Synthesis, characterization, anti-bacterial, anti-fungal and nematicidal activities of 2-amino-3-cyanochromenes

Article abstract of DOI:10.1016/j.jphotobiol.2016.09.032

Soil-borne plant pathogens such as nematodes, fungi and some bacteria not only affect the plant cultures but also economy and environmental implications. As a result of these pathogens attacks, the yield and quality of crops is affected. Therefore, synthe

Full text of DOI:10.1016/j.jphotobiol.2016.09.032

Journal of Photochemistry & Photobiology, B: Biology 164 (2016) 160–163
Contents lists available at ScienceDirect
Journal of Photochemistry & Photobiology, B: Biology
journal homepage: www.elsevier.com/locate/jphotobiol
Synthesis, characterization, anti-bacterial, anti-fungal and nematicidal
activities of 2-amino-3-cyanochromenes
b
c
Muhammad Nawaz a, , Muhammad Waseem Abbasi , Soleiman Hisaindee
⁎
a
Department of Nano-Medicine Research, Institute for Research and Medical Consultations (IRMC), University of Dammam, Dammam 31441, Saudi Arabia
b
c
Department of Botany, University of Karachi, Karachi 75250, Pakistan
Department of Chemistry, United Arab Emirates University, Al-Ain 15551, United Arab Emirates
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 June 2016
Received in revised form 22 September 2016
Accepted 24 September 2016
Available online xxxx
Soil-borne plant pathogens such as nematodes, fungi and some bacteria not only affect the plant cultures but also
economy and environmental implications. As a result of these pathogens attacks, the yield and quality of crops is
affected. Therefore, synthesis of new compounds to control these pathogens is very important and need of time.
Chromenes are considered important group of heterocyclic compounds and exhibited significant biological activ-
ities. 2-amino-3-cyano chromenes are considered important medicinal scaffolds among the chromenes. We de-
scribe three component microwave assisted synthesis of 2-amino-3-cyano chromenes. The versatility of the
reaction was examined by varying the aldehydes in the reaction mixture which lead to the synthesis of series
of 2-amino-3-cyanochromenes (1–9). The structural elucidations of the compounds were studied by 1H NMR,
13C NMR, HRMS and FTIR spectrometer and results were well correlated. The synthesized compounds were eval-
uated for their anti-bacterial, anti-fungal and nematicidal activities. Among the synthesized compounds, com-
pound 6 showed good anti-bacterial activity while compound 9 exhibited high anti-fungal activity. In case of
nematicidal activity, compound 8 indicated high activity as compare with other compounds followed by com-
pound 9. Results indicate that these synthesized compounds could be used as effective control for soil-borne
plant pathogens such as nematodes, fungi and bacteria and can help to improve the plant production.
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Chromenes
Microwave synthesis
Biological activities
1. Introduction
for the synthesis of 2-amino-3-cyano chromenes due to their impor-
tance in medicinal chemistry.
Chromenes are getting prestigious position in the heterocyclic
chemistry due to their extraordinary significance in biologically active
molecules, natural products, and synthetic drugs [1]. Among the various
types of chromenes, 2-amino-3-cyano chromenes are considered im-
portant medicinal scaffolds [2–10] 2-amino-3-cyano chromenes
exhibiting numerous biological activities such as anti-bacterial [11],
anti-proliferative [12], anti-viral [13,14] anti-cancer [9,10,15] anti-
tumor [16] and central nerve activities [17]. Besides this; they are part
of many natural products and used in biodegradable agrochemicals
[18–21].
