Synthesis and biological evaluation of novel chromonyl enaminones as α-glucosidase inhibitors

Article abstract of DOI:10.1007/s00044-019-02320-w

Series of novel chromonyl enaminones 1a–e and 2a–e and 3-alkylated chromones 3a–e were synthesized and evaluated in vitro as α-glucosidase inhibitors as well as antioxidant and antifungal agents. Antifungal activity was tested on strains of Candida albicans. Compounds 2a and 2d–e showed good inhibition of the α-glucosidase enzyme (IC₅₀ = 5.5, 0.9, and 1.5 mM, respectively), their effect being better than that of 1a–e, 3a–e, and acarbose (the standard, IC₅₀ = 7.73 ± 0.9 mM). The structure–activity relationship suggests that the phenyl group at the C-3 position of the chromone ring system and the 4-chlorophenyl group at the enaminone moiety (derivatives 2) increased the inhibition of α-glucosidase. Compounds 2a–e exhibited a slight antioxidant effect, and compounds 3a–e a moderate antifungal activity against C. albicans (IC₅₀ 70.5–83.1 μg/mL). Docking studies revealed that compounds 2 interact with the α-glucosidase residues of the binding pocket. Therefore, these chromone derivatives may be considered as potential α-glucosidase inhibitors, as well as antifungal agents against some Candida strains of yeast.

Full text of DOI:10.1007/s00044-019-02320-w

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-019-02320-w
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel chromonyl enaminones
as α-glucosidase inhibitors
1,2
Catalina Rugerio-Escalona1 Nemesio Villa-Ruano3 Rsuini U. Gutierrez2
●
●
●
●
Aarón Mendieta-Moctezuma
Fabiola E. Jiménez-Montejo1 M. Jonathan Fragoso-Vázquez4 José Correa-Basurto4 María C. Cruz-López1
●
●
●
●
Francisco Delgado2 Joaquín Tamariz2
●
Received: 20 December 2018 / Accepted: 21 February 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
Series of novel chromonyl enaminones 1a–e and 2a–e and 3-alkylated chromones 3a–e were synthesized and evaluated
in vitro as α-glucosidase inhibitors as well as antioxidant and antifungal agents. Antifungal activity was tested on strains of
Candida albicans. Compounds 2a and 2d–e showed good inhibition of the α-glucosidase enzyme (IC50 = 5.5, 0.9, and 1.5
mM, respectively), their effect being better than that of 1a–e, 3a–e, and acarbose (the standard, IC50 = 7.73 0.9 mM). The
structure–activity relationship suggests that the phenyl group at the C-3 position of the chromone ring system and the 4-
chlorophenyl group at the enaminone moiety (derivatives 2) increased the inhibition of α-glucosidase. Compounds 2a–e
exhibited a slight antioxidant effect, and compounds 3a–e a moderate antifungal activity against C. albicans (IC50 70.5–83.1
µg/mL). Docking studies revealed that compounds 2 interact with the α-glucosidase residues of the binding pocket.
Therefore, these chromone derivatives may be considered as potential α-glucosidase inhibitors, as well as antifungal agents
against some Candida strains of yeast.
●
●
●
Keywords Chromonyl enaminones Chromones α-glucosidase inhibitors Candida albicans
Introduction
Heterocycles are very important molecular components for
Supplementary information The online version of this article (https://
doi.org/10.1007/s00044-019-02320-w) contains supplementary
material, which is available to authorized users.
drug design and discovery (Keri et al. 2014). Chromones
are oxygenated heterocyclic compounds with a benzo-
annelated γ-pyrone ring (4H-chromen-4-one, 4H-1-benzo-
pyran-one) that are present in numerous naturally occurring
and synthetic compounds. They are well-known for their
wide range of pharmacological activity, including anti-
microbial (Dofe et al. 2017a, b), antitumor (Sun et al. 2013),
cytotoxic (Xiu et al. 2017), antioxidant (Csepanyi et al.
2017), anti-HIV (Kim et al. 2013), anti-inflammatory
(Gaspar et al. 2014), and anti-diabetes (Reis et al. 2017).
There are various reports on chromone derivatives as
potent α-glucosidase inhibitors (Philip et al. 2017; Zhen
et al. 2017; Wang et al. 2017, 2018; Jose et al. 2018).
Previous docking and structure–activity relationship (SAR)
studies suggest that binding with the α-glucosidase enzyme
is favored (thus increasing inhibition) by the inclusion of a
tertiary amino group and an aromatic ring substituted with a
hydrogen acceptor at the C-6 or C-7 position of the chro-
mone ring (Zhen et al. 2017; Wang et al. 2018). Hence,
* Aarón Mendieta-Moctezuma
amendietam@ipn.mx
* Joaquín Tamariz
jtamarizm@ipn.mx
jtamariz@woodward.encb.ipn.mx
1
Centro de Investigación en Biotecnología Aplicada, Instituto
Politécnico Nacional, Carretera Estatal Santa Inés Tecuexcomac-
Tepetitla, Km 1.5, 90700 Tlaxcala, Mexico
2
Departamento de Química Orgánica, Escuela Nacional de Ciencias
Biológicas, Instituto Politécnico Nacional, Prol. Carpio y Plan de
Ayala S/N, 11340 Ciudad de México, Mexico
3
Universidad de la Sierra Sur, Ciudad Universitaria, Guillermo
Rojas Mijangos S/N, Miahuatlán de Porfirio Díaz, 70800
Oaxaca, Mexico
4
Laboratorio de Desarrollo de Fármacos y Productos
Biotecnológicos, Escuela Superior de Medicina, Instituto
Politécnico Nacional, Plan de San Luis y Díaz Mirón S/N, 11340
Ciudad de México, Mexico

Medicinal Chemistry Research
modifications in the structure of this type of compound offer
an alternative in the search for novel therapeutic agents.
Type 2 diabetes is caused by hyperglycemia in the blood
due to a scarce production or malfunction of insulin, which
can also lead to serious complications of the heart, blood
vessels, nerves, kidney, and eyes. One therapeutic treatment
for diabetes is to delay glucose absorption by inhibiting
digestive enzymes such as amylases and glucosidases
(Kerru et al. 2018). α-Glucosidase inhibitors, which include
acarbose, miglitol, and voglibose, are first-line drugs for the
treatment of type-2 diabetes because they decrease post-
prandial hyperglycemia (Wang et al. 2017; Upadhyay et al.
2018). However, the drugs currently used for controlling
type 2 diabetes have many negative side effects (Upadhyay
et al. 2018). In the search for safer and more efficient
inhibitors, new drugs have been designed and developed to
control diabetes (Kerru et al. 2018).
One of the complications associated with diabetes is the
susceptibility of contracting infections by opportunistic
microorganisms, especially yeasts of the genus Candida
(Brunel and Guery 2017). When sugar levels are elevated,
diabetic patients tend to be more susceptible, although the
mechanisms involved have not been fully elucidated. It
appears that hyperglycemia suppresses the immune system
of the diabetic patient, thus fostering an increased pre-
valence of infections by drug-resistant pathogens. The
synthesis of new compounds to cope with microbial resis-
tance to antibiotics has become an urgent priority for
medicinal chemistry (Dofe et al. 2017a, b; Reis et al. 2017),
highlighting the need for novel and more effective drugs
(Brunel and Guery 2017; Jose et al. 2018). To meet this
challenge, it is possible to modify existing molecules or
design new ones in accordance with the therapeutic targets.
For the development of potent and efficient molecules
with biological activity, the chromone and flavonoid scaf-
folds are important to consider (Reis et al. 2017; Lu et al.
2017). We herein describe the design and synthesis of a
hybrid scaffold that incorporates chromone and enaminone
moieties in a single molecule mimicking the structure of
known α-glucosidase inhibitors (Fig. 1) (Zhen et al. 2017;
Wang et al. 2018). The synthesized compounds were
evaluated for α-glucosidase inhibition as well as antioxidant
and antifungal activity. The most promising compounds in
the experimental assays (2a, 2d, and 2e) were subjected to
docking studies on α-glucosidase in order to explore their
recognition properties.
Materials and methods
Chemistry
Melting points were determined on an electrothermal
1
apparatus and are uncorrected. H (300 or 500 MHz) and
13C (75 or 125 MHz) NMR spectra were recorded on a
Varian Mercury-300 or Varian VNMR system instrument.
The chemical shifts (δ) are expressed in ppm relative to the
TMS as the internal standard. Mass spectra were obtained
(in electron impact (EI) mode) on a Polaris Q-Trace GC
Ultra/Finnigan Co apparatus, and the high-resolution mass
spectra (HRMS, in EI), were obtained on a Jeol JSM-
GCMatell instrument. Infrared spectra (IR) were recorded
on a FT-IR 2000 Perkin-Elmer spectrometer. Elemental
analyses were performed on a CE-440 Exeter Analytical
apparatus. Commercial reagents were employed as received
from Sigma-Aldrich and anhydrous solvents were obtained
by a distillation process. Thin layer chromatography was
carried out on precoated silica gel plates (Merck 60F254).
Silica gel (230–400 mesh) was used for flash column
chromatography. The preparation of compounds 4a–c, 6a–
6c, 6e, 7a–b, 7d, and 8a–8b has been previously described
(Mendieta et al. 2014; Musso et al. 2010; Huls 1958; Zoe
et al. 2010; Jha et al. 1981; Goto et al. 2009; Rao and
Krupadanam 1994; Moore et al. 1934).
General procedure for the synthesis of 2-acyl phenols 6–8
BF3·OEt2 (1.0 mol equiv.) was added to a solution of phe-
nols 9a–c (2.0 mol equiv. for 9a–b and 1.0 mol equiv. for
9c) and the corresponding acyl chloride (2.0 mol equiv.)
under nitrogen atmosphere at 0 °C. The mixture was then
stirred at 80 °C for 3 h. After pouring the residue into ice
water (10 mL), adjusted to neutral pH with an aqueous
saturated solution of NaHCO3, and extracted with EtOAc
(3 × 30 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure, followed by purifying
Fig. 1 Structures of known flavanone and chromone as α-glucosidase inhibitors, and the novel chromone-enaminones 1–2 herein described

