Ultrasonic Irradiation: Synthesis, Characterization, and Preliminary Antimicrobial Activity of Novel Series of 4,6-Disubstituted-1,3,5-triazine Containing Hydrazone Derivatives

Article abstract of DOI:10.1155/2016/3464758

Novel series of 4,6-disubstituted-1,3,5-triazines containing hydrazone derivatives were synthesized employing ultrasonic irradiation and conventional heating. The ultrasonication gave the target products in higher yields and purity in shorter reaction time compared with the conventional method. IR, NMR (H 1 and C 13), elemental analysis, and LC-MS confirmed the structures of the new products. The antimicrobial and antifungal activities were evaluated for all the prepared compounds against some selected Gram-positive and Gram-negative bacterial strains. The results showed that only two compounds 7i (pyridine derivative) and 7k (4-chlorobenzaldehyde derivative) displayed biological activity against some Gram-positive and Gram-negative bacteria, while the rest of the tested compounds did not display any antifungal activity.

Full text of DOI:10.1155/2016/3464758

Hindawi Publishing Corporation
Journal of Chemistry
Volume 2016, Article ID 3464758, 9 pages
http://dx.doi.org/10.1155/2016/3464758
Research Article
Ultrasonic Irradiation: Synthesis, Characterization, and
Preliminary Antimicrobial Activity of Novel
Series of 4,6-Disubstituted-1,3,5-triazine Containing
Hydrazone Derivatives
Hessa H. Al-Rasheed,1 Monirah Al Alshaikh,1 Jamal M. Khaled,2,3
Naiyf S. Alharbi,2 and Ayman El-Faham1,4
1 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
2Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia
3Department of Biotechnology and Food Technology, amar University, Dhamar, Yemen
4Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 12321, Egypt
Correspondence should be addressed to Jamal M. Khaled; gkhaled@ksu.edu.sa and
Ayman El-Faham; aymanel faham@hotmail.com
Received 1 September 2016; Revised 19 October 2016; Accepted 31 October 2016
Academic Editor: Andrea Penoni
Copyright © 2016 Hessa H. Al-Rasheed 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.
Novel series of 4,6-disubstituted-1,3,5-triazines containing hydrazone derivatives were synthesized employing ultrasonic irradiation
and conventional heating. e ultrasonication gave the target products in higher yields and purity in shorter reaction time compared
13
with the conventional method. IR, NMR (1 and
), elemental analysis, and LC-MS confirmed the structures of the new
C
H
products. e antimicrobial and antifungal activities were evaluated for all the prepared compounds against some selected Gram-
positive and Gram-negative bacterial strains. e results showed that only two compounds 7i (pyridine derivative) and 7k (4-
chlorobenzaldehyde derivative) displayed biological activity against some Gram-positive and Gram-negative bacteria, while the
rest of the tested compounds did not display any antifungal activity.
1. Introduction
Richards and Loomis first reported the chemical effects
of ultrasound in 1927 [11]. e effect of ultrasound during
organic reaction is due to cavitation, which led to sep-
aration of molecules of liquids and then the collapse of
the bubbles offers strong impulsions that generate short-
lived regions with high pressure and temperature. Such
localized hot spots act as microreactors in which the
sound energy converted into beneficial chemical form
[12–14].
Recently Schiff base hydrazone derivatives have attracted
great attention in many applications [15–17]. Compounds
bearing hydrazone moiety exhibit a broad range of biological
activities, including antifungal, antibacterial, antiviral, anti-
malarial, antiproliferative, anti-inflammatory, and antipyretic
properties [18–22].
Ultrasound has been employed more and more frequently
in organic synthesis [1, 2], because it improved the reaction
rate and could adjust the selectivity performance of the
reaction [3]. Comparing with traditional methods, ultrasonic
irradiation is suitable and simply controlled and it considered
as a green powerful synthetic technique in chemical pro-
cesses. Ultrasonic irradiation has proven to be a particularly
important tool for meeting goals of the green chemistry,
which is minimization of waste, and decreasing of the energy
required for the reaction [4]. Applications of ultrasonic
irradiation in organic synthesis are playing important role,
especially in cases where traditional methods require drastic
conditions or elongated reaction time [5–10].

2
Journal of Chemistry
HNu1, ≤0∘C
−HCl
were obtained using a Bruker micrOTOF-Q II instrument
operating at room temperature and a sample concentration
of approximately 1 ppm. Ultrasonic bath was purchased from
Selecta (Barcelona, Spain). All compounds were named by
using ChemBioDraw Ultra version 14.0, Cambridge Sof
Corporation (Cambridge, MA, USA).
Nu1
Cl
HNu2, r.t
−HCl
N
N
N
N
HNu3, ≥60∘C
−HCl
Nu3
Nu2
N
N
1
Cl
Cl
HNu1, HNu2, HNu3 = N, O, P, S, F nucleophiles
(i) General Method for the Synthesis of 2-Hydrazino-4,6-di-
morpholinio or Dimethoxy-1,3,5-triazine (3 and 5). Hydrazine
hydrate (10 mL, 80%) was added dropwise to a solution of
2-chloro-4,6-dimorpholino or dimethoxy-1,3,5-triazine 2 or
4 (20 mmol) in 50 mL ethanol at room temperature and
then the reaction mixture was sonicated for 60 min at 60∘C.
