Design, synthesis, and biological evaluation of 4-H pyran derivatives as antimicrobial and anticancer agents

Article abstract of DOI:10.1007/s00044-017-1982-y

A series of pyran derivatives (5–27) were synthesized in good yields by utilizing Baylis–Hillman chemistry and were further investigated for their in vitro anticancer, antibacterial, and antifungal activities. Most of the tested compounds exhibited promis

Full text of DOI:10.1007/s00044-017-1982-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-017-1982-y
ORIGINAL RESEARCH
Design, synthesis, and biological evaluation of 4-H pyran
derivatives as antimicrobial and anticancer agents
1,4
Mettu Ravinder1 Raktani Bikshapathi1
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●
Thatikonda Narendar Reddy
Pombala Sujitha2 C. Ganesh Kumar2 Vaidya Jayathirtha Rao1,3
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Received: 17 September 2016 / Accepted: 2 July 2017
© Springer Science+Business Media, LLC 2017
Abstract A series of pyran derivatives (5–27) were syn-
thesized in good yields by utilizing Baylis–Hillman chem-
istry and were further investigated for their in vitro
anticancer, antibacterial, and antifungal activities. Most of
the tested compounds exhibited promising antibacterial
activity as compared to the standard towards Gram-positive
bacterial strains. The compounds 5–7, 11–13, and 17–19
displayed two-fold higher activity whereas compound 21
showed four-fold higher antibacterial activity against Sta-
phylococcus aureus MTCC 96 as compared to the standard
Neomycin. Some of these compounds exhibited moderate
antifungal activity against all the tested fungal strains. Two
compounds 16 and 23 showed promising anticancer activity
against selected four human cancer cell lines such as A549,
DU145, HeLa, and MCF7.
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Keywords 4-H pyran Baylis–Hillman reaction
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Antibacterial activity Antifungal activity Cytotoxicity
Introduction
The pyran core structure is a prominent heterocyclic fra-
mework, frequently found in both numerous natural pro-
ducts and bioisnpired synthetic compounds (Pettit et al.
1993; Smith et al. 1998; Hatakeyama et al. 1988; Uckun
et al. 2000; Smith et al. 2002; Hu et al. 2012; Bensoussan
et al. 2013; Armaly et al. 2015). From a medicinal chem-
istry perspective, it plays a significant functional role due to
its diverse pharmacological activities (Green et al. 1995).
Functionally, the substituted 4-H pyran scaffolds include
chromenes which are more potential in exhibiting anti-
bacterial (Kumar et al. 2009), antiviral (Wyatt et al. 2001),
anti-coagulant (Zhang et al. 1982), anti-anaphylactic (Foye
1991), anti-cancer (Kemnitzer et al. 2008), and diuretic
activities (Bonsignore et al. 1993). Furthermore, they are
useful for the treatment of neurodegenerative disorders such
as Parkinson’s, Huntington’s, and Alzheimer’s diseases
(Gourdeau et al. 2004; Kemnitzer et al. 2004). Recent stu-
dies revealed that 4-H pyran compounds, which structurally
resemble 1,4-dihydropyridines also exhibit calcium channel
antagonist activity (Atwal et al. 1990; Kappe 1998; Urbahns
et al. 2003; Kang et al. 2013). In addition, some of the pyran
derivatives find use in cosmetics, fluorescent materials,
organic light-emitting diodes, agrochemicals and in large
number of 2-amino 4-H pyran derivatives as photoactive
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-017-1982-y) contains supplementary material,
which is available to authorized users.
* Thatikonda Narendar Reddy
tnarendarreddyphd@gmail.com
* C. Ganesh Kumar
cgkumar@iict.res.in
* Vaidya Jayathirtha Rao
jrao@iict.res.in
vaidya.opv@gmail.com
1
Crop Protection Chemicals Division, CSIR-Indian Institute of
Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007,
India
2
Medicinal Chemistry and Pharmacology Division, CSIR-Indian
Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad 500007, India
3
Academy of Scientific and Innovation Research, CSIR-Indian
Institute of Chemical Technology, Uppal Road, Tarnaka,
Hyderabad 500007, India
4
Present address: Genomics Research Center, Academia Sinica,
128 Academia Road, Section 2, Nankang, Taipei 115, Taiwan

Med Chem Res
materials (Armetso et al. 1989; Lee et al. 2010; Guo et al.
2012). Moreover, 4-H pyrans are privileged structural
motifs for the synthesis of pharmaceutically relevant
molecules such as 1,4-dihydropyridines, pyridines, 2-pyr-
idones, pyrano-pyrimidines, and oxazins (Quintela et al.
1995; Bhattacharyya et al. 2012; Lin et al. 2012). Hence,
the synthesis of 4-H pyran motifs has gained renewed
interest among the synthetic organic chemists.
Over the past few decades, the Baylis–Hillman reaction
has been a prevailing tool for making various functionalized
scaffolds (Drewes and Roos 1988; Basavaiah et al. 1996
2003). In the recent years, our group has principally
focussed on the synthesis of molecules based on
Baylis–Hillman chemistry and its application towards the
synthesis of new heterocyclic compounds (Narender et al.
2006; Ravinder et al. 2009, 2010). Some of our most pro-
mising constructs has displayed good biological profile
(Narender et al. 2006; Pavan Kumar et al. 2011; Ravinder
et al. 2012; Narendar Reddy et al. 2014; Bharath Kumar
et al. 2014, Ramasatyaveni et al. 2016). In view of the
widespread biological profile of pyran derivatives and in
continuation to our efforts on Baylis–Hillman chemistry,
herein we describe the synthesis of multi-substituted 4-H-
pyran derivatives by using the Baylis–Hillman chemistry
approach and further evaluation of their biological
activities.
to stir at room temperature until completion of the reaction
(10–12 h). Upon completion, the reaction mixture was
diluted with water (15 mL) and extracted with diethyl ether
(3 × 25 mL). The combined organic layers were dried over
Na2SO4, concentrated under reduced pressure and purified
by column chromatography using 10% EtOAc in hexane as
eluent to afford pure Baylis–Hillman adducts (3a–3w) in
80–90% yield. The spectroscopic and analytical data of all
the synthesized compounds were in good agreement with
those reported in the literature (Singh and Batra 2008;
Basavaiah et al. 2010; Narendar Reddy et al. 2014).