Medicinal Chemistry Research
the residue by column chromatography over silica gel
(hexane/EtOAc, 9:1) to give the respective acyl phenols 6–8
(Mendieta et al. 2014).
(CH2-C2), 56.5 (OCH3), 103.6 (C-3′), 110.2 (C-6′), 111.7 (C-
1′), 139.7 (C-5′), 153.5 (C-4′), 160.3 (C-2′), 204.2 (CO); MS
(70 eV) m/z 210 (M+, 35), 195 (7), 182 (10), 167 (100), 152
(10), 111 (11). HRMS (70 eV) Calculated for: C11H14O4.
210.0892. Found: 210.0886.
1-(2-Hydroxy-4,5-dimethoxyphenyl)ethanone (6a) White
solid (88%). Rf 0.20 (hexane/EtOAc, 8:2); mp 106–107 °C
(Lit. 107–108 °C, Mendieta et al. 2014).
1-(2,4-Dihydroxy-5-methoxyphenyl)-2-phenylethan-1-one
(7d) White solid (50%). Rf 0.34 (hexane/EtOAc, 6:4); mp
91–92 °C (Lit. 88–89 °C, Goto et al. 2009).
1-(2-Hydroxy-4,5-dimethoxyphenyl)propan-1-one
(6b)
White solid (92%). Rf 0.34 (hexane/EtOAc, 8:2); mp 124–
125 °C (Lit. 118–119 °C, Musso et al. 2010).
1-(5-Chloro-2,4-dihydroxyphenyl)propan-1-one (8a) White
solid (99%). Rf 0.75 (hexane/EtOAc, 6:4); mp 101–102 °C
(Lit. 90 °C, Rao and Krupadanam 1994).
1-(2-Hydroxy-4,5-dimethoxyphenyl)butan-1-one (6c) Col-
orless solid (85%). Rf 0.25 (hexane/EtOAc, 8:2); mp 77–78 °C
(Lit. 76–77 °C, Mendieta et al. 2014).
1-(5-Chloro-2,4-dihydroxyphenyl)butan-1-one (8b) White
solid (90%). Rf 0.31 (hexane/EtOAc, 8:2); mp 91–92 °C
(Lit. 84–85 °C, Moore et al. 1934).
1-(2-Hydroxy-4,5-dimethoxyphenyl)pentan-1-one
(6d)
Yellow solid (88%). Rf 0.37 (hexane/EtOAc, 8:2); mp 93–
94 °C; IR (KBr) νmax: 2955, 2869, 1629, 1582, 1510, 1390,
1270, 1249, 1196, 1156 cm−1; 1H NMR (500 MHz, CDCl3)
δ: 0.97 (m, 3H, CH3, H-5), 1.43 (m, 2H, CH2, H-4), 1.72
(m, 2H, CH2, H-3), 2.88 (q, J = 7.2 Hz, 2H, CH2, H-2), 3.86
(s, 3H, OCH3-C5′), 3.90 (s, 3H, OCH3-C4′), 6.45 (s, 1H, H-
3′), 7.09 (s, 1H, H-6′), 12.78 (s, 1H, OH); 13C NMR (125
MHz, CDCl3) δ: 13.8 (CH3-5), 22.4 (CH2-4), 26.6 (CH2-3),
37.7 (CH2-2), 56.0 (OCH3-4′), 56.6 (OCH3-5′), 100.5 (C-
3′), 111.1 (C-1′), 111.2 (C-6′), 141.7 (C-5′), 156.5 (C-4′),
160.1 (C-2′), 204.5 (CO); MS (70 eV) m/z 238 (M+, 36),
209 (14), 196 (45), 181 (100), 125 (33), 110 (11), 95 (10),
55 (14). HMRS (70 eV) Calculated for: C13H18O4.
238.1205. Found: 238.1199.
General procedure for the synthesis of aryloxycarbonylic
compounds 4–5
A solution of acyl phenols 7 and 8 (1.0 mol equiv.) and
K2CO3 (1.5 mol equiv.) in dry acetone (7 mL) was stirred at
25 °C for 15 min. Subsequently, the corresponding α-halo-
carbonyl compound 11a–b (1.5 mol equiv.) was added
dropwise and the reaction mixture was refluxed at 60 °C for
3 h. After the reaction was completed (according to TLC
monitoring), the mixture was filtered, and the solvent
removed over vacuum. The residue was purified by flash
chromatography to give the respective compounds 4 and 5
(Jiménez et al. 2010).
1-(2-Hydroxy-4,5-dimethoxyphenyl)-3-methylbutan-1-one
(6e) Yellow solid (84%). Rf 0.40 (hexane/EtOAc, 8:2); mp
60–61 °C (Lit. 62 °C, Huls 1958).
Methyl 2-(4-acetyl-5-hydroxy-2-methoxyphenoxy)acetate
(4a) White solid (90%). Rf 0.30 (hexane/EtOAc 6:4); mp
133–134 °C (Lit. 132–133 °C, Mendieta et al. 2014).
1-(2,4-Dihydroxy-5-methoxyphenyl)ethan-1-one (7a) White
solid (86%). Rf 0.49 (hexane/EtOAc, 6:4); mp 171–172 °C
(Lit. 170–171 °C, Zou et al. 2010).
Methyl 2-(5-hydroxy-2-methoxy-4-propionylphenoxy)acet-
ate (4b) White solid (97%). Rf 0.5 (hexano/EtOAc 6:4);
mp 119–121 °C (Lit. 119–120 °C, Mendieta et al. 2014).
1-(2,4-Dihydroxy-5-methoxyphenyl)propan-1-one (7b) White
solid (80%). Rf 0.51 (hexane/EtOAc, 6:4); mp 124–125 °C (lit
mp not given, Jha et al. 1981).
Methyl 2-(4-butyryl-5-hydroxy-2-methoxyphenoxy)acetate
(4c) White solid (95%). Rf 0.53 (hexane/EtOAc 7:3); mp
121–122 °C (Lit. 122–123 °C, Mendieta et al. 2014).
1-(2,4-Dihydroxy-5-methoxyphenyl)butan-1-one (7c) White
solid (85%). Rf 0.57 (hexane/EtOAc, 6:4); mp 98–99 °C. IR
(KBr)νmax: 3303, 2962, 1637, 1600, 1510, 1430, 1374, 1302,
1226, 1201, 1164, 1025, 838, 741, 675 cm−1; 1H NMR (500
MHz, CDCl3) δ: 1.03 (t, J = 7.5 Hz, 3H, CH3, H-4), 1.78
(sext, t, J = 7.5 Hz, 2H, CH2, H-3), 2.86 (t, J = 7.5 Hz, 2H,
CH2, H-2), 3.90 (s, 3H, OCH3), 6.34 (s, 1H, OH-4′), 6.51 (s,
1H, H-3′), 7.08 (s, 1H, H-6′), 12.73 (s, 1H, OH-2′); 13C NMR
(125 MHz, CDCl3) δ: 13.9 (CH3-C4), 18.0 (CH2-C3), 39.9
Methyl 2-(2-chloro-5-hydroxy-4-propionylphenoxy)acetate
(4d) White solid (74%). Rf 0.42 (hexane/EtOAc, 8:2);
mp 142–143 °C. IR (KBr)νmax: 3085, 2956, 1772, 1636,
1
1498, 1439, 1370, 1211, 1188, 1084, 827 cm−1; H NMR
(300 MHz, CDCl3) δ: 1.22 (t, J = 7.5 Hz, 3H, CH3-3″), 2.95
(q, J = 7.5 Hz, 2H, CH2-2″), 3.83 (s, 3H, OCH3), 4.75 (s,
2H, CH2-2), 6.33 (s, 1H, H-6′), 7.77 (s, 1H, H-3′), 12.70 (s,
1H, OH); 13C NMR (75 MHz, CDCl3) δ: 8.1 (CH3-3″), 31.3
(CH2-2″), 52.6 (OCH3), 65.5 (CH2-2), 101.6 (C-6′), 113.2

