Synthesis and antibacterial evaluation of diaminomaleonitrile-based azo-Schiff bases and 8,9-dihydro-7H-purine-6-carboxamides

Article abstract of DOI:10.1007/s11164-020-04175-y

Some new DAMN-based Schiff base 6a–6g were synthesized via a condensation reaction of the corresponding azo dyes with 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea. In continuation, facile synthesis of new 8,9-dihydro-7H-purine-6-carboxamide 7a–7g was reported via an efficient reaction of azo dyes and 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea in the presence of triethylamine as catalyst. All the synthesized compounds were evaluated for their antibacterial activities against both Gram-positive (Micrococcus luteus and Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escherichia coli) bacteria.

Full text of DOI:10.1007/s11164-020-04175-y

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04175-y
Synthesis and antibacterial evaluation
of diaminomaleonitrile‑based azo‑Schif bases
and 8,9‑dihydro‑7H‑purine‑6‑carboxamides
Ammar Sheykhi‑Estalkhjani1 · Nosrat O. Mahmoodi1 · Asieh Yahyazadeh1 ·
Meysam Pasandideh Nadamani1
Received: 18 December 2019 / Accepted: 6 May 2020
© Springer Nature B.V. 2020
Abstract
Some new DAMN-based Schif base 6a–6g were synthesized via a condensation
reaction of the corresponding azo dyes with 1-(2-amino-1,2-dicyanovinyl)-3-phe-
nylurea. In continuation, facile synthesis of new 8,9-dihydro-7H-purine-6-carbox-
amide 7a–7g was reported via an efcient reaction of azo dyes and 1-(2-amino-
1,2-dicyanovinyl)-3-phenylurea in the presence of triethylamine as catalyst. All the
synthesized compounds were evaluated for their antibacterial activities against both
Gram-positive (Micrococcus luteus and Staphylococcus aureus) and Gram-negative
(Pseudomonas aeruginosa and Escherichia coli) bacteria.
Keywords Diaminomaleonitrile · Azo dye · Schif base · Purine-6-carboxamides
Introduction
Diaminomaleonitrile (DAMN), a tetramer of hydrogen cyanide, was considered as
one of the versatile precursors to nucleotides and has been extensively utilized in
the synthesizing of a wide variety of heterocyclic compounds. Over the last decade,
there has been a great deal of interest in DAMN and its derivatives as intermediates
for heterocyclic synthesis, including pyrimidines [1], purines [2, 3], imidazoles [4],
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4-020-04175-y) contains supplementary material, which is available to authorized users.
*
*
Nosrat O. Mahmoodi
mahmoodi@guilan.ac.ir
Asieh Yahyazadeh
yahyazadeh@guilan.ac.ir
1
Department of Chemistry, Faculty of Science, University of Guilan, P.O. Box 41335-1914,
Rasht, Iran
Vol.:(0123456789)
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A. Sheykhi-Estalkhjani et al.
pyrazines [5], porphyrazines [6] and diimines [7]. The reaction of DAMN with aro-
matic aldehydes is widely known to produce DAMN-based Schif base [8–11].
Structurally, Schif bases are nitrogen analogs of aldehyde- or ketone-like com-
pounds in which the carbonyl group is replaced by an imine or azomethine group.
Schif bases are important as synthetic intermediates, and they are also used in the
synthetic precursor of jet-printing inks, optically active materials, chemical sensors,
aggregation-enhanced emission luminogen, fuorescent and in the thermostable opti-
cal material industry [12–15]. Schif base ligands are easily synthesized and form
complexes with almost all metal ions. Many Schif base complexes show excellent
catalytic activity, pharmaceutical and biologically activities such as anticancer, anti-
malarial, anti-infuenza, antiviral, antioxidative and antimicrobial activities [16–21].
The DAMN derivatives in the past decades have been widely used in synthetic
dye chemistry due to their impressive and useful physical and chemical properties
[22, 23]. Since azomethine and azo groups are chemically stable, it has prompted
immense study of DAMN-based azo materials as new chemical sensors, thermally
stable and optically active materials [24, 25].
As mentioned before, DAMN is widely used as a precursor to the synthesis of
heterocyclic compounds like pyrimido–pyrimidines and purines which are the most
widely distributed nitrogen heterocycles in nature. Purine bases have a key role in
the structure of the most important biomolecules: DNA, RNA, adenosine triphos-
phate (ATP), nicotinamide adenine dinucleotide (NAD), alkaloids, coenzyme, etc.
Purine bases show a wide range of pharmaceutical and biological activity such as
antiviral, antimycobacterial, anti-favivirus, antioxidant and anticancer activity
[26–32]. For this reasons, purines have been raised as promising structural units in
the feld of medicinal chemistry.
Previously, we reported versatile functionalized Schif bases as the benzylidene
hydrazides and sulfde connections to bind various transition metals and nanoparti-
cles surfaces [12, 33]. In continuation of our previous works, in this work, frst we
synthesized a modifed DAMN-based Schif bases 6a–6g (Scheme 1); then, in con-
tinuation of this research, we investigated the reaction between phenylurea 5 and azo
dyes (3a–3i) in the presence of NEt3 as a catalyst. A comprehensive investigation
1
of the spectroscopic data including FT-IR, H NMR, 13CNMR and mass spectrom-
etry indicated that the obtained products are 8,9-dihydro-7H-purine-6-carboxamide
7a–7g (Scheme 1). In the end, all the synthesized compounds were evaluated for
their antibacterial activities against both Gram-positive (Micrococcus luteus and
Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa and Escheri-
chia coli) bacteria.
Results and discussion
Synthesis and spectral studies
Our approach involves an efcient method and convenient multi-component synthe-
sis of DAMN-based Schif bases (pathway A) and purine-6-carboxamides (pathway
B) by the reaction of diferent azo dyes 3a–3i and phenylurea 5 that catalyzed by
1 3