General procedure for the synthesis of [E]-α-
cyanocinnamaldehydes (4a–4w)
A stirred solution of BH adduct (3a–3w) (1 mmol) and
NaNO3 (1 mmol) in 1 mL of [Hmim]HSO4 was heated at
80 °C for 1–2 h. The reaction progress was monitored by
TLC. Upon completion, the reaction mixture was cooled to
room temperature and extracted with ethyl acetate (3 × 15
mL). The combined organic layers were dried over Na2SO4,
filtered and evaporated under reduced pressure. The
resulting crude product was purified by column chromato-
graphy using 10% EtOAc in hexane as eluent to afford pure
[E]-α-cyanocinnamaldehyde derivatives (4a–4w). The
characterization data of the known compounds were in good
agreement with the reported data (Basavaiah et al. 1999;
Yadav et al. 2008; Narendar Reddy et al. 2014) and new
compounds data were given below.
Experimental section
General
(E)-2-formyl-3-(3-methoxyphenyl)acrylonitrile (4h)
1
All commercially available chemicals were used without
further purification. Melting points were determined on a
Mel-Temp apparatus and were uncorrected. IR spectra were
recorded using a Thermo Nicolet Nexus 670 FTIR spec-
trometer. The NMR spectra were recorded on Bruker
White solid; Yield: 71%; mp: 80–83 °C; H NMR (300
MHz, CDCl3): δ 9.57 (s, 1H, CHO), 7.83 (s, 1H, C=CH),
7.69–7.67 (m, 1H, ArH), 7.50–7.40 (m, 2H, ArH),
7.16–7.12 (m, 1H, ArH), 3.89 (s, 3H, OCH3); ESIMS (m/z)
188 [M + H]+.
1
Avance 300 spectrometer at 300 MHz for H and 75 MHz
for 13C, respectively, using TMS as internal standard. The
chemical shifts were expressed as δ values in parts per
million (p.p.m.) and the coupling constants (J) were given
in Hertz ( Hz). ESI-MS were obtained on Thermo-Finnigan
MAT-1020B instrument. Elemental analyzes were carried
out using a Perkin Elmer 2400 Series II elemental analyzer.
Column chromatography was performed using silica gel
(60–120 mesh, Acme, India).
(E)-3-(2-fluorophenyl)-2-formylacrylonitrile (4l)
1
White solid; Yield: 65%; mp: 86–88 °C; H NMR (300
MHz, CDCl3): δ 9.63 (s, 1H, CHO), 8.51–8.44 (m, 1H,
ArH), 8.26 (s, 1H, C=CH), 7.69–7.57 (m, 1H, ArH), 7.35
(t, J = 7.5 Hz, 1H, ArH), 7.29–7.21 (m, 1H, ArH); ESIMS
(m/z) 176 [M + H]+.
(E)-3-(2-bromophenyl)-2-formylacrylonitrile (4o)
General procedure for the synthesis of Baylis–Hillman
adducts (3a–3w)
1
White solid; Yield: 68%; mp: 110–112 °C; H NMR (300
MHz, CDCl3): δ 9.66 (s, 1H, CHO), 8.37 (s, 1H, C = CH),
8.33 (d, J = 7.6 Hz, 1H, ArH), 7.76 (d, J = 7.6 Hz, 1H,
ArH), 7.51, (t, J = 7.6 Hz, 1H, ArH), 7.44 (t, J = 7.6 Hz,
1H, ArH); ESIMS (m/z) 254 [M + NH4]+.
Aromatic aldehydes (1a–1w) (10 mmol), acrylonitrile (2)
(20 mmol) and 1,4-Diazabicyclo[2.2.2]octane (DABCO)
(30 mol% with respect to aldehyde) were mixed and allowed

Med Chem Res
(E)-3-(3-chlorophenyl)-2-formylacrylonitrile (4q)
2-amino-4-(4-isopropylphenyl)-4H-pyran-3,5-
dicarbonitrile (7)
1
White solid; Yield: 62%; mp: 92–94 °C; H NMR (300
1
MHz, CDCl3): δ 9.60 (s, 1H, CHO), 8.00–7.95 (m, 2H,
ArH), 7.85 (s, 1H, C=CH), 7.60 (d, J = 7.7 Hz, 1H, ArH),
7.51 (t, J = 7.7 Hz, 1H, ArH). ESIMS (m/z) 209 [M +
NH4]+.
White solid; Yield: 73%; mp: 151–153 °C; H NMR (300
MHz, DMSO-d6): δ 7.34 (s, 1H, =CH-O), 7.23 (d, J = 8.1
Hz, 2H, ArH), 7.17 (d, J = 8.1 Hz, 2H, ArH), 6.69 (s, 2H,
NH2), 4.13 (s, 1H, CHAr), 2.96–2.87 (m, 1H, CH(CH3)2),
1.26 (d, J = 6.9 Hz, 6H, CH3); 13C NMR (75 MHz,
DMSO-d6): δ 158.0, 150.0, 147.8, 139.1, 127.5, 126.7,
119.0 (CN), 116.3 (CN), 94.3, 55.6, 37.2, 32.9, 23.7; IR
(KBr) νmax: 3432, 3338, 3216, 3094, 2962, 2228, 2199,
1680, 1634, 1597, 1400, 1208, 1174 cm−1; ESIMS (m/z)
288 [M + Na]+; Anal. Calcd for C16H15N3O: C, 72.43; H,
5.70; N, 15.84; Found: C, 72.46; H, 5.74; N, 15.89.
General procedure for the synthesis of pyran derivatives
(5–27)
To a well stirred solution of cyanocinnamaldehyde (4a–4w,
1 mmol) in absolute ethanol propanedinitrile (1 mmol) and
catalytic amount of piperidine (10 mol%) were added at
room temperature and allowed to stir for 10–15 min. During
the reaction in most cases precipitation of the product was
observed. Upon completion, filtered the precipitated product
and recrystallized from ethanol. In case if product was not
precipitated in the reaction mixture then the solvent was
removed under reduced pressure and recrystallized from
ethanol. Compounds 5 and 8 are previously reported in the
literature (Ciller et al. 1985). All the newly synthesized
compounds were well characterized using spectral data (1H
NMR, 13C NMR, mass, IR, and elemental analysis) are in
full agreement with proposed structures. New compounds
data were given below.
