Synthesis and biological activity evaluation of some new mixed azines appended tetrahydro-1,2,4-triazines

Article abstract of DOI:10.1080/00397911.2021.1882497

A series of 6-acetyl-2,4-diaryl-2,3,4,5-tetrahydro-1,2,4-triazines (2a–2f) was synthesized by double Mannich reaction of the hydrazone 1a or 1b with formaldehyde and the appropriate amine. A similar reaction of 1a with the appropriate diamine afforded the bis(tetrahydro-triazines) 3a–b, and 4a–b. Whereas, the 6-cinnamoyl derivatives 5a-c were obtained by the reaction of 2a with the appropriate aldehyde. The hydrazone 7, derived from 2a, was treated with the appropriate aldehyde or ketone to afford the mixed azines 8–12 and 13–16. The biological activity, antibacterial, antifungal and antioxidants of the most newly synthesized compounds of these derivatives were screened. Compounds 2b, 3a and 7 revealed the best results against all screened biological activity.

Full text of DOI:10.1080/00397911.2021.1882497

Synthetic Communications
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Synthesis and biological activity evaluation
of some new mixed azines appended
tetrahydro-1,2,4-triazines
Ebrahim Abdel-Galil, Anas M. Arab & Elsayed M. Afsah
To cite this article: Ebrahim Abdel-Galil, Anas M. Arab & Elsayed M. Afsah (2021) Synthesis
and biological activity evaluation of some new mixed azines appended tetrahydro-1,2,4-triazines,
Synthetic Communications, 51:9, 1373-1383, DOI: 10.1080/00397911.2021.1882497
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 9, 1373–1383
https://doi.org/10.1080/00397911.2021.1882497
Synthesis and biological activity evaluation of some new
mixed azines appended tetrahydro-1,2,4-triazines
Ebrahim Abdel-Galil , Anas M. Arab , and Elsayed M. Afsah
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
ABSTRACT
ARTICLE HISTORY
Received 13 December 2019
A series of 6-acetyl-2,4-diaryl-2,3,4,5-tetrahydro-1,2,4-triazines (2a–2f)
was synthesized by double Mannich reaction of the hydrazone 1a or
1b with formaldehyde and the appropriate amine. A similar reaction
of 1a with the appropriate diamine afforded the bis(tetrahydro-tria-
zines) 3a–b, and 4a–b. Whereas, the 6-cinnamoyl derivatives 5a-c
were obtained by the reaction of 2a with the appropriate aldehyde.
The hydrazone 7, derived from 2a, was treated with the appropriate
aldehyde or ketone to afford the mixed azines 8–12 and 13–16. The
biological activity, antibacterial, antifungal and antioxidants of the
most newly synthesized compounds of these derivatives were
screened. Compounds 2b, 3a and 7 revealed the best results against
all screened biological activity
KEYWORDS
6-Cinnamoyl-triazines;
mixed azines; pyrazoline;
tetrahydro-1,2,4-triazines
GRAPHICAL ABSTRACT
Introduction
The chemistry of 1,2,4-triazines and related compounds have been the subject of wide
interest, due to their wide range of biological and pharmacological activities. The litera-
ture dealing with the chemistry and pharmacological activities of 1,2,4-triazines has
been reviewed.[1–3] 1,2,4-Triazines have several biological activities such as anti-
cancer,[3–6] cytotoxic,[7,8] antimicrobial,[9,10] antifungal,[11] anti-inflammatory and anal-
gesic,[12] antimalarial,[13] antibacterial[14–16] and antidiabetics.[17]
CONTACT Ebrahim Abdel-Galil
msebrahim2002@gmail.com
Chemistry Department, Faculty of Science, Mansoura
University, Mansoura, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