Synthesis and antibacterial evaluation of…
Scheme 1 Synthesis of diaminomaleonitrile-based Azo-Schif bases 6a–6g and azo-purine-6-carboxam-
ides 7a–7g
glacial-AcOH or NEt3, respectively, in MeOH under refux conditions. The reactions
of DAMN with phenyl isocyanate proceeded as expected to give the phenylurea 5 in
excellent yields. The azo-aldehyde dye precursors (3a–3i) separately were synthe-
sized by the reaction of o-vanillin or salicylaldehyde with benzene diazonium chlo-
ride salts that in sequence made by diazotization of corresponding aniline deriva-
tives (Scheme 1).
Initially, in order to optimize the reaction conditions, the reaction of azo dyes
3h and 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea 5 was selected as a typical reac-
tion under the aspects of catalyst, temperature, solvent and reaction time. The con-
ditions were optimized, and the results are shown in Table 1. Several solvents such
as MeOH, EtOH, DMF, CH2Cl2, H2O and CH3CN at r.t. and refux condition were
1 3

A. Sheykhi-Estalkhjani et al.
Table 1 Variation of reaction conditions for the synthesis of 6d
Entry
Catalyst
Solvent
Temperature (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
–
EtOH
EtOH
CH3CN
CH2Cl2
H2O
r.t
r.t
r.t
r.t
r.t
r.t
r.t
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
Refux
180
60
60
60
60
60
60
60
60
60
60
60
60
20
20
20
20
20
55
25
10
–
45
64
79
78
42
20
77
80
79
78
76
80
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
Glacial-AcOH
DMF
MeOH
EtOH
CH3CN
CH2Cl2
H2O
9
10
11
12
13
14
15
16
17
DMF
MeOH
EtOH
CH3CN
DMF
MeOH
examined. As shown in Table 1, entry 1, in the absence of catalyst, this reaction was
very slow, and only 20% of the desired product was isolated after 2 h. When this
reaction was carried out over acid catalysts glacial-AcOH, the yield and rate of the
reaction were increased (entry 2). The reaction efciency in CH3CN was 25% (entry
3). When the solvent was replaced by DMF or CH3OH, the reaction yields decreased
to 45% and 64%, respectively (Table 1, entries 6 and 7). In continuance, in order to
further improve the efciency of the reaction, the reaction was carried out at refux
condition. The results showed that the reaction efciency in the MeOH as solvent is
higher at both refux and r.t. than the other solvents (Table 1, entries 7, 13 and 17).
As a result, the presence of glacial-AcOH as the catalyst in MeOH at refux condi-
tion for 20 min was found to be the best reaction conditions to give 6d in an 80%
yield (Table 1, entry 17). The precursors dissolve in H2O in very small amounts,
which is why low efciency is seen in H2O. The CH2Cl2 has the lowest polarity
solvent, and the lowest yield was observed. Among the other solvents, MeOH and
EtOH, which are protic solvents, show slightly higher yields.
After reaction optimization, all the DAMN-based Schif bases 6a–6g were syn-
thesized using glacial-AcOH in MeOH at refux temperature with high yields and
simple product isolation. In most cases, upon addition of precursor 5 to a solution
of azo dyes (3a, b, c, f, g, h, i) in optimized condition, after 5 min desired product
was precipitated and purifed by crystallization. The products were characterized by
FT-IR, 1H NMR, 13C NMR and mass spectrometry. The structure and physical prop-
erties are summarized in Table 2.
The characteristic FT-IR absorption bands of compounds were determined
in KBr disk. The total absence of aldehyde C=O absorption band in the FT-IR
1 3

Synthesis and antibacterial evaluation of…
Table 2 Physical properties of DAMN-based Schif bases 6a–6g
Entry
Compounds
M.p. (°C) λmax(in DMSO) Yield%
Color
199–200
373
86
6a
221–222
233–234
243–245
250
374
378
383
382
88
78
80
81
6b
6c
6d
6e
spectra of 6a–6g together with the appearance of new imine absorption bands,
in the range of 1598–1605 cm−1, clearly indicated that new Schif base com-
pound had formed in 6a–6g. The NH stretching band of 6a–6g was observed in
the region of 3236–3344 cm−1 and a CN absorption bands of medium intensity at
2224–2226 cm−1. The 1H NMR spectra of 6a–6g revealed an imine proton (CH=N)
as singlet signal between 8.94 and 8.98 ppm. The OH and NH protons appeared
1 3

A. Sheykhi-Estalkhjani et al.
Table 2 (continued)
Entry
Compounds
M.p. (°C) λmax(in DMSO) Yield%
Color
225
75
74
6f
387
385
223–224
6g
in the region of 11.15–11.94 and 9.72–9.81 ppm, respectively. Furthermore, aro-
matic protons and aliphatic protons were observed in the expected regions around
1
7.11–8.85 and 1.25–4.02 ppm, respectively. The H NMR spectrum of 6a showed
1
two sets of signals in H NMR with an approximate ratio of 71:29 (~2.5:1) due
to the two possible stereoisomers (Fig. 1). Additional support for the structures of
6a–6g was provided by 13C NMR spectra, which provided the right number of car-
bons at the expected ppms. These results are in agreement with the proposed struc-
tures (see Experimental section).
Scheme 1 shows that in the presence of TEA as a catalyst (pathway B), the reac-
tion proceeds from cyclocondensation, the precursors cyclized rapidly to 8,9-dihy-
dro-7H-purine-6-carboxamide 7a–7g. It seems practical to assume that a com-
parable cyclization may occur with the phenylurea derivative 5 in the presence
of a base. The rapid 6e-cyclocondensation followed by oxidative cyclization in
the presence of molecular oxygen from air led to the aromatic target compounds
7a–7g [34]. The structure of products was characterized by FT-IR, NMR and mass
spectrometry (see Table 3 and supporting data). The IR spectrum of compounds
7a–7g revealed the presence of stretching OH absorption at 3429–3493 cm−1 and
vibration for NH bands at 3233–3380 cm−1. Furthermore, absorption bands in the
1662–1748 cm−1 region corresponding to C=O stretching bands and absorption
bands in the 1584–1600 cm−1 region indicate the presence of C=N stretching bands.
The absence of CN groups is consistent with cyclization. The NMR spectra of
7a–7g were recorded in DMSO at 25 °C. The 1H NMR spectra showed a singlet at δ
12.85–13.16 ppm (1H) due to the NH proton of the imidazol-2-one ring (Scheme 2)
which is consistent with the literature reports in this regard (δ 9–13 ppm) [35, 36].
The OH proton appeared as a broad singlet signal at δ 11.97–12.09 ppm. The amide
protons of 6-carboxamido group have diferent chemical shifts which is typical
for the amide group in 8,9-dihydro-7H-purine-6-carboxamide. The amide protons
1 3