Usually, 2-amino-3-cyanochromenes are synthesized by three com-
ponent reaction employing phenol or resorcinol with malononitrile and
arylaldehydes as precursors in the presence of catalyst. Many catalysts
are used for such reactions including piperidine [22] basic alumina
[23] K2CO3 [24] and cetyltrimethylammonium chloride [25]. However,
most of the reported work has disadvantage due to long reaction time,
toxic solvents, poor yield and limited application [22–24]. Therefore,
there is need for the development of an efficient and fast methodology
Soil-borne plant pathogens (nematodes, fungi and some bacteria)
are considered equally important as other pathogens because they af-
fect the plant cultures and finally economy and environmental implica-
tions. These pathogens cause severe damage to different vegetables and
crops as a result the yield and quality of crops is affected. Some of them
infect plant roots and cause disruption of nutrients absorption and
water from the soil which may result in mortality. The root-knot nema-
todes (Meloidogyne spp.) are widely distributed and reproduce on over
2000 species of plants [26]. Root-knot nematodes (Meloidogyne species)
are obligate parasites and cause root cells to become giant and multinu-
cleated. Macrophomina phaseolina causes rotting of roots, stem and pods
of hundreds of cultivated plant species [27]. M. phaseolina has a wide
distribution and it can survive in soil and dead plant debris for several
years by forming sclerotia. Symptoms including appearance of lesions
on roots, stem and other parts of plants which result in stunted growth,
yellowing of leaves and reduction in yield [28]. Fusarium species are also
very common plant pathogens that causes root and stem rot and wilt
diseases on a variety of crop plants.
Until now, there is no report for the application of 2-amino-3-
cyanochromenes for the remediation of plant pathogens. Herein, we
report a fast and efficient three component reaction for the synthesis
⁎
Corresponding author.
E-mail address: nawwaz@gmail.com (M. Nawaz).
http://dx.doi.org/10.1016/j.jphotobiol.2016.09.032
1011-1344/© 2016 Elsevier B.V. All rights reserved.

M. Nawaz et al. / Journal of Photochemistry & Photobiology, B: Biology 164 (2016) 160–163
161
of 2-amino-3-cyanochromenes series by using microwave and
screening of their anti-bacterial, anti-fungal and nematicidal activities.
3.67 (s, 6H), 4.81 (s, 1H), 6.96–6.72 (m, 1H), 6.85–6.87 (m, 2H),7.10–
7.12 (m, 2H), 7.51–7.62 (m, 3H),7.85 (d, J = 8.4 Hz, 1H), 8.20 (d, J =
8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 55.9, 56.7, 111.8, 112.3,
112.4, 118.5, 120.2, 121.0, 121.1, 123.2, 124.2, 126.7, 127.1, 127.1,
128.1, 133.1, 138.6, 142.9, 148.2, 149.1, 160.5, 161.1; HRMS (+ESI):
calcd. for C22H18N2O3, 358.1312, found 358.1314.
2. Experimental
2.1. General
Reagent grade chemicals and solvents were purchased from Sigma
Aldrich and were used without further purification. Thin-layer chroma-
tography (TLC) was performed on silica gel glass plates (Silica gel, 60
F254, Fluka) and spots were visualized under UV lamp. Melting points
of the complexes were determined on Gallenkamp apparatus and re-
ported as uncorrected. Infrared (IR) spectra of the compounds were re-
2.1.6. 2-Amino-3-cyano-4-(2-methoxyphenyl)-4H-benzo[h]chromene (5)
Yield: 2.26 g (69%); mp: 200–203 °C; IR (KBr pellet, cm−1): 3577,
3458, 3327, 3200, 2190, 1667, 1610, 1573, 1462; 1H NMR (400 MHz,
DMSO-d6): δ3.77 (s, 3H), 4.40 (m, 0.5H), 5.25 (s, 1H), 6.81–6.85 (m,
1H), 6.96–7.18(m, 6H), 7.49–7.61 (m, 3H), 7.82 (d, J = 8.0 Hz, 1H),
8.24 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 19.0, 34.8,
56.0, 112.0, 119.0, 121.08, 121.1, 121.3, 123.2, 124.2, 126.3, 127.0,
128.1, 128.7129.5, 133.1, 133.8143.5, 156.8, 161.3; HRMS (+ESI):
calcd. for C21H16N2O2, 328.1206, found 328.1187.
corded on a Nicolet Impact 410 FT-IR spectrometer (4000–400 cm−1
)
as a potassium bromide (KBr) pellets. 1H NMR and 13C NMR spectra
were conducted on Varian 400 MHz NMR spectrometer in DMSO-d6.
