Synthesis and evaluation of chromone-2-carboxamide derivatives as cytotoxic agents and 5-lipoxygenase inhibitors

Article abstract of DOI:10.1007/s00044-016-1691-y

In the present study, we prepared a series of 21 chromone carboxamide derivatives bearing diverse amide side chains. Their potency to inhibit the proliferation of breast (MCF-7), ovarian (OVCAR and IGROV), and colon (HCT-116) cancer cell lines, was evaluated in vitro using the MTT assay. Among these compounds, 13 showed promising cytotoxic activity against at least one cancer cell line with IC₅₀ in the range 0.9–10 μM. Our compounds were also screened for their anti-inflammatory activity as putative inhibitors of 5-lipoxygenase. Structure-activity relationships studies on our chromone carboxamide derivatives revealed that the presence of a 6-fluoro substituent on the chromone nucleus (R₁) or propyl and 3-ethylphenyl groups on the amide side chain (R₂) has a positive impact on the cytotoxic activity. In terms of the anti-inflammatory activity, hydrophilic chromone carboxamide derivatives showed greater 5-lipoxygenase inhibition. The physico-chemical properties of chromone carboxamides are in accordance with the general requirements of drug development process and ligand efficiency values allow further structure optimization, with compound 4b as a lead.

Full text of DOI:10.1007/s00044-016-1691-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1691-y
ORIGINAL RESEARCH
Synthesis and evaluation of chromone-2-carboxamide derivatives as
cytotoxic agents and 5-lipoxygenase inhibitors
Fatima Bousejra-ElGarah1 Barbora Lajoie1 Jean-Pierre Souchard2
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Geneviève Baziard1 Jalloul Bouajila2 Salomé El Hage1
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Received: 18 September 2015 / Accepted: 14 July 2016
© Springer Science+Business Media New York 2016
Abstract In the present study, we prepared a series of 21
chromone carboxamide derivatives bearing diverse amide
side chains. Their potency to inhibit the proliferation of
breast (MCF-7), ovarian (OVCAR and IGROV), and colon
(HCT-116) cancer cell lines, was evaluated in vitro using
the MTT assay. Among these compounds, 13 showed
promising cytotoxic activity against at least one cancer cell
line with IC50 in the range 0.9–10 μM. Our compounds
were also screened for their anti-inflammatory activity as
putative inhibitors of 5-lipoxygenase.
drug development process and ligand efficiency values
allow further structure optimization, with compound 4b as
a lead.
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Keywords Chromone carboxamides Cytotoxic activity
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Anti-inflammatory effect Lipophilicity SAR
Structure-activity relationships studies on our chromone
carboxamide derivatives revealed that the presence of a 6-
fluoro substituent on the chromone nucleus (R1) or propyl
and 3-ethylphenyl groups on the amide side chain (R2) has
a positive impact on the cytotoxic activity. In terms
of the anti-inflammatory activity, hydrophilic chromone
carboxamide derivatives showed greater 5-lipoxygenase
inhibition.
Introduction
The chromone scaffold [(4H)-1-benzopyran-4-one] is well
known as a pharmacophore of a large number of natural and
synthetic bioactive molecules. This heterocycle constitutes
the basic nucleus of flavones, an important and widespread
class of compounds from plants with a large number of
biological activities (Gaspar et al., 2014, Keri et al., 2014).
Natural and synthetic chromones have shown a large
spectrum of biological activities such as anti-inflammatory
(Khan et al., 2010, Thanigaimalai et al., 2010), antimalarial
(Auffret et al., 2007), and anticancer activity (Budzisz et al.,
2002, Barve et al., 2006), associated with low toxicity (do
Rocio Andrade Pires et al., 2016)
With 8.2 million deaths and 14.1 million new cases in
2012 (WHO, 2013), and given the fact that this number will
reach 22.2 million by 2030, cancer has become one of the
major health problems worldwide (Bray et al., 2012). The
situation is expected to worsen because of the increase of
multidrug resistances in various types of cancer (e.g., breast,
ovarian, gastrointestinal, lung cancers) making the devel-
opment of new active compounds a real challenge for the
coming years (Pan et al., 2016).
The physico-chemical properties of chromone carbox-
amides are in accordance with the general requirements of
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1691-y) contains supplementary material,
which is available to authorized users.
* Jalloul Bouajila
jalloul.bouajila@univ-tlse3.fr
* Salomé El Hage
salome.elhage@univ-tlse3.fr
1
Laboratoire de Génie Chimique, Université de Toulouse, CNRS,
INPT, UPS, Faculté des Sciences Pharmaceutiques, 35 chemin des
Maraîchers, 31062 , Toulouse cedex 09, France
2
Université de Toulouse 3 Paul-Sabatier, Faculté des Sciences
In the search for new efficient anticancer drugs, chro-
mones in particular carboxamides, can play an important
Pharmaceutiques, Laboratoire des IMRCP UMR 5623 CNRS, 35
chemin des Maraîchers, 31062, Toulouse cedex 09, France

Med Chem Res
role as demonstrated by the growing interest toward this
class of compounds. Indeed, several chromone carbox-
amides have been reported as potent and selective cytotoxic
agents (Bhatnagar et al., 2010, Nam et al., 2010, Valdameri
et al., 2012, Redda et al., 2014) and others were evaluated
as monoamine oxidase inhibitors (Gaspar et al., 2011) or
adenosine receptor ligands (Gaspar et al., 2012).