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E. ABDEL-GALIL ET AL.
Scheme 1. Synthesis of 6-acetyl- and 6-cinnamoyl-2,4-diaryl-tetrahydro-1,2,4-triazines and bis(tetrahy-
dro-1,2,4-triazines).
On the other hand, azines and mixed azines are receiving attention due to their anti-
bacterial and antifungal,[18–20] antimalarial,[21] cytotoxic[22–24] and antioxidant[25] activ-
ity. In addition, a number of azines have also been used as ligands.[26–28]
However, a limited number of azines and mixed azines incorporated into heterocyclic
systems are reported in the literature.[29] In view of this, and in connection with our
studies in this area,[29] the synthesis of some new 6-acetyl tetrahydro-1,2,4-triazines and
their conversion into mixed azines was investigated.
Results and discussion
A series of 6-acetyl-2,4-diaryl-2,3,4,5-tetrahydro-1,2,4-triazines (2a–f) was prepared by a
double Mannich reaction of pyruvaldehyde phenylhydrazone (1a)[30] or pyruvaldehyde p-
tolylhydrazone (1b) with formaldehyde and the appropriate aromatic amine, according to
an earlier report[31] (Scheme 1). Compounds 2b–f are reported for the first time by this
study. Confirmatory evidence for the structures of compounds 2–4 is provided by analytical
and spectral data. The main characteristic features of the 1H NMR and 13C NMR spectrum

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SYNTHETIC COMMUNICATIONSV
1375
of these compounds are the presence of signals assignable to (3-H2) and (5-H2) of triazine
moiety. The structure of 2d, as an example, was elucidated by its 1H and 13C NMR spectra.
The 1H NMR spectrum assigned in addition to representative signals at d 6.94–7.42ppm for
9 Ar-H and –NH protons, four singlet signals at d 2.16, 2.46, 4.26 and 5.07ppm characteris-
tic for two methyl and two methylene groups, respectively. Furthermore, the 13C NMR spec-
trum showed signals for two methyl groups at 23.6 and 24.3ppm, while the methylene
groups of the triazine ring appeared at 45.7 and 62.2 ppm.
This reaction was developed by treating 1a or 1b with formaldehyde and p-phenylenedi-
amine in molar ratio (2:4:1) to afford the 4,40-p-phenylenebis-(6-acetyl-2-aryl-2,3,4,5-tetra-
hydro-1,2,4-triazines) (3a and 3b), respectively (Scheme 1). A similar reaction of 1a or 1b
with ethylenediamine and formaldehyde gave 1,2-bis(6-acetyl-2-phenyl-2,3,4,5-tetrahydro-
1,2,4-triazine-4-yl)ethane (4a) and the 2-(p-tolyl) analogue (4b), respectively. Confirmatory
evidence for the structures of compounds 3 and 4 is provided by analytical and spectral
1
data. For example, the H NMR spectrum of compound 4a exhibited four singlets at 2.43,
2.71, 3.65 and 4.58ppm assignable to CH3 and CH2 protons. The 13C NMR spectrum also
confirmed the structure of 4a through the appearance of signals at 23.5, 46.06, 51.4 and
64.6 ppm related to CH3 and CH2 carbons.
On the other hand, the synthesis of 6-cinnamoyl-2,4-diphenyl-2,3,4,5-tetrahydro-
1,2,4-triazine (5a) and its derivatives 5b–c, has been achieved by the base catalyzed con-
densation of 2a with appropriate aromatic aldehyde (Scheme 1). The formation of the
chalcone type compounds 5a–c, incorporating tetrahydro-1,2,4-triazine moiety, is of
biological interest because a variety of chalcones have been reported to exhibit multifari-
ous pharmacological effects, including antibacterial,[32,33] anti-tumor,[34–36] antifun-
gal,[37] and anti-inflammatory.[38–40] In addition, compounds 5a–c are used as
precursors for the synthesis of the pyrazoline/tetrahydro-1,2,4-triazine hybrids 6a–c, by
treating with hydrazine hydrate. The analytical and spectral data of compounds 5a–c
and 6a–c are consistent with their structures. For example, the IR spectra of the pyrazo-
line derivatives 6a–c exhibited disappearance of the carbonyl (C¼O) peak at 1650 cmꢀ1
and appearance of –NH stretching vibration in the region of 3307 cmꢀ1 revealed the
1
formation of pyrazolines. In the H NMR spectrum of 6b, the 4-Ha, 4-Hb and 5-H pro-
tons of the pyrazoline ring exhibited doublets of doublets at d 3.060–3.124 ppm, 4-Ha, d
3.46–3.53 ppm, 4-Hb and d 4.85–4.89 ppm, 5-H, respectively. Additionally, the 13C NMR
of compound 6b showed signals at 39.9, 61.6 and 148.4 distinguishing for C4, C5 and
C¼N of the pyrazoline ring, along with signals at 21.1, 46.6 and 63.4 for CH3- and two
methylene groups of triazine ring.
The condensation of 2a with hydrazine hydrate afforded 6-(1-hydrazonoethyl)-2,4-
41
diphenyl-2,3,4,5-tetrahydro-1,2,4-triazine (7)[ ] which reacts with the appropriate aromatic
aldehyde namely, benzaldehyde, furfural, and cinnamaldehyde, in refluxing ethanol, to
afford, in each case, a sole product, identified as mixed unsymmetrical azines 8a–c as
depicted in (Scheme 2).
1
Elemental analyses and spectral data (FT-IR, H and MS) confirmed the structure of
the products. The FT-IR spectrum of azine 8c, as a representative example, showed
strong absorption bands at 1625 and 1593 cmꢀ1 due to C¼N and C¼C functions,
1
respectively. Its H-NMR spectrum revealed, in addition to expected aromatic signals,
three singlet signals at d 2.41, 4.51, 5.13 ppm assignable to the protons of methyl and