The proton chemical shifts were reported in parts per million (δ ppm)
and coupling constants (J) in Hertz (Hz) and s, d, t, m, br refer to singlet,
doublet, triplet, multiplet and broad respectively. JMS-600H high reso-
lution mass spectrometer (JEOL) was used for recording ESI-MS and
HRMS spectra of the compounds.
2.1.7. 2-Amino-3-cyano-4-(3-hydroxyphenyl)-4H-benzo[h]chromene (6)
Yield: 2.58 g (82%); mp: 261–263.5 °C; IR (KBr pellet, cm−1): 3391,
2836, 2694, 2171, 1904, 1666, 1481, 1183, 1051; 1H NMR (400 MHz,
DMSO-d6): δ 4.78 (s, 1H), 6.63–6.73 (m, 3H), 7.08–7.19 (m, 4H), 7.49–
7.61 (m, 3H), 7.82 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 9.41 (s,
1H); 13C NMR (100 MHz, DMSO-d6): δ 41.3, 56.8, 114.5, 114.87, 118.5,
118.8, 121.8, 123.2, 124.3, 126.7, 127.1, 127.2, 128.1, 130.1, 133.1,
143.2, 147.7, 158.2, 160.6; HRMS (+ESI): calcd. for C24H15ClN4O,
410.0929, found 410.0915.
2.1.1. General Method for the Synthesis of Compounds (1–9)
A stirred mixture of 1-naphthol 1.44 g, (10 mmol), aldehyde (10
mmol), malonitrile (0.660 g, 10 mmol) and two drops of piperidine
in bench ethanol (10 mL) was refluxed in microwave reactor at 80 °C
(dynamic power 25–30 W) for 5–15 min. The solid product was
obtained; it was filtered, washed several times with cold ethanol and
dried under vacuum.
2.1.8.
2-Amino-3-cyano-4-(2-(4-chlorophenyl)pyrimidin-5-yl-4H-
benzo[h]chromene (7)
Yield: 3.00 g (73%); mp: 239–240 °C; IR (KBr pellet, cm−1): 3458,
3336, 2188, 1663, 1577, 1424; 1H NMR (400 MHz, DMSO-d6): δ 5.13
(s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.37 (s, 2H), 7.54–7.66 (m, 5H), 7.90
(d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H); 8.32–8.34 (m, 2H), 8.81
(s, 2H); 13C NMR (100 MHz, DMSO-d6): δ 36.4, 54.7, 116.2, 120.7,
121.3, 123.2, 124.8, 126.3, 127.3, 127.6, 128.2, 129.3, 129.9, 133.4,
136.1, 136.2, 137.3, 143.6, 157.6, 160.8, 161.7; HRMS (+ESI): calcd.
for C24H15ClN4O, 410.0929, found 410.0915.
2.1.2. 2-Amino-3-cyano-4-phenyl-4H-benzo[h]chromene (1)
Yield: 2.77 g (93%); mp: 220–223 °C; IR (KBr pellet, cm−1): 3441,
3299, 3184, 2205, 1653, 1600, 1399;1H NMR (400 MHz, DMSO-d6): δ
4.87 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.15–7.29 (m, 6H), 7.50–7.62 (m,
3H), 7.83 (d, J = 8.4 Hz, 1H), 8.24–8.26 (m, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 41.4, 56.7, 118.4, 121.1, 121.2, 123.2, 124.3, 126.7, 127.1,
127.2, 127.4, 128.1, 129.2, 133.1, 143.2, 146.2, 160.6; HRMS (+ESI):
calcd. for C20H14N2O, 298.1101, found 298.1077.