Besides, the association between cancer and inflamma-
tion has long been established (Balkwill and Mantovani,
2012). For instance, the involvement of the 5-lipoxygenase
enzyme (5-LOX) and its products have been implicated in
the development and progression of colon cancer (Sou-
maoro et al., 2006). 5-LOX has been reported to induce
inflammation via the catalysis of the production of leuko-
trienes from arachidonic acid (Shimizu et al., 1984) and it is
therefore an important target for mechanism-based drugs for
the treatment of inflammatory disorders, often associated
with other diseases including cancer. Therefore, anti-
inflammatory agents that inhibit leukotriene production may
have a beneficial effect in both the prevention and treatment
of cancer (Aggarwal et al., 2006).
In the present study, we synthesized 21 substituted
chromone carboxamides, among which 12 are newly
described, and evaluated their potency to inhibit the pro-
liferation of breast, ovarian, and colon cancer cell lines. Our
compounds were also screened for their anti-inflammatory
activity as putative inhibitors of 5-LOX. Additionally, an in
silico study of the “drug-likeliness” properties for our
derivatives was carried out by investigating their Lipinski
parameters (Lipinski et al., 1997) and calculating their
ligand efficiency values (Abad-Zapatero, 2007) to discuss
structure–activity relationships (SAR).
theoretical values. Mass spectra, electrospray ionization-
method, were recorded on DSQ Thermo Fisher Scientific
mass spectrometer; signals were given as m/z.
Commercially available chromone-2-carboxylic acids
1a–1e, amine derivatives and all other reagents were pur-
chased from Acros Organics (Halluin, France) and used
without additional purification. Chemical structures were
confirmed by infrared (IR), 1H NMR, 13C NMR, and
ESI–MS.
The physico-chemical properties of compounds pre-
viously described 3a, 3c, 3d, 3e (Ellis and Shaw, 1972), 4a,
5a (Gaspar et al., 2011), 8a (Gaspar et al., 2011), 9a
(Gaspar et al., 2012), and 10a (Gaspar et al., 2012) are in
agreement with the literature data.
General procedure for the synthesis of acyl chloride 2
4-oxo-4H-1-benzopyran-2-carbonyl chloride derivatives
were prepared according to a previously described method
(Payard, 1973). Phosphorus pentachloride (0.028 mol; 1.1
equiv.) was added to a solution of substituted chromone-2-
carboxylic acid (0.025 mol) in dry cyclohexane (50 mL).
The mixture was stirred under reflux for 1 h with the for-
mation of the corresponding acyl chloride. After cooling,
the formed solid was filtered and used without purification.
General procedure for the synthesis of compounds 3–14
An equimolar amount of the suitable acyl chloride was
slowly added to a stirred solution of the corresponding amine
(0.015 mol) in dry dichloromethane (DCM) (ammonium
hydroxide, aniline, propylamine, 3-ethylaniline, 4-methyla-
niline, 4-chloroaniline, 4-fluoroaniline, 4-hydroxyaniline,
4-amino-α-diethylamino-O-cresol dihydrochloride, N,N-die-
thylpentyl-2,5-diamine, aminomorpholine, 1-(pyrrolidino-
carbonylmethyl)piperazine) in presence of triethylamine
(1 equiv.). The solution was stirred at room temperature and
monitored by TLC. The mixture was washed with water,
10 % Na2CO3 and brine. Purification by flash silica gel
chromatography (0–8 % MeOH in DCM) provided the
desired amides.
Materials and methods
Chemistry
Melting points were determined on a DSC-50 Shimadzu
apparatus (Kyoto, Japan). Infra-red spectra were recorded
on a Perkin–Elmer Spectrum One fourier transform infrared
spectrometer (Perkin–Elmer, USA). Proton nuclear mag-
netic resonance (1H NMR) (300 MHz) and 13C NMR
(75 MHz) spectra were obtained in CDCl3 or DMSO-d6 on
a DPX 300 spectrometer (Brüker Biosciences, USA), and
peak positions are given as s (singlet), d (doublet), t (triplet),
q (quadruplet) or m (multiplet). Chemical shift (δ) values
are given in parts per million. Reactions were monitored by
thin-layer chromatography (TLC) using pre-coated silica
gel plates 60 F-254. All yields are calculated for analytically
pure materials. The microanalyses were performed in the
Microanalytical Laboratory of ENSIACET in Toulouse,
France, and the results obtained were within 0.4 % of the
6-Fluoro-4-oxo-4H-1-benzopyran-2-carboxamide
(3b)
Yield: 91 %; m.p.: 131 °C; IR (KBr) v cm−1: 3362 (NH2),
3073, 3050, 2927 (CH), 1738, 1696 (CONH2), 1635 (CO),
1
1624 (C=C); H NMR (CDCl3): δ 6.95 (s, 1H, H3), 7.80–
7.94 (m, 3H, H5, H7, H8), 8.33, and 8.70 (2s, 2H, NH2); 13
C
NMR (DMSO-d6) δ: 177.30 (C4), 161.02 (C6), 158.45 (C2),
156.51 (CO–NH2), 152.04 (C8a), 125.29 (C4a), 123.47 (C7),
122.16 (C8), 110.17 (C3), 109.88 (C5); MS (m/z) 208.0 [M
+H]+. Anal. calcd. for C10H6FNO3: C, 57.98; H, 2.92; N,
6.76 %. Found: C, 57.83; H, 2.97; N, 6.84 %.