2-amino-4-p-tolyl-4H-pyran-3,5-dicarbonitrile (8)
1
White solid; Yield: 69%; mp: 185–188 °C; H NMR (300
MHz, DMSO-d6): δ 7.70 (s, 1H, =CH–O), 7.22 (d, J = 7.9
Hz, 2H, ArH), 7.16 (d, J = 7.9 Hz, 2H, ArH), 7.12 (s, 2H,
NH2), 4.26 (s, 1H, CHAr), 2.31 (s, 3H, CH3); 13C NMR
(75 MHz, DMSO-d6): δ 158.0, 149.9, 138.6, 137.1, 129.39,
127.6, 118.9 (CN), 116.29 (CN), 94.39, 55.7, 37.2, 20.6; IR
(KBr): 3377, 3325, 3194, 3092, 2208, 1675, 1603, 1509,
1399, 1201, 1174 cm−1; ESIMS (m/z) 260 [M + Na]+;
Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67; N, 17.71;
Found: C, 70.86; H, 4.69; N, 17.68.
2-amino-4-phenyl-4H-pyran-3,5-dicarbonitrile (5)
2-amino-4-m-tolyl-4H-pyran-3,5-dicarbonitrile (9)
1
White solid; Yield: 70%; mp: 206–208 °C; H NMR (300
1
White solid; Yield: 72%; mp: 182–184 °C; H NMR (300
MHz, DMSO-d6): δ 7.68 (s, 1H, =CH–O), 7.41–7.28 (m,
5H, ArH), 6.57 (s, 2H, NH2), 4.17 (s, 1H, CHAr); 13C NMR
(75 MHz, DMSO-d6): δ 158.0, 150.1, 141.7, 128.8, 127.8,
127.6, 118.9 (CN), 116.2 (CN), 94.2, 55.59, 37.5; IR (KBr)
MHz, DMSO-d6): δ 7.71 (s, 1H, = CH-O), 7.42–7.27 (m,
1H, ArH), 7.13–7.07 (m, 5H, ArH, NH2), 4.26 (s, 1H,
CHAr), 2.33 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6):
δ 158.0, 150.1, 141.7, 138.0, 128.7, 128.6, 128.5, 128.1,
124.9, 118.9 (CN), 116.2 (CN), 94.2, 55.6, 37.5, 20.9; IR
(KBr) νmax: 3405, 3329, 3213, 2924, 2224, 2196, 1673,
1597, 1407, 1203, 1173 cm−1; ESIMS (m/z) 260 [M +
Na]+; Anal. Calcd for C14H11N3O: C, 70.87; H, 4.67; N,
17.71; Found: C, 70.83; H, 4.65; N, 17.75.
ν
max: 3384, 3320, 3206, 2870, 2224, 2194, 1673, 1600,
1402, 1211, 1183 cm−1; ESIMS (m/z) 246 [M + Na]+;
Anal. Calcd for C13H9N3O: C, 69.95; H, 4.06; N, 18.82;
Found: C, 69.99; H, 4.09; N, 18.85.
2-amino-4-(4-ethylphenyl)-4H-pyran-3,5-dicarbonitrile (6)
2-amino-4-o-tolyl-4H-pyran-3, 5-dicarbonitrile (10)
1
White solid; Yield: 75%; mp: 136–138 °C; H NMR (300
1
MHz, DMSO-d6): δ 7.36 (s, 1H, =CH–O), 7.22–7.15 (m,
4H, ArH), 6.74 (s, 2H, NH2), 4.13 (s, 1H, CHAr),
2.69–2.62 (q, J = 7.5 Hz, 2H, CH2), 1.25 (t, J = 7.5 Hz,
3H, CH3); 13C NMR (75 MHz, DMSO-d6): δ 158.0, 150.0,
143.3, 139.1, 128.2, 127.6, 119.0 (CN), 116.3 (CN), 94.2,
55.7, 37.3, 27.7, 15.3; IR (KBr) νmax: 3413, 3321, 3206,
3096, 2966, 2931, 2207, 1674, 1597, 1398, 1203, 1116
cm−1; ESIMS (m/z) 274 [M + Na]+; Anal. Calcd for
C15H13N3O: C, 71.70; H, 5.21; N, 16.72; Found: C, 71.77;
H, 5.24; N, 16.76.
White solid; Yield: 82%; mp: 201–203 °C; H NMR (300
MHz, DMSO-d6): δ 7.40 (s, 1H, =CH–O), 7.26–7.17 (m,
4H, ArH), 6.75 (s, 2H, NH2), 4.52 (s, 1H, CHAr), 2.44 (s,
3H, CH3); 13C NMR (75 MHz, DMSO-d6): δ 158.1, 150.2,
139.6, 135.4, 130.6, 128.7, 127.5, 126.8, 119.0 (CN), 116.3
(CN), 94.0, 55.4, 33.9, 18.7; IR (KBr) νmax: 3399, 3324,
3210, 3106, 2220, 2198, 1673, 1640, 1601, 1401, 1210,
1180 cm−1; ESIMS (m/z) 260 [M + Na]+; Anal. Calcd for
C14H11N3O: C, 70.87; H, 4.67; N, 17.71; Found: C, 70.81;
H, 4.70; N, 17.69.

Med Chem Res
2-amino-4-(4-methoxyphenyl)-4H-pyran-3,5-dicarbonitrile
(CN).0, 115.3 (CN), 115.0, 94.7, 56.39, 37.4; IR (KBr)
(11)
νmax: 3384, 3328, 3213, 3105, 2222, 2199, 1676, 1603,
1510, 1401, 1210, 1184 cm−1; ESIMS (m/z) 264 [M +
Na]+; Anal. Calcd for C13H8FN3O: C, 64.73; H, 3.34; N,
17.42; Found: C, 64.74; H, 3.36; N, 17.44.