Ethanol and excess hydrazine were removed under vacuum
and then excess diethyl ether was added to afford the product
as a white solid in yield >90%. e spectral data of the
two products 3 and 5 were in good agreement with the
reported data [40, 42] and were used directly without further
purification.
Scheme 1: Nucleophilic substitution reaction of cyanuric chloride.
On the other hand, cyanuric chloride 1 is the most impor-
tant reagent for s-triazine derivatives, because of the selective
reactivity of its chlorine atoms toward nucleophiles. Cyanuric
chloride 1 is commercially available and a very cheap reagent,
which makes its applications even more attractive [23–29].
e easy displacement of chlorine atoms in cyanuric chloride
by various nucleophiles was controlled by temperature to run
in a stepwise manner as shown in Scheme 1.
Several derivatives of s-triazine have exhibited antimicro-
bial [30], antibacterial, [31] antifungal [32], anti-HIV [33],
and anticancer [34, 35] properties and a wide array of other
biological activities [36, 37]. Recently some of 1,3,5-triazine–
Schiff bases have reported a significant activity against
Mycobacterium tuberculosis H37Rv [38] and moderate to
excellent antiproliferative activity and high selectivity against
the human lung cancer cell line H460 [39].
(ii) General Method for the Synthesis of 1,3,5-Triazine-hydra-
zone Derivatives.
Method A: Conventional Method. 2-Hydrazino-4,6-disubsti-
tuted-1,3,5-triazine 3 or 5 (10 mmol) was added to a solu-
tion of aldehyde or ketone 6 (10 mmol) in ethanol (30 mL)
containing 2-3 drops of acetic acid and then the reaction
mixture was stirred under reflux for 3 hours. Afer completion
of the reaction, the solvent was reduced under vacuum
and the precipitated product was filtered off, dried at room
temperature, and then recrystallized from ethyl acetate to
afford the target product (Table 1).
As part of our continuous research on s-triazine deriva-
tives and their biological activities [40, 41], we report here the
synthesis and the preliminary antimicrobial activity of novel
series of 4,6-disubstituted-s-triazine containing hydrazone
derivatives.
Method B: Ultrasound Assisted Method. A mixture of aldehyde
or ketone 6 (10 mmol) in ethanol (30 mL), 2-hydrazino-4,6-
disubstituted-1,3,5-triazine 3 or 5 (10 mmol), and 2-3 drops
of acetic acid in a flask was heated into a sonicator at 40∘C
for 30–60 min. Afer completion of reaction (TLC, methanol-
chloroform 1 : 9) UV lamp was used for spot visualization at
2. Experimental Section
2.1. Chemistry
2.1.1. Materials. All solvents were of analytical reagent grade
1
and used without further purification. e
NMR and
H
ꢂ
254; the solvent was removed under vacuum and the
13
max
NMR spectra were recorded on a JEOL 400 MHz and
C
precipitated product was recrystallized from ethyl acetate to
AVANCE III 400 MHz (Bruker, Germany) spectrometer at
room temperature (see Figures S1–S10, S12, and S14–S17 in
Supplementary Material available online at http://dx.doi.org/
10.1155/2016/3464758) in CDCl and/or DMSO-d using
afford the target product (Table 1).
2.1.2. (E)-2-(2-Benzylidenehydrazinyl)-4,6-dimethoxy-1,3,5-
triazine (7a, Supporting Information Figure S1 in Supple-
mentary Material). e product was obtained as a yellow
3
6
internal standard ꢀ = 0 ppm. Elemental analysis was per-
formed on Perkin-Elmer 2400 elemental analyzer. Melting
points were determined on a Mel-Temp apparatus and are
uncorrected. Fourier transform infrared spectroscopy (FTIR)
spectra were recorded on Nicolet 6700 spectrometer from
KBr discs. e reaction was follow-up and checks of the
purity using TLC on silica gel-protected aluminum sheets
(Type 60 GF254, Merck) using a mixture of methanol-
chloroform (1 : 9) as an eluent. LC-MS (see Figures S11,
S13, and S18 in Supplementary Material) was performed on
solid in yield 74% (A), 93% (B); mp. 235–237∘C; IR (KBr,
cm−1): 3219 (NH), 1561 (C=N), 1467, 1386 (C=C);
NMR
1
H
(DMSO-d ): ꢀ = 3.89 (s, 6H, 2 OCH ), 7.41–7.43 (m, 3H,
6
3
Ar), 7.66 (d, 2H, J = 6.4 Hz, Ar), 8.17 (s, 1H, CH), 11.68 (s,
1H, NH); 13 NMR (DMSO-d ): ꢀ = 54.5, 126.8, 128.8, 129.8,
C
6
134.4, 144.9, 166.3 ppm; Anal. Calc. for C H N O (259.27):
12 13
5
2
C, 55.59; H, 5.05; N, 27.01. Found: C, 55.89; H, 5.16; N, 27.23.