2.1.9. 2-Amino-3-cyano-4-(thiophen-2-yl)-4H-benzo[h]chromene (8)
Yield: 1.85 g (61%); mp: 152–155 °C; IR (KBr pellet, cm−1): 3466,
3330, 2187, 1657, 1620, 1569,1410, 1373, 1260; 1H NMR (400 MHz,
DMSO-d6): δ 5.24 (s, 1H), 6.91–6.93 (m, 1H), 7.06–7.07 (m, 1H), 7.22–
7.35 (m, 4H), 7.53–7.61 (m, 2H), 7.84–7.91 (m, 1H), 8.20–8.25(1H),
8.67 (s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 114.1, 114.8, 118.1,
120.9, 121.2, 123.1, 124.4, 125.0, 126.0, 126.5, 127.2, 127.3, 128.1,
129.6, 133.3, 135.8, 139.1, 140.9, 142.8, 151.2, 153.9, 161.7; HRMS
(+ESI): calcd. for C18H12N2OS,304.0665, found 304.0650.
2.1.3. 2-Amino-3-cyano-4-(3-fluorophenyl)-4H-benzo[h]chromene (2)
Yield: 2.09 g (66%); mp: 204–206 °C; IR (KBr pellet, cm−1): 3462,
3327, 3196, 2194, 1660, 1635, 1610, 1485, 1447; 1H NMR (400 MHz,
DMSO-d6): δ 4.94 (s, 1H), 6.99–7.10 (m, 4H), 7.25–7.35 (m, 3H), 7.51–
7.62(m, 3H), 7.84(d, J = 8 Hz, 1H), 8.24 (d, J = 8 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 40.5, 56.5, 56.1, 114.1, 114.3, 114.7, 114.9,
117.7, 120.9, 121.2, 123.2, 124.2, 124.3, 124.5, 126.5, 127.2, 127.3,
128.1, 131.1, 131.2, 133.2, 143.2, 148.97, 149.03, 160.7, 161.5, 163.96;
HRMS (+ESI): calcd. for C20H13FN2O, 316.1006, found 316.0986.
2.1.10. 2-Amino-3-cyano-4-(furan-2-yl)-4H-benzo[h]chromene (9)
Yield: 0.83 g (30%); mp: 154–157 °C; IR (KBr pellet, cm−1): 3444,
3328, 3194, 2195, 1665, 1604, 1569, 1505, 1409;1H NMR (400 MHz,
DMSO-d6): δ 5.03 (s, 1H), 6.24 (d, J = 3.2 Hz, 1H), 6.33–6.35 (m,
1H),7.20–7.23 (m, 2H), 7.49–7.64 (m, 3H), 7.89 (d, J = 8.0 Hz, 1H),
8.12 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6): δ 35.0, 53.6,
106.6, 110.9, 115.9, 120.7, 121.1123.2, 124.33, 126.3, 127.2, 127.3,
128.2, 133.3, 143.2, 143.5, 156.8, 161.3; HRMS (+ESI): calcd. for
C18H12N2O2, 288.0893, found 288.0906.
2.1.4.
2-Amino-3-cyano-4-(2-trifluoromethyl)phenyl)-4H-
benzo[h]chromene (3)
Yield: 2.3 g (63%); mp: 217–219 °C; IR (KBr pellet, cm−1): 3423,
3323, 3195, 3058, 2192, 1658, 1601, 1450, 1403; 1H NMR (400 MHz,
DMSO-d6): δ 3.41(s, 2H), 5.16 (s, 1H), 6.83 (d, J = 8.4 Hz,1H), 7.26–
7.77 (m, 2H), 7.37–7.41 (m, 1H), 7.52–7.58 (m, 2H), 7.61–7.65 (m,
1H), 7.70–7.72 (m, 1H), 7.85 (d, J = 8 Hz, 1H), 8.26(d, J = 8.4 Hz,
1H); 13C NMR (100 MHz, DMSO-d6):
δ 36.7, 56.8, 117.5,
120.17,120.20, 121.3, 123.5, 124.8, 125.39, 125.44, 125.9, 126.2, 126.5,
126.8, 127.3, 127.5, 127.9, 128.1, 132.4, 133.2, 133.9, 143.3, 145.4,
160.4, 160.5; HRMS (+ESI): calcd. for C21H13F3N2O, 366.0974, found
366.0967.