1
White solid; Yield: 71%; mp: 149–151 °C; H NMR (300
MHz, DMSO-d6): δ 7.46 (s, 1H, =CH–O), 7.19 (d, J = 8.4
Hz, 2H, ArH), 6.91 (d, J = 8.4 Hz, 2H, ArH), 6.86 (s, 2H,
NH2), 4.13 (s, 1H, CHAr), 3.79 (s, 3H, OCH3); 13C NMR
(75 MHz, DMSO-d6): δ 158.8, 157.9, 149.8, 133.8, 128.9,
119.0 (CN), 116.3 (CN), 114.1, 94.5, 55.0 (2), 36.8; IR
(KBr) νmax: 3406, 3329, 3210, 3104, 2923, 2204, 1673,
1600, 1513, 1401, 1262, 1176, 1027 cm−1; ESIMS (m/z)
276 [M + Na]+; Anal. Calcd for C14H11N3O2: C, 66.40; H,
4.38; N, 16.59; Found: C, 66.44; H, 4.42; N, 16.60.
2-amino-4-(3-fluorophenyl)-4H-pyran-3,5-dicarbonitrile
(15)
1
White solid; Yield: 62%; mp: 170–172 °C; H NMR (300
MHz, DMSO-d6): δ 7.75 (s, 1H, =CH–O), 7.50–7.43 (m,
1H, ArH), 7.26 (m, 2H, ArH), 7.21–7.13 (m, 3H, ArH,
NH2), 4.40 (s, 1H, CHAr); 13C NMR (75 MHz, DMSO-d6):
δ 163.8, 160.6, 158.1, 150.5, 144.6 (d), 130.9 (d), 123.8 (d),
118.7 (CN), 116.0 (CN), 114.8, 114.6 (d), 114.3, 93.5, 55.0,
37.1; IR (KBr) νmax: 3402, 3325, 3209, 3103, 2226, 2195,
1674, 1595, 1402, 1212, 1181 cm−1; ESIMS (m/z) 264 [M
+ Na]+; Anal. Calcd for C13H8FN3O: C, 64.73; H, 3.34; N,
17.42; Found: C, 64.77; H, 3.33; N, 17.49.
2-amino-4-(3-methoxyphenyl)-4H-pyran-3,5-dicarbonitrile
(12)
1
White solid; Yield: 70%; mp: 184–186 °C; H NMR (300
MHz, DMSO-d6): δ 7.62 (s, 1H, =CH–O), 7.33–7.30 (t, J
= 7.9 Hz, 1H, ArH), 7.04 (s, 2H, NH2), 6.88 (d, J = 7.9 Hz,
1H, ArH), 6.84 (d, J = 7.9 Hz, 1H, ArH), 6.79 (s, 1H,
ArH), 4.21 (s, 1H, CHAr), 3.78 (s, 3H, OCH3); 13C NMR
(75 MHz, DMSO-d6): δ 159.4, 158.1, 150.2, 143.3, 130.0,
119.8 (CN), 118.9 (CN), 116.2, 113.7, 112.8, 94.1, 55.5,
55.0, 37.5; IR (KBr) νmax: 3406, 3325, 3208, 3106, 2925,
2207, 1674, 1596, 1490, 1397, 1211, 1176 cm−1; ESIMS
(m/z) 254 [M + H]+; Anal. Calcd for C14H11N3O2: C,
66.40; H, 4.38; N, 16.59; Found: C, 66.43; H, 4.40; N,
16.62.
2-amino-4-(2-fluorophenyl)-4H-pyran-3,5-dicarbonitrile
(16)
1
White solid; Yield: 83%; mp: 203–205 °C; H NMR (300
MHz, DMSO-d6): δ 7.78 (s, 1H, =CH–O), 7.45–7.33 (m,
2H, ArH), 7.31–7.21 (m, 4H, ArH, NH2), 4.59 (s, 1H,
CHAr);13C NMR (75 MHz, DMSO-d6): δ 161.9, 158.4,
150.8, 130.1, 128.09, 127.9, 125.0, 118.7 (CN), 115.99
(CN), 115.7, 92.7, 54.1, 32.1; IR (KBr) νmax: 3430, 3318,
3202, 2200, 2196, 1676, 1632, 1583, 1404, 1208, 1177
cm−1; ESIMS (m/z) 264 [M + Na]+; Anal. Calcd for
C13H8FN3O: C, 64.73; H, 3.34; N, 17.42; Found: C, 64.68;
H, 3.34; N, 17.42.
2-amino-4-(2-methoxyphenyl)-4H-pyran-3,5-dicarbonitrile
(13)
1
White solid; Yield: 80%; mp: 168–171 °C; H NMR (300
MHz, DMSO-d6): δ 7.31–7.26 (m, 2H, =CH–O, ArH), 7.18
(d, J = 7.6 Hz, 1H, ArH), 7.00–6.94 (m, 2H, ArH), 6.62 (s,
2H, NH2), 4.64 (s, 1H, CHAr), 3.86 (s, 3H, OCH3); 13C
NMR (75 MHz, DMSO-d6): δ 158.8, 157.0, 150.5, 129.3,
129.09, 120.9 (2), 119.1 (CN), 116.4 (CN), 111.7, 93.6,
55.7, 54.7, 31.9; IR (KBr) νmax: 3411, 3324, 3212, 3089,
3002, 2834, 2223, 2204, 1677, 1600, 1493, 1405, 1267,
1204, 1169 cm−1; ESIMS (m/z) 254 [M + H]+; Anal. Calcd
for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59; Found: C,
66.47; H, 4.38; N, 16.62.
2-amino-4-(4-bromophenyl)-4H-pyran-3,5-dicarbonitrile
(17)
1
White solid; Yield: 65%; mp: 110–113 °C; H NMR (300
MHz, DMSO-d6): δ 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.36 (s,
1H, =CH–O), 7.22 (d, J = 8.0 Hz, 2H, ArH), 6.76 (s, 2H,
NH2), 4.20 (s, 1H, CHAr); 13C NMR (75 MHz, DMSO-d6):
δ 158.1, 150.4, 141.1, 131.7, 129.9, 121.0, 118.8 (CN),
116.0 (CN), 93.6, 55.0, 36.9; IR (KBr) νmax: 3404, 3328,
3213, 3106, 2922, 2224, 2195, 1672, 1637, 1598, 1487,
1408, 1202, 1112 cm−1; ESIMS (m/z) 303 [M + H]+; Anal.
Calcd for C13H8BrN3O: C, 51.68; H, 2.67; N, 13.91;
Found: C, 51.71; H, 2.69; N, 13.99.