Medicinal Chemistry Research
(C-2′), 114.0 (C-4′), 131.1 (C-3′), 158.8 (C-1′), 163.2 (C-
5′), 167.7 (CO-1), 204.9 (CO-1″); MS (70 eV) m/z 274
(M+ + 2, 12), 272 (M+, 36), 245 (36), 243 (100), 185 (13),
183 (15), 171 (15). HRMS (70 eV) Calculated for
C12H13ClO5: 272.0451. Found: 272.0457.
1-(4-(2-(4-Chlorophenyl)-2-oxoethoxy)-2-hydroxy-5-meth-
oxyphenyl)butan-1-one (5c) White solid (70%). Rf 0.48
(hexane/EtOAc, 7:3); mp 152–153 °C. IR (KBr)νmax: 3384,
3092, 2967, 1702, 1616, 1507, 1451, 1388, 1329, 1254,
1202, 1158, 1093, 1021, 965, 855, 826, 779 cm−1; 1H NMR
(500 MHz, CDCl3) δ: 1.03 (t, J = 7.5 Hz, 3H, CH3-4), 1.77
(sext, J = 7.5 Hz, 2H, CH2-3), 2.87 (t, J = 7.5 Hz, 2H, CH2-
2), 3.89 (s, 3H, OCH3), 5.36 (s, 2H, OCH2, H-1″), 6.30 (s,
1H, H-3′), 7.17 (s, 1H, H-6′), 7.46–7.50 (m, 2H, H-3‴),
7.91–7.96 (m, 2H, H-2‴), 12.65 (s, 1H, OH); 13C NMR
(125 MHz, CDCl3) δ: 13.9 (CH3-4), 17.9 (CH2-3), 40.0
(CH2-2), 57.1 (OCH3), 70.8 (CH2-1″), 102.0 (C-3′), 112.4
(C-1′), 112.5 (C-6′), 129.3 (C-3‴), 129.5 (C-2‴), 132.5 (C-
1‴), 140.7 (C-4‴), 142.0 (C-5′), 154.7 (C-4′), 159.7 (C-2′),
191.6 (CO-2″), 204.5 (CO-1); MS (70 eV) m/z 364 (M+ +
2, 38), 362 (M+, 100), 321 (31), 319 (99), 167 (33), 153
(20), 141 (22), 139 (74), 125 (30). HRMS (70 eV) Calcu-
lated for C19H19ClO5: 362.0921. Found: 362.0924.
Methyl 2-(4-butyryl-2-chloro-5-hydroxyphenoxy)acetate (4e)
White solid (80%). Rf 0.62 (hexane/EtOAc, 7:3); mp 118–119
°C. IR (KBr)νmax: 3425, 2966, 1771, 1632, 1494, 1371, 1208,
1
1085, 819 cm−1; H NMR (500 MHz, CDCl3) δ: 1.02 (t, J =
7.5 Hz, 3H, CH3-4″), 1.76 (sext, J = 7.5 Hz, 2H, CH2-3″), 2.88
(t, J = 7.5 Hz, 2H, CH2-2″), 3.82 (s, 3H, CO2CH3), 4.75 (s, 2H,
CH2-2), 6.34 (s, 1H, H-6′), 7.76 (s, 1H, H-3′), 12.74 (s, 1H,
OH); 13C NMR (125 MHz, CDCl3) δ: 13.8 (CH3-4″), 17.9
(CH2-3″), 40.0 (CH2-2″), 52.5 (CO2CH3), 65.5 (CH2-2), 101.7
(C-6′), 113.3 (C-2′), 114.3 (C-4′), 131.3 (C-3′), 158.9 (C-1′),
163.5 (C-5′), 167.7 (CO2CH3-1), 204.6 (CO-1″). HRMS (70
eV) Calculated for C13H15ClO5: 286.0608. Found: 286.0619.
2-(4-Acetyl-5-hydroxy-2-methoxyphenoxy)-1-(4-chlorophe-
nyl)ethan-1-one (5a) White solid (83%). Rf 0.31 (hexane/
EtOAc, 7:3); mp 148–149 °C. IR (KBr)νmax: 3397, 3087,
2938, 1710, 1629, 1589, 1510, 1402, 1373, 1334, 1266,
1-(4-Chlorophenyl)-2-(5-hydroxy-2-methoxy-4-(2-phenyla-
cetyl)phenoxy)ethan-1-one (5d) White solid (80%). Rf
0.65 (hexane/EtOAc, 6:4); mp 151–152 °C. IR (KBr)νmax
:
3449, 3068, 2932, 1700, 1631, 1590, 1510, 1400, 1358,
1
1232, 1202, 1090, 980, 837, 803 cm−1
;
1H NMR (500
1263, 1233, 1159, 974, 825 cm−1; H NMR (500 MHz,
MHz, CDCl3) δ: 2.56 (s, 3H, CH3-1‴), 3.89 (s, 3H, OCH3),
5.36 (s, 2H, CH2-2), 6.30 (s, 1H, H-6″), 7.12 (s, 1H, H-3″),
7.46–7.50 (m, 2H, H-3′), 7.91–7.95 (m, 2H, H-2′), 12.50 (s,
1H, OH); 13C NMR (125 MHz, CDCl3) δ: 26.4 (CH3-2‴),
57.0 (OCH3), 70.8 (OCH2-2), 101.8 (C-6″), 112.7 (C-4″),
113.0 (C-3″), 129.3 (C-3′), 129.4 (C-2′), 132.4 (C-1′),
140.7 (C-4′), 142.0 (C-2″), 154.9 (C-1″), 159.5 (C-5″),
191.6 (CO-1), 202.2 (CO-1‴); MS (70 eV) m/z 336 (M+ +
2, 23), 334 (M+, 68), 195 (14), 167 (16), 141 (38), 140 (48),
139 (100). HRMS (70 eV) Calculated for C17H15ClO5:
334.0608. Found: 334.0613.
CDCl3) δ: 3.83 (s, 3H, OCH3), 4.21 (s, 2H, CH2-2‴), 5.35
(s, 2H, OCH2), 6.29 (s, 1H, H-6″), 7.22 (s, 1H, H-3″), 7.26–
7.29 (m, 3H, H-2IV, H-4IV), 7.32–7.37 (m, 2H, H-3IV),
7.46–7.50 (m, 2H, H-3′), 7.90–7.94 (m, 2H, H-2′), 12.47 (s,
1H, OH); 13C NMR (125 MHz, CDCl3) δ: 45.5 (CH2-2‴),
56.8 (OCH3), 70.8 (OCH2), 101.9 (C-6″), 111.9 (C-4″),
112.7 (C-3″), 127.2 (C-4IV), 128.8 (C-3IV), 129.2 (C-2IV),
129.3 (C-3′), 129.4 (C-2′), 132.4 (C-1′), 134.3 (C-1IV),
140.7 (C-4′), 142.0 (C-2″), 154.9 (C-1″), 160.1 (C-5″),
191.5 (CO-1), 201.6 (CO-1‴); MS (70 eV) m/z 410 (M+,
22), 321 (35), 319 (100), 195 (21), 167 (59), 153 (43), 139
(35), 125 (37), 111 (22). HRMS (70 eV) Calculated for
C23H19ClO5: 410.0921. Found: 410.0941.
1-(4-(2-(4-Chlorophenyl)-2-oxoethoxy)-2-hydroxy-5-meth-
oxyphenyl)propan-1-one (5b) White solid (88%). Rf 0.42
(hexane/EtOAc, 7:3); mp 130–131 °C. IR (KBr)νmax: 3401,
3098, 2945, 1713, 1634, 1616, 1588, 1505, 1394, 1253,
1-(5-Chloro-4-(2-(4-chlorophenyl)-2-oxoethoxy)-2-hydroxyphe-
nyl)propan-1-one (5e) White solid (80%). Rf 0.65 (hexane/
EtOAc, 8:2); mp 166–168 °C. IR (KBr)νmax: 3373, 3105, 2925,
1698, 1632, 1589, 1491, 1374, 1236, 1216, 1190, 1093, 973,
824 cm−1; 1H NMR (300 MHz, DMSO-d6) δ: 1.12 (t, J = 7.2
Hz, 3H, CH3-3), 2.90 (q, J = 7.2 Hz, 2H, CH2-2), 5.53 (s, 2H,
OCH2), 6.49 (s, 1H, H-3′), 7.38–7.46 (m, 2H, H-3‴), 7.75 (s,
1H, H-6′), 7.90–8.15 (m, 2H, H-2‴), 12.52 (s, 1H, OH); 13C
NMR (75 MHz, DMSO-d6) δ: 7.7 (CH3-3), 30.8 (CH2-2), 70.7
(OCH2), 101.8 (C-3′), 112.3 (C-5′), 113.3 (C-1′), 128.6 (C-3‴),
129.3 (C-2‴), 130.6 (C-6′), 132.0 (C-1‴), 139.6 (C-4‴), 158.6
(C-4′), 162.6 (C-2′), 191.3 (CO-2″), 204.4 (CO-1); MS (70 eV)
m/z 354 (M+ + 2, 8), 352 (M+, 12), 317 (34), 141 (33), 139
(100), 125 (16). HRMS (70 eV) Calculated for C17H14Cl2O4:
352.0269. Found: 352. 0271.
1
1223, 1162, 1088, 979, 819 cm−1; H NMR (500 MHz,
CDCl3) δ: 1.23 (t, J = 7.3 Hz, 3H, CH3-3), 2.94 (q, J = 7.3
Hz, 2H, CH2-2), 3.88 (s, 3H, OCH3), 5.36 (s, 2H, CH2-1″),
6.30 (s, 1H, H-3′), 7.16 (s, 1H, H-6′), 7.46–7.50 (m, 2H, H-
3‴), 7.90–7.95 (m, 2H, H-2‴), 12.59 (s, 1H, OH); 13C NMR
(125 MHz, CDCl3) δ: 8.3 (CH3-3), 31.4 (CH2-2), 57.0
(OCH3), 70.7 (CH2-1″), 101.9 (C-3′), 112.1 (C-1′), 112.2
(C-6′), 129.3 (C-3‴), 129.4 (C-2‴), 132.4 (C-1‴), 140.6 (C-
4‴), 142.0 (C-5′), 154.6 (C-4′), 159.4 (C-2′), 191.6 (CO-
2″), 204.9 (CO-1); MS (70 eV) m/z 350 (M+ + 2, 37), 348
(M+, 99), 321 (33), 319 (100), 167 (37), 153 (22), 141 (35),
139 (94), 125 (31). HRMS (70 eV) Calculated for
C18H17ClO5: 348.0764. Found: 348.0771.