1376
E. ABDEL-GALIL ET AL.
Scheme 2. Synthesis of mixed azines 8a–c and bis(azines) 9–12.
two methylene groups of triazine ring, respectively. In addition, the mass spectrum of
8c revealed a molecular ion peak at m/z 407 (Mþ) corresponding to a molecular for-
mula (C26H25N5)
In addition, the reaction of the hydrazone 7 with the appropriate dialdehyde, could
be valuable in the synthesis of mixed bis(azines) incorporating two tetrahydro-1,2,4-tria-
zine moieties. In view of this, 7 was treated with glyoxal, malonaldehyde diethyl acetal,
and glutaric dialdehyde to give 1,2-bis((1-(2,4-diphenyl-2,3,4,5-tetrahydro-1,2,4-triazin-
6-yl)ethylidene)hydrazono)ethane (9), 1,3-bis((1-(2,4-diphenyl-2,3,4,5-tetrahydro-1,2,4-
triazin-6-yl)ethylidene)hydrazono)propane (10) and 1,5-bis((1-(2,4-diphenyl-2,3,4,5-tet-
rahydro-1,2,4-triazin-6-yl)ethylidene)hydrazono)pentane (11), respectively. A similar
reaction of 7 with terephthaldehyde afforded the mixed bis(azine) 12. The structures of
1
the synthesized compounds were elucidated by spectral data. In the H NMR spectra of
the symmetrical bis-azine 9, the protons of two methylene groups give singlet signals at
d 4.52, 5.12 ppm assignable to the protons of four methylene groups. Furthermore, a
singlet signal at 2.23 ppm for CH3 protons and the chemical shift observed at 8.18 ppm
1
as a singlet is assigned to the protons of the imine group (CH ¼ N). The H NMR spec-
tral data of the new bis-azine 9 was also supported by its 13C-NMR spectrum.