2-amino-4-(4-fluorophenyl)-4H-pyran-3,5-dicarbonitrile
(14)
1
White solid; Yield: 63%; mp: 171–173 °C; H NMR (300
2-amino-4-(3-bromophenyl)-4H-pyran-3,5-dicarbonitrile
MHz, DMSO-d6): δ 7.30–7.26 (t, J = 8.3 Hz, 2H, ArH),
7.23 (s, 1H, =CH–O), 7.11–7.05 (t, J = 8.3 Hz, 2H, ArH),
6.45 (s, 2H, NH2), 4.19 (s, 1H, CHAr); 13C NMR (75 MHz,
DMSO-d6): δ 163.3, 157.7, 148.3, 136.2, 129.0, 128.9, 118
(18)
1
White solid; Yield: 65%; mp: 128–130 °C; H NMR (300
MHz, DMSO-d6): δ 7.76 (s, 1H, ArH), 7.55 (d, J = 7.9 Hz,

Med Chem Res
1H, ArH), 7.50 (s, 1H, =CH–O), 7.39 (t, J = 7.4 Hz, 1H,
ArH), 7.33–7.29 (m, 3H, ArH, NH2), 4.40 (s, 1H, CHAr);
13C NMR (75 MHz, DMSO-d6): δ 158.1, 150.5, 144.4,
131.0, 130.7, 130.3, 126.9, 122.0, 118.7 (CN), 116.0 (CN),
93.4, 54.9, 37.0; IR (KBr) νmax: 3417, 3330, 3213, 3086,
2202, 1679, 1598, 1401, 1208, 1176 cm−1; ESIMS (m/z)
303 [M + H]+; Anal. Calcd for C13H8BrN3O: C, 51.68; H,
2.67; N, 13.91; Found: C, 51.70; H, 2.69; N, 13.93.
2-amino-4-(2-chlorophenyl)-4H-pyran-3,5-dicarbonitrile
(22)
1
White solid; Yield: 84%; mp: 206–209 °C; H NMR (300
MHz, DMSO-d6): δ 7.78 (s, 1H, =CH–O), 7.50 (d, J = 7.5
Hz, 1H, ArH), 7.43–7.37 (m, 3H, ArH), 7.26 (s, 2H, NH2),
4.80 (s, 1H, CHAr); 13C NMR (75 MHz, DMSO-d6): δ
158.4, 150.9, 138.0, 132.4, 130.9, 129.89, 129.7, 128.0,
118.6 (CN), 115.9 (CN), 92.6, 54.2, 35.2; IR (KBr) νmax
:
3398, 3325, 3213, 3107, 2222, 2199, 1674, 1601, 1468,
1403, 1213, 1181 cm−1; ESIMS (m/z) 280 [M + Na]+;
Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31;
Found: C, 60.63; H, 3.16; N, 16.35.
2-amino-4-(2-bromophenyl)-4H-pyran-3,5-dicarbonitrile
(19)
1
White solid; Yield: 85%; mp: 189–191 °C; H NMR (300
MHz, DMSO-d6): δ 7.78 (s, 1H, ArH), 7.66 (d, J = 7.9 Hz,
1H, ArH), 7.47 (t, J = 7.3, 7.7 Hz, 1H, ArH), 7.39 (s, 1H,
=CH–O), 7.31–7.28 (m, 3H, ArH, NH2), 4.79 (s, 1H,
CHAr); 13C NMR (75 MHz, DMSO-d6): δ 158.39, 150.9,
139.79, 133.0, 131.0, 130.0, 128.7, 122.6, 118.5 (CN),
115.8 (CN), 92.7, 54.4, 37.4; IR (KBr) νmax: 3401, 3326,
3213, 3109, 2220, 2196, 1674, 1600, 1403, 1211, 1180
cm−1; ESIMS (m/z) 303 [M + H]+; Anal. Calcd for
C13H8BrN3O: C, 51.68; H, 2.67; N, 13.91; Found: C,
51.69; H, 2.69; N, 13.93.
2-amino-4-(furan-2-yl)-4H-pyran-3,5-dicarbonitrile (23)
1
White solid; Yield: 68%; mp: 160–161 °C; H NMR (300
MHz, DMSO-d6): δ 7.47 (s, 1H, =CH–O), 7.43–7.41 (m,
1H, ArH), 6.87 (s, 2H, NH2), 6.37 (m, 1H, ArH), 6.30 (d, J
= 5.3 Hz, 1H, Ar–H), 4.35 (s, 1H, CHAr); 13C NMR (75
MHz, DMSO-d6): δ 158.5, 152.9, 151.0, 143.39, 118.6
(CN), 115.8 (CN), 110.5, 107.5, 91.9, 53.1, 31.4; IR (KBr)
ν
max: 3431, 3318, 3292, 3201, 3084, 2890, 2226, 2196,
1676, 1635, 1586, 1404, 1208, 1178, 1145 cm−1; ESIMS
(m/z) 236 [M + Na]+: Anal. Calcd for C11H7N3O2: C,
61.97; H, 3.31; N, 19.71; Found: C, 62.01; H, 3.28; N,
19.73.
2-amino-4-(4-chlorophenyl)-4H-pyran-3,5-dicarbonitrile
(20)
2-amino-4-(thiophen-2-yl)-4H-pyran-3,5-dicarbonitrile
(24)
1
White solid; Yield: 62%; mp: 168–171 °C; H NMR (300
MHz, DMSO-d6): δ 7.39 (m, 3H, =CH–O, ArH), 7.28 (d, J
= 8.3 Hz, 2H, ArH), 6.85 (s, 2H, NH2), 4.21 (s, 1H, CHAr);
13C NMR (75 MHz, DMSO-d6): δ 158.0, 150.3, 140.7,
132.4, 129.6, 128.8, 118.7 (CN), 116.0 (CN), 93.7, 55.1,
36.9; IR (KBr): 3406, 3329, 3213, 2924, 2224, 2197, 1674,
1597, 1491, 1408, 1204, 1174, 1093 cm−1; ESIMS (m/z)
280 [M + Na]+; Anal. Calcd for C13H8ClN3O: C, 60.60; H,
3.13; N, 16.31; Found: C, 60.72; H, 3.11; N, 16.39.