Medicinal Chemistry Research
Methyl (E)-2-(4-(3-(dimethylamino)acryloyl)-5-hydroxy-2-
methoxyphenoxy)acetate (E-12). Methyl (Z)-2-(4-(3-
(dimethylamino)acryloyl)-5-hydroxy-2-methoxyphenoxy)
acetate (Z-12). Methyl 2-((6-methoxy-4-oxo-4H-chromen-7-
yl)oxy)acetate (13) A mixture of the compound 4a (1.0
mol equiv.) with dimethylformamide dimethyl acetal
(DMFDMA, 1.5 mol equiv.) was refluxed at 120 °C for 12 h
(Correa et al. 2008; Labarrios et al. 2014). The reaction was
cooled, filtered, and concentrated over vacuum. The residue
was purified by flash chromatography to give a mixture of
enaminones (E/Z)-12 (72:28) as white solid (26%); Rf 0.22
(hexane/EtOAc, 1:2); mp 201–204 °C; and chromone 13 as
white solid (44%); Rf 0.54 (EtOAc); mp 158–159 °C. Data
for (E)-12: IR (KBr)νmax: 3462, 2952, 1743, 1629, 1533,
1501, 1434, 1379, 1292, 1249, 1230, 1156, 1112, 905, 843,
Methyl (Z)-3-(dimethylamino)-2-((6-methoxy-4-oxo-4H-chro-
men-7-yl)oxy)acrylate (1a) Yellow solid (48%). Rf 0.42
(EtOAc); mp 181–183 °C. IR (KBr)νmax: 2925, 1694, 1632,
1
1433, 1299, 1205, 1115, 1088, 872, 764 cm−1; H NMR
(300 MHz, CDCl3) δ: 2.95 (s, 6H, N(CH3)2), 3.61 (s, 3H,
CO2CH3), 3.96 (s, 3H, OCH3), 6.27 (d, J = 6.0 Hz, 1H, H-
3′), 6.90 (s, 1H, H-8′), 7.21 (s, 1H, H-3), 7.56 (s, 1H, H-5′),
7.77 (d, J = 6.0 Hz, 1H, H-2′); 13C NMR (75 MHz, CDCl3)
δ: 41.8 (N(CH3)2), 51.3 (CO2CH3), 56.4 (OCH3), 102.6 (C-
8′), 105.2 (C-5′), 112.2 (C-3′), 114.2 (C-2), 119.2 (C-4a′),
139.7 (C-3), 147.4 (C-6′), 152.3 (C-8a′), 154.2 (C-7′), 154.6
(C-2′), 165.5 (CO2Me), 176.8 (CO-4′); MS (70 eV) m/z 319
(M+, 7), 274 (47), 260 (100), 232 (27), 203 (64), 189 (47),
160 (38), 144 (61), 134 (26), 116 (46), 84 (41). HRMS (70
eV) Calculated for C16H17NO6: 319.1056. Found: 319.1064.
1
775 cm−1; H NMR (500 MHz, CDCl3) δ: 2.98 (br, 3H, N
(CH3)), 3.18 (br, 3H, N(CH3)), 3.80 (s, 3H, OCH3-1), 3.88
(s, 3H, OCH3-2′), 4.71 (s, 2H, CH2, H-2), 5.61 (d, J = 12.0
Hz, 1H, H-2″), 6.31 (s, 1H, H-6′), 7.16 (s, 1H, H-3′).
Signals attributed to the minor isomer (Z)-12: 3.83 (s,
OCH3), 3.98 (s, OCH3), 4.80 (s, 2H, H-2), 6.30 (d, J = 6.0
Hz, 1H, H-2″), 6.78 (s, H-6′), 7.58 (s, H-3′), 7.79 (d, J =
6.0 Hz, 1H, H-3). 13C NMR (125 MHz, CDCl3) δ: 37.4
(NCH3), 45.2 (NCH3), 52.3 (OCH3-1), 57.5 (OCH3-2′),
65.4 (C-2), 89.7 (C-2″), 102.0 (C-6′), 112.4 (C-3′), 112.9
(C-4′), 141.3 (C-2′), 153.0 (C-1′), 154.3 (C-3″), 159.7 (C-
5′), 168.4 (CO-1), 190.2 (CO-1″). Signals attributed to the
minor isomer (Z)-12: 52.5, 56.4, 66.0, 101.5, 105.2, 112.4,
119.3, 147.8, 152.3, 154.6, 168.1. HRMS (70 eV) Calcu-
lated for C15H19O6: 309.1212. Found: 309.1220. Data for
13: IR (KBr)νmax: 2926, 1743, 1649, 1505, 1468, 1429,
Methyl (Z)-3-(dimethylamino)-2-((6-methoxy-3-methyl-4-oxo-
4H-chromen-7-yl)oxy)acrylate (1b) Yellow solid (65%). Rf
0.48 (EtOAc); mp 190–191 °C. IR (KBr)νmax: 2920, 1674,
1638, 1605, 1507, 1475, 1437, 1270, 1224, 1160, 1060, 864,
821, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ: 2.02 (d, J =
1.2 Hz, 3H, CH3-C3′), 2.98 (s, 6H, N(CH3)2), 3.64 (s, 3H,
CO2CH3), 3.99 (s, 3H, OCH3), 6.89 (s, 1H, H-8′), 7.23 (s, 1H,
H-3), 7.61 (s, 1H, H-5′), 7.74 (q, J = 1.2 Hz, 1H, H-2′); 13C
NMR (75 MHz, CDCl3) δ: 11.2 (CH3-C3′), 41.8 (N(CH3)2),
51.2 (CO2CH3), 56.3 (OCH3), 102.4 (C-8′), 105.1 (C-5′),
114.3 (C-2), 117.9 (C-4a′), 119.8 (C-3′), 139.7 (C-3), 147.2
(C-6′), 151.1 (C-2′), 152.4 (C-8a′), 153.8 (C-7′), 165.8
(CO2Me), 177.4 (CO-4′); MS (70 eV) m/z 333 (M+, 22), 274
(100), 246 (7), 217 (27), 203 (7). HRMS (70 eV) Calculated
for C17H19NO6: 333.1212. Found: 333.1206.
1
1301, 1229, 1205, 1088, 842, 818 cm−1; H NMR (500
MHz, CDCl3) δ: 3.83 (s, 3H, OCH3-1), 3.98 (s, 3H, OCH3-
6′), 4.80 (s, 2H, CH2-2), 6.30 (d, J = 6.0 Hz, 1H, H-3′),
6.78 (s, 1H, H-8′), 7.58 (s, 1H, H-5′), 7.79 (d, J = 6.0 Hz,
1H, H-2′); 13C NMR (125 MHz, CDCl3) δ: 52.5 (OCH3-1),
56.4 (OCH3-6′), 66.0 (C-2), 101.5 (C-8′), 105.3 (C-5′),
112.4 (C-3), 119.4 (C-4a), 147.9 (C-6′), 152.0 (C-8a), 152.4
(C-7′), 154.6 (C-2′), 168.1 (CO-1), 176.6 (CO-4′); HRMS
(70 eV) Calculated for C13H12O6: 264.0634. Found:
264.0645.
Methyl (Z)-3-(dimethylamino)-2-((3-ethyl-6-methoxy-4-oxo-
4H-chromen-7-yl)oxy)acrylate (1c) White solid (48%). Rf
0.57 (EtOAc); mp 138–139 °C. IR (KBr)νmax: 2936, 1690,
1621, 1469, 1433, 1301, 1267, 1226, 1181, 1207, 1086,
878, 760 cm−1; 1H NMR (500 MHz, CDCl3) δ: 1.19 (t, J =
7.0 Hz, 3H, CH3CH2), 2.45 (q, J = 7.0 Hz, 2H, CH3CH2),
2.97 (s, 6H, N(CH3)2), 3.64 (s, 3H, CO2CH3), 4.00 (s, 3H,
OCH3), 6.88 (s, 1H, H-8′), 7.22 (s, 1H, H-3), 7.61 (s, 1H,
H-5′), 7.68 (s, 1H, H-2′); 13C NMR (125 MHz, CDCl3) δ:
13.0 (CH3CH2), 19.1 (CH3CH2), 42.0 (N(CH3)2), 51.3
(CO2CH3), 56.4 (OCH3), 102.5 (C-8′), 105.4 (C-5′), 114.5
(C-2), 118.3 (C-4a′), 125.3 (C-3′), 139.7 (C-3), 147.2 (C-
6′), 150.9 (C-2′), 152.3 (C-8a′), 154.0 (C-7′), 165.7
(CO2Me), 176.9 (CO-4′); MS (70 eV) m/z 347 (M+, 33),
288 (100), 260 (11), 231 (24), 217 (11). HRMS (70 eV)
Calculated for C18H21NO6: 347.1369. Found: 347.1377.
General procedure for the synthesis of chromonyl
enaminones 1–2 and 3-alkyl chromones 3
A mixture of the corresponding acyl phenol 6 or arylox-
ycarbonyl compound 4–5 (1.0 mol equiv.) with DMFDMA
(3.0 mol equiv.) was refluxed at 120 °C for 48 h (Correa
et al. 2008; Labarrios et al. 2014). The reaction was cooled,
filtered, and concentrated over vacuum. The residue was
purified by flash chromatography to give the respective
chromones 1–3.
Methyl (Z)-2-((6-chloro-3-methyl-4-oxo-4H-chromen-7-yl)
oxy)-3-(dimethylamino)acrylate
(1d) 6-Chloro-7-meth-
oxy-3-methyl-4H-chromen-4-one (14a): 1d: White solid