2.1.3. (E)-2-(2-(4-Chlorobenzylidene)hydrazinyl)-4,6-dime-
thoxy-1,3,5-triazine (7b, Supporting Information Figure S2
in Supplementary Material). e product was obtained as
Shimadzu 2020 UFLC-MS using an YMC Triart C (5 ꢁm,
18
4.6×150 mm) column, and data processing was carried out by
the LabSolution sofware. Buffer A: 0.1% formic acid in H O
2
a white solid in yield 71% (A), 92% (B); mp. 215–217∘C; IR
and buffer B: 0.1% formic acid in CH CN in 30 min at ꢂ
254 nm were used. High-resolution mass spectrometric dmataax
(KBr, cm−1): 3228 (NH), 1614 (C=N), 1577, 1473 (C=C);
H
3
1

Journal of Chemistry
3
Table 1: Yield, reaction time, and melting point of 7a–o deriva-
2.1.6. (E)-2-(2-(4-Bromobenzylidene)hydrazinyl)-4,6-dime-
thoxy-1,3,5-triazine (7e, Supporting Information Figure S5
in Supplementary Material). e product was obtained as
tivesusing conventional method and ultrasonic irradiation.
Method A
Conventional
method
Method B
Ultrasonic
irradiation
a white solid in yield 75% (A), 95% (B); mp. 220–222∘C; IR
1
(KBr, cm−1): 3217 (NH), 1578 (C=N), 1460, 1368 (C=C);
H
Compd.
number
Mp (∘C)
NMR (DMSO-d ): ꢀ = 3.89 (s, 6H, 2 OCH ), 7.64 (s, 4H, Ar),
6
3
Time
(min)
13
Yield (%) Time (h) Yield (%)
8.15 (s, 1H, CH), 11.74 (s, 1H, NH);
NMR (DMSO-d ):
C
6
ꢀ = 54.5, 122.9, 128.7, 131.87, 133.7, 143.8, 166.3 ppm; Anal.
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
74
71
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
4-5
93
92
93
93
95
93
93
92
92
95
94
94
96
92
90
30
30
30
30
30
60
60
60
30
30
30
60
60
60
60
235–237
215–217
204–206
188–190
220–222
225–227
227–229
230–232
212–214
225–227
233–235
236–238
213–215
228–230
232–234
Calc. for C H BrN O (338.17): C, 42.62; H, 3.58; N, 20.71.
12 12
5
2
Found: C, 42.88; H, 3.64; N, 20.98.
70
68
75
75
75
71
2.1.7. (E)-4-((2-(4,6-Dimethoxy-1,3,5-triazin-2-yl)hydrazon-
o)methyl) phenol (7f, Supporting Information Figure S6 in
Supplementary Material). e product was obtained as a
white solid in yield 75% (A), 93% (B); mp. 225–227∘C; IR
(KBr, cm−1): 3229 (OH), 3135 (NH), 1609 (C=N), 1567, 1493
(C=C); 1 NMR (DMSO-d ): ꢀ = 3.88 (s, 3H, OCH ), 3.90
H
6
3
71
(s, 3H, OCH ), 6.81 (d, 2H, J = 8.0 Hz, Ar), 7.52 (d, 2H, J =
3
75
70
72
74
70
71
8.0 Hz, Ar), 8.07 (s, 1H, CH), 9.93 (s, 1H, OH), 11.47 (s, 1H,
13
NH);
NMR (DMSO-d ): ꢀ = 54.5, 115.8, 125.5, 128.8,
C
6
145.5, 159.2, 166.1, 171.8 ppm; Anal. Calc. for C H N O
12 13
5
3
(275.27): C, 52.36; H, 4.76; N, 25.44. Found: C, 52.21; H, 4.89;
N, 25.63.
2.1.8. (E)-4-((2-(4,6-Dimethoxy-1,3,5-triazin-2-yl)hydrazon-
o)methyl)-N,N-dimethylaniline (7g, Supporting Information
Figure S7 in Supplementary Material). e product was
obtained as a yellow solid in yield 75% (A), 93% (B); mp.
227–229∘C; IR (KBr, cm−1): 3211 (NH), 1567 (C=N), 1459,
NMR (DMSO-d ): ꢀ = 3.89 (s, 6H, 2 OCH ), 7.47 (d, 2H, ꢃ =
6
3
8.8 Hz, Ar), 7.69 (d, 2H, J = 8.8 Hz, Ar), 8.15 (s, 1H, CH), 11.73
1362 (C=C); 1 NMR (DMSO-d ): ꢀ = 2.95 (s, 6H, N(CH ) ),
13
H
6
3 2
(s, 1H, NH);
NMR (DMSO-d ): ꢀ = 54.5, 128.4, 128.9,
C
6
3.86 (s, 3H, OCH ), 3.89 (s, 3H, OCH ), 6.71 (d, 2H, J =
3
3
133.4, 134.1, 143.6, 166.3 ppm; Anal. Calc. for C H ClN O
12 12
5
2
7. 2 Hz, Ar), 7. 52 (d, 2H, J = 8.8 Hz, Ar), 8.03 (s, 1H, CH),
(293.07): C, 49.07; H, 4.12; N, 23.84. Found: C, 48.92; H, 4.22;
13
11.38 (s, 1H, NH);
NMR (DMSO-d ): ꢀ = 40.4, 55.0,
C
6
N, 24.03.