Med Chem Res
6-Fluoro-N-propyl-4-oxo-4H-chromene-2-carboxamide
(4b) Yield: 32 %; m.p.: 196 °C; IR (KBr) v cm−1: 3412
(NH), 3303, 2964, 2936, 2879 (CH, CH2, CH3), 1686
(CONH), 1642 (CO), 1618, 1540 (C=C); 1H NMR
(DMSO-d6): δ 0.91 (t, 3H, CH3, J = 7.5Hz), 1.57 (m, 2H,
CH2–CH2–CH3,), 3.26 (m, 2H, NH–CH2), 6.83 (s, 1H, H3),
7.71–7.86 (m, 3H, H5, H7, H8), 9.14 (s br, 1H, NH); 13C
NMR (DMSO-d6): δ 177.25 (C4), 160.89 (C6), 158.45 (C2),
156.46 (CO–NH), 152.00 (C8a), 125.31 (C4a), 123.72 (C7),
122.14 (C8), 110.15 (C3), 109.91 (C5), 41.47, 22.57 (2
CH2), 11.83 (CH3); MS (m/z) 250.0 [M+H]+. Anal. calcd.
for C13H12FNO3: C, 62.65; H, 4.85; N, 5.62 %. Found: C,
62.76; H, 4.97; N, 5.46 %.
3.1 Hz), 7.95 (dd, 1H, H5, J = 9.2, 4.4 Hz), 10.68 (s br, 1H,
NH); 13C NMR (DMSO-d6): δ 177.24 (C4), 160.97 (C6),
158.53 (C2), 156.39 (CO-NH), 152.03 (C8a), 144.94 (C3′),
137.89 (C1′), 129.22 (C5′), 125.38 (C4′), 125.31 (C4a),
123.55 (C7), 122.30 (C8), 120.88 (C2′), 118.96 (C6′), 110.68
(C3), 109.93 (C5) 28.67 (CH2), 15.94 (CH3); MS (m/z) 312.1
[M+H]+. Anal. calcd. for C18H14FNO3: C, 69.45; H, 4.53;
N, 4.50 %. Found: C, 69.57; H, 4.65; N, 4.39 %.
6-Bromo-N-(3′-ethylphenyl)-4-oxo-4H-chromene-2-car-
boxamide (6d) Yield: 52 %; m.p.: 227 °C; IR (KBr)
v cm−1: 3267 (NH), 3075, 2961, 2960, 2927, (CH, CH2,
CH3), 1683 (CONH), 1637 (CO), 1608, 1597, 1541 (C=C);
1H NMR (DMSO-d6): δ 1.34 (t, 3H, CH3, J = 7.6 Hz), 2.76
(q, 2H, CH2, J = 7.6 Hz), 7.13 (s, 1H, H3), 7.19 (d, 1H, H4′,
J = 7.6 Hz), 7.46 (t, 1H, H5′, J = 7.7 Hz), 7.75 (m, 2H, H2′,
H6′), 7.96 (d, 1H, H8, J = 8.9 Hz), 8.22 (dd, 1H, H7, J = 8.9,
2.5 Hz), 8.28 (d, 1H, H5, J = 2.5 Hz), 10.4 (s br, 1H, NH);
13C NMR (DMSO-d6): δ 176.68 (C4), 157.80 (C2), 156.38
(CO–NH), 154.58 (C8a), 144.95 (C3′), 138.16 (C7), 137.88
(C1′), 129.23 (C5′), 127.49 (C5), 125.63 (C4a), 125.04 (C4′),
122.17 (C8), 120.88 (C2′), 119.04 (C6), 118.97 (C6′),
111.51 (C3), 28.67 (CH2), 15.94 (CH3); MS (m/z) 372.0 and
374.0 [M+H]+. Anal. calcd. for C18H14BrNO3: C, 58.08; H,
3.79; N, 3.76 %. Found: C, 58.29; H, 3.64; N, 3.89 %.
6-Bromo-N-propyl-4-oxo-4H-chromene-2-carboxamide
(4d) Yield: 33 %; m.p.: 210 °C; IR (KBr) v cm−1: 3291
(NH), 3075, 2965, 2932, 2873 (CH, CH2, CH3), 1687
(CONH), 1646 (CO), 1600, 1536 (C=C); 1H NMR
(DMSO-d6): δ 0.90 (t, 3H, CH3, J = 7.4 Hz), 1.57 (m, 2H,
CH2–CH2–CH3), 3.26 (m, 2H, NH–CH2), 6.85 (s, 1H, H3),
7.71 (d, 1H, H8, J = 8.9 Hz), 8.06 (dd,1H, H7, J = 8.8, 2.5
Hz), 8.11 (d, 1H, H5, J = 2.5 Hz), 9.14 (s br, 1H, NH); 13C
NMR (DMSO-d6): δ 176.61 (C4), 159.07 (C2), 156.40
(CO–NH), 154.51 (C8a), 138.03 (C7), 127.48 (C5), 125.57
(C4a), 121.90 (C8), 118.85 (C6), 110.85 (C3), 41.49, 22.58
(2 CH2), 11.85 (CH3); MS (m/z) 310.0 and 312 [M+H]+.
Anal. calcd. for C13H12BrNO3: C, 50.34; H, 3.90; N, 4.52 %.
Found: C, 50.45; H, 3.79; N, 4.63 %.