Medicinal Chemistry Research
(91%); Rf 0.42 (hexane/EtOAc, 1:2); mp 205–207 °C. 14a:
White solid (9%); Rf 0.65 (hexane/EtOAc, 6:4); mp 201–
203 °C. Data for 1d: IR (KBr)νmax: 2946, 1699, 1635,
1605, 1440, 1308, 1255, 1217, 1182, 1167, 1084, 904, 761,
(Z)-7-((3-(4-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-
en-2-yl)oxy)-6-methoxy-4-oxo-4H-chromene-3-carbalde-
hyde (2a) Yellow solid (82%). Rf 0.37 (EtOAc); mp 232–
233 °C; IR (KBr)νmax: 2926, 1631, 1586, 1545, 1493, 1436,
1374, 1293, 1226, 1156, 1114, 960, 906, 845, 778 cm−1; 1H
NMR (300 MHz, CDCl3) δ: 3.08 (s, 6H, N(CH3)2), 4.02 (s,
3H, OCH3), 6.95 (s, 1H, H-8), 7.15 (br s, 1H, H-1′), 7.28–
7.40 (m, 2H, H-3″), 7.56-7.67 (m, 2H, H-2″), 7.63 (s, 1H,
H-5), 8.45 (s, 1H, H-2), 10.36 (s, 1H, CHO); 13C NMR (75
MHz, CDCl3) δ: 41.7 (N(CH3)2), 56.5 (OCH3), 103.1 (C-
8′), 105.6 (C-5′), 119.52 (C-3), 119.53 (C-4a), 125.9 (C-2′),
128.3 (C-3″), 129.7 (C-2″), 136.6 (C-4″), 137.2 (C-1″),
144.7 (C-1′), 148.2 (C-6), 151.8 (C-8a), 153.9 (C-7), 159.8
(C-2), 175.0 (CO-4), 186.0 (CO-3′), 188.9 (CHO); MS (70
eV) m/z 427 (M+, 22), 288 (100), 260 (23), 231 (22), 218
(48), 191 (26), 139 (20). Anal. calcd for C22H18ClNO6Cl: C,
61.76; H, 4.24; N; 3.27. Found: C, 61.73; H, 4.27; N, 3.27.
1
701 cm−1; H NMR (300 MHz, CDCl3) δ: 2.00 (d, J = 0.9
Hz, 3H, CH3), 3.00 (s, 6H, N(CH3)2), 3.66 (s, 3H,
CO2CH3), 6.91 (s, 1H, H-8′), 7.24 (s, 1H, H-3), 7.73 (br s,
1H, H-2′), 8.24 (s, 1H, H-5′); 13C NMR (75 MHz, CDCl3)
δ: 11.1 (CH3), 42.5 (N(CH3)2), 51.3 (CO2CH3), 103.0 (C-
8′), 114.3 (C-2), 118.6 (C-6′), 120.4 (C-4a), 120.5 (C-3′),
127.0 (C-5′), 139.8 (C-3), 151.4 (C-2′), 156.4 (C-8a′),
158.7 (C-7′), 165.2 (CO2Me), 176.7 (CO-4′). HRMS (70
eV) Calculated for C16H16ClNO5: 337.0717. Found:
337.0718. Data for 14a: IR (KBr)νmax: 2924, 1649, 1606,
1453, 1267, 1168, 1047, 1018, 892, 848, 774, 693 cm−1; 1H
NMR (300 MHz, CDCl3) δ: 2.01 (d, J = 1.2 Hz, 3H, CH3),
3.99 (s, 3H, CO2CH3), 6.85 (s, 1H, H-8), 7.73 (br s, 1H, H-
2), 8.19 (s, 1H, H-5); 13C NMR (75 MHz, CDCl3) δ: 11.1
(CH3), 56.6 (OCH3), 100.0 (C-8), 117.6 (C-6), 120.7 (C-3),
120.9 (C-4a), 126.5 (C-5), 151.3 (C-2), 156.6 (C-8a), 158.8
(C-7), 176.6 (CO-4). Anal. calcd for C11H9ClO3: C, 58.81;
H, 4.04. Found: C, 60.37; H, 4.67. HRMS (70 eV) Calcu-
lated for C11H9ClO3: 224.0240. Found: 224.0239.
(Z)-7-((3-(4-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-
en-2-yl)oxy)-6-methoxy-3-methyl-4H-chromen-4-one (2b)
Yellow solid (73%). Rf 0.25 (hexane/EtOAc 1:2). mp 239–
241 °C; IR (KBr)νmax: 2928, 1637, 1606, 1580, 1556, 1481,
1
1327, 1269, 1206, 1176, 1123, 937, 841, 755 cm−1; H
NMR (500 MHz, CDCl3) δ: 1.99 (d, J = 1.0 Hz, 3H, CH3),
3.06 (s, 6H, N(CH3)2), 3.98 (s, 3H, OCH3), 6.84 (s, 1H, H-
8), 7.16 (br s, 1H, H-1′), 7.30 (br d, J = 8.0 Hz, 2H, H-3″),
7.56 (s, 1H, H-5), 7.62 (br d, J = 8.0 Hz, 2H, H-2″), 7.68
(br s, 1H, H-2); 13C NMR (125 MHz, CDCl3) δ: 11.2 (CH3),
41.7 (N(CH3)2), 56.4 (OCH3), 102.5 (C-8), 105.5 (C-5),
118.1 (C-4a), 119.9 (C-3), 126.2 (C-2′), 128.2 (C-3″), 129.8
(C-2″), 136.6 (C-4″), 137.4 (C-1″), 144.7 (C-1′), 147.2 (C-
6), 151.1 (C-2), 152.4 (C-8a), 153.2 (C-7), 177.3 (CO-4),
186.5 (CO-3′); MS (70 eV) m/z 415 (M+ + 2, 12), 413 (M+,
29), 383 (6), 274 (100), 246 (18), 217 (23), 204 (43) 191
(12), 139 (15), 111 (9). Anal. calcd for C22H20ClNO5: C,
63.85; H, 4.87; N, 3.38. Found: C, 63.86; H, 4.88; N, 3.40.
Methyl (Z)-2-((6-Chloro-3-ethyl-4-oxo-4H-chromen-7-yl)oxy)-
3-(dimethylamino)acrylate (1e) 6-Chloro-3-ethyl-7-meth-
oxy-4H-chromen-4-one (14b): 1e: White solid (71%); Rf
0.37 (hexane/EtOAc, 1:1); mp 147–148 °C. 14b: White
solid (11%); Rf 0.71 (hexane/EtOAc, 1:1); mp 160–161 °C.
Data for 1e: IR (KBr)νmax: 2946, 1699, 1639, 1605, 1467,
1439, 1354, 1303, 1254, 1218, 1183, 1122, 1085, 759, 694
1
cm−1; H NMR (500 MHz, CDCl3) δ: 1.18 (t, J = 7.5 Hz,
3H, CH3CH2), 2.48 (br q, J = 7.5 Hz, 2H, CH3CH2), 2.99 (s,
6H, N(CH3)2), 3.66 (s, 3H, CO2CH3), 6.90 (s, 1H, H-8′),
7.23 (s, 1H, H-3), 7.67 (br s, 1H, H-2′), 8.24 (s, 1H, H-5′);
13C NMR (125 MHz, CDCl3) δ: 12.9 (CH3CH2), 19.0
(CH3CH2), 42.5 (N(CH3)2), 51.3 (CO2CH3), 103.0 (C-8′),
114.5 (C-2), 119.0 (C-6′), 120.5 (C-4a′), 126.0 (C-3′), 127.1
(C-5′), 139.7 (C-3), 151.3 (C-2′), 156.3 (C-8a′), 158.8 (C-
7′), 165.2 (CO2Me), 176.2 (CO-4′). HRMS (70 eV) Calcu-
lated for C17H18NClO5: 351.0873. Found: 351.0870. Data
for 14b: IR (KBr)νmax: 2925, 1642, 1611, 1441, 1298, 1261,
1228, 1038, 894, 831 cm−1; 1H NMR (500 MHz, CDCl3) δ:
1.19 (t, J = 7.5 Hz, 3H, CH3CH2), 2.48 (br q, J = 7.5 Hz,
2H, CH3CH2), 3.98 (s, 3H, OCH3), 6.85 (s, 1H, H-8), 7.68
(s, 1H, H-2), 8.19 (s, 1H, H-5); 13C NMR (125 MHz,
CDCl3) δ: 12.8 (CH3CH2), 19.0 (CH3CH2), 56.6 (OCH3),
100.0 (C-8), 118.0 (C-6), 121.0 (C-4a), 126.1 (C-3), 126.7
(C-5), 151.1 (C-2), 156.5 (C-8a), 158.8 (C-7), 176.2 (CO-4).
HRMS (70 eV) Calculated for C12H11ClO3: 238. 0397.
Found: 238.0394.
(Z)-7-((3-(4-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-en-2-
yl)oxy)-3-ethyl-6-methoxy-4H-chromen-4-one
(2c) Yellow
solid (94%). Rf 0.28 (hexane/EtOAc, 1:2); mp 176–177 °C. IR
(KBr)νmax: 2963, 1640, 1578, 1487, 1432, 1329, 1269, 1209,
1
1120, 1056, 958, 919, 837, 754 cm−1; H NMR (300 MHz,
CDCl3) δ: 1.17 (t, J = 7.5 Hz, 3H, CH3CH2), 2.47 (br q, J =
7.5 Hz, 2H, CH3CH2), 3.06 (s, 6H, N(CH3)2), 3.98 (s, 3H,
OCH3), 6.85 (s, 1H, H-8), 7.18 (br s, 1H, H-1′), 7.27–7.36 (m,
2H, H-3″), 7.57 (s, 1H, H-5), 7.60–7.70 (m, 2H, H-2″), 7.66 (br
s, 1H, H-2); 13C NMR (75 MHz, CDCl3) δ: 12.9 (CH3CH2),
19.0 (CH3CH2), 41.7 (N(CH3)2), 56.2 (OCH3), 102.3 (C-8),
105.4 (C-5), 118.2 (C-4a), 125.2 (C-3), 126.1 (C-2′), 128.1
(C-3″), 129.7 (C-2″), 136.4 (C-4″), 137.2 (C-1″), 144.7 (C-1′),
147.1 (C-6), 150.9 (C-2), 152.1 (C-8a), 153.1 (C-7), 176.8

Medicinal Chemistry Research
(CO-4), 186.3 (CO-3′); MS (70 eV) m/z 429 (M+ + 2, 9), 427
(M+, 28), 410 (5), 396 (4), 288 (100), 260 (16), 231 (21), 218
(35), 217 (20), 208 (9), 191 (10), 139 (12). Anal. calcd for
C23H22ClNO5: C, 64.56; H, 5.18; N, 3.27. Found: C, 64.56; H,
5.18; N, 3.29.
3a: IR (KBr)νmax: 3071, 1697, 1645, 1619, 1504, 1475,
1
1437, 1303, 1270, 1246, 1157, 1000, 780 cm−1; H NMR
(500 MHz, CDCl3) δ: 4.00 (s, 6H, (OCH3)2), 6.94 (s, 1H,
H-8), 7.61 (s, 1H, H-5), 8.49 (s, 1H, H-2), 10.41 (s, 1H,
CHO); 13C NMR (125 MHz, CDCl3) δ: 56.5 (OCH3), 56.6
(OCH3), 100.1 (C-8), 104.6 (C-5), 118.7 (C-4a), 119.8 (C-
3), 148.6 (C-6), 152.3 (C-8a), 155.1 (C-7), 159.6 (C-2),
177.3 (CO-4), 189.0 (CHO); MS (70 eV) m/z 234 (M+, 3),
206 (100), 191 (51), 183 (12), 137 (16), 107 (20). HRMS
(70 eV) Calculated for C12H10O5: 234.0528. Found:
(Z)-7-((3-(4-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-
en-2-yl)oxy)-6-methoxy-3-phenyl-4H-chromen-4-one (2d)
Yellow solid (67%). Rf 0.34 (hexane/EtOAc, 1:2); mp 205–
206 °C. IR (KBr)νmax: 2925, 1639, 1579, 1488, 1468, 1430,
1326, 1267, 1210, 1123, 960, 827, 793, 748 cm−1; 1H NMR
(300 MHz, CDCl3) δ: 3.06 (s, 6H, N(CH3)2), 3.99 (s, 3H,
OCH3), 6.91 (s, 1H, H-8), 7.17 (br s, 1H, H-1″), 7.28–7.46
(m, 5H, H-3′, H-4′, H-3‴), 7.51–7.57 (m, 2H, H-2′), 7.61–
7.70 (m, 3H, H-2‴, H-5), 7.91 (s, 1H, H-2); 13C NMR (75
MHz, CDCl3) δ: 41.5 (N(CH3)2), 56.4 (OCH3), 102.5 (C-8),
106.0 (C-5), 119.0 (C-4a), 124.6 (C-3), 126.1 (C-2″), 128.0
(C-4′), 128.2 (C-3‴), 128.4 (C-2′), 128.9 (C-3′), 129.8 (C-
2‴), 132.0 (C-1′), 136.6 (C-4‴), 137.2 (C-1‴), 144.6 (C-
1″), 147.5 (C-6), 151.8 (C-8a), 152.4 (C-2), 153.4 (C-7),
175.2 (CO-4), 186.3 (CO-3″); MS (70 eV) m/z 477 (M+ +
2, 8), 475 (M+, 19), 458 (5), 444 (4), 336 (100), 308 (16),
279 (16), 266 (41), 139 (12). Anal. calcd for C27H22ClNO5:
C, 68.14; H, 4.66; N, 2.94. Found: C, 68.15; H, 4.66; N,
2.95.
1
234.0528. Data for (E)-15: H NMR (500 MHz, CDCl3)
δ: 2.98 (br, 3H, N(CH3)), 3.18 (br, 3H, N(CH3)), 3.86 (s,
3H, OCH3-5′), 3.89 (s, 3H, OCH3-4′), 5.61 (d, J = 12.5
Hz, 1H, H-2), 6.45 (s, 1H, H-3′), 7.11 (s, 1H, H-6′), 7.85
(d, J = 12.5 Hz, 1H, H-3). Signals attributed to the minor
isomer (Z)-15: 3.98 (s, OCH3), 4.00 (s, OCH3), 6.30 (d, J
= 6.0 Hz, H-2), 6.87 (s, H-3′), 7.54 (s, H-6′), 7.80 (d, J =
6.0 Hz, H-3). 13C NMR (125 MHz, CDCl3) δ: 37.4
(NCH3), 45.2 (NCH3), 55.9 (OCH3-4′), 57.1 (OCH3-5′),
89.7 (C-2), 100.8 (C-3′), 111.1 (C-6′), 111.7 (C-1′), 141.2
(C-5′), 154.1 (C-3), 155.0 (C-4′), 160.1 (C-2′), 190.3
(CO). Signals attributed to the minor isomer (Z)-15: 99.3,
104.0, 112.3, 159.1. HRMS (70 eV) Calculated for
C13H17NO4: 251.1158. Found: 251.1156.
6,7-Dimethoxy-3-methyl-4H-chromen-4-one (3b) White solid
(96%). Rf 0.23 (hexane/EtOAc, 6:4); mp 151–152 °C. IR
(KBr)νmax: 2956, 1640, 1602, 1508, 1477, 1430, 1325, 1268,
(Z)-6-chloro-7-((3-(4-chlorophenyl)-1-(dimethylamino)-3-
oxoprop-1-en-2-yl)oxy)-3-methyl-4H-chromen-4-one (2e)
6-Chloro-7-methoxy-3-methyl-4H-chromen-4-one (14a):
2a: White solid (82%); Rf 0.22 (hexane/EtOAc, 6:4); mp
225–226 °C. 14a: White solid (9%); Rf 0.65 (hexane/
1
1228, 1177, 1026, 770 cm−1; H NMR (500 MHz, CDCl3) δ:
2.03 (s, 1H, CH3), 3.97 (s, 3H, OCH3), 3.98 (s, 3H, OCH3),
6.83 (s, 1H, H-8), 7.56 (s, 1H, H-5), 7.74 (br s, 1H, H-2); 13
C
EtOAc, 6:4); mp 202–203 °C. Data for 2e: IR (KBr)νmax
:
RMN (125 MHz, CDCl3) δ: 11.2 (CH3), 56.2 (OCH3), 56.3
(OCH3), 99.5 (C-8), 104.3 (C-5), 117.0 (C-4a), 120.0 (C-3),
147.4 (C-6), 151.0 (C-2), 152.7 (C-8a), 154.1 (C-7), 177.4
(CO); MS (70 eV) m/z 220 (M+, 100), 219 (33), 205 (26), 191
(17), 177 (30), 174 (36), 161 (16), 149 (17), 137 (12). HRMS
(70 eV) Calculated for: C12H12O4. 220.0736. Found: 220.0744.
3056, 2924, 1640, 1602, 1443, 1327, 1258, 1219, 1171,
1
1122, 995, 937, 840 cm−1; H NMR (300 MHz, CDCl3) δ:
1.98 (d, J = 1.2 Hz, 3H, CH3), 3.08 (s, 6H, N(CH3)2), 6.86
(s, 1H, H-8), 7.23 (br s, 1H, H-1′), 7.29–7.40 (m, 2H, H-3″),
7.57–7.74 (m, 2H, H-2″), 7.68 (br s, 1H, H-2), 8.19 (s, 1H,
H-5); 13C NMR (75 MHz, CDCl3) δ: 11.1 (CH3), 41.7 (N
(CH3)2), 102.9 (C-8), 118.7 (C-6), 120.4 (C-4a), 120.6 (C-
3), 126.2 (C-2), 127.1 (C-5), 128.3 (C-3″), 129.8 (C-2″),
136.8 (C-1″), 136.9 (C-4″), 144.1 (C-1′), 151.4 (C-2), 156.3
(C-8a), 157.8 (C-7), 176.6 (CO-4), 186.1 (CO-3′). Anal.
calcd for C21H17NO4Cl2: C, 60.30; H, 4.10; N, 3.35. Found:
C, 60.31; H, 4.13; N, 3.33.
3-Ethyl-6,7-dimethoxy-4H-chromen-4-one (3c) White solid
(98%). Rf 0.38 (hexane/EtOAc, 6:4); mp 117–118 °C. IR
(KBr)νmax: 2966, 1641, 1605, 1506, 1473, 1430, 1299,
1
1267, 1244, 1224, 1194, 1145, 1008, 820, 755 cm−1; H
NMR (500 MHz, CDCl3) δ: 1.20 (t, J = 7.5 Hz, 3H,
CH3CH2), 2.50 (q, J = 7.5 Hz, 2H, CH3CH2), 3.96 (s, 3H,
OCH3), 3.97 (s, 3H, OCH3), 6.82 (s, 1H, H-8), 7.55 (s, 1H,
H-5), 7.70 (s, 1H, H-2); 13C NMR (125 MHz, CDCl3) δ:
12.9 (CH3CH2), 19.1 (CH3CH2), 56.2 (OCH3), 56.3
(OCH3), 99.4 (C-8), 104.3 (C-5), 117.2 (C-4a), 125.3 (C-3),
147.3 (C-6), 150.8 (C-2), 152.5 (C-8a), 154.0 (C-7), 176.8
(CO); MS (70 eV) m/z 234 (M+, 100), 233 (83), 219 (25),
191 (21), 175 (14). HRMS (70 eV) Calculated for
C13H14O4: 234.0892. Found: 234.0889.
6,7-Dimethoxy-4-oxo-4H-chromene-3-carbaldehyde
(3a) (E/Z)-3-(Dimethylamino)-1-(2-hydroxy-4,5-dime-
thoxyphenyl)prop-2-en-1-one (15): 3a: Yellow solid
(67%); Rf 0.26 (hexane/EtOAc, 6:4); mp 211–212 °C (Lit.
226.0–226.5 °C, Nohara et al. 1974). (E/Z)-15 (85:15):
Yellow solid (23%); Rf 0.31 (hexane/EtOAc, 1:2); mp
155–158 °C (Lit. 157–158 °C, Chin et al. 2015). Data for