112.5, 122.4, 128.8, 146.6, 151.9, 166.5 ppm; Anal. Calc. for
C H N O (302.34): C, 55.62; H, 6.00; N, 27.80. Found: C,
14 18
6
2
2.1.4. (E)-2,4-Dimethoxy-6-(2-(4-methylbenzylidene)hydrazi-
nyl)-1,3,5-triazine (7c, Supporting Information Figure S3 in
Supplementary Material). e product was obtained as a light
55.88; H, 6.20; N, 28.04.
yellow solid in yield 70% (A), 93% (B); mp. 204–206∘C; IR
2.1.9. (E)-4-(1-(2-(4,6-Dimethoxy-1,3,5-triazin-2-yl)hydrazon-
o)ethyl)phenol (7h, Supporting Information Figure S8 in Sup-
plementary Material). e product was obtained as a yellow
solid in yield 71% (A), 92% (B); mp. 230–232∘C; IR (KBr,
1
(KBr, cm−1): 3219 (NH), 1564 (C=N), 1465, 1367 (C=C);
H
NMR (DMSO-d ): ꢀ = 2.33 (s, 3H, CH ), 3.90 (s, 6H, 2
6
3
OCH ), 7.24 (d, 2H, J = 8.0 Hz, Ar), 7.58 (d, 2H, J = 8.08 Hz,
3
cm−1): 3466 (OH), 3364 (NH), 1576 (C=N), 1475, 1374 (C=C);
Ar), 8.15 (s, 1H, CH), 11.62 (s, 1H, NH); 13 NMR (DMSO-d ):
C
6
1
NMR (DMSO-d ): ꢀ = 2.26 (s, 3H, CH ), 3.91 (s, 6H,
H
ꢀ = 21.0, 54.5, 126.8, 129.4, 131.7, 139.6, 145.1, 166.2 ppm; Anal.
6
3
2OCH ), 6.78 (d, 2H, J = 8.8 Hz, Ar), 7.68 (d, 2H, J = 8.4 Hz,
Calc. for: C H N O (273.12): C, 57.13; H, 5.53; N, 25.63.
3
13 15
5
2
Ar), 9.78 (s, 1H, OH), 10.47 (s, 1H, NH); 13 NMR (DMSO-
C
Found: C, 57.33; H, 5.41; N, 25.80.
d ): ꢀ = 13.9, 54.4, 115.2, 127.9, 129.2, 151.3, 158.6, 166.9 ppm;
6
Anal. Calc. for C H N O (289.30): C, 53.97; H, 5.23; N,
13 15
5
3
2.1.5.
(E)-2,4-Dimethoxy-6-(2-(4-methoxybenzylidene)hy-
24.2. Found: C, 53.77; H, 5.33; N, 24.43.
drazinyl)-1,3,5-triazine (7d, Supporting Information Figure S4
in Supplementary Material). e product was obtained as a
light yellow solid in yield 68% (A), 93% (B); mp. 188–190∘C;
2.1.10. (E)-2,4-Dimethoxy-6-(2-(pyridin-2-ylmethylene)hy-
drazinyl)-1,3,5-triazine (7i, Supporting Information Figure S9
in Supplementary Material). e product was obtained as a
pale yellow solid in yield 69% (A), 91% (B); mp. 212–214∘C;
IR (KBr, cm−1): 3244 (NH), 1570 (C=N), 1479, 1364 (C=C);
1
NMR (DMSO-d ): ꢀ = 3.80 (s, 3H, OCH ), 3.91 (s,
H
6
3
6H, 2OCH ), 7.04 (d, 2H, J = 8.0 Hz, Ar), 7.62 (d, 2H, J =
3
13
8.08 Hz, Ar), 8.12 (s, 1H, CH), 11.56 (s, 1H, NH);
NMR
IR (KBr, cm−1): 3236 (NH), 1572 (C=N), 1467, 1366 (C=C);
C
1
(DMSO-d ): ꢀ = 54.5, 55.3, 114.3, 127.0, 128.5, 130.0, 144.9,
NMR (DMSO-d ): ꢀ = 3.92 (s, 6H, 2OCH ), 7.39(t, 1H, J
H
6
6
3
160.6, 166.1 ppm; Anal. Calc for C H N O (289.30): C,
= 5.6, Ar), 7.88 (t, 1H, J = 7.2 Hz, Ar), 7.96 (d, 1H, J = 8.0 Hz,
Ar), 8.22 (s, 1H, CH), 8.59 (d, 1H, J = 5.2 Hz, Ar), 11.38 (s, 1H,
13 15
5
3
53.97; H, 5.23; N, 24.21. Found: C, 53.73; H, 5.07; N, 24.00.

4
Journal of Chemistry
NH); 13 NMR (DMSO-d ): ꢀ = 54.1, 119.7, 123.9, 136.9, 144.4,
2.1.15. (E)-4-((2-(4,6-Dimorpholino-1,3,5-triazin-2-yl)hydra-
zono)methyl)-N,N-dimethylaniline (7n, Supporting Informa-
tion Figure S16 in Supplementary Material). e product was
obtained as a yellow solid in yield 70% (A), 92% (B); mp
228–230∘C; IR (KBr, cm−1): 3277 (NH), 1529 (C=N), 1490,
C
6
149.2, 153.3, 166.5, 171.6 ppm; Anal. Calc. for C H N O
1
12
6
2
(260.26): C, 50.77; H, 4.65; N, 32.29. Found: C, 50.96; H, 4.73;
N, 32.40.