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Scheme 3. Synthesis of the azines 13–16.
The chemical shift observed at 12.2, 46.4, 61.8 and 158.0 ppm are attributed to methyl,
methylene groups of triazine moiety and the imine carbons respectively.
On the other hand, the synthesis of the symmetrical bis(azine) 13 has been achieved
by the reaction of 7 with 2a. Compound 13 was identified by analytical and spectral
1
data. Its H-NMR spectrum showed, in addition to expected aromatic signals, three
singlet signals at d 2.20, 4.54, 5.13 ppm assignable to the protons of methyl and two
methylene groups of triazine ring, respectively. In addition, its 13C NMR spectrum dis-
played two characteristic peaks for two imine carbons at d 157.5 ppm (Scheme 3).
In connection with this study, treatment of the hydrazone 7 with ketones, namely isa-
tin, acetophenone and 1,4-diacetylbenzene led to the formation of the mixed azines 14,
15 and 16, respectively (Scheme 3). The mass spectra of the latter products showed, in
1
each case, the molecular ion peak. The H NMR spectrum of the symmetrical azine 16
revealed four singlet signals at d 2.27, 2.37, 4.55, and 5.13 ppm characteristic for four
methyl and four methylene groups.
Biological activity
Most of the newly synthesized tetrahydro-1,2,4-triazine derivatives were subjected to
biological screening. The results shown in Tables 1–3 indicate that most of the newly
synthesized tetrahydro-1,2,4-triazine derivatives revealed excellent to good activities as,
antibacterial, antifungal and antioxidant activities compared with Ampicillin,
Colitrimazole and (L)-Ascorbic acid as references.

1378
E. ABDEL-GALIL ET AL.
Table 1. Antibacterial activity against Escherichia coli and Staphylococcus aureus bacteria.
Diameter of inhibition zone (mm)
% Activity index
Compound number
E. coli (mg/mL)
S. aureus (mg/mL)
E. coli (mg/mL)
S. aureus (mg/mL)
2b
2c
2d
2e
2f
3a
3b
4a
4b
7
8a
8b
8c
9
10
11
12
13
15
16
Ampicillin
20
10
9
13
9
18
11
6
7
14
4
NA
NA
2
2
8
23
18
15
17
14
21
17
10
11
20
9
2
NA
4
5
13
7
76.9
38.5
34.6
50.0
34.6
69.2
42.3
23.1
26.9
53.8
15.4
—
—
7.7
7.7
30.8
15.4
—
—
11.5
95.8
75.0
62.5
70.8
58.3
87.5
70.8
41.7
45.8
83.3
37.5
8.3
—
16.7
20.8
54.2
29.2
8.3
8.3
25.0
100
4
NA
NA
3
2
2
6
24
26
100
Antimicrobial activity
The results shown in Table 1 indicate that most of the synthesized compounds have
low activities against the standard chemotherapeutics, whereas compound 2b exhibited
good activities against Escherichia coli, compounds 2e, 3a, and 7 showed moderate
activities against Escherichia coli. Furthermore, compounds 2b, 3a, and 7 exhibited
excellent activities against Staphylococcus aureus, compounds 2c, 2e, and 3b showed
good activities against Staphylococcus aureus.
On the other hand, from the results indicated in Table 2, compounds 2b, 3a, and 7
showed excellent activities against fungi Candida albicans. Whereas, compounds 2c, 2d,
2e, 3b, and 11 exhibited good activity against Candida albicans Therefore, the presence
of tetrahydro-1,2,4-triazine moiety in the synthesized compounds possess a good activity
against Escherichia coli, Staphylococcus aureus and Candida albicans.
Antioxidant screening for [ABTS]
Most of the synthesized triazines are tested as antioxidant agents. As shown in Table 3,
most of these compounds showed different antioxidant activity. Although Compounds
2b and 3a and 7 exhibited excellent antioxidant activity, other tested compounds
showed moderate antioxidant activity
Conclusion
In the present work, various derivatives of tetrahydro-1,2,4-triazines, 6-cinnamoyl-2,4-
diaryl-tetrahydro-1,2,4-triazines and mixed azines were synthesized. All the newly