Synthesis and antibacterial evaluation of…
Fig. 1 1H NMR of 6a indicates a mixture of two isomers with a ratio of 71:29
appear at the region of δ 8.03–8.63 ppm as two separate NH peaks due to the rota-
tion inhibition around the partial double bond, and because of the anisotropic efect,
Hf appears in the lower feld (Scheme 2). Furthermore, deuterium (D2O) NMR data
showed that there are three diferent exchangeable NH protons which confrm the
8,9-dihydro-7H-purine-6-carboxamide structure (Fig. 2). The 13C NMR spectra of
7a–7g are in agreement with the proposed structures. In 13C NMR of 7e, two kinds
of carbon appeared in the aliphatic region, the signal at δ 56.2 ppm is attributed to
O–CH3, the C=O and C=N signals appeared at δ 141.3–165.6 ppm and other aro-
matic carbons appeared at δ 102.3–132.6 ppm (see Experimental section).
Antibacterial activity
The in vitro antibacterial activity of compounds 6a–6g and 7a–7g was evaluated
against Gram-negative and Gram-positive bacteria including: Micrococcus luteus
(M. luteus), Staphylococcus aureus (S. aureus), Escherichia coli (E. coli) and Pseu-
domonas aeruginosa (Ps. aeruginosa) by zone inhibition method (mm). The results
of preliminary antibacterial testing of the compounds are reported in Table 4. Tet-
racycline and Ampicillin were used as standard drugs, and DMSO was used as a
negative control. The examination of antibacterial screening data showed that the
compound importance antibacterial activity against Micrococcus luteus is: 6d>6b
>6a>6f>6g=6e>6c and 7e>7g>7b>7a>7f>7c=7d.
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A. Sheykhi-Estalkhjani et al.
Table 3 Physical properties of target azo- purine-6-carboxamides 7a–7g
M.p.
(°C)
Entry
Compounds
λmax(in DMSO) Yield%
Color
> 320
352
351
365
88
92
78
7a
> 320
> 320
7b
7c
> 320
> 320
> 320
356
355
364
87
85
75
7d
7e
7f
> 320
358
82
7g
Antibacterial activity depends on the nature of the bacterial strain, the chelat-
ing ability of the Schif base and the solubility of the compounds [37]. The mor-
phology of the cell wall is a key factor that infuences the activity of antibacte-
rial agents. In this study, all compounds show more strong antibacterial activity
against Gram-positive bacteria, namely M. luteus and S. aureus compared with
1 3

Synthesis and antibacterial evaluation of…
Scheme 2 Rotation inhibition around the partial double bond in 6-carboxamido group
b
a
Fig. 2 a 1H NMR spectra of compound 7e b D2O exchange
Gram-negative bacteria. This may be due to the nature of the bacteria cell wall.
Gram-negative bacteria have an outer lipid membrane, and this usually poses a
barrier to the degree of difusion of antibiotics and antibacterial agents.
It is believed that Schif bases form a chelate with the bacterial strain by mak-
ing hydrogen bondings through the phenolic and azomethine group with the
active centers of cell constituents thus resulting in interference with normal cell
process. Therefore, any factor that infuences the rate of hydrogen bond forma-
tion also afects the antibacterial power. In general, it can be said that compounds
7e, 7b and 6b can better form hydrogen bonds because of their electron donor
substituents and hence have higher antibacterial activity. On the other hand,
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A. Sheykhi-Estalkhjani et al.
Table 4 Antimicrobial activity of compounds 6a–6g and 7a–7g
Entry
Compound
Conc. in DMSO
µg per 0.1 mL
Antimicrobial activity (zone of inhibition in mm)
M. luteus
S. aureus
E. coli
Ps. aeruginosa
1
2
3
4
5
6
7
8
6a
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
13
15
6
18
9
12
9
15
16
8
5
8
2
10
15
8
4
–
–
8
6
5
9
4
5
0
2
6
2
5
21
8
–
6
2
–
6
4
7
11
6
5
3
8
8
2
10
19
0
6b
6c
6d
6e
6f
6g
8
7a
10
12
6
14
12
5
15
21
22
–
9
7b
10
11
12
13
14
13
14
15
7c
7d
8
7e
22
12
18
25
27
–
7f
7g
Tetracycline
Ampicillin
DMSO
–
compounds with NO2 substituent as a strong electron-withdrawing group (7f, 7c,
6f, 6g, 6c) have less antibacterial activity.
It is interesting to note that compounds 7a–7g compared with 6a–6g showed
greater penetration power to the membranous wall of the bacteria. This increase in
antibacterial activity may be due to the presence of the purine heterocyclic ring in
the structure of compounds 7a–7g, which its antibacterial properties have already
been reported [38, 39].
Conclusion
Here, we have been successfully synthesized eight symmetric DAMN-functional-
ized Schif bases in good yields via a simple reaction between DAMN and azo-cou-
pled to o-vanillin or salicylaldehyde precursors. In continuation, a facile synthesis of
new 8,9-dihydro-7H-purine-6-carboxamide was reported via an efcient two-com-
ponent reaction of azo dyes and 1-(2-amino-1,2-dicyanovinyl)-3-phenylurea in the
presence of triethylamine as catalyst. The simplicity, easy execution, simple workup
and good yields together with the use of easily accessible starting materials are char-
acteristics of this process. The antibacterial activities of all newly synthesized com-
pounds showed signifcantly strong activity against Gram-positive bacteria, namely
M. luteus and S. aureus. Compounds 7a–7g compared with 6a–6g showed greater
penetration power to the membranous wall of the bacteria.
1 3