Medicinal Chemistry Research
6,7-Dimethoxy-3-propyl-4H-chromen-4-one
(3d) White
5139; No. of observed reflections: 2935; data collection
range: 3.147 < θ < 32.412°; R: 0.0638; wR: 0.1374; GOF:
1.034. The authors have deposited the atomic coordinates
for this structure with the Cambridge Crystallographic Data
Centre (CCDC 1884808). The coordinates can be obtained,
on request, from the Director Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
solid (99%). Rf 0.44 (hexane/EtOAc, 6:4); mp 107–108 °C.
IR (KBr)νmax: 2956, 1641, 1607, 1505, 1474, 1432, 1324,
1269, 1225, 1149, 1080, 1002, 821, 767 cm−1; H NMR
1
(500 MHz, CDCl3) δ: 0.97 (t, J = 7.5 Hz, 3H, CH3CH2CH2),
1.62 (sext, J = 7.5 Hz, 2H, CH3CH2CH2), 2.44 (t, J = 7.5
Hz, 2H, CH3CH2CH2), 3.96 (s, 3H, OCH3), 3.97 (s, 3H,
OCH3), 6.82 (s, 1H, H-8), 7.55 (s, 1H, H-5), 7.69 (s, 1H, H-
2); 13C NMR (125 MHz, CDCl3) δ: 13.7 (CH3CH2CH2),
21.5 (CH3CH2CH2), 27.8 (CH3CH2CH2), 56.1 (OCH3), 56.2
(OCH3), 99.4 (C-8), 104.4 (C-5), 117.3 (C-4a), 123.7 (C-3),
147.3 (C-6), 151.2 (C-2), 152.5 (C-8a), 154.1 (C-7), 176.9
(CO); MS (70 eV) m/z 248 (M+, 70), 247 (38), 233 (84), 220
(100), 205 (19), 191 (19), 174 (26). HRMS (70 eV) Calcu-
lated for C14H16O4: 248.1049. Found: 248.1040.
Biological evaluation
Enzyme inhibition study
The determination of α-glucosidase inhibition was carried
out according to a published method (Salehi et al. 2013),
with some modifications. A solution of 20 µL α-glucosidase
(0.5 unit/mL), 120 µL of 0.1 M phosphate buffer (pH 6.9)
and 10 µL of the sample was prepared at various con-
centrations. The solution was incubated in 96-well plates at
37 °C for 15 min. Then the enzymatic reaction was initiated
by adding 20 µL of 5 mM p-nitrophenyl-α-D-glucopyrano-
side solution in 0.1 M phosphate buffer (pH 6.9), followed
by incubation of the mixture for another 15 min at 37 °C.
The reaction was ended by adding 80 µL of 0.2 M sodium
carbonate solution and then absorbance was read was
recorded at 405 nm by a microplate reader (Epoch, Bio-
Tek®). The reaction system without test compounds served
as the control, and the system without α-glucosidase was as
the blank for correcting the background absorbance. The
percentage of α-glucosidase inhibition produced by the
sample was calculated by using Eq. (1).
3-Isopropyl-6,7-dimethoxy-4H-chromen-4-one (3e) White
solid (98%). Rf 0.50 (hexane/EtOAc, 6:4); mp 92–93 °C. IR
(KBr)νmax: 2957, 1632, 1602, 1508, 1479, 1456, 1271,
1225, 1065, 822, 765 cm−1; 1H NMR (500 MHz, CDCl3) δ:
1.23 (d, J = 7.5 Hz, 6H, (CH3)2CH), 3.16 (sept, J = 7.5 Hz,
1H, (CH3)2CH), 3.97 (s, 6H, (OCH3)2), 6.83 (s, 1H, H-8),
7.56 (s, 1H, H-5), 7.67 (s, 1H, H-2); 13C NMR (125 MHz,
CDCl3) δ: 21.5 ((CH3)2), 25.0 ((CH3)2CH), 56.2 (OCH3),
56.3 (OCH3), 99.4 (C-8), 104.5 (C-5), 117.4 (C-4a), 129.5
(C-3), 147.3 (C-6), 150.5 (C-2), 152.3 (C-8a), 154.1 (C-7),
176.4 (CO); MS (70 eV) m/z 248 (M+, 77), 247 (43), 233
(100), 220 (91), 205 (14), 189 (16), 174 (15). HRMS (70
eV) Calculated for C14H16O4: 248.1049. Found: 248.1041.
ꢀ
ꢁ
Single-crystal X-ray crystallography
Control absorbance À sample absorbance
% de inhibition ¼
 100
ð1Þ
Control absorbance
Enaminone 1b was obtained as colorless crystals by crys-
tallization from EtOAc/CH2Cl2 (9:1), which were mounted
on glass fibers. Crystallographic measurements were per-
formed on an Oxford XCalibur diffractometer with Mo Kα
radiation (λ = 0.71073 Å; graphite monochromator) at room
temperature, with a CCD detector. Empirical (multi-scan)
absorption corrections were applied. Unit cell parameters
were obtained from a least-squares refinement and inten-
sities were corrected for Lorentz and polarization effects.
Hydrogen atoms were placed from an electron density map
and their atomic coordinates refined. Unit weights were
used in the refinement. After being solved with SHELXT
(Sheldrick 2008, 2015), implemented in the WinGX suite
(Farrugia 1999, 2012), and refined within WinGX using
SHELXL (Sheldrick 2015). ORTEP diagram was made
with ORTEP3 (Farrugia 1997, 2012). Data from 1b: For-
mula: C17H19NO6: molecular weight: 333.33; cryst. syst.:
triclinic; space group: P-1; unit cell parameters: a, 6.2438
(3), b, 11.2551(5), c, 12.7475(7) (Å); α, 65.846(5)°, β,
84.544(4)°, γ, 89.373(4)°; temp. (K): 292(2); Z: 2; No. of
reflections collected: 10497; No. of independent reflections:
DPPH radical scavenging assay
The scavenging of free radicals by the chromones was
assessed with a DPPH assay as previously described
(Cevallos-Casals and Cisneros-Zevallos 2003), with slight
modifications. Concentrations were prepared of 10, 1.0, and
0.1 mM of each of the compounds, to which a solution of
2,2-diphenyl-1-picrylhydrazyl radical (DPPH) (133.33 µM)
was added at a ratio of 1:3 (v/v). The mixture was incubated
at 37 °C for 30 min and read at 517 nm. Antioxidant activity
was expressed as the percentage of decrease of DPPH at 10
mM (%).
Antimicrobial activity
Compounds 1–3 were evaluated for their inhibition of two
strains (ATCC 90028/ATCC 10231) and 20 clinical isolates
of Candida albicans. The broth microdilution method was