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Table 2. Antifungal activity against Candida albicans fungi.
Compound number
Diameter of inhibition zone (mm)
% Activity index
2b
2c
2d
2e
2f
3a
3b
4a
4b
7
8a
8b
8c
9
10
11
25
21
15
16
12
23
16
9
10
24
7
NA
NA
3
92.6
77.8
55.5
59.2
44.4
85.2
59.2
33.3
37.0
88.9
25.9
—
—
11.1
14.8
51.8
22.2
—
4
14
6
12
13
NA
15
16
2
5
27
7.4
18.5
100
Clotrimazole
Table 3. Antioxidant activity by ABTS method.
Compounds
Samples absorbance
% inhibition
ABTS control
Ascorbic-acid
0.520
0.060
0.061
0.270
0.317
0.295
0.325
0.071
0.315
0.351
0.350
0.068
0.359
0.383
0.392
0.376
0.370
0.321
0.360
0.390
0.382
0.364
0
88.3%
87.9%
46.5%
37.2%
41.6%
35.6%
85.9%
37.6%
30.5%
30.7%
86.5%
28.9%
24.1%
22.4%
25.5%
26.7%
36.4%
28.7%
22.8%
24.3%
27.9%
2b
2c
2d
2e
2f
3a
3b
4a
4b
7
8a
8b
8c
9
10
11
12
13
15
16
synthesized products were screened against antimicrobial and antioxidant activities,
compounds 2b, 3a, and 7 have the highest activity.
Experimental
All melting points were measured on a Gallenkamp electric melting point apparatus
(Sanyo Gallenkamp, Southborough, UK) and were uncorrected. Elemental microanalyses
were carried out on a Carlo Erba 1108 Elemental Analyzer (Heraeus, Hanau, Germany)

1380
E. ABDEL-GALIL ET AL.
at the Microanalytical Unit, Al-Azhar University. Infrared spectra were measured on a
Mattson 5000 FTIR spectrometer (Mattson Instruments, Inc., Madison, WI, USA). The
1H NMR data were obtained in CDCl3 solution on a Varian XL 400 MHz instrument
(Varian, Inc., CA, USA) and a Jeol Resonance apparatus (500 MHz), using TMS as
internal standard. Chemical shifts are reported in ppm (d) downfield from internal TMS.
The 13C NMR data were obtained in CDCl3 solution on a Jeol Resonance apparatus
(125 MHz), using TMS as internal standard. Chemical shifts are reported in ppm (d). The
mass spectra were recorded on a GC-MS QP–1000 EX Shimadzu instrument (Shimadzu,
Tokyo, Japan). The course of the reaction and the purity of the synthesized compounds
were monitored by TLC using EM science silica gel coated plates, 0.25 nm, 60 GF 254
(Merck, Darmstadt, Germany) with visualization by irradiation with an ultraviolet lamp.
Synthesis of 6-acetyl-2,4-diaryl-2,3,4,5-tetrahydro-1,2,4-triazines (2a–2e)
General procedure
A mixture of pyruvaldehyde phenylhydrazone (1a) (0.53 g, 3.3 mmol), the appropriate
primary aromatic amine (3.3 mmol) and formalin 37% (0.54 mL, 6.6 mmol) in ethanol
(20 mL) was refluxed on water bath for 2 h. The product obtained by cooling filtered
and crystallized from ethanol to give compounds 2a–e.
6-Acetyl-2,4-diphenyl-2,3,4,5-tetrahydro-1,2,4-triazine (2a). Yield 60%, (yellow needles),
1
mp 119–121 ꢁC (119–121 ꢁC[31]). H NMR (CDCl3): d ¼ 2.21 (s, 3H, CH3), 4.51 (s, 2H,
N-CH2-C), 5.11 (s, 2H, N-CH2-N), 6.95–7.42 ppm (m, 10H, Ar-H)
6-Acetyl-4-(4-hydroxyphenyl)-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine (2b). Yield 73%,
(yellow needles), mp 180–182 ꢁC; IR (KBr): ꢀ ¼ 3473 (OH), 1651 (C¼O), 1575, 1507,
1
1272, 1308, 1201, 817, 753, 692, 558 cmꢀ1; H NMR (CDCl3): d ¼ 2.44 (s, 3H, CH3),
4.17 (s, 2H, N-CH2-C), 4.99 (s, 2H, N-CH2-N), 6.72–7.41 ppm (m, 9H, Ar-H and OH);
MS (EI, 70 eV): m/z (%) ¼ 297 (1) [M þ 2]þ, 296 (2) [M þ 1]þ, 295 (5) [M]þ, 294 (36)
[M ꢀ 1]þ, 283 (56), 218 (1) [M – Ph]þ, 97 (21), 85 (21), 83 (31), 82 (39), 81 (21), 77
(100) [Ph]þ, 76 (59), 70 (44), 69 (43), 57 (35), 55 (50). Anal. Calcd for C17H17N3O2
(295.34): Calcd C 69.14, H 5.80, N 14.23. Found C 69.28, H 5.98, N 14.30.
6-Acetyl-4-(p-tolyl)-2-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine (2c). Yield 60%, (yellow
peels), mp 122–123 ꢁC; IR (KBr): ꢀ ¼ 1654 (C ¼ O), 1597, 1552, 1503, 1263, 1138, 881,
1
752, 690 cmꢀ1; H NMR (CDCl3): d ¼ 2.29 (s, 3H, COCH3), 2.47 (s, 3H, Ar-CH3), 4.26
(s, 2H, N-CH2-C), 5.06 (s, 2H, N-CH2-N), 6.88–7.45 ppm (m, 9H, Ar-H); MS (EI,
70 eV): m/z (%) ¼ 294 (7) [M þ 1]þ, 293 (21) [M]þ, 288 (100), 283 (47), 278 (30) [M –
Me]þ, 264 (49), 216 (6) [M – Ph], 104 (73), 77 (9) [Ph]þ, 51 (22). Anal. Calcd for
C18H19N3O (293.37): Calcd C 73.69, H 6.53, N 14.32. Found C 73.52, H 6.35, N 14.30.
Microbiological procedure for the activity study
Antimicrobial the antibacterial activity of the synthesized compounds was tested against
gram-positive bacteria (Staphylococcus aureus) and gram-negative bacteria (Escherichia