Synthesis and antibacterial evaluation of…
Experimental
Materials and apparatus
The diaminomaleonitrile (DAMN) was purchased from Merck and used without
further modifcation. The azo dyes 3a–3i have been prepared from our reported
method [40]. The structure of products has been well characterized by FT-IR,
UV–Vis, NMR and mass spectrometry. The NMR spectra were obtained in
DMSO-d6 at 25 °C on a Bruker Avance spectrometer, operating at 400 MHz and
1
500 MHz (1H NMR) and 125 MHz (13C NMR). The internal standard for the H
and 13C NMR spectra was TMS. Chemical shifts (δ) are reported in ppm, and the
coupling constants (J) are given in Hertz (Hz). Elemental analysis was made by
a Carlo-Erba EA1110 CNNO-S analyzer and agreed with the calculated values.
The FT-IR spectra for the samples were obtained using Shimadzu FT-IR-8900
spectrophotometer by using KBr pellets. Melting points were determined with an
Electrothermal model 9100 apparatus and are uncorrected.
Synthesis of 1‑(2‑amino‑1,2‑dicyanovinyl)‑3‑phenylurea 5
The DAMN 4 (1.08 g, 10 mmol) was dissolved in acetonitrile (10 mL) in an ice
bath, and the solution was stirred vigorously for 5 min. Then, phenyl isocyanate
(1.09 mL, 10 mmol) was added and the mixture stirred at 0 °C for 10 min. The
reaction was then stirred for a further 24 h at room temperature to give the pheny-
lurea derivative 5. The product was collected by fltration and washed with ace-
tonitrile. Yield: 89%, m.p. 182–185 °C (reported 180–210) [41]; FT-IR (KBr, υ/
cm−1): 3452 and 3354 (NH2 stretch), 3262 (N–H stretch), 3017 (aromatic C–H
stretch), 2219 (CN), 1689 (C=O stretch), 1604 (C=C stretch), 1550, 1512,
1377 (CH2 bend), 752 (aromatic C–H out-of-plane bending). Anal. Calcd. for
Cl1H9N5O (%): C, 58.14; H, 3.99; N, 30.82. Found: C, 58.19; H, 3.95; N, 30.87.
Path A: general procedure for the synthesis of DAMN‑based Schif bases deriva‑
tives 6a–6g
In a 25-mL round bottom fask, corresponding premade azo dyes 3a–3i (1 mmol)
were dissolved in 10 mL of MeOH and a few drops of AcOH were added. The
mixture was stirred at 40 °C for 5 min, and then, phenylurea 5 (1 mmol) was
added and the mixture stirred at refux condition for further 25 min. After com-
pletion of the reaction, product was collected by fltration, washed with MeOH
and recrystallized from DMF/H2O.
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A. Sheykhi-Estalkhjani et al.
1‑(1,2‑dicyano‑2‑((‑2‑hydroxy‑5‑(phenyldiazenyl)benzylidene)amino)vinyl)‑3‑phe‑
nylurea 6a
Orange powder, Yield: 86%, m.p. 199–200 °C, EtOH; FT-IR (KBr, cm−1): 3316
(NH), 3064 (aromatic C–H), 2224 (CN), 1664 (C=O), 1599 (C=N), 1556 (C=C),
1488 (N=N), 1352 (C=C), 1237 (C–O). 1H NMR (400 MHz, DMSO-d6) δ (ppm):
Isomer 115a: 11.67 (br, 1H, Hg), 9.79 (m, 2H, Hd, He), 8.96 (s, 1H, Hf), 8.77 (d,
J = 2.6 Hz, 1H, Hj), 8.02 (dd, J = 8.9, 2.5 Hz, 1H, Hi), 7.91–7.87 (m, 2H, Hk),
7.65–7.56 (m, 3H, Hl, Hm), 7.53 (d, J = 7.7 Hz, 2H, Hc), 7.38 (t, J = 7.9 Hz, 2H,
Hb), 7.24–7.20 (m, 1H, Hh), 7.11 (t, J = 7.4 Hz, 1H, Ha). Isomer 115a’: 11.55 (br,
1H, Hg’), 9.79 (m, 2H, Hd, He), 8.87 (s, 1H, Hf’), 8.21 (d, J = 2.5 Hz, 1H, Hj’),
8.12 (dd, J = 8.8, 2.5 Hz, 1H, Hi’), 7.91–7.87 (m, 1H, Hk’), 7.65–7.56 (m, 2H,
Hl’, Hm’), 7.45 (d, J = 7.8 Hz, 1H, Hc’), 7.29 (t, J = 7.9 Hz, 1H, Hb’), 7.24–7.20
(m, 1H, Hh’), 6.99 (t, J = 7.3 Hz, 1H, Ha’). 13C NMR (100 MHz, DMSO) δ (ppm):
163.8, 162.8, 157.4, 152.8, 152.4, 149.4, 145.8, 139.9, 138.5, 131.6, 130.2, 130.0,
129.9, 129.6, 129.2, 126.7, 126.4, 124.2, 123.9, 123.1, 122.9, 122.8, 121.7, 119.3,
118.9, 118.4, 118.2, 116.2, 113.7, 112.8. HRMS-ESI (m/z) calcd. for C24H17N7O2
[M+] 435.1444, found 435.1449.
1‑(1,2‑dicyano‑2‑((5‑((4‑ethylphenyl)diazenyl)‑2‑hydroxybenzylidene)amino)
vinyl)‑3‑phenylurea 6b
Orange powder, Yield: 88%, m.p. 221–222 °C, EtOH; FT-IR (KBr, cm−1): 3445
(OH), 3344 and 3236 (NH), 2964 and 2931 (aliphatic C–H), 2225 (CN), 1663
(C=O), 1599 (C=N), 1538 (C=C), 1494 (N=N), 1345(C=C), 1232(C–O). 1H NMR
(400 MHz, DMSO-d6) δ (ppm): 11.63 (br, 1H, Hg), 9.80–9.78 (m, 2H, Hd, He), 8.95
(s, 1H, Hf), 8.74 (d, J=2.5 Hz, 1H, Hj), 8.00 (dd, J=8.9, 2.6 Hz, 1H, Hi), 7.83 (d,
J=8.3 Hz, 2H, Hk), 7.53 (d, J=7.7 Hz, 2H, Hc), 7.46 (d, J=8.5 Hz, 2H, Hl), 7.38
(t, J=7.9 Hz, 2H, Hb), 7.20 (d, J=8.9 Hz, 1H, Hh), 7.11 (t, J=7.3 Hz, 1H, Ha), 2.72
(q, J=7.6 Hz, 2H, Hm), 1.25 (t, J=7.6 Hz, 3H, Hn). 13C NMR (100 MHz, DMSO)
δ (ppm): 163.6, 157.4, 152.8, 147.9, 145.3, 138.5, 130.2, 129.6, 129.3, 129.3, 129.2,
126.5, 126.4, 123.0, 122.9, 119.3, 118.9, 118.9, 118.1, 116.2, 28.5, 15.8. HRMS-
ESI (m/z) calcd. for C26H21N7O2 [M+] 463.1757, found 463.1750.
1‑(1,2‑dicyano‑2‑((2‑hydroxy‑5‑((4‑nitrophenyl)diazenyl)benzylidene)amino)
vinyl)‑3‑phenylurea 6c
Orange powder, Yield: 78%, m.p. 233–234 °C, EtOH; FT-IR (KBr, cm−1): 3444
(OH), 3319 and 3236 (NH), 2226 (CN), 1662 (C=O), 1605 (C=N), 1547 (C=C),
1
1491 (N=N), 1343 (C=C), 1236 (C–O). H NMR (400 MHz, DMSO-d6) δ (ppm):
11.94 (br, 1H, Hg), 9.79 (s, 2H, He, Hd), 8.94 (s, 1H, Hf), 8.85 (d, J=2.5 Hz, 1H,
Hj), 8.48 (d, J=9 Hz, 2H, Hl), 8.09–8.06 (m, 3H, Hk, Hi), 7.53 (d, J=7.8 Hz, 2H,
Hc), 7.38 (t, J=7.9 Hz, 2H, Hb), 7.24 (d, J=9 Hz, 1H, Hh), 7.11 (t, J=7.4 Hz, 1H,
Ha). 13C NMR (100 MHz, DMSO) δ (ppm): 164.9, 163.8, 155.8, 155.7, 149.3,
1 3