2.2. Biological Studies
2.2.1. Bacterial and Fungal Cultures
2.1.5. 2-Amino-3-cyano-4-(3,4-dimethoxyphenyl)-4H-benzo[h]chromene
(4)
Cultures of Fusarium species, Aspergillus niger and Bacillus cereus
were obtained from culture collection unit of department of Botany.
Culture of Escherichia coli was obtained from department of Microbiolo-
gy, University of Karachi. Fungal cultures were maintained on Potato
Yield: 2.57 g (72%); mp: 134–139 °C; IR (KBr pellet, cm−1): 3472,
3336,2193, 1659, 1570, 1510, 1466; 1H NMR (400 MHz, DMSO-d6): δ

162
M. Nawaz et al. / Journal of Photochemistry & Photobiology, B: Biology 164 (2016) 160–163
Table 1
dextrose agar (PDA), B. cereus was grown on Lauria Bertani agar, while
Escherichia coli were grown on nutrient agar.
Synthesis of 2-amino-3-cyano-4-phenyl-4H-benzo[h]chromenes.
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
C6H5
3-FC6H4
1
2
3
4
5
6
7
8
9
93
66
63
72
69
82
73
61
30
2.2.2. Anti-bacterial and Anti-fungal Activities
Anti-bacterial and anti-fungal activities of all compounds (1–9)
were tested against Bacillus cereus, Escherichia coli, Fusarium species
and Aspergillus niger by disc diffusion technique [29]. Bacterial cells
were spread on the surface of agar plate; while 6 mm culture disc of ac-
tively growing fungi were placed at the center of agar plate. Each disc
(6 mm) was impregnate with 50 μL of compound and placed on inocu-
lated agar surface. Two concentrations (1000 and 500 ppm) for each
compound (1–9) were used. For controls DMSO treated disc was used
in each agar plate. Plates were incubated for 48 h (for Bacteria) and
5 days (for fungi) at 37 °C in dark and the zone of growth inhibition
was measured to the nearest mm around each of the antibiotic disc.
2-CF3C6H4
3,4-(OCH3)2C6H3
3-OCH3C6H4
3-OHC6H4
C10H6ClN2
C4H3S
C4H3O
3.2. Biological Studies
The synthesized compounds (1–9) were evaluated for their biologi-
cal activities. All the tested compounds showed varied response against
variety of microorganisms. However, it was noticed that most of the
compounds showed increased activities (P b 0.001) at higher tested
concentration (1000 ppm) against microorganisms. Compound 6 at
1000 ppm concentration exhibited largest zone (12 mm) of inhibition
of Bacillus cereus as compare with other compounds. Compounds 3, 4
and 7 found ineffective against B. cereus at both concentrations (500
and 1000 ppm) and showed no zone of inhibition. Similarly, maximum
growth of E. coli was inhibited by compound 6 at 1000 ppm (12 mm)
and largest zone was recorded. Compound 5 produces no effect on
growth of E. coli at both tested concentrations (Table 2).
Antifungal activities of these compounds were assessed against Fu-
sarium species and Aspergillus niger. Compound 9 at 1000 ppm concen-
tration greatly inhibited growth of Fusarium species, where largest zone
of inhibition (16 mm) was observed (P b 0.001). Followed by compound
5 at 1000 ppm, where Fusarium species showed zone of inhibition of
14 mm, respectively. Most of the other compounds revealed no re-
sponse to Fusarium species at tested concentrations. Similarly, all com-
pounds failed to exhibit any effect on A. niger. J2 of root-knot
nematodes Meloidogyne javanica mortality was tested after 72 h expo-
sure to compounds (1–9). Significant increased (P b 0.001) in mortality
was noticed in most of the treatments compared to controls. Highest
mortality was noticed by the exposure of compound 8 at 1000 ppm
(58%) followed by compound 9 (37%) and compound 4 (18%). However
for other compounds, mortality was ranged 4–14%. We also tested the
reactants for nematicidal, antibacterial or antifungal activity; however,
reactants did not show any activity.