1441 (C=C); 1 NMR (DMSO-d ): ꢀ = 3.62–3.69 (m, 16H, 4
2.1.11. (E)-4,4ꢀ-(6-(2-Benzylidenehydrazinyl)-1,3,5-triazine-
2,4-diyl)dimorpholine (7j, Supporting Information Figure S10
in Supplementary Material). e product was obtained as
a white solid in yield 75% (A), 95% (B); mp. 215–217∘C; IR
H
6
N-CH -CH -O), 6.72 (d, 2H, J = 8.04 Hz, Ar), 7.44 (d, 2H, J
2
2
= 8.8 Hz, Ar), 7.95 (s, 1H, CH), 10.52 (s, 1H, NH); 13 NMR
C
(DMSO-d ): ꢀ 43.8, 66.6, 112.4, 123.2, 128.2, 143.3, 151.4, 164.5,
6
165.3 ppm; Anal. Calc. for C H N O (412.50): C, 58.24; H,
(KBr, cm−1): 3267 (NH), 1546 (C=N), 1479, 1450 (C=C); 1
H
20 28
8
2
6.84; N, 27.17. Found: C, 58.51; H, 6.99; N, 27.36.
NMR (CDCl ): ꢀ = 3.70–3.74 (m, 8H, 4 OCH -), 3.75–3.84
3
2
(m, 8H, 4 NCH -), 7.35–7.41 (m, 3H, Ar), 7.70–7.73 (m, 2H,
2
Ar), 7.82 (s, 1H, CH), 8.31 (s, 1H, NH); 13 NMR (CDCl ): ꢀ =
2.1.16. (E)-4-(1-(2-(4,6-Dimorpholino-1,3,5-triazin-2-yl)hy-
drazono)ethyl)phenol (7o, Supporting Information Figure S17
in Supplementary Material). e product was obtained as
a white solid in yield 71% (A), 90% (B); mp.232–234∘C; IR
(KBr, cm−1): 3452 (OH), 3350 (NH), 1563 (C=N), 1524, 1487
C
3
43.6, 43.7, 66.8, 66.9, 127.1, 128.6, 129.6, 134.2, 142.5, 165.4 ppm;
Anal. Calc. for C H N O (369.43): C, 58.52; H, 6.28; N,
18 23
7
2
26.54. Found: C, 58.74; H, 6.43; N, 26.79. (m/z) Calcd:
369.43; LC-MS (M+H) Found: 370 at ꢄꢁ 14.11 min (supporting
information Figure S11 in Supplementary Material).
(C=C); 1 NMR (CDCl ): ꢀ = 2.24 (s, 3H, CH ), 3.70–3.83
H
3
3
(m, 16H, 4 N-CH -CH -O), 6.80 (d, 2H, J = 8.8 Hz, Ar), 7.69
2
2
2.1.12. (E)-4,4ꢀ-(6-(2-(4-Chlorobenzylidene)hydrazinyl)-1,3,5-
triazine-2,4-diyl)dimorpholine (7k, Supporting Information
Figure S12 in Supplementary Material). e product was
obtained as a white solid in yield 70% (A), 94% (B); mp.
233–235∘C; IR (KBr, cm−1): 3270 (NH), 1516 (C=N), 1480,
(d, 2H, J = 8.46 Hz, Ar), 7.91 (s, 1H, CH), 8.01 (brs, 1H, NH);
13
NMR (CDCl ): ꢀ = 12.7, 43.7, 66.9, 115.3, 127.8, 128.2,
C
3
130.9, 146.9, 156.8, 164.7, 165.2, 165.4 ppm; Anal. Calc. for
C H N O (399.46): C, 57.13; H, 6.31; N, 24.55. Found: C,
19 25
7
3
57.35; H, 6.44; N, 24.80. (m/z) Calcd: 399.46; LC-MS (M+H)
Found: 400 at ꢄꢁ 13.4 min (supporting information Figure S18
in Supplementary Material)
1
1442 (C=C);
NMR (CDCl ): ꢀ = 3.71–3.74 (m, 8H, 4
H
3
OCH -), 3.75–3.84 (m, 8H, 4 NCH -), 7.36 (d, 2H, J =
2
2
4.0 Hz, Ar), 7.72 (d, 2H, J = 4.0 Hz, Ar), 7.82 (s, 1H, CH),
13
8.31 (brs, 1H, NH);
NMR (CDCl ): ꢀ = 43.6, 43.7, 66.8,
C
3
2.2. Biology
66.9, 128.2, 128.9, 132.8, 135.4, 141.1, 165.4 ppm; Anal. Calc. for
C H ClN O (403.87): C, 53.53; H, 5.49; N, 24.28. Found: C,
2.2.1. Antimicrobial Activity. e antimicrobial activities of
all compounds 7a–o were evaluated against some selected
pathogenic Gram-positive, Gram-negative, and filamentous
fungus strains by using the disc diffusion method [43].
Staphylococcus aureus (ATCC 29213); Neisseria meningi-
tides (ATCC 1302); Streptococcus mutans (ATCC 35668);
Escherichia coli (ATCC 25922); Pseudomonas aeruginosa
(ATCC 27584); Salmonella typhimurium (ATCC 14028);
Brevibacillus laterosporus Wild strain; Candida parapsilo-
sis (ATCC 22019); Cryptococcus neoformans Wild strain;
Candida albicans (ATCC 60193), Penicillium chrysogenum
(AUMC 9476), Aspergillus niger (AUMC 8777), and Fusarium
sp were used in the evaluation test.