Synthesis and antibacterial evaluation of…
148.6, 138.4, 129.9, 129.6, 129.2, 126.8, 125.7, 125.6, 125.2, 123.8, 123.7, 122.7,
119.3, 119.1, 116.0. HRMS-ESI (m/z) calcd. for C24H16N8O4 [M+] 480.1295, found
480.1289.
1‑(2‑((5‑((4‑chlorophenyl)diazenyl)‑2‑hydroxy‑3‑methoxybenzylidene)
amino)‑1,2‑dicyanovinyl)‑3‑phenylurea 6d
Orange powder, Yield: 78%, m.p. 233–34 °C, EtOH; FT-IR (KBr, cm−1): 3321
(NH), 3074 (aromatic C–H), 2949 (aliphatic C–H), 2226 (CN), 1659 (C=O), 1602
1
(C=N), 1552 (C=C), 1485 (N=N), 1289 (C–O). H NMR (400 MHz, DMSO-d6) δ
(ppm): 11.15 (br, 1H, Hg), 9.8 (s, 1H, Hd), 9.74 (s, 1H, He), 8.97 (s, 1H, Hf), 8.47 (d,
J=2.2 Hz, 1H, Hj), 7.91 (d, J=8.7 Hz, 2H, Hl), 7.69 (d, J=8.6 Hz, 2H, Hk), 7.62
(d, J=2.2 Hz, 1H, Hi), 7.52 (d, J=7.7 Hz, 2H, Hc), 7.38 (t, J=7.9 Hz, 2H, Hb), 7.11
(t, J=7.5 Hz, 1H, Ha), 4.00 (s, 3H, Hh).13C NMR (100 MHz, DMSO-d6) δ (ppm):
157.2, 154.7, 152.8, 150.9, 150, 144.7, 139.9, 136, 130.1, 129.6, 129.2, 127.5,
124.5, 124.5, 122.7, 119.1, 118.9, 117.8, 114.7, 107.5, 56.8. HRMS-ESI (m/z) calcd.
for C25H18ClN7O3 [M+] 499.1160, found 499.1169.
1‑(2‑((5‑((4‑bromophenyl)diazenyl)‑2‑hydroxy‑3‑methoxybenzylidene)
amino)‑1,2‑dicyanovinyl)‑3‑phenylurea 6e
Light brown powder, Yield: 81%, m.p. 250–252 °C, EtOH; FT-IR (KBr, cm−1):
3316 (NH), 3074 (aromatic C–H), 2949 (aliphatic C–H), 2226 (CN), 1660 (C=O),
1603 (C=N), 1574, 1552 (C=C), 1485 (N=N), 1354 (C=C), 1288 (C–O).1H NMR
(400 MHz, DMSO-d6) δ (ppm): 11.16 (br, 1H, Hg), 9.80 (s, 1H, Hd), 9.75 (s, 1H,
He), 8.98 (s, 1H, Hf), 8.48 (d, J=2.2 Hz, 1H, Hj), 7.84 (s, 4H, Hk, Hl), 7.63 (d,
J=2.1 Hz, 1H, Hi), 7.52 (d, J=7.9 Hz, 2H, Hc), 7.38 (t, J=7.9 Hz, 2H, Hb), 7.12 (t,
J=7.3 Hz, 1H, Ha), 4.00 (s, 3H, Hh). 13C NMR (100 MHz, DMSO) δ (ppm): 157.2,
152.8, 149.8, 149.3, 145.2, 138.4, 133.1, 133.0, 133.0, 129.6, 129.2, 124.7, 124.7,
122.6, 119.3, 118.9, 118.2, 116.1, 112.8, 107.5, 56.7. HRMS-ESI (m/z) calcd. for
C25H18BrN7O3 [M+] 543.0655, found 543.0645.
1‑(1,2‑dicyano‑2‑((2‑hydroxy‑3‑methoxy‑5‑((4‑nitrophenyl)diazenyl)benzylidene)
amino)vinyl)‑3‑phenylurea 6f
Orange powder, Yield: 75%, m.p. 225 °C, EtOH; FT-IR (KBr, cm−1): 3446 (OH),
2225 (CN), 1658 (C=O), 1600 (C=N), 1553 (C=C), 1460 (N=N), 1343 (C=C),
1
1263 (C–O). H NMR (400 MHz, DMSO-d6) δ (ppm): 11.41 (br, 1H, Hg), 9.80 (s,
1H, Hd), 9.76 (br, 1H, He), 8.97 (s, 1H, Hf), 8.56 (d, J=2.2 Hz, 1H, Hj), 8.48 (d,
J=9 Hz, 2H, Hl), 8.07 (d, J=8.9 Hz, 2H, Hk), 7.66 (d, J=2.1 Hz, 1H, Hi), 7.52 (d,
J=8 Hz, 2H, Hc), 7.38 (t, J=7.9 Hz, 2H, Hb), 7.11 (t, J=7.4 Hz, 1H, Ha), 4.01 (s,
3H, Hh). 13C NMR (100 MHz, DMSO) δ (ppm): 156.9, 149.3, 138.4, 129.6, 125.7,
125.6, 123.9, 119.3, 116.0, 56.8. (The product shows low solubility in any appropri-
ate solvents to allow for structural characterization using 13C NMR.). HRMS-ESI
(m/z) calcd. for C25H18N8O5 [M+] 510.1400, found 510.1411.
1 3