2.2.3. Nematicidal Activity
Egg masses of root-knot nematodes (Meloidogyne javanica) was col-
lected from infested roots with the help of a fine needle under stereomi-
croscope and transferred into cavity blocks containing sterile distilled
water. After hatching, number of second stage juveniles (J2) maintained
around 50 to 60/4 mL in each cavity block. 100 μL of compound was
added in each cavity block. Two concentrations (1000 ppm and
500 ppm) were assessed for each compound. Cavity blocks with
100 μL of DMSO were considered as controls. Three replicates were
made for each treatment. Nematodes were considered dead if they did
not move when probed with a fine needle [30]. Data of dead juveniles
were expressed as mortality percent.
2.3. Data Analysis
Data were subjected to two factor analysis of variance (ANOVA),
followed by Fisher's least significant test [31] using the software
STATISTICA version 5.0 (Statsoft Inc., Tulsa, Oklahoma, USA).
3. Results and Discussion
3.1. Chemistry
In our synthesis protocol, we synthesized 2-amino-3-
cyanochromenes (1–9) by a three component reaction of 1-napthol,
aryl aldehydes and malononitrile using piperidine as a catalyst. The re-
action was performed in ethanol as solvent under microwave irradia-
tion (dynamic power 25–30 W) for 5–15 min (Scheme 1, Table 1). In
comparison with microwave method, we also conducted reaction by
conventional method using same solvent and catalyst. We found that
reaction was completed between 5 and 6 h. The structures of synthe-
sized compounds were elucidated by 1H NMR, 13C NMR, HRMS and
FT-IR spectrometer, results show good agreement with the structures.
4. Conclusion
A series of 2-amino-3-cyanochromenes were synthesized by utiliz-
ing microwave energy by using piperidine as a catalyst and ethanol as
a solvent. The method was more efficient as compare with conventional
method (5–6 h) and completed within 5–15 min. This methodology has
Scheme 1. Synthesis of 2-amino-3-cyano-4-phenyl-4H-benzo[h]chromenes (1–9).

M. Nawaz et al. / Journal of Photochemistry & Photobiology, B: Biology 164 (2016) 160–163
163
Table 2
Anti-bacterial, anti-fungal and nematicidal activities of compounds at different concentrations (500 and1000 ppm).
Compounds
B. cereus
E. coli
Fusarium species
A. niger
M. javanica mortality %
Zone of inhibition in mm
Control
1. 500
1000
2. 500
1000
3. 500
1000
4. 500
1000
5. 500
1000
6. 500
1000
7. 500
1000
8. 500
1000
0
6.33
9
2
4
0
0
0
0
0
0
8
9
7.33
8
7.33
8
0
6.33
0
0
0
0
0.58
0.88
0.58
0.33
0
0
0
0
0
0
10
0
0
0
0
5.67
14
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4.96
1.06
0.84
2.88
0.38
2.21
1.31
1.94
2.81
3.13
1.60
3.69
1.22
4.47
0.33
14.30
12.49
11.88
8.94
0
2
2
0
0
0
0
0
0
0
0
0
8.48
10.46
15.90
18.40
9.08
14.87
9.63
13.89
7.0800.8
8.30
48.16
58.72
27.80
37.31
3.18
8
0.58
0
0
0.67
10.66
6.33
12
0
0
6.33
7.67
0
0.33
0.33
1
0
5.67
12
0.33
0
0.58
0.88
0.65
0.88
0.33
0.88
0.67
0
0
0
0
0
0
0
0
7.66
7.8
7.33
8.67
6.33
7.67
0.75
6.04
7.04
3.25
2.10
0.33
0.33
9. 500
1000
0
8.33
0.33
16
2
aLSD0.05
Compound
Concentration
1.46
0.623
1.77
0.755
1.14
0.485
0
0
5.96
2.44
a
Fisher's least significant difference, Data comprises mean of three replicates standard error.
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