N-(3′-ethylphenyl)-6-methyl-4-oxo-4H-chromene-2-car-
boxamide (6e) Yield: 33 %; m.p.: 202 °C; IR (KBr) v
cm−1: 3326 (NH), 3074, 2928, 2850, (CH, CH2, CH3), 1681
1
N-(3′-ethylphenyl)-4-oxo-4H-chromene-2-carboxamide
(6a) Yield: 71 %; m.p.: 168 °C; IR (KBr) v cm−1: 3268
(NH), 2960, 2927, 2868 (CH, CH2, CH3), 1682 (CONH),
1640 (CO), 1615, 1540 (C=C); 1H NMR (CDCl3) δ: 1.29 (t,
3H, CH3, J = 7.6 Hz), 2.71 (q, 2H, CH2, J = 7.6 Hz), 7.09
(d, 1H, H8, J = 7.5 Hz), 7.32 (s,1H, H3), 7.35 (t, 1H, H5’,
J = 7.8 Hz), 7.49–7.64 (m, 4H, H6, H2’ H4’, H6’), 7.79 (td,
1H, H7, J = 7.2, 1.7 Hz), 8.27 (dd, 1H, H5, J = 7.9, 1.6 Hz),
8.54 (s br, 1H, NH); 13C NMR (DMSO-d6): δ 177.79 (C4),
158.08 (C2), 156.19 (CO-NH), 155.62 (C8a), 144.90 (C3′),
137.99 (C1′), 135.49 (C7), 129.19 (C5′), 126.56 (C6),
125.39 (C5), 124.94 (C4′), 124.15 (C4a), 120.89 (C2′),
119.49 (C8), 118.97 (C6′), 111.48 (C3), 28.68 (CH2), 15.94
(CH3); MS (m/z) 294.1 [M+H]+. Anal. calcd. for
C18H15NO3: C, 73.71; H, 5.15; N, 4.78 %. Found: C, 73.59;
H, 5.28; N, 4.92 %.
(CONH), 1637 (CO), 1610, 1594, 1541 (C=C); H NMR
(DMSO-d6): δ 1.21 (t, 3H, CH2-CH3, J = 7.6 Hz), 2.48 (s,
3H, CH3), 2.64 (q, 2H, CH2, J = 7.6 Hz), 6.94 (s, 1H, H3),
7.07 (d, 1H, H4′, J = 8.0 Hz), 7.33 (t, 1H, H5′, J = 8.0 Hz),
7.65 (m, 2H, H2′, H6′), 7.75 (m, 2H, H7, H8), 7.87 (s, 1H,
H5), 10.66 (s br, 1H, NH); 13C NMR (DMSO-d6): δ 177.72
(C4), 158.13 (C2), 156.04 (CO–NH), 153.88 (C8a), 144.89
(C3′), 137.99 (C7), 136.56 (C1′), 136.29 (C6), 129.18 (C5′),
124.92 (C4′), 124.62 (C5), 123.86 (C4a), 120.86 (C2′),
119.27 (C8), 118.94 (C6′), 111.31 (C3), 28.68 (CH2), 20.94
and 15.94 (2 CH3); MS (m/z) 308.1 [M+H]+. Anal. calcd.
for C19H17NO3: C, 74.25; H, 5.58; N, 4.56 %. Found: C,
74.37; H, 5.42; N, 4.69 %.
N-(4′-fluorophenyl)-4-oxo-4H-chromene-2-carboxamide
(7a) Yield: 48 %; m.p.: 222 °C; IR (KBr) v cm−1: 3338
(NH), 3138, 3072 (CH), 1697 (CONH), 1630 (CO), 1573,
1508 (C=C); 1H NMR (DMSO-d6): δ 6.98 (s,1H, H3), 7.27
(m, 2H, H3′, H5′), 7.57 (m, 1H, H6), 7.82–7.85 (m, 4H, H7,
H8, H2′, H6′), 8.08 (dd, 1H, H5, J = 7.9, 1.6 Hz), 10.82
(s,1H, NH); 13C NMR (DMSO-d6): δ 177.73 (C4), 160.66
(C4′), 158.25 (C2), 156.01 (CO–NH), 155.60 (C8a), 135.48
(C7), 134.35 (C1′), 126.55 (C6), 125.39 (C5), 124.14 (C4a),
123.60 (C6′), 123.52 (C2′), 119.47 (C8), 116.03 (C5′),
115.80 (C3′), 111.56 (C3); MS (m/z) 284.0 [M+H]+. Anal.
6-Fluoro-N-(3′-ethylphenyl)-4-oxo-4H-chromene-2-carbox-
amide (6b) Yield: 54 %; m.p.: 198 °C; IR (KBr) v cm−1:
3280 (NH), 3081, 2962, 2929, (CH, CH2, CH3), 1685
1
(CONH), 1637 (CO), 1612, 1593, 1543 (C=C); H NMR
(DMSO-d6): δ 1.21 (t, 3H, CH3, J = 7.6 Hz), 2.64 (q, 2H,
CH2, J = 7.6 Hz), 6.98 (s, 1H, H3), 7.06 (d, 1H, H4’, J = 7.6
Hz), 7.33 (t, 1H, H5′, J = 7.6 Hz), 7.64 (m, 2H, H2′, H6′),
7.77 (dd, 1H, H8, J = 8.3, 3.1 Hz), 7.85 (td, 1H, H7, J = 8.1,

Med Chem Res
calcd. for C16H10FNO3: C, 67.84; H, 3.56; N, 4.94 %.
Found: C, 67.53; H, 3.62; N, 4.88 %.