A. Sheykhi-Estalkhjani et al.
1‑(1,2‑dicyano‑2‑((2‑hydroxy‑3‑methoxy‑5‑((3‑nitrophenyl)diazenyl)benzylidene)
amino)vinyl)‑3‑phenylurea 6g
Yellow powder, Yield: 74%, m.p. 223–224 °C, EtOH; FT-IR (KBr, cm−1): 3447
(OH), 3331 (NH), 3088 (aromatic C–H), 2986 (aliphatic C–H), 2225 (CN), 1666
(C=O), 1600 (C=N), 1556 (C=C), 1458(N=N), 1351(C=C), 1265(C–O). 1H NMR
(400 MHz, DMSO-d6) δ (ppm): 11.30 (br, 1H, Hg), 9.81 (s, 1H, Hd), 9.72 (br, 1H,
He), 8.96 (s, 1H, Hf), 8.60 (t, J=2.1 Hz, 1H, Hk), 8.54 (d, J=2.3 Hz, 1H, Hj), 8.40
(d, J=8.2 Hz, 1H, Hn), 8.35 (d, J=8.4 Hz, 1H, Hl), 7.92 (t, J=8.1 Hz, 1H, Hm),7.68
(d, J=2.3 Hz, 1H, Hi), 7.52 (d, J=7.8 Hz, 2H, Hc), 7.37 (t, J=7.9 Hz, 2H, Hb),
7.11 (t, J=7.3 Hz, 1H, Ha), 4.02 (s, 3H, Hh). 13C NMR (100 MHz, DMSO) δ (ppm):
155.4, 152.8, 150.1, 149.2, 144.6, 139.9, 131.6, 129.9, 129.6, 129.2, 127.5, 126.8,
125.5, 122.8, 122.7, 119.8, 119.2, 118.9, 116.1, 114.7, 107.6, 90.8, 56.9. HRMS-
ESI (m/z) calcd. For C25H18N8O5 [M+] 510.1400, found 510.1407.
Path B: general procedure for the synthesis of azo‑8,9‑dihydro‑7H‑purine‑6‑car‑
boxamide 7a–7g
In a 25-mL round bottom fask, corresponding premade azo dyes 3a–3i (1 mmol)
were dissolved in 10 mL of MeOH and a few drops of triethylamine were added.
The mixture was stirred at 40 °C for 5 min, and then, phenylurea 5 (1 mmol) was
added and the mixture stirred at refux condition for further 25 min. Thin-layer chro-
matography (TLC) was used to monitor the progress of the reaction (EtOAc/n-hex-
ane 3:6). After completion of the reaction, the product was collected by fltration,
washed with MeOH and recrystallized from DMF/H2O.
2‑(2‑hydroxy‑5‑(phenyldiazenyl)phenyl)‑8‑oxo‑9‑phenyl‑8,9‑dihydro‑7H‑pu‑
rine‑6‑carboxamide 7a
Orange powder, Yield: 88%, m.p.>320 °C; FT-IR (KBr, υ/cm−1): 3443 (OH), 3237
1
(NH), 1742 (C=O), 1689 (C=O), 1584 (C=N), 1488 (N=N). H NMR (500 MHz,
DMSO-d6) δ: 12.85 (s, 1H, Hd), 11.97 (s, 1H, Hg), 9.07 (s, 1H, Hj), 8.50 (s, 1H,
Hf), 8.05 (s, 1H, He), 7.88–7.84 (m, 3H, Hi, Hk), 7.72 (d, J=7.8 Hz, 2H, Hc), 7.65
(t, J=7.8 Hz, 2H, Hb), 7.59–7.50 (m, 4H, Ha, Hl, Hm), 7.07(d, J=8.8 Hz, 1H,
Hh). 13C NMR (100 MHz, DMSO-d6, ppm) δ: 165.6, 161.8, 154.4, 152.5, 151.9,
145.6, 133.4, 132.6, 131.2, 129.8, 129.8, 129.8, 129.7, 129.0, 128.0, 126.9, 123.7,
122.7, 119.6, 119.1. HRMS-ESI (m/z) calcd. For C24H17N7O3 [M+] 451.1393, found
451.1399.
2‑(5‑((4‑ethylphenyl)diazenyl)‑2‑hydroxyphenyl)‑8‑oxo‑9‑phenyl‑8,9‑dihy‑
dro‑7H‑purine‑6‑carboxamide 7b
Orange powder, Yield: 92%, m.p.>320 °C; FT-IR (KBr, υ/cm−1): 3449 (OH), 3233
1
(NH), 2964 (aliphatic C–H), 1742 (C=O), 1663 (C=O), 1597 (C=N). H NMR
1 3