Mueller-Hinton agar (Scharlau Microbiology, Spain) was
used and prepared according to manufacturer’s guidelines,
where 1 L of medium was prepared containing 17.5, 1.5, and
17 gm of peptone, meat infusion solid, starch, and agar,
respectively. For preparation of 1 L of medium, 21 gm of
powder was dissolved in 1 L of distilled water and sterilized
at 121∘C for 15 min by an autoclave (HL-321, Taiwan). Afer
sterilization and cooling to 50∘C, the medium dispensed in
Petri dishes and lef to cool down to 25∘C. en, they were
inoculated with the bacterial strains by streaking. In the anti-
fungal test, a potato dextrose agar (PDA) (Scharlau, Spain)
was used and prepared according to the manufacturer’s
directions, where 39 gm PDA dissolved in 1 L of distilled
water and then followed the previously described method.
e microbial inoculation suspensions were prepared
in sterile sodium chloride solution (0.89%) from activated
18 22
7
2
53.78; H, 5.60; N, 24.51. (m/z) Calcd: 403.87; LC-MS (M+H)
Found: 404 at ꢄꢁ 15.8 min (supporting information Figure S13
in Supplementary Material)
2.1.13. (E)-4,4ꢀ-(6-(2-(4-Bromobenzylidene)hydrazinyl)-1,3,5-
triazine-2,4-diyl) dimorpholine (7l, Supporting Information
Figure S14 in Supplementary Material). e product was
obtained as a white solid in yield 72% (A), 94% (B); mp 236–
238∘C; IR (KBr, cm−1): 3273 (NH), 1515 (C=N), 1479, 1441
1
(C=C);
NMR (DMSO-d ): ꢀ = 3.62 (m, 8H, 4 OCH -),
H
6
2
3.70 (m, 8H, 4 NCH ), 7.59 (s, 4H, Ar), 8.03 (s, 1H, CH),
2
13
10.90 (s, 1H, NH);
NMR (CDCl ): ꢀ = 43.8, 66.6, 122.6,
C
3
128.8, 132.3, 134.9, 141.0, 164.7, 165.3 ppm; Anal. Calc. for
C H BrN O (448.33): C, 48.22; H, 4.95; N, 21.87. Found:
18 22
7
2
C, 48.44; H, 5.08; N, 22.03.
2.1.14. (E)-4-((2-(4,6-Dimorpholino-1,3,5-triazin-2-yl)hydra-
zono)methyl)phenol (7m, Supporting Information Figure S15
in Supplementary Material). e product was obtained as a
white solid in yield 74% (A), 96% (B); mp 213–215∘C; IR (KBr,
cm−1): 3448 (OH), 3250 (NH), 1543 (C=N), 1493, 1443 (C=C);
1
NMR (CDCl ): ꢀ = 3.62–3.74 (m, 16H, 4 N-CH -CH -O),
H
3
3
2
2
6.74 (d, 2H, J = 8.56 Hz, Ar), 7.51 (d, 2H, J = 8.60 Hz, Ar), 7.68
(s, 1H, CH), 8.02 (brs, 1H, NH); 13 NMR (CDCl ): ꢀ = 43.6,
C
3
43.7, 66.8, 66.9, 115.6, 126.8, 128.9, 157.4, 165.4 ppm; Anal. Calc.
for C H N O (385.43): C, 56.09; H, 6.02; N, 25.44. Found:
18 23
7
C, 56.23; H, 6.21; N, 25.69.

Journal of Chemistry
5
NH2
HN
Cl
NH2NH2
N
N
Ethanol/US
N
N
60 min/60∘C
N
N
N
N
N
N
O
O
O
O
3
2
Cl
N
N
NH2
N
Cl
Cl
Cl
N
HN
1
NH2NH2
N
N
N
N
Ethanol/US
60 min/60∘C
MeO
OMe
N
MeO
OMe
4
5
Scheme 2: Synthesis of 2-hydrazino-4,6-disubstituted-1,3,5-triazine derivatives and US: ultrasonic irradiation.
microbial cultures. e optical densities of microbial suspen-
sions were adjusted to 0.64 at 600 nm. A sterile swab was
moistened with the microbial suspensions and inoculating
the dried surface of the medium in a Petri dish. Afer
inoculation, all Petri dishes were kept at 25∘C for 5–10
minutes before dispensing the standard antibiotic agents
and the prepared compounds discs on the surface of the
media.
dimorpholino derivative 2, the reaction temperature raised
gradually to room temperature and kept under stirring for
12 h at the same temperature, while the reported method [40,
42] was used for the preparation of the dimethoxy derivative
4 (Scheme 2). e products 2 and 4 were obtained in good
yields and their spectral data agreed with the reported data
[40, 42].
e hydrazine derivatives 3 and 5 were obtained by treat-
In the present work, tobramycin (10 ꢁg/desk), chlo-
ment of 2 or 4 with hydrazine hydrate (80%) in ethanol for
ramphenicol (30 ꢁg/disk), fusidic acid (10 ꢁg/disk), aug-
60 min at 60∘C employing ultrasonic irradiation (Scheme 2)
mentin (10 ꢁg/disk), cycloheximide (30 ꢁg/disk), canesten
(10 ꢁg/disk), and caspofungin (10 ꢁg/disk) were used as stan-
dard antibacterial and antifungal agents. To prepare disks
(4 mg/disk) from the tested compounds, 200 mg from each
compound was dissolved in dimethylsulfoxide (DMSO) and
then 20 ꢁL of the solution was added on the sterile filter disk
(6 mm) and then allowed to dry at room temperature inside
the safety biological cabinet. Afer 18–24 h of incubation at
37∘C for bacteria and 48–72 h at 25∘C for fungi, the minimum
inhibitory concentration (MIC mg/mL) of the prepared
compounds was measured [44]. e microdilution assay
was applied in 96-well plate (Corning Incorporated, USA)
using twofold serial dilution. e original concentration was
4 mg/mL and the total volume was 200 ꢁL (1 : 1, chemical
suspension: bacterial suspension); 4-iodonitrotetrazolium
violet (Sigma, USA) reagent was added afer the incubation to
measure the bacterial growth through the emergence of violet
color.