2-[4(N-pyrrolidinylcarbonylmethyl)-piperazinylcarbonyl]-
4H-chromen-4-one (14a) Yield: 55 %; m.p.: 117 °C; IR
(KBr) v cm−1: 3052, 2973, 2955, 2867, 2820 (CH, CH2,
CH3), 1662 (CONH), 1644 (CO), 1617, 1573, 1510 (C=C);
1H NMR (CDCl3): δ 1.89 and 1.98 (2m, 4H, H3″, H4″), 2.7
(m, 4H, H2″, H5″), 3.22 (s, 2H, N–CH2–CO–), 3.48 (m, 4H,
H3′, H5′), 3.62, and 3.85 (2m, 4H, H2′, H6′), 6.53 (s, 1H,
H3), 7.46 (t, 1H, H6, J = 7.1 Hz), 7.52 (d, 1H, H8, J = 8.6
Hz), 7.76 (td, 1H, H7, J = 7.1, 1.7 Hz), 8.25 (dd, 1H, H5,
J = 8.0, 1.5 Hz); 13C NMR (DMSO-d6): δ 177.08 (C4),
167.66 (CO–CH2), 160.52 (CO–NH), 158.46 (C2), 155.91
(C8a), 135.51 (C7), 126.57 (C6), 125.39 (C5), 124.16 (C4a),
119.08 (C8), 111.01 (C3), 60.22 (CO–CH2–N), 53.06 and
52.23 (2C pyrrolidine), 46.99, 45.99, 45.81 and 42.20 (4C
piperazine), 26.16 and 24.12 (2C pyrrolidine); MS (m/z)
370.2 [M+H]+. Anal. calcd. for C20H23N3O4: C, 65.03; H,
6.28; N, 11.37 %. Found: C, 65.21; H, 6.15; N, 11.25 %.
N-[3-((diethylamino)methyl)-4-hydroxyphenyl]-4-oxo-4H-
chromene-2-carboxamide (11a) Yield: 26 %; m.p.: 186 °
C; IR (KBr) v cm−1: 3470 (OH), 3339 (NH), 3075, 2975,
2827 (CH, CH2, CH3), 1685 (CONH), 1638 (CO), 1616,
1
1560, 1512 (C=C); H NMR (DMSO-d6): δ 1.05 (t, 6H,
CH2–CH3, J = 6.8 Hz), 2.56 (m, 4H, N–CH2–CH3), 3.33 (s
br, 1H, OH), 3.73 (s, 2H, Ar–CH2–N), 6.73 (d, 1H, H5′, J =
8.4 Hz), 6.94 (s, 1H, H3), 7.54 (m, 2H, H6 and H6′), 7.70 (s,
1H, H2′), 7.85 (d, 1H, H8, J = 8.7 Hz), 7.93 (t, 1H, H7, J =
7.5 Hz), 8.08 (d, 1H, H5, J = 6.9 Hz), 10.56 (s br, 1H, NH);
13C NMR (DMSO-d6): δ 177.92 (C4), 157.70 (C2), 156.36
(CO–NH), 155.61 (C8a), 154.92 (C4′), 135.54 (C7), 129.32
(C1′), 129.30 (C6′), 126.52 (C6), 125.39 (C5), 125.37 (C3′),
124.07 (C4a), 123.29 (C2′), 119.48 (C8), 115.91 (C5′),
111.27 (C3), 53.19 (Ar–CH2–N), 46.65 (N–CH2), 10.51
(CH3); MS (m/z) 367.2 [M+H]+. Anal. calcd. for
C21H22N2O4: C, 68.84; H, 6.05; N, 7.65 %. Found: C,
68.92; H, 6.24; N, 7.52 %.
Pharmacology
Anti-inflammatory activity
N-(5-(diethylamino)pent-2-yl)-4-oxo-4H-chromene-2-car-
boxamide (12a) Yield: 57 %; m.p.: 110 °C; IR (KBr) v
cm−1: 3475, 3428, 3370 (NH), 2978, 2939, 2633 (CH, CH2,
CH3), 1679 (CONH), 1647 (CO), 1608, 1572, 1528 (C=C);
1H NMR (DMSO-d6): δ 1.19 (t, 6H, CH2–CH3, J = 7.2 Hz),
1.23 (d, 3H, CH–CH3, J = 6.6 Hz), 1.62 (m, 4H, CH–CH2–
CH2–CH2–N), 3.05 (m, 6H, 3 CH2–N), 4.05 (m, 1H, CH),
6.85 (s, 1H, H3), 7.55 (td, 1H, H6, J = 7.9, 0.9 Hz), 7.82 (d,
1H, H8, J = 7.8 Hz), 7.91 (td, 1H, H7, J = 8.5, 1.6 Hz), 8.05
(dd, 1H, H5, J = 7.9, 1.3 Hz), 10.13 (s br, 1H, NH); 13C
NMR (DMSO-d6): δ 177.86 (C4), 159.02 (C2), 156.27 (CO-
NH), 155.60 (C8a), 135.38 (C7), 126.49 (C6), 125.30 (C5),
124.05 (C4a), 119.51 (C8), 110.97 (C3), 50.76 and 46.50 (2
CH2), 45.42 (CH), 32.96 (CH2), 20.89 (CH3) 20.48 (CH2),
8.82 (CH3); MS (m/z) 331.2 [M+H]+. Anal. calcd. for
C19H26N2O3: C, 69.06; H, 7.93; N, 8.48 %. Found: C,
69.23; H, 7.72; N, 8.33 %.
The anti-inflammatory activity of compounds was deter-
mined by the inhibition of soybean lipoxygenase. Chro-
mone derivatives were dissolved in dimethyl sulfoxide
(DMSO) and solutions were diluted in sodium phosphate
buffer (pH 7.4). Diluted solutions of compounds (20 μL)
were mixed individually with 30 μL of sodium phosphate
buffer containing 5-LOX and 60 μL of linoleic acid (3.5
mM) in a 96-well microliter plate. Addition of 90 μL buffer
gave a total volume of 200 μL and a final concentration of
chromone carboxamide of 100 μM. The DMSO concentra-
tion did not exceed 1 %. The mixture was incubated at 25 °
C for 10 min, and the absorbance was recorded at 234 nm
using a Thermo Scientific Multiskan GO Microplate Spec-
trophotometer. The absorption changes with the conversion
of linoleic acid to 13-hydroperoxyoctadeca-9,11-dienoate.