Synthesis and antibacterial evaluation of…
(400 MHz, DMSO-d6) δ: 12.88 (s, 1H, Hd), 12.09 (s, 1H, Hg), 9.11 (d, J=2.6 Hz,
1H, Hj), 8.63 (s, 1H, Hf), 8.13 (s, 1H, He), 7.89 (dd, J=8.8, 2.6 Hz, 1H, Hi), 7.82
(d, J=8.1 Hz, 2H, Hk), 7.73 (d, J=7.9 Hz, 2H, Hc), 7.67 (t, J=7.7 Hz, 2H, Hb),
7.57 (t, J=7.3 Hz, 1H, Ha), 7.44 (d, J=8.2 Hz, 2H, Hl), 7.09 (d, J=8.8 Hz, 1H,
Hh), 2.72 (q, J=7.6 Hz, 2H, Hm), 1.25 (t, J=7.6 Hz, 3H, Hn). 13C NMR (100 MHz,
DMSO-d6, ppm) δ: 165.6, 161.6, 154.4, 153.2, 151.9, 150.7, 147.6, 145.6, 133.4,
132.6, 129.8, 129.2, 129.1, 129.1, 127.9, 126.9, 123.7, 122.9, 119.6, 119.1, 28.5,
15.8. HRMS-ESI (m/z) calcd. For C26H21N7O3 [M+] 479.1706, found 479.1713.
2‑(2‑hydroxy‑5‑((4‑nitrophenyl)diazenyl)phenyl)‑8‑oxo‑9‑phenyl‑8,9‑dihy‑
dro‑7H‑purine‑6‑carboxamide 7c
Orange powder, Yield: 78%, m.p.>320 °C; FT-IR (KBr, υ/cm−1): 3321 and 3283
(NH), 3062 (aromatic C–H), 2926 and 2875 (aliphatic C–H), 2223 (CN), 1659
1
(C=O), 1609 (C=N), 1233 and 1194 (C–O). H NMR (500 MHz, DMSO-d6) δ:
13.07 (s, 1H, Hd), 12.08 (s, 1H, Hg), 9.22 (s, 1H, Hj), 8.62 (s, 1H, Hf), 8.44 (d,
J=8.6 Hz, 2H, Hk), 8.10 (s, 1H, He), 8.06(d, J=8.7 Hz, 2H, Hl), 7.96 (dd, J=8.8,
2.5 Hz, 1H, Hi), 7.72 (d, J=7.8 Hz, 2H, Hc), 7.67 (t, J=7.9 Hz, 2H, Hb), 7.56 (t,
J=7.3 Hz, 1H, Ha), 7.13(d, J=8.7 Hz, 1H, Hh). The product was too insoluble for
analysis by 13C NMR spectroscopy. HRMS-ESI (m/z) calcd. For C24H16N8O5 [M+]
496.1244, found 496.1239.
2‑(2‑hydroxy‑3‑methoxy‑5‑(phenyldiazenyl)phenyl)‑8‑oxo‑9‑phenyl‑8,9‑dihy‑
dro‑7H‑purine‑6‑carboxamide 7d
Yellow powder, Yield: 87%, m.p.>320 °C; FT-IR (KBr, υ/cm−1): 3429 (OH),
3333 and 3265(NH), 3063 (aromatic C–H), 2937 (aliphatic C–H), 1734 (C=O),
1
1680 (C=O), 1600 (C=N), 1120 (C–O). H NMR (500 MHz, DMSO-d6) δ: 13.14
(s, 1H, Hd), 12.01 (s, 1H, Hg), 8.75 (s, 1H, Hj), 8.51 (s, 1H, Hf), 8.08 (s, 1H, He),
7.85 (d, J=7.6 Hz, 2H, Hk), 7.70 (d, J=7.9 Hz, 2H, Hc), 7.64 (t, J=7.7 Hz, 2H,
Hb), 7.58–7.49 (m, 4H, Ha, Hl, Hm), 7.45 (s, 1H, Hi), 3.86 (s, 3H, Hh). 13C NMR
(100 MHz, DMSO-d6, ppm) δ: 165.5, 164.8, 154.5, 153.2, 152.9, 152.5, 151.8,
150.0, 149.9, 147.6, 144.6, 132.6, 131.1, 129.8, 129.8, 129.0, 129.0, 126.8, 122.7,
118.9, 56.2. HRMS-ESI (m/z) calcd. For C25H19N7O4 [M+] 481.1499, found
481.1490.
2‑(2‑hydroxy‑3‑methoxy‑5‑(p‑tolyldiazenyl)phenyl)‑8‑oxo‑9‑phenyl‑8,9‑dihy‑
dro‑7H‑purine‑6‑carboxamide 7e
Orange powder, Yield: 85%, m.p.>320 °C; FT-IR (KBr, υ/cm−1): 3447 (OH),
1
3237 (NH), 2932 (aliphatic C–H), 1748 (C=O), 1666 (C=O), 1597 (C=N). H
NMR (400 MHz, DMSO-d6, ppm) δ: 13.14 (s, 1H, Hd), 12.09 (s, 1H, Hg), 8.81(d,
J=2.3 Hz, 1H, Hj), 8.62 (s, 1H, Hf), 8.12 (s, 1H, He), 7.81 (d, J=8.1 Hz, 2H, Hk),
7.72 (d, J=7.4 Hz, 2H, Hc), 7.68 (t, J=7.7 Hz, 2H, Hb), 7.57 (t, J=7.2 Hz, 1H,
Ha), 7.51 (d, J=2.3 Hz, 1H, Hi), 7.40 (d, J=8.1 Hz, 2H, Hl), 3.89 (s, 3H, Hh), 2.42
(s, 3H, Hm). 13C NMR (100 MHz, DMSO-d6, ppm) δ: 165.6, 154.5, 153.2, 152.6,
1 3