1
White solid; Yield: 69%; mp: 158–160 °C; H NMR (300
MHz, DMSO-d6): δ 7.42 (s, 1H, =CH–O), 7.36 (d, J = 4.3
Hz, 1H, ArH), 7.02–6.97 (m, 2H, ArH), 6.92 (s, 2H, NH2),
4.54 (s, 1H, CHAr); 13C NMR (75 MHz, DMSO-d6): δ
157.9, 149.8, 146.5, 127.0, 126.4, 125.8, 118.7 (CN), 115.9
(CN), 94.5, 56.0, 32.8; IR (KBr) νmax: 3371, 3323, 3206,
3083, 2925, 2230, 2198, 1673, 1597, 1408, 1208, 1180
cm−1; ESIMS (m/z) 230 [M + H]+; Anal. Calcd for
C11H7N3OS: C, 57.63; H, 3.08; N, 18.33; S, 13.99; Found:
C, 57.60; H, 3.04; N, 18.34; S, 13.93.
2-amino-4-(3-chlorophenyl)-4H-pyran-3,5-dicarbonitrile
(21)
2-amino-4-(naphthalen-1-yl)-4H-pyran-3,5-dicarbonitrile
(25)
1
White solid; Yield: 60%; mp: 171–173 °C; H NMR (300
MHz, DMSO-d6): δ 7.75 (s, 1H, =CH–O), 7.46–7.40 (m,
2H, ArH), 7.36 (s, 1H, ArH), 7.29–7.26 (m, 3H, ArH, NH2),
4.41 (s, 1H, CHAr); 13C NMR (75 MHz, DMSO-d6): δ
158.1, 150.6, 144.2, 133.4, 130.79, 127.9, 127.5, 126.5,
1
White solid; Yield: 61%; mp: 97–100 °C; H NMR (300
MHz, DMSO-d6): δ 8.32 (d, J = 7.1 Hz, 1H, ArH),
8.01–7.97 (m, 1H, ArH), 7.93 (d, J = 8.1 Hz, 1H, ArH),
7.81 (s, 1H, =CH–O), 7.61–7.53 (m, 3H, ArH), 7.49 (d, J
= 7.1 Hz, 1H, ArH), 7.19 (s, 2H, NH2), 5.30 (s, 1H, CHAr);
13C NMR (75 MHz, DMSO-d6): δ 158.1, 150.29, 133.4,
130.79, 128.6, 128.3, 127.1, 126.3, 125.8, 125.7, 122.8,
118.7 (CN), 116.0 (CN), 93.4, 54.9, 37.09; IR (KBr) νmax
:
3420, 3332, 3209, 3060, 2224, 2193, 1671, 1592, 1435,
1399, 1200, 1175 cm−1; ESIMS (m/z) 280 [M + Na]+;
Anal. Calcd for C13H8ClN3O: C, 60.60; H, 3.13; N, 16.31;
Found: C, 60.65; H, 3.17; N, 16.34.
118.8 (CN), 116.1 (CN), 94.5, 59.6, 55.9; IR (KBr) νmax
:

Med Chem Res
3331, 3250, 3103, 2925, 2220, 2195, 1674, 1629, 1592,
1397, 1210, 1174 cm−1; ESIMS (m/z) 296 [M + Na]+;
Anal. Calcd for C17H11N3O: C, 74.71; H, 4.06; N, 15.38;
Found: C, 74.73; H, 4.01; N, 15.35.
showing the inhibition zone is considered as the minimum
inhibitory concentration. All experiments were carried out in
duplicates and the mean values are represented.
2-amino-4-(naphthalen-2-yl)-4H-pyran-3,5-dicarbonitrile
Results and discussion
Chemistry
(26)
1
White solid; Yield: 70%; mp: 171–173 °C; H NMR (300
MHz, DMSO-d6): δ 7.99–7.92 (m, 3H, ArH), 7.82 (s, 1H,
ArH), 7.80 (s, 1H, =CH–O), 7.56–7.53 (m, 2H, ArH),
7.45–7.42 (d, J = 8.3 Hz, 1H, ArH), 7.25 (s, 2H, NH2), 4.51
(s, 1H, CHAr); 13C NMR (75 MHz, DMSO-d6): δ 158.0,
150.2, 139.0, 132.7, 132.4, 128.7, 127.7, 127.5, 126.4,
126.2, 125.3, 118.8 (CN), 116.19 (CN), 94.0, 55.5, 37.8; IR
(KBr) νmax: 3411, 3322, 3208, 3110, 3064, 2217, 2203,
1673, 1638, 1599, 1400, 1209, 1176, 1124 cm−1; ESIMS
(m/z) 274 [M + H]+; Anal. Calcd for C17H11N3O: C, 74.71;
H, 4.06; N, 15.38; Found: C, 74.78; H, 4.09; N, 15.32.
A series of pyran derivatives were synthesized as compiled in
Scheme 1. Initially we synthesized various Baylis–Hillman
(BH) adducts (3a–3w) by coupling the substituted aromatic
aldehydes (1a–1w) with acrylonitrile using DABCO in cata-
lytic amount at room temperature under solvent-free condi-
tions (Singh and Batra 2008; Basavaiah et al. 2010; Narendar
Reddy et al. 2014). Thus synthesized BH adducts were con-
verted into corresponding substituted cinnamyl aldehydes
(4a–4w) by treating them with ionic liquid (Yadav et al. 2008;
Basavaiah et al. 1999) [Hmim]HSO4 and NaNO3 by the
reported procedure (Scheme 1). Next, [E]-α-cyanocinna-
maldehydes (4a–4w) were treated with malanonitrile in pre-
sence of piperidine to afford pyran derivatives (5a–5w) via a
cascade of Michael addition followed by spontaneous intra-
molecular cyclization and the reaction was completed within
10–20 min (Scheme 1). The crude product was isolated as
crystalline solids by recrystallization from ethanol to afford
the desired product in good yields (Table 1).
To our delight, the electronic and steric effect of cyano-
cinnamaldehydes on this transformation was executed under
the standard reaction conditions. The cyanocinnamaldehydes
with electron-donating groups (methyl, methoxy, ethyl, and
isopropyl) and electron-withdrawing groups (fluoro, chloro,
and bromo) were well tolerated, and the corresponding
products could be isolated successfully. Moreover, it was
noted that phenyl group in cyanocinnamaldehyde having
ortho substitution gave good yields as compared to the
phenyl group possessing para and meta substitution, not-
withstanding the electronic character of the substituents. In
addition, cyanocinnamaldehyde bearing heteroaromatics
such as 2-thienyl, 2-furyl and also extended aromatics such
as 1-napthyl and 2-napthyl were smoothly tolerated resulting
in desired constructs with satisfactory yields.