Medicinal Chemistry Research
utilized with resazurin as an indicator of cell viability
(Sarker et al. 2007). For the incubations (at 30 °C), different
concentrations of the test compounds (10–500 µg/mL, each
with 5 × 105 CFU) were placed in each well of a 96-well
plate containing PDB medium and resazurin to reach a final
volume of 0.3 mL in quintuplicate (n = 15). Fluconazole
was used as the reference (0.1–200 µg/mL). The absorbance
was recorded at 545 nm after 12 h. The MIC value was
considered as the initial concentration capable of avoiding
any change of absorbance in the dose response curves. The
inhibitory efficiency of each chromone was validated by
ANOVA and the Tukey test (p < 0.05) on GraphPad Prism
7.0 software.
performed with blind docking, adjusting the grid box size to
60 × 60 × 60 Å with grid point spacing of 0.375 Å3. The
focus was CZ of Arg197 because it is a key residue that
participates in the recognition process of other reported
ligands (Jhon et al. 2015). All docking simulations were
based on the Lamarckian genetic algorithm considering a
randomized initial population of 100 individuals and a
maximum number of energy evaluations of 1 × 107. The
atomic affinity maps were generated on the AutoGrid 4.0
program. The 3-D ligand–receptor complexes were visua-
lized and analyzed on the AutoDock Tools program, taking
into account the different interactions formed in each
complex and selecting the complex with the lowest free
energy values. This was the procedure for identifying the
key residues involved in the process of molecular recogni-
tion of ligands by the receptor. The main criterion for
choosing the best molecules was free energy (ΔG) because
it determines the dissociation constant (Kd) or inhibitory
constant (Ki) and the binding pose.
Docking studies
The proposed chemical structures (Scheme 1) were drawn
in 2D format on ACD/ChemSketch 14.01 software (ACD/
ChemSketch 2012). Subsequently, explicit hydrogen atoms
were added to the molecule, and a geometric 3D pre-
optimization was performed. The Z matrix of each molecule
was created on the GaussView 5.0.9 package (Dennington
et al. 2012). The molecules were submitted to a geometric
and energetic optimization with semi-empirical molecular
orbitals AM1 (Austin Model 1) on the GAUSSIAN 09W
9.5 program (Dennington et al. 2012). The results were
converted to a.mol file with the GaussView graphical
interface (Dennington et al. 2012) and then to pdb with
Pymol (DeLano 2002), these being the input files for
docking simulations.
The molecular docking studies were carried out on the
AutoDock 4.2 program (Morris et al. 2009) using the α-
glucosidase 3D structure located at Protein Data Base
(PDB: 2ZE0). Polar hydrogen atoms and atomic partial
charges were included by using the AutoDock Tools 1.5.6
program. To examine the electrostatic contribution of the
ligand–receptor interaction, the Kollman partial charges
were calculated (Morris et al. 2009). The analysis was
Results and discussion
Chemistry
Based on previously reported results from biological and
docking studies using chromone inhibitors (Philip et al.
2017; Zhen et al. 2017; Wang et al. 2017, 2018; Jose et al.
2018; Soengas et al. 2016), we designed the target com-
pound series 1–3. To each series, an alkyl chain or a phenyl
group was added to the C-3 position of the pyrone ring.
Considering the introduction of a tertiary amino group for
compounds 1–2, an enaminone scaffold was added at the
C-7 position of the aromatic ring of the chromone. For
compounds 3a–e, a methoxy group was incorporated at this
position (Scheme 1).
Detailed procedures for the synthesis of 2-acyl phenols
6a and 6c (Mendieta et al. 2014), 6b (Musso et al. 2010), 6e
Scheme 1 Retrosynthesis of
alkyl chromones derivatives 1–3

Medicinal Chemistry Research
(Huls 1958), 8a (Zoe et al. 2010), 8b (Jha et al. 1981), 8d
(Goto et al. 2009), 9a (Rao and Krupadanam 1994), and 9b
(Moore et al. 1934) have been described. Thus, the series of
compounds 6–8 were prepared by acylation of phenols 9a–c
with the corresponding acyl chlorides 10a–e, in the pre-
sence of boron trifluoride etherate (BF3·OEt2) at 80 °C for 3
Initially, the aryloxyacetic ester 4a was reacted with
DMFDMA (1.5 mol equiv.) at 120 °C for 12 h. However, a
mixture of enaminones E/Z-12 (72:28) (26%) and chromone
13 (44%) were isolated as the main products (Scheme 2).
Since the series of compounds 4 and 5 possess two acti-
vated methylene groups, the DMFDMA reagent had to be
used in an excess (3.0 mol equiv.) at 120 °C for longer
reaction times (48 h), resulting in the corresponding chro-
monyl enaminones 1a–e and 2a–e in moderate to good
yields (Table 3). Unexpectedly, when the reaction was
carried out with 4d–e and 5e, chromones 14a–b were iso-
lated as by-products in low yields. These were probably
generated by breakage of the phenoxyacetate group by the
methoxy ion (stemming from the decomposition of
DMFDMA), and then methylation of the resulting phenol
by an attack on the methyl group of the dimethyliminium
ion (Jerezano et al. 2011; Belov et al. 2011).
1
h, to give 2-acyl phenols in high yields (Table 1). The H
NMR spectra of the acyl phenols 6–8 show a single signal
for the hydroxyl group in the 12.65–12.75 ppm range. The
13C NMR spectra display a signal at around 204 ppm, which
is characteristic of the C-1 carbonyl group.
Subsequently, the series of compounds 7 and 8 were
subjected to the O-alkylation reaction by employing α-
bromoester (11a) or α-bromoacetophenone (11b) in the
presence of potassium carbonate in acetone at reflux,
obtaining the corresponding series of aryloxycarbonyl
1
compounds 4–5 in high yields (Table 2). The H NMR
1
spectra of these two series show a single signal in the range
of 4.63–5.53 ppm, which is attributed to the methylene
protons of the oxyacetic group. In the 13C NMR spectra,
there is a signal at around 168 or 191 ppm assigned to the
C-1 carbonyl group.
Ketones and esters containing an α-methylene group
readily condense with DMFDMA to afford enaminones
under solvent-free thermal conditions (Correa et al. 2008).
In the H NMR spectra of compounds 1–2, a singlet in
the 2.98–3.08 ppm range indicates the presence of dime-
thylamino protons. The C2′-H proton of the chromone ring
appears as a singlet at around at 7.67–8.45 ppm, while the
C3-H vinyl proton is seen in the 7.15–7.73 ppm range. The
full assignment of proton and carbon signals was accom-
plished by 2D NMR experiments (HMQC and HMBC).
Enaminones 1–2 were obtained as a single stereoisomer,
Table 1 Preparation of acyl phenols 6–8
Acyl chloride
R1
R2
R3
Product (%)a
δH (ppm) (HO-2′)
δC (ppm) (C-1)
10a
10b
10c
10d
10e
10a
10b
10c
10f
OMe
OMe
OMe
OMe
OMe
OH
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Cl
Me
Et
6a (88)
6b (92)
6c (85)
6d (88)
6e (84)
7a (86)
7b (80)
7c (85)
7d (50)
8a (99)
8b (90)
12.65
12.76
12.79
12.78
12.89
12.55
12.66
12.72
12.53
12.60
12.65
202.0
204.7
204.3
204.5
204.1
201.3
204.6
204.2
201.3
204.8
204.4
n-Pr
n-Bu
i-Bu
Me
Et
OH
OH
n-Pr
Bn
OH
10b
10c
OH
Et
OH
Cl
n-Pr
aAfter column chromatography

Medicinal Chemistry Research
Table 2 Preparation of aryloxycarbonyl compounds 4–5
Substrate
α-Bromo compound
R2
R3
R4
Product (%)a
δH (ppm) (H-2)
δC (ppm) (C-1)
7a
7b
7c
8a
8b
7a
7b
7c
7d
8a
11a
11a
11a
11a
11a
11b
11b
11b
11b
11b
OMe
OMe
OMe
Cl
Me
Et
OMe
4a (90)
4b (97)
4c (95)
4d (74)
4e (80)
5a (83)
5b (88)
5c (70)
5d (80)
5e (80)
4.75
4.74
4.74
4.75
4.75
5.36
5.36
5.35
5.34
5.53
168.0
168.1
168.1
167.7
167.7
191.5
191.6
191.6
191.5
191.2
OMe
n-Pr
Et
OMe
OMe
Cl
n-Pr
Me
Et
OMe
OMe
OMe
OMe
OMe
Cl
C6H4-4-Cl
C6H4-4-Cl
C6H4-4-Cl
C6H4-4-Cl
C6H4-4-Cl
n-Pr
Bn
Et
aAfter column chromatography
Scheme 2 Preparation of E/Z-12
(72:28) and 13 by reacting 4a
with DMFDMA (1.5 mol equiv.)
whose Z geometry was established by NOE experiments.
The irradiation of the signal assigned to the methyl protons
of the dimethylamino group of compound 1b enhanced the
signals corresponding to the aryloxy ring of the chromone
scaffold. The same stereoselectivity has been observed in
similar systems (Correa et al. 2008; Jerezano et al. 2011;
Labarrios et al. 2014), probably due to the greater stability
achieved by the planar π-conjugated acrylate system when
the bulky dimethylamino group is located at the opposite
side of the carbonyl group.
The Z-configuration of 1b was confirmed by X-ray
crystallography (Fig. 2). In the crystal lattice, the acrylate
system adopts a planar s-cis conformation, keeping the
oxychromenyl ring system distant from the enaminone
moiety and in a noncoplanar conformation [C(7′)-O(C(2)-C
(1)) = 81.14°] with respect to the carbonyl group.
Following the same approach and reacting the corre-
sponding alkyl-(ortho-hydroxyaryl) ketones 6a–e with
DMFDMA at 120 °C for 12 h, the 3-alkyl chromones 3
were synthesized in good to excellent yields (67–99%,
Table 4). When utilizing substrate 6a, 3-formylchromone
3a was provided in 67% yield along with by-product 15 in
low yield, as a mixture of E/Z (85:15). The generation of 3-
formylchromones in low yields has previously been repor-
ted when using analogous ketones (Gaspar et al. 2014).
Considering these results and the reports concerning the
formation of 3-formyl chromones and enaminones (Gaspar
et al. 2014; Correa et al. 2008; Jerezano et al. 2011;
Labarrios et al. 2014), a possible mechanism is proposed for
the formation of chromonyl enaminones (Scheme 2). Initi-
ally, the presence of the methoxy ion promotes the forma-
tion of enolate I of ketones 4–5, which reacts with the
iminium ion produced by DMFDMA to give species II.
Demethoxylation of the latter affords species III, followed
by deprotonation to furnish enaminone 12, and then an
intramolecular cyclization type 6-exo-trig converts this into
the unsubstituted chromones 13. For 6a (R1=H), a second
attack from the iminium ion provides the 3-formyl chro-
mone 3a. Chromone 13 forms the enolate ketone of the
ester group, which attacks the iminium ion to complete the
synthesis of chromonyl enaminones 1 (Scheme 3).
α-Glucosidase inhibition activity
α-Glucosidase inhibitors act by delaying glucose absorp-
tion, making them potent drugs for the control of blood