to afford the products in excellent yields (>90%) and purity.
e products 7a–o were obtained by condensation of the
hydrazine derivative 3 or 5 with substituted benzaldehyde or
acetophenone 6 in ethanol containing 2-3 drops of glacial
acetic acid using ultrasonic irradiation for 30–60 min at 40∘C
(Scheme 3) to afford the target products in excellent yields
and purity as observed from LC-MS (see Supplementary
Figures S11, S13, and S18). Ultrasonic irradiation gave the
target products in high yields in shorter reaction time
compared with the conventional heating as shown in Table 1.
1
e
NMR spectrum of 7k as a prototype for the
H
benzaldehyde derivatives showed a multiplet peak in the
range at ꢀ 3.71–3.74 ppm related to 4 methylene groups (4
OCH -), another multiplet peak in the range at ꢀ 3.75–
2
3.84 ppm related to 4 methylene groups (4 NCH -), doublet
2
at ꢀ 7.36 ppm for the two aromatic protons H-3 and H-5,
doublet at ꢀ 7.72 for the twoaromatic protons H-2 and H-6,
singlet at ꢀ 7.82 related to the CH (CH=N- group), and a broad
13
singlet at ꢀ 8.31 for the NH. e
NMR spectrum of 7k
C
showed absorption peak for the morpholine residue at ꢀ 43.6,
3. Results and Discussion
43.7, 66.8, and 66.9 related to 2 CH -N-CH , and 2 CH -O-
2
2
2
CH respectively, absorption peaks at ꢀ 128.2, 128.9, 132.8, and
3.1. Chemistry. Compounds2 and 4 were obtained using one-
step reaction, where cyanuric chloride 1 was reacted with
morpholine (2 equiv.) in acetone-water media or methanol
2
135.4 ppm related to the aromatic carbons, and absorption
peaks at ꢀ 142.5 and 165.4 ppm for C=N.
e LC-MS of compound 7k using buffer A, 0.1% formic
(as a solvent) in the presence of NaHCO as hydrogen
3
chloride removal at 0∘C for 2 h. In the case of the synthesis of
acid in H O, and buffer B, 0.1% formic acid in CH CN, in
2
3

6
Journal of Chemistry
N
N
N
HN
N
N
CHO
MeO
N
OMe
7i
Y
Z
O
Z
NH2
HN
N
N
Ethanol (2-3) dr
ops AcOH
HN
N
N
US/30–60 min/40∘C
+
X
N
X
N
Y
6
X
X
N
X = morpholine; 3
X = OMe; 5
7a–h, J–o
Z = H, Y = H, Cl, Br, CH3, OH, OCH3, NMe2
Z = CH3, Y = OH
Scheme 3: Synthesis of 4,6-disubstituted-s-triazine-Schiff base derivatives and US: ultrasonic irradiation.
O
O
N
N
Cl
N
N
N
N
N
N
N
H
N
N
N
H
N
N
O
O
Z
E
Cl
Scheme 4: E- and Z-isomer of compound 7k.
30 min showed one peak at ꢄꢁ 15.8 min with the expected
mass [M+H] 404 (m/z cacld. 403.87, Figure S13 in the Sup-
plementary Material).
s-triazine hydrazone preferred the E-isomer rather than the
Z- ones [41].
As a prototype for acetophenone derivatives, the 1 NMR
H
Compound 7k as an example could adopt two different
geometrical isomers (E, Z; Scheme 4). erefore, 7k was
demonstrated using molecular mechanics MM2 calculations.
In addition, quantum chemical calculations were carried
spectrum of 7o showed a singlet peak at ꢀ 2.24 ppm for
the methyl group of the acetophenone moiety, two multiplet
peaks in the range ꢀ 3.70–3.83 ppm related to the 8 methylene
groups of the two morpholino rings (4 -N-CH -CH -O),
2
2
out with the GAUSSIAN 98 suite of programs. Geom-
and a broad singlet at ꢀ 8.01 ppm related to the NH, beside
etry optimization was carried out using the DFT level
(B3LYP/6-31G∗∗) of theory to assess the relative stability
of the E-Z isomeric species. Computed relative energies
two doublets forming an AB system at ꢀ 6.80 (J = 8.8 Hz)
and 7.698 ppm (J = 8.46) for the aromatic protons H-3, H-5,
and H-2, H-6 respectively. e 13 NMR spectrum showed
C
of 7k indicated that the E-isomer (total energy content
absorption peak at ꢀ 12.7 related to methyl group and two
47.7837 kcal/mol) is more stable than the Z ones (total
energy content 41.7295 kcal/mol) by 6.0542 kcal/mol. is
observation agreed with our reported data in which the
peaks at ꢀ 43.7 and 66.9 ppm related to the methylene groups
(-NCH and O-CH , resp.); the absorption peaks at ꢀ 156.8,
2
2
164.7, 165.2, and 165.4 ppm were assigned for carbons of

Journal of Chemistry
7
Table 2: Antimicrobial activity (zones of inhibition, mm) and a minimum inhibitory concentration (MIC, mg/ml) of 7i and 7k comparing
with several standard antimicrobial drugs.