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1381
coli). The antifungal activity of the compounds was tested against one fungus (Candida
albicans). A solution of each compound in DMSO with concentration 1 mg/mL was pre-
pared and a solution separately paper disks of Whatman filter paper were prepared with
standard size (5 cm) were cut and sterilized in an autoclave. The paper disks soaked in
the desired concentration of the complex solution were placed aseptically in the petri
dishes containing nutrient agar media (agar 20 g þ beef extract 3 g þ peptone 5 g) seeded
with Staphylococcus aureus, E. coli and Candida albicans. The petri dishes were incu-
bated at 36 ꢁC and the inhibition zones were recorded after 24 h of incubation. Each
treatment was replicated three times. The antibacterial activity of a common standard
antibiotic ampicillin and antifungal colitrimazole was also recorded using the same pro-
cedure as above at the same concentration and solvents. The % activity index for the
compound was calculated by the formula as under:
%Activity Index ¼ Zone of inhibition by test compound ðdiameterÞ=
Zone of inhibition by stander ðdiameterÞ:
Antioxidant screening using 2,20-azinobis-(3-ethylbenzthiazoline-6-sulphonic acid)
(ABTS). The antioxidant screening of the examined compounds was determined
in vitro using the technique prescribed in the literature.[42] The inhibition for each
derivative was calculated using the following mathematical equation.
%Inhibition ¼ ½Abs ðcontrolÞ ꢀ Abs ðtestÞ=Abs ðcontrolÞꢂ ꢃ 100
1
Full experimental details and spectroscopic data H NMR for compounds 2b–2f–16,
13C NMR for compounds 2d, 4a, 6b, 6c, 9 and 13 can be found via the Supplementary
Content section of this article’s Web page.
ORCID
Ebrahim Abdel-Galil
http://orcid.org/0000-0002-1960-9583
Anas M. Arab
Elsayed M. Afsah
http://orcid.org/0000-0002-0349-4160
http://orcid.org/0000-0003-4776-6946
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