Nordihydroguaiaretic acid (NDGA) was used as positive
control. Percentage inhibition of enzyme was determined by
comparison of rates of reaction of samples relative to blank
sample using the formula (E−S)/E × 100, where E is the
activity of enzyme without test sample and S is the activity
of enzyme with test sample. The percentage of inhibition of
each compound was determined in triplicate.
N-morpholino-4-oxo-4H-chromene-2-carboxamide (13a)
Yield: 57 %; m.p.: 271 °C; IR (KBr) v cm−1: 3219 (NH),
3061, 2962, 2938, 2874 (CH), 1684 (CONH2), 1644 (CO),
1
1620, 1607, 1511 (C=C); H NMR (DMSO-d6): δ 2.94 (t,
4H, O–CH2–CH2–N, J = 4.6 Hz), 3.69 (t, 4H, O–CH2–
CH2–N, J = 4.6 Hz), 6.82 (s, 1H, H3), 7.55 (td, 1H, H6, J =
8.0, 1.0 Hz), 7.76 (d, 1H, H8, J = 7.9 Hz), 7.90 (m, 1H, H7),
Cytotoxicity evaluation
8.05 (dd, 1H, H5, J = 7.9, 1.6 Hz), 10.20 (s br, 1H, NH); 13
C
NMR (DMSO-d6): δ 177.69 (C4), 157.30 (C2), 156.15
(CO–NH), 155.57 (C8a), 135.51 (C7), 126.57 (C6), 125.39
(C5), 124.09 (C4a), 119.34 (C8), 111.25 (C3), 66.39 (2 CH2),
54.63 (2 CH2); MS (m/z) 275.0 [M+H]+. Anal. calcd. for
C14H14N2O4: C, 61.31; H, 5.14; N, 10.21 %. Found: C,
61.45; H, 5.06; N, 10.36 %.
The cytotoxicity of compounds was estimated on human
cancer cell lines (MCF-7, HCT-116, OVCAR, IGROV)
using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl
tetrazolium bromide) assay. Cells were distributed in 96-well
plates at 3 × 104 cells/well in 100 μL culture medium, and
then 100 μL of medium containing the chromone

Med Chem Res
carboxamide at various concentrations were added. MTT is
a yellow water-soluble tetrazolium salt, which metabolically
active cells convert to water-insoluble dark blue formazan by
reductive cleavage of the tetrazolium ring. All compounds
were dissolved in DMSO followed by dilution in buffer so
that the DMSO concentration did not exceed 1 %. The level
of blue formazan is then used as indirect index of cell
density. The optical density of each sample was measured
with a Thermo Scientific Multiskan GO Microplate Spec-
trophotometer at 500 nm. Four replicates were performed for
each sample. Tamoxifen was used as positive control.
four human cancer cell lines: MCF-7 (hormone dependent
breast cancer), OVCAR and IGROV (ovary cancer) and
HCT-116 (colon cancer) using the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay as
described by Mosmann (1983) with modifications (Bekir
et al., 2013). The results, expressed as IC50 values (μM),
i.e., the concentration required to inhibit cell proliferation
by 50 % after exposure of cells to test compounds, are
summarized in Table 1 and tamoxifen was used as
reference.
Among these compounds, 13 showed good cytotoxic
activity against at least one cancer cell line (IC50 ≤ 10 μM).
In the case of the breast cancer cell line MCF-7, five
compounds were active with the best antiproliferative
activity observed for 4b (IC50 = 0.9 μM). Eight compounds
were active against OVCAR cells (lowest IC50 for 4b and
11a = 5.1 μM), eight derivatives were cytotoxic against
IGROV cells (lowest IC50 for 4b and 10a = 3.2 μM), and
four compounds were active against colon HTC-116 cells
(lowest IC50 for 4d = 4.5 μM).
Results and discussion
Chemistry
Chromone carboxamides derivatives were obtained by
functionalization of the chromone nucleus at position C2 of
the γ-pyrone ring.
Structural modifications have been made in order to
evaluate the SAR on cytotoxicity and 5-LOX inhibition.
Particularly, (i) the introduction of a halide or methyl group
on the 6-position of the chromone nucleus (R1, scheme 1),
(ii) the side chain nature, either aliphatic or aromatic (R2),
(iii) the substitution on the aromatic moiety, and (iv) the
functionalization of the hydroxyl group have been con-
sidered. The molecular diversity in this library of com-
pounds was further increased by preparing analogs 12a,
13a, and 14a bearing nitrogen-containing side chains.
Syntheses were carried out starting from 6-substituted 2-
chromone carboxylic acids, prepared according to a pre-
viously described method (Payard et al., 1974). The car-
boxamide derivatives were prepared in a two-step process,
involving first the conversion, in quantitative yield, of the
carboxylic acid into the acylchloride 2 using PCl5 (Payard,
1973), and then the condensation with the appropriate
amine to give amides 3–14 (scheme 1). The main advantage
of this synthetic procedure is that no coupling reagents are
needed. Chromone carboxamides were synthesized in a
range of 30–90 % yields, similar to those reported with the
use of coupling agents such as phosphonium salts (BOP or
PyBOP) (Gaspar et al., 2011). Their chemical structures
The tests showed that the primary amide analogs 3a–3e
are not cytotoxic, except the 6-fluorinated compound 3b,
which had an interesting activity against the two cancer cell
lines OVCAR and IGROV (IC50 = 10.1 and 11.8 μM,
respectively).