Compounds
Antifungal agent
Antibacterial agents
Microorganisms
mM
mg/mL
∗
Cy.
Co.
N.T
N.T
N.T
N.T
N.T
N.T
N.T
—
25
46
30
23
Ca.
N.T
N.T
N.T
N.T
N.T
N.T
N.T
—
—
20
—
20
To.
14
—
20
15
14
21
—
Ch.
30
35
40
13
Fu.
23
20
—
—
—
20
20
N.T
N.T
N.T
N.T
N.T
N.T
7i
15
10
—
—
—
15
20
—
—
—
—
—
—
7k
—
—
<8
—
<8
17
7i
7k
—
—
—
—
—
0.10
—
—
—
—
—
—
—
∗∗
Sa.
N.T
N.T
N.T
N.T
N.T
N.T
N.T
—
0.10
0.20
—
—
—
0.10
0.05
—
—
—
Sm.
Ec.
Pa
Bacteria
Fungi
St.
30
34
35
N.T
N.T
N.T
N.T
N.T
N.T
Nm
BL
—
—
—
—
—
—
—
Cp.
Cn.
Ca.
Pc.
An.
Fs.
N.T∗∗∗
32
N.T
N.T
N.T
N.T
—
23
22
30
—
—
—
15
—
N.T
∗
∗∗
Cy: cycloheximide, Co: canesten, Ca: caspofungin, To: tobramycin, Ch: chloramphenicol, and Fu: fusidic acid. ꢂꢃ : Staphylococcus aureus ATCC 29213, Nm:
Neisseria meningitides ATCC 1302, Sm: Streptococcus mutans ATCC 35668, EC: Escherichia coli ATCC 25922, Pa: Pseudomonas aeruginosa ATCC 27584, St:
Salmonella typhimurium ATCC 14028, Cp: Candida parapsilosis ATCC 22019, Cn: Cryptococcus neoformans Wild strain, C: Candid albicans ATCC 60193, BL:
∗∗∗
Brevibacillus laterosporus Wild strain, Pc: Penicillium chrysogenum AUMC 9476, An: Aspergillus niger AUMC 8777, and Fs: Fusarium sp. N.T : not tested.
C=N and the remaining five peaks at ꢀ 115.3, 127.8, 128.2,
130.9, and 146.9 ppm related to the aromatic carbons of the
acetophenone moiety.
E. coli and S. typhimurium. e other derivatives in the same
family did not show any biological activity; this observation
agreed with the reported data for substituted s-triazine [45].
e presence of pyridine ring (compound 7o) in place of
the benzaldehyde ring (compound 7a) changed the biological
activity significantly as observed from Table 2; on the other
hand, all the tested compounds did not show any antifungal
activity; this observation also agreed with the reported data
for s-triazine derivatives [45].
e LC-MS of compound 7o using buffer A, 0.1% formic
acid in H O, and buffer B, 0.1% formic acid in CH CN, in
2
3
30 min showed one peak at ꢄꢁ 13.4 min with the expected
mass [M+H] 400 (m/z calcd 399.46, Figure S18 in the
Supplementary Material)
3.2. Biology. e antimicrobial activities of the prepared
compounds against several pathogenic tested organisms
are represented in Table 2. e results revealed that only
two compounds 7i and 7k from all the tested compounds
were biologically active with different spectrum activity; on
the other hand, they did not show any antifungal activity
(Table 2). e results in Table 2 showed that 7i had good
biological activity against S. aureus, N. meningitides, and
tobramycin resistant B. laterosporus, while it had poor bio-
logical activity against S. mutans (10 mm). Compound 7k
showed a good biological activity against N. meningitides
(17 mm) and a very weak activity (<8) against E. coli and S.
typhimurium. e measured minimum inhibitory concen-
trations (MIC) of 7i that inhibited S. aureus, S mutans, N.
meningitides, and B. laterosporus were 0.10, 0.20, 0.10 and
0.05 mg/mL, respectively, while the MIC of 7k that inhibited
N. meningitides was 0.10 mg/mL.
4. Conclusion
e target products (7a–o) were prepared using conventional
heating and ultrasonic irradiation. e ultrasonic irradia-
tion affords the products in higher yields and purity in
shorter reaction time. e biological activity for the prepared
compounds showed that only two compounds 7i (pyridine
derivative) and 7k (4-chlorobenzaldehyde derivative) have
biological activities against some Gram-positive and Gram-
negative bacteria, while all tested compounds did not show
any antifungal activity. It is obvious that changing the
substituent in the s-triazine ring as well as the benzylidene
moiety may affect the antimicrobial activity. Further inves-
tigations are run in our lab to get insights into the mode of
action and the relation between the biological activity and
substituent effect in the pattern in s-triazine.
It is obvious from Table 2 that a small structural variation
in s-triazine ring may induce an effect on antibacterial
activity. By observing the antibacterial activities of all the
derivatives, it is interesting to note that the dimorpholino-4-
chlorophenyl-s-triazine derivatives 7k show good antibacte-
rial activity against N. meningitides and weak activity against
Competing Interests
e authors declare no conflict of interests.

8
Journal of Chemistry
Acknowledgments
2-carbohydrazide and its metal complexes,” Heterocyclic Letters,
vol. 5, no. 2, pp. 251–259, 2015.
e 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).
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