2-amino-4-(2,4-dichlorophenyl)-4H-pyran-3,5-
dicarbonitrile (27)
1
White solid; Yield: 78%; mp: 159–161 °C; H NMR (300
MHz, DMSO-d6): δ 7.80 (s, 1H, =CH–O), 7.69 (d, J = 2.2
Hz, 1H, ArH), 7.52 (d, J = 2.2 Hz, 1H, ArH), 7.47 (s, 1H,
ArH), 7.32 (s, 2H, NH2), 4.82 (s, 1H, CHAr); 13C NMR
(75 MHz, DMSO-d6): δ 158.4, 151.1, 137.1, 133.4, 133.39,
132.3, 129.29, 128.29, 118.4 (CN), 115.7 (CN), 92.1, 53.8,
34.8; IR (KBr) νmax: 3394, 3326, 3211, 3071, 2226, 2204,
1677, 1596, 1470, 1403, 1206, 1178 cm−1; ESIMS (m/z)
293 [M + H]+; Anal. Calcd for C13H7Cl2N3O: C, 53.45; H,
2.42; N, 14.38; Found: C, 53.43; H, 2.38; N, 14.39.
Antimicrobial activity assay The antimicrobial activity of
the synthesized compounds was determined using the well
diffusion method (Amsterdam 1996) against different patho-
genic reference bacterial and Candida strains were procured
from Microbial Type Culture Collection and Gene Bank
(MTCC), CSIR-Institute of Microbial Technology, Chandi-
garh, India. The pathogenic reference strains were seeded on
the surface of the media Petri plates, containing
Muller–Hinton agar with 0.1 ml of previously prepared
microbial suspensions individually containing 1.5 × 108 cfu
ml−1 (equal to 0.5 McFarland). Wells of 6.0 mm diameter
were prepared in the media plates using a cork borer and the
synthesized compounds at a dose range of 300–1.4 µg well−1
were added in each well under sterile conditions in a laminar
air flow chamber. Standard antibiotic solutions of Neomycin
and Miconazole at a dose range of 300–1.4 µg well−1 were
used as positive controls and the well containing methanol
served as a negative control. The plates were incubated for 24
h at 30 °C and the well containing the least concentration
Biology
Antibacterial activity
All the synthesized compounds were screened for in vitro
antibacterial activity towards six strains of bacteria, includ-
ing four Gram-positive bacterial strains: Staphylococcus
aureus MTCC 96, S. aureus MLS16 MTCC 2940, Bacillus
subtilis MTCC 121, and Micrococcus luteus MTCC 2470,

Med Chem Res
Table 1 Synthesis of pyran derivatives
Table 1 continued
S.No Aldehyde
Product
Isolated
Yield (%)
S.No Aldehyde
Product
Isolated
Yield (%)
1
70
7
71
2
3
4
75
8
70
73
9
80
10
63
69
11
62
5
72
12
83
6
82

Med Chem Res
Table 1 continued
Table 1 continued
S.No Aldehyde
Product
Isolated
S.No Aldehyde
Product
Isolated
Yield (%)
Yield (%)
13
65
19
20
21
68
69
61
14
65
15
85
22
70
16
62
23
78
17
60
18
84

Med Chem Res
and three Gram-negative bacterial strains: Escherichia coli
MTCC 739, Klebsiella planticola MTCC 530, and Pseu-
domonas aeruginosa MTCC 2453 by well diffusion method
(Amsterdam 1996) and Neomycin was used as a standard.
The MIC (minimum inhibitory concentrations) values of
these title compounds are depicted in Table 2.
The antibacterial data (Table 2) revealed that most of the
tested compounds exhibited promising antibacterial activity
towards Gram-positive bacterial strains and less effective
towards Gram-negative bacterial strains as compared to the
standard, Neomycin. The compounds 5, 6, 7, 11, 12, 13, 17,
18, and 19 displayed 2-fold increase in activity (9.37 µg/
mL), whereas compound 21 showed 4-fold higher activity
(4.68 µg/mL) and compounds 25, 26, and 27 showed
equipotent (18.75 µg/mL) antibacterial activity, while the
remaining compounds displayed no activity towards S.
aureus MTCC 96 as compared to standard Neomycin (MIC
value of 18.75 µg/mL).
B. subtilis MTCC 121 as compared to standard Neomycin,
while the remaining compounds showed no activity. How-
ever, compounds 5–22 showed no activity, while the
compounds 23, 24, 25, 26, and 27 displayed equipotent
activity (18.75 µg/mL) against S. aureus MLS16 MTCC
2940 as compared to standard. In addition, compounds
5–18 and 24–27 were highly active (9.37 µg/mL), whereas
the remaining compounds showed no activity towards M.
luteus MTCC 2470. The compounds 22 and 23 were
exhibited moderate activity (37.5 µg/mL) against K. plan-
ticola MTCC 530, while the remaining compounds showed
either poor or no activity. None of the tested compounds
showed promising antibacterial activity against E. coli
MTCC 739 and P. aeruginosa MTCC 2453.