A. Sheykhi-Estalkhjani et al.
151.9, 150.5, 150.1, 144.6, 141.3, 132.6, 130.4, 129.8, 129.1, 126.9, 122.9, 122.8,
122.4, 119.0, 116.0, 102.3, 56.2, 21.5. HRMS-ESI (m/z) calcd. For C26H21N7O4
[M+] 495.1655, found 495.1664.
2‑(2‑hydroxy‑3‑methoxy‑5‑((4‑nitrophenyl)diazenyl)phenyl)‑8‑oxo‑9‑phenyl‑8,9‑di‑
hydro‑7H‑purine‑6‑carboxamide 7f
Orange powder, Yield: 75%, m.p.>320 °C; FT-IR (KBr, υ/cm−1): 3457 (OH), 3094
(aromatic C–H), 2928 (aliphatic C–H), 1744 (C=O), 1678 (C=O), 1600 (C=N),
1
1528 and 1349 (NO2). H NMR (500 MHz, DMSO-d6) δ: 13.16 (s, 1H, Hd), 11.99
(s, 1H, Hg), 8.79 (s, 1H, Hj), 8.52 (s, 1H, Hf), 8.03 (s, 1H, He), 7.89 (d, J=8.3 Hz,
2H, Hk), 7.71 (d, J=7.9 Hz, 2H, Hc), 7.67–7.63 (m, 4H, Hb, Hl), 7.55 (t, J=7.4 Hz,
1H, Ha), 7.51 (s, 1H, Hi), 3.88 (s, 3H, Hh). The product was too insoluble for anal-
ysis by 13C NMR spectroscopy. HRMS-ESI (m/z) calcd. For C25H18N8O6 [M+]
526.1349, found 526.1358.
2‑(5‑((4‑chlorophenyl)diazenyl)‑2‑hydroxy‑3‑methoxyphenyl)‑8‑oxo‑9‑phe‑
nyl‑8,9‑dihydro‑7H‑purine‑6‑carboxamide 7g
Yellow powder, Yield: 82%, m.p.>320 °C; FT-IR (KBr, υ/cm−1: 3423 (OH),),
1
3332 (NH), 3263(NH), 1740(C=O), 1680 (C=O), 1598 (C=N), 1461 (N=N). H
NMR (500 MHz, DMSO-d6) δ: 13.31 (s, 1H, Hd), 11.97 (s, 1H, Hg), 8.84(s, 1H, Hj),
8.53–7.48 (m, 12H, Ha, Hb, Hc, He, Hf, Hi, Hk, Hl), 3.87 (s, 3H, Hh). The product was
too insoluble for analysis by 13C NMR spectroscopy. HRMS-ESI (m/z) calcd. For
C25H18ClN7O4 [M+] 515.1109, found 515.1102.
Determination of antibacterial activity
A colony of each standard test organism was sub-cultured in order to obtain fresh
bacteria on the nutrient agar plates at 37 °C for 18 h. For preparations of suspen-
sions of microorganisms (0.5 McFarland), one to two colonies from each plate were
dissolved in isotonic saline solution. Then, Mueller–Hinton agar (Merck) plates
were prepared according to manufacturers’ instructions in order to evaluate the
antibacterial activities of compounds. The sterile Mueller–Hinton agar plates were
inoculated with the bacteria. 0.01 g of test samples was dissolved in 1 mL dime-
thyl sulfoxide (DMSO) to obtain a stock solution. A concentration of 100 μg/0.1 mL
of each sample was prepared. 0.1 mL of prepared samples was dropped into each
respective labeled well aseptically. The inoculated plates were left on the table for
1 h to allow each sample to difuse into the agar. For comparison, Erythromycin and
Tetracycline were used as positive control and DMSO as a negative control. The
plates were incubated overnight at 37 °C, and zones of inhibition were measured in
millimeters. All the tests were performed in triplicate, and the average was taken as
the fnal reading. The bacterial strains isolated from clinical specimens were used in
the study.
1 3

Synthesis and antibacterial evaluation of…
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