Berad, Synthesis and antibacterial activity of 1,3,5-thiadiazines
and their isomerism into 1,3,5-triazines, Indian J. Chem. 44B (2005) 638e639.
76e78 ꢁC); 1H NMR (CDCl3)
d: 4.14 (6H, s, 2OCH3); 13C NMR (CDCl3) d: 56.8,
171.4, 172.5). The product 6 was obtained as white solid in yield 96%; mp
87 ꢁC (Lit. [47] yield 98 %; mp 86e87 ꢁC); 1H NMR (CDCl3)
d: 4.12 (3H, s,
OCH3).
[48] S.N. Mikhaylichenko, S.M. Patel, S. Dalili, A.A. Chesnyuk, V.N. Zaplishny, Syn-
thesis and structure of new 1,3,5-triazine-pyrazole derivatives, Tetrahedron
Lett. 50 (2009) 2505e2508. The product 3a obtained as a white solid in 93%
yield; m.p131-132oC.
[49] N. Sari, D. Nartop, F. Karci, A. Disli, Novel hydrazine derivatives and their
tetracoordinated metal complexes, Asian J. Chem. 20 (2008) 1975e1985.

A. El-Faham et al. / Journal of Molecular Structure 1125 (2016) 121e135
135
[50] Y. Inoue, Y. Kamo, M. Togo, Y.-C. Hsu, T. Keumi, H. Kitajima, Synthesis of
phenylazo-1,3,5-triazines by the oxidative coupling of hydrazine-1,3,5-
triazines with N,N-disubstituted anilines, Chem. Lett. (1981) 1733e1736.
The product 3b obtained as white solid in 95% yield; m.p. 180e181 ꢁC;
(Lit.[46] yield 74 %; m.p. 183e185 ꢁC).
[51] D. Zhang, Y. Ma, R. An, New colorimetric chemosensor based on rhodamine
hydrazide to detect Cu2þ ions by naked eye, Res. Chem. Intermed. 41 (2015)
5059e5069. The product 5 was obtained as white solid in yield 96 %; m.p
177 ꢁC (dec).
H.K. Fun, F. Albericio, One pot synthesis, molecular structure and spectro-
scopic studies (X-ray, IR, NMR, UVeVis) of novel 2-(4,6-dimethoxy-1,3,5-
triazin-2-yl) amino acid ester derivatives, Spectrochim. Acta Part A: Mol.
Biomol. Spectrosc. 159 (2016) 184e198.
[63] V.P. Gupta, A. Sharma, V. Virdi, V.J. Ram, Structural and spectroscopic studies
on some chloropyrimidine derivatives by experimental and quantum chem-
ical methods, Spectrochim. Acta A 64 (2006) 57e67.
[64] G. Huang, X. Zhang, Y. Fan, C. Bi, X. Yan, Z. Zhang, N. Zhang, Synthesis, Crystal
Structure and Theoretical Calculation of
a novel nickel(II) complex with
[52] G.M. Sheldrick,
A
short history of SHELX, Acta Crystallogr.
A
64 (2008)
dibromotyrosine and 1,10-Phenanthroline, Bull. Korean Chem. Soc. 34 (2013)
2889e2894.
112e122.
[53] G.M. Sheldrick, SHELXTL-PC (Version 5.1), Siemens Analytical Instruments,
Inc., Madison, WI, 1997.
[65] J.B. Foresman, A.E. Frisch, Exploring Chemistry with Electronic Structure
Methods, second ed., Gaussian, Pittsburgh, PA, 1996.
[54] M.J. Frisch, G.W. Trucks, H.B. Schlegel, et al., Gaussian-03, Revision C.01,
Gaussian, Inc., Wallingford, CT, 2004 (supporting information).
[55] R. Dennington II, T. Keith, J. Millam, Gauss View, Version 4.1, SemichemInc.,
Shawnee Mission, KS, 2007.
[66] R. Chang, Chemistry, seventh Ed., McGraw-Hill, New York, 2001.
[67] B. Kosar, C. Albayrak, Spectroscopic investigations and quantum chemical
computational study of (E)-4-methoxy-2-[(p-tolylimino)methyl]phenol,
Spectrochim. Acta A 78 (2011) 160e167.
[56] E.D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO Version 3.1, CI,
University of Wisconsin, Madison, 1998.
[68] T.A. Koopmans, Über die Zuordnung von Wellenfunktionen und Eigenwerten
zu den Einzelnen Elektronen Eines Atoms, Physica 1 (1934) 104e113.
[69] R.G. Parr, Y. Weitao, Density-functional Theory of Atoms and Molecules, Ox-
ford University Press, New York, 1989.
[57] A.E. Reed, L.A.F. Curtiss, Intermolecular interactions from a natural bond
orbital, donor-acceptor viewpoint, Chem. Rev. 88 (1988) 899e926.
[58] M.J. Frisch, J.A. Pople, J.S. Binkley, Self-consistent molecular orbital methods
25. Supplementary functions for Gaussian basis sets, J. Chem. Phys. 80 (1984)
3265e3269.
ꢀ
[70] R.G. Parr, L. von Szentpaly, S.B. Liu, Electrophilicity index, J. Am. Chem. Soc.
121 (1999) 1922e1924.
[71] R.N. Singh, A. Kumar, R.K. Tiwari, P. Rawat, V.P. Gupta, A combined experi-
mental and quantum chemical (DFT and AIM) study on molecular structure,
spectroscopic properties, NBO and multiple interaction analysis in a novel
[59] T. Mosmann, MTT colorimetric assay for cell growth and survival, J. Immunol.
Methods 65 (1983) 55e63 (supporting information).
[60] F.H. Allen, O. Kennard, D.G. Watson, L. Brammer, A.G. Orpen, R. Taylor,
Tables of bond lengths determined by x-ray and neutron diffraction, Part. J.
Chem. Soc. Perkins Trans. II (1987) 1e19.
[61] Z. Otwinowski, W. Minor, Processing of X-ray diffraction data collected in
oscillation mode, in: C.W. Carter, R. Sweet (Eds.), Methods in Enzymology,
Macromolecular Crystallography, Part a, Vol. 276, Academic press, New York,
1997, pp. 307e326.
ethyl
4-[2-(carbamoyl)hydrazinylidene]-3,5-dimethyl-1H-pyrrole-2-
carboxylate and its dime, J. Mol. Struct. 1035 (2013) 427e440.
[72] S. Sebastian, N. Sundaraganesan, The spectroscopic (FT-IR, FT-IR gas phase, FT-
Raman and UV) and NBO analysis of 4-Hydroxypiperidine by density func-
tional method, Spectrochim. Acta Part A 75 (2010) 941e952.
[73] I.H. Joe, I. Kostova, C. Ravikumar, M. Amalanathan, S.C. Pinzaru, Theoretical
and vibrational spectral investigation of sodium salt of acenocoumarol,
J. Raman Spectrosc. 40 (2009) 1033e1038.
[62] A. El-Faham, S.M. Soliman, S.M. Osman, H.A. Ghabbour, M.R. Siddiqui,