Amide alkylation by a propyl side chain (compounds
4a–4d) had a significantly positive impact on the cytotoxic
activity. For instance the 6-fluorinated propyl carboxamide
4b (IC50 range: 0.9–22.2 μM) was more cytotoxic than its
primary analog 3b (IC50 range: 10.1–44.2 μM). Compound
4b was also the most potent compound against hormone
dependent breast cancer cells MCF-7 with an IC50 value in
the same range as tamoxifen (IC50 = 0.9 and 0.39 μM,
respectively). Regarding the non-substituted chromone
series (R1 = H), alkylation by a 3-ethylphenyl ring also had
a positive impact as compound 6a exhibited IC50 values
against the four cell lines in the same range as the propyl
carboxamide derivative 4a (IC50 range: 5.3–18.0 μM).
However, the positive effect of the 6-fluoro substituent on
activity showed with compounds 3b and 4b was not
observed with derivative 6b, less active than its 6-bromi-
nated and 6-methylated analogs (6d and 6e).
The beneficial effect of fluorine seen with the 6-fluoro
chromone series was not observed when the fluorine atom was
placed on the phenylcarboxamide side chain (compound 7a)
as the toxicity towards the tested cell lines was not enhances
compared to the chloro (8a) and methyl (9a) analogs.
The presence of a hydroxyl group in the para position of
the phenylcarboxamide produced a beneficial effect as
compound 10a showed IC50 values from 3.2 to 12.3 μM.
On adding a methyldiethylamino chain in the meta position
(compound 11a), only the activity against OVCAR cells
was conserved (IC50 = 5.1 μM).
1
were confirmed by IR, H NMR, 13C NMR and ESI–MS.
Reactions conditions: i) PCl5/dry cyclohexane; ii) R2-
NH2/TEA/dry DCM.
Pharmacology
Cytotoxicity
Twenty one chromone carboxamide derivatives were
assayed for their in vitro anti-proliferative effect against

Med Chem Res
Scheme 1 Synthesis of
compounds 3–14
Reactions conditions: i) PCl5/dry cyclohexane; ii) R2-NH2/TEA/dry DC
R1
H
R2
-NH2
-NH2
-NH2
-NH2
3a
F
3b
3c
Cl
Br
3d
3e
CH3 -NH2
H
F
-NH-C3H7
4a
-NH-C3H7
4b
4d
5a
Br
H
H
F
-NH-C3H7
-NH-Ph
-NH-(3’-C2H5)-Ph
-NH-(3’-C2H5)-Ph
-NH-(3’-C2H5)-Ph
6a
6b
6d
6e
Br
CH3 -NH-(3’-C2H5)-Ph
H
H
H
H
H
H
H
H
-NH-(4’-F)-Ph
7a
-NH-(4’-Cl)-Ph
8a
-NH-(4’-CH3)-Ph
9a
-NH-(4’- OH)-Ph
10a
11a
12a
13a
14a
-NH-(4’-OH, 3’-CH2-N(C2H5)2)-Ph
-NH-CH(CH3)-(CH2)3-N(C2H5)2
-NH-morpholino
-N-2-(4-pyrrolidinylcarbonylmethyl)-piperazinyl
To widen the panel of structures, we also studied chro-
mone carboxamides bearing various non-aromatic nitrogen-
containing side chains: N,N-(diethyl)pentanamine, mor-
pholine and N-substituted piperazine (12a–14a). The impact
of these groups on the activity was not the same depending
on the cell line but one can note that the IC50 values were
kept below 10 μM against at least one cell line.
Overall, while several compounds in the present library
possess IC50 values below 10 μM, none of them displays
good selectivity, i.e., activity against one cell line 10-fold
higher than the three other cell lines.
Racine, 2003) with modifications. Among 20 chromone
carboxamide derivatives tested as putative inhibitors of the
5-LOX enzyme, 10 were totally inactive or showed low
activity (<20 %) and 10 showed moderate to good activity
(Table 1).
The 6-fluorinated compound 3b showed interesting
inhibition (79.9 %). Here again, the effect of a 6-fluoro
substituent was positive for 5-LOX inhibition compared to
its 6-Cl, 6-Br, and 6-methyl analogs (3c–3e). The presence
of the propyl side chain (4b) led to a decreased activity
(68.0 % instead of 79.9 % for 3b).
Alkylation with a phenyl moiety, either substituted or not
with ethyl, fluoro, chloro, or methyl groups (compounds
6a–e, 7a–9a) had a major negative impact on the anti-
inflammatory activity. However, using a para phenol as
alkylating group (compound 10a) had a positive effect on
the anti-inflammatory activity as 5-LOX inhibition
increased up to 73.5 % compared to 55.2 % for the primary
amide homolog 3a. The beneficial effect of a para phenol
Anti-inflammatory activity
In order to study the ability of compounds 3–14 to directly
inhibit the catalytic activity of 5-LOX, a cell-free assay
using purified 5-LOX enzyme in the presence of 100 μM of
the chromone derivative was applied, according to the
method described by Baylac and Racine (Baylac and

Med Chem Res
Table 1 In vitro cytotoxicity against four human cancer cell lines and anti-inflammatory activity of compounds 1, 3–14
Antiproliferative activity IC50 (μM)
Anti-inflammatory
activity %
inhibition
(100 μM)
R1
R2
MCF-7
OVCAR
IGROV
HCT-116
5-Lipoxygenase
1a
3a
3b
3c
3d
3e
4a
H
OH
>100
>100
20.2 4.1
>100
14.4 1.3
>100
ND
H
NH2
NH2
NH2
NH2
NH2
>100
>100
55.2 4.0
79.9 6.6
41.8 6.1
15.5 1.2
12.9 0.6
67.2 3.4
F
44.2 5.0
89.2 13.2
>100