Antifungal activity
The synthesized compounds were screened for in vitro anti-
fungal activity against 14 fungal strains, including C. albicans
MTCC 183, C. albicans MTCC 227, C. albicans MTCC 854,
Compounds 5, 6, 7, 17, 18, 19, 23, 24, 25, 26, and
27 exhibited equipotent (18.75 µg/mL) activity against
Table 2 Antibacterial activity of synthesized compounds
Compounds Minimum inhibitory concentration (µg/mL)
Staphylococcus
aureus MTCC 96
Bacillus
subtilis
MTCC 121 MTCC 2940
Staphylococcus
aureus MLS16
Micrococcus
luteus MTCC
2470
Klebsiella
planticola
MTCC 530
Escherichia
coli MTCC 739 aeruginosa MTCC
Pseudomonas
2453
a
5
9.37
9.37
9.37
–
18.75
–
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
9.37
–
–
–
–
6
18.75
–
–
–
–
7
18.75
–
300
–
–
8
–
–
–
–
–
–
–
–
–
–
9
–
–
–
–
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
–
–
–
–
–
9.37
9.37
9.37
–
–
150
–
–
–
–
–
–
–
–
–
–
–
300
–
–
–
–
–
–
–
–
–
–
–
–
–
–
9.37
9.37
9.37
–
18.75
18.75
18.75
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4.68
–
–
–
–
–
–
–
–
–
–
37.5
37.5
–
–
–
–
18.75
18.75
18.75
18.75
18.75
18.75
18.75
18.75
18.75
18.75
18.75
18.75
–
–
–
–
9.37
9.37
9.37
9.37
18.75
–
–
18.75
18.75
18.75
–
–
–
–
–
–
–
–
–
Neomycin 18.75
18.75
18.75
18.75
a
No activity

Med Chem Res

Med Chem Res
C. albicans MTCC 1637, C. albicans MTCC 1962, C. albi-
cans MTCC 3017, C. albicans MTCC 3018, C. albicans
MTCC 3019, C. albicans MTCC 3958, C. albicans MTCC
4748, C. albicans MTCC 7315, C. parapsilopsis MTCC
1744, Issatchenkia orientalis MTCC 3020, and I. hanoiensis
MTCC 4755 by well diffusion method (Amsterdam 1996)
and Miconazole was used as a standard drug. The MIC
(minimum inhibitory concentrations) values of these target
compounds were compiled in Table 3.
The investigation of antifungal data (Table 3) revealed
that compounds 5–10 and 21–27 showed moderate anti-
fungal activity, with MIC values ranging between
18.75–150 µg/mL, while the remaining compounds showed
no antifungal activity as compared with the standard Mico-
nazole (9.37 µg/mL) towards all the tested fungal strains.
Table 4 In vitro cytotoxicity of synthesized compounds
Compound
IC50 values (in μM)
Anti-cancer activity
A549
DU145
HeLa
MCF7
a
5
–
49.3
115.7
75.7
39.5
81.9
–
–
–
–
–
–
–
All the title compounds were evaluated for their cytotoxic
activity against a panel of four human cancer cell lines:
A549 (Lung cancer, american type culture collection
(ATCC) No. CCL-185), MCF7 (Breast cancer, ATCC No.
HTB-22), DU145 (Prostate cancer, ATCC No. HTB-81),
and HeLa (Cervical cancer, ATCC No. CCL-2) using the
standard MTT assay (Mosmann 1983). The results of the
assay are compiled in Table 4 (where the IC50 value is
defined as the concentration of the compound that corre-
sponds to 50% growth inhibition). The results of the cyto-
toxic study indicate that most of the tested compounds, with
the exception of 5, 11, 12, and 14 showed cytotoxic activity
on all tested cell lines. Among them, compound 16 showed
promising anticancer activity on both A549 (4.3 μM) and
DU145 (4.4 μM) cell lines and moderate activity on HeLa
(8.9 μM) and MCF7 (7.9 μM) cell lines as compared to the
standard Doxorubicin. Compound 23 also showed promis-
ing activity against DU145 (4.5 μM) cell line and good
activity on A549 (5.5 μM), HeLa (5.1 μM) and MCF7 (5.9
μM) cell lines. Compounds 17–22, 24–27 displayed good
(5.9–8.9 μM) to moderate (10.1–24.5 μM) anticancer
activity towards the four human cancer cell lines. From a
structure-activity relationship (SAR) perspective, it can be
noted that the phenyl moiety bearing o-fluoro functionality
and as well 2-furyl motif exhibited more activity as com-
pared to other compounds.
6
7
–
–
100.4
–
8
69.8
33.9
78.1
–
74.1
37.1
–
9
29.8
–
10
11
–
–
12
–
–
–
–
13
43.4
–
39.8
–
42.1
–
40.2
–
14
15
309.5
4.3
–
–
231.2
7.9
14.1
7.9
8.2
24.5
8.9
12.1
5.9
17.1
13.9
11.7
15.4
0.6
16
4.4
13.8
6.8
8.9
20.3
10.7
10.1
4.5
15.9
13.2
11.1
15.2
0.8
8.9
12.9
5.9
7.9
21.3
9.8
11.2
5.1
16.3
12.9
12.3
14.3
0.7
17
14.0
7.8
18
19
8.1
20
19.6
10.6
10.8
5.5
21
22
23
24
16.4
14.0
10.9
16.2
0.7
25
26
27
Doxorubicin
a
No activity
Scheme 1 Synthesis of pyran
derivatives. Reagents and
conditions: a DABCO (30 mol
%), overnight; b [Hmim]HSO4,
NaNO3, 80°C, c Malanonitrile,
Piperidine, Etahnol, r.t

Med Chem Res
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Baylis−Hillman reaction and applications. Chem Rev
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(2013) Iron-catalyzed cross-coupling between C-bromo manno-
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cinnamyl-substituted isatin derivatives. Med Chem Res
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Conclusions
In conclusion, we have described efficient reaction condi-
tions for the synthesis of pyran derivatives from
Baylis–Hillman adducts and characterized by spectral ana-
lyzes. All the synthesized compounds were screened for
their in vitro antibacterial, antifungal, and anti-cancer
activities. The investigation of antibacterial data showed
that compounds 5–7, 11–13, and 17–19 were two fold
higher activity, whereas compound 21 was four fold higher
antibacterial activity as compared to that of standard Neo-
mycin against S. aureus MTCC 96. Some of these com-
pounds had moderate antifungal activity against the tested
fungal strains. Compounds bearing o-fluoro functionality
(16) and 2-furyl motif (23) exhibited more anticancer
activity against the tested cell lines. Based on these results,
we understand that these compounds are promising leads
with diverse biological activities and are new chemical
entities.
Acknowledgements The authors thank the Director, CSIR-Indian
Institute of Chemical Technology for encouragement. V.J.R. thanks,
CSC-0108-ORIGIN project, and CSIR-New Delhi for Emeritus Sci-
entist honor. T.N.R. and R.B.P. acknowledge the CSIR-UGC New
Delhi, while M.R. and P.S. acknowledge the CSIR, New Delhi for
research fellowships.
Gourdeau H, Leblond L, Hamelin B, Desputeau C, Dong K, Kianicka
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Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no compet-
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