10.1 1.3
>100
11.8 1.3
>100
33.2 2.2
>100
Cl
Br
CH3
H
>100
>100
>100
80.2 13.2
11.2 1.1
>100
>100
>100
10.1 1.1
5.4 0.3
20.2 1.1
4b
4d
5a
F
0.9 0.0
12.6 1.0
>100
5.1 0.3
25.2 2.3
>100
3.2 0.1
7.2 0.4
>100
22.2 2.2
4.5 0.2
>100
68.0 1.8
30.5 5.1
ND
Br
H
6a
6b
6d
6e
H
5.3 0.6
56.1 6.4
6.3 0.4
18.0 2.2
8.0 0.4
5.8 0.3
20.1 3.3
9.2 1.3
18.0 2.0
13.2 1.2
8.0 1.2
5.9 0.0
14.2 0.9
32.3 4.4
>100
NA
NA
NA
NA
F
Br
CH3
>100
7a
H
H
H
H
63.2 5.3
>100
>100
18.0 2.1
22.1 1.2
25.4 2.2
3.2 0.0
25.2 3.2
9.0 0.4
11.3 1.2
9.0 1.3
NA
8a
>100
NA
9a
>100
>100
NA
10a
12.3 1.0
6.3 0.2
73.5 3.4

Med Chem Res
Table 1 continued
Antiproliferative activity IC50 (μM)
Anti-inflammatory
activity %
inhibition
(100 μM)
R1
H
R2
MCF-7
OVCAR
5.1 0.3
IGROV
HCT-116
40.0 3.0
5-Lipoxygenase
11a
12a
34.8 3.2
12.0 0.4
52.0 4.9
H
40.2 2.0
10.4 1.2
6.8 0.4
36.2 3.1
48.6 2.3
13a
14a
H
H
8.3 0.1
6.0 0.5
25.3 2.4
28.0 2.2
13.1 1.2
10.1 0.2
5.8 1.1
68.8 4.6
62.3 2.9
31.3 3.3
Tamoxifen
0.39 0.01
0.52 0.04
0.82 0.10
0.37 0.02
—
NDGA (13 μM)
—
—
—
—
50.0 2.7
NDGA nordihydroguaiaretic acid, NA not active, ND not determined
was reduced when a N-diethylmethyl side chain was added
in the meta position of the phenyl group (52.0 % for com-
pound 11a).
Amidation using other nitrogen containing side chains
(N-diethylpentyl 12a, morpholinyl 13a, and substituted
piperazinyl 14a) showed good activity with 5-LOX inhi-
bition from 48.6 % up to 68.8 %.
molecule uses its structural features in binding the target.
LE is therefore a useful metric to normalize the affinities of
hits to identify the best starting points for optimization, i.e.,
those with the highest LE values (Hopkins et al., 2014).
From the data obtained, one can observe that all the
chromone derivatives possess LogP values compatible with
those required to cross membranes and no violations of
Lipinski’s rules were found (Table 2), thus making our
chromone derivatives promising therapeutic agents with a
good potential for eventual development as orally active
drug candidates. Lipophilicity does seem to play a sig-
nificant role for 5-LOX inhibition as, except for 11a, deri-
vatives with logP ≥ 3.01 were totally inactive (compounds
6a–9a) and the six most potent chromone carboxamides had
a logP value < 2.47.
Theoretical evaluation of “drug-likeliness” properties
To predict their overall “drug-likeness”, an in silico com-
putational study of the synthesized chromone carboxamides
3–14 was performed by determining Lipinski parameters
(Lipinski et al., 1997) using the molinspiration online
software (www.molinspiration.com) (Table 1 of supple-
mentary material). To better understand the therapeutic
potential of chromone derivatives, we also calculated their
ligand efficiency (LE) for all the cell lines (Table 2 of
supplementary material). LE is a measure of the in vitro
biological activity corrected for the physico-chemical
properties of the molecule and quantify how effectively the
Overall, the lowest IC50 value was displayed by com-
pound 4b against MCF-7 cell line. In order to see if this
compound is the one which should be selected as a lead for
further investigations, we calculated the LE values for all
compounds against this cell line. Results showed that LE
values are in the range 0.36–0.46 kcal/mol/non-H atom.

Med Chem Res
Table 2 LogP and LE values of the chromone derivatives
Overall, the physico-chemical properties (lipophilicity,
molecular weight, number of H acceptors/donnors) of
chromone carboxamides are in accordance with the general
requirements of drug discovery and development process
and LE values allow further structure optimization, with
compound 4b as a lead. Other compounds such as 6a or 10a
are also promising compounds. Therefore, this study pro-
vides a solid base for further research on chromone car-
boxamides to get more potent and selective cytotoxic
agents.
LogPa
MW
IC50 (μM)
LEMCF-7
b
N°
3b
3c
0.04
1.53
1.30
2.13
1.30
2.91
3.84
3.01
4.62
4.26
3.11
2.47
3.42
2.90
0.09
1.14
207.16
223.61
203.19
231.25
249.24
310.14
293.32
311.31
372.21
307.34
283.25
281.26
366.41
330.42
274.27
369.41
44.2
89.2
80.2
11.2
0.9
0.40
0.37
0.38
0.40
0.46
0.38
0.33
0.26
0.31
0.28
0.28
0.32
0.23
0.25
0.35
0.27
3e
4a
4b
4d
6a
12.6
5.3
6b
6d
6e
56.1
6.3
Acknowledgments We are thankful to Laurent Amielet, Christelle
Récochet-Gueriot and Sylvie Cazaux for technical support. We are
grateful to the “VLM” association for financial support.
18.0
63.2
12.3
34.8
40.2
8.3
7a
10a
11a
12a
13a
14a
a
Compliance with ethical standards
Conflict of interest The authors declare that they have no com-
peting interests.
6.0
LogP values were determined with molinspiration software (www.
molinspiration.com)
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