Medicinal Chemistry Research
Table 3 Synthesis of chromonyl enaminones 1–2
Substrate
R1
R2
R4
Product (%)a
δH (ppm) (H-3)
δC (ppm) (C-3)
4a
4b
4c
4d
OMe
OMe
OMe
OMe
OMe
OMe
OMe
Cl
H
1a (48)
1b (65)
1c (48)
1d (91)
14a (9)
1e (71)
14b (11)
2a (82)
2b (73)
2c (94)
2d (67)
2e (82)
14a (9)
7.21
139.7
Me
Et
7.23
139.6
7.22
139.7
Me
Me
Et
7.24
139.8
7.73 (H-2)
7.23
151.3 (C-2)
139.5
4e
OMe
Cl
Et
7.68 (H-2)
7.15
151.1 (C-2)
144.7
5a
5b
5c
5d
5e
4-Cl-Ar
4-Cl-Ar
4-Cl-Ar
4-Cl-Ar
4-Cl-Ar
OMe
OMe
OMe
OMe
Cl
CHO
Me
Et
7.16
144.7
7.18
144.7
Ph
7.17
144.6
Me
Me
7.23
144.1
7.73 (H-2)
151.3 (C-2)
aAfter column chromatography
capacity of the new chromone derivatives 1–3 to inhibit α-
glucosidase activity. Acarbose was the positive control
(Table 5). Compounds 2a and 2c–e were highly active
inhibitors (>89.93%, at 10 mM), suggesting a key role
played by the 4-chlorophenyl group in the enaminone
moiety. Derivatives 1a–e and 3a–e did not show significant
activity.
The best activity was found when the 4-chlorophenyl
was located in the enaminone fragment (i.e., derivatives
2a–e, of which 2b exhibited the lowest inhibition). The
comparison of the chromonyl enaminones 2a–e with their
chromonyl acrylate analogs 1a–e revealed that the repla-
cement of the methyl ester by the 4-chlorophenyl ketone
significantly increased the activity. According to a recent
report, the presence of 4-halophenyl groups in the benzo-
pyran ring favors the inhibition of α-glucosidase (Wang
et al. 2018). Interestingly, the highest activity (IC50 = 0.89
mM) was detected for compound 2d (with a phenyl group at
the C-3 position of the benzopyran ring) indicating that a C-
3 aryl group enhances this capacity. The structure of com-
pound 2d without the enaminone fragment is analogous to
afromosin, a known natural isoflavonoid, which also exerts
Fig. 2 X-ray structure of 1b (ellipsoids with 30% probability)
glucose levels in diabetic patients (Kerru et al. 2018).
Because the chromone scaffold has proved to be a pro-
mising ring system for the design and synthesis of new
molecules with different biological effects, an in vitro
determination was herein carried out in relation to the

Medicinal Chemistry Research
Table 4 Preparation of 3-alkyl chromones 3
Compound
R2
Product (%)a
δH (ppm) (H-2)
δC (ppm) (HC=)
6a
CHO
3a (67)
15 (23)
3b (96)
3c (98)
3d (99)
3e (98)
8.48
5.61, 7.85b
159.6
89.7, 154.1c
6b
6c
6d
6e
Me
Et
7.74
151.0
7.70
150.8
n-Pr
i-Pr
7.69
151.2
7.67
150.5
aAfter column chromatography
bδ H-2, H-3 for isomer E
Cδ C-2, C-3 for isomer E
Scheme 3 Proposal mechanism
for the formation of chromonyl
enaminones 1 and chromones 12
and 13

Medicinal Chemistry Research
Table 5 DPPH-scavenging and α-glucosidase inhibition found for
compounds 1–3
Compounds 1b, 1d, 2a–b, 2d, and 3a exhibited an
approximate 10–30% decrease in the DPPH radical. How-
ever, no antioxidant effect was found for chromonyl
enaminones 1a, 1c and 1e, 2c, 2e and 3-alkyl chromones
3b–e. In summary, the presence of the acrylate or the
enaminone fragment in the chromone scaffold showed the
best reduction in DPPH.
Compound % DPPH scavenging
activity (10 mM)
% α-Glucosidase inhibition
% (10 mM) (IC50 mM)
1a
0.0 0.50
11.56 0.74
16.78 0.20
16.05 0.62
13.09 0.85
43.43 1.69
14.54 0.57
6.73 0.96
10.75 1.09
0.0 0.78
26.93 0.12
1b
2.2 0.06
1c
17.9 0.58
1d
13.6 0.19
In vitro antifungal activity
1e
38.5 1.00
2a
89.3 0.54 5.38 0.9
33.8 0.58 11.05 0.7
92.3 0.89 8.20 0.06
93.92 0.89 0.89 0.03
93.24 0.74 1.47 0.02
22.0 1.43
Derivatives of 3-oxyalkyl chromones have been described
as promising antimicrobial agents (Dofe et al. 2017a, b).
Previous reports suggest that 3-substituted chromones exert
a significant activity against C. albicans (Chohan et al.
2006, Dofe et al. 2017a, b). Consequently, the 3-substituted
chromones 1–3 were herein tested in vitro as possible
antimicrobial agents against both standard strains and wild
strains of C. albicans. This unicellular pathogen is known to
cause superficial infections of the oral and vaginal mucosa,
which is often disseminated through the bloodstream and
deep into tissues, thus producing thousands of deaths in the
world annually (Whaley et al. 2017). Azole antifungals
(e.g., fluconazole) are often used for the treatment of C.
albicans infections, but there is growing evidence of the
resistance of wild strains of C. albicans to these drugs
(Canno et al. 2007; Berkow and Lockhart 2017).
2b
2c
2d
2e
3a
18.73 0.60
1.30 0.50
2.44 0.33
1.41 0.50
5.60 0.69
3b
2.8 0.66
3c
8.0 0.96
3d
9.9 1.40
3e
12.1 0.32
b
BHT
Acarbose
85.02 3.33a
b
63.18 0.7
7.73 0.9
aIC50 = 0.84 mM
bNot determined
Compounds 3c–e induced significant growth inhibition
(MIC, 70–83 µg/mL) against the fluconazole susceptible
strain ATCC® 90028. Remarkably, the three chromones
showed moderate activity against C. albicans (MIC < 300
μg/mL) and 20 clinical isolates (Table 6), though inhibition
of the resistant C. albicans strain ATCC® 10231 was
modest. Regarding the latter strain, compound 3d displayed
the best MIC value, being only four times less effective than
fluconazole. Hence, this chromone should certainly be
useful as a starting material for designing new more potent
analogs.
These data suggest that inhibition of C. albicans was
significantly enhanced in chromones containing ortho-
methoxy groups in the aromatic ring but not in those with
an enaminone group in the C-7 position of the aromatic ring
(not shown in Table 6). Furthermore, antifungal activity is
possibly improved by an unbranched aliphatic chain adja-
cent to the unsaturated γ-pyran ring (Lu et al. 2017; Seleem
et al. 2017).
an inhibitory effect on the α-glucosidase enzyme (Boon-
sombat et al. 2017). Therefore, the 4-chlorophenyl group
adjacent to the carbonyl group of the π-conjugated enam-
inone system seems to be very active pharmacophore in the
improvement of α-glucosidase inhibition.
Evaluation of the antioxidant activity
Antioxidants are important agents in the prevention of many
human diseases, including diabetes mellitus. Oxidative
stress plays a pivotal role in the development of diabetes
and in the pathogenesis of late diabetic complications
(Soengas et al. 2016). Considering, that α-glucosidase
inhibitors are potent drugs for treating of diabetes, studies
have previously explored the inhibitory capacity of a series
of chromones derivatives as well as their radical scavenging
activity (Soengas et al. 2016; Takao et al. 2014). To
determine the potential of chromonyl enaminones and 3-
alkyl chromones 1–3 as antioxidants, all new compounds
were assessed for their 2,2-diphenyl-1-picrylhydrazyl
(DPPH) free radical scavenging, which was tested by the
reduction in color intensity and expressed as the percentage
of decrease in DPPH (Table 5). Butylated hydroxytoluene
(BHT) served as the positive control. Compounds 1–3
Docking results
The molecular docking results for 2a, 2d, and 2e, the active
α-glucosidase inhibitors, are summarized in Table 7. The
free energy (ΔG) was lower for compound 2d than the other
two compounds, perhaps due to its aromatic electron-rich
displayed
a low level of free radical scavenging.

Medicinal Chemistry Research
Table 6 In vitro anti-C. albicans
activity of compounds 3c–e
(MIC SD, n = 15, µg/mL)
Strain
3c*
75.6 0.04b
3d*
70.5 0.54b
3e*
83.1 0.14a
Fluconazole
ATCC®90028TM
ATCC®10231TM
0.94
71.6
0.89
0.8
310.3 0.21b
132.2 0.12b
100.4 0.03b
148.4 0.24b
186.2 0.27a
198.6 0.14a
154.7 0.75b
124.1 0.17b
85.2 0.43b
110.1 0.18a
213.8 0.41b
129.4 0.08b
77.2 0.11b
122.9 0.74b
167.4 0.16a
176.8 0.63a
155.4 0.31b
275.2 0.13a
84.8 0.27b
99.2 0.53b
125.6 0.86a
287.2 0.12b
74.8 0.19c
84.7 0.26b
76.9 0.51c
85.1 0.78b
126.5 0.32b
111.3 0.25c
88.9 0.06c
73.9 0.18b
95.4 0.14a
153.9 0.86c
87.5 0.16c
70.4 0.07a
115.3 0.69b
99.1 0.14b
121.7 0.88b
107.4 0.37c
174.9 0.92b
72.3 0.74b
84.5 0.36b
86.2 0.43b
365.4 0.82a
184.2 0.24a
155.7 0.53a
172.9 0.39a
177.3 0.11a
143.7 0.72b
243.8 0.61a
259.5 0.34a
157.5 0.51a
99.6 0.26a
267.8 0.91a
195.6 0.33b
86.9 0.72a
201.2 0.51a
178.3 0.65a
203.6 0.46a
243.5 0.81a
254.3 0.34a
137.5 0.02a
145.5 0.14a
135.8 0.71a
1
2
3
0.91
1.6
4
5
2.8
6
0.97
4.7
7
8
1.6
9
0.9
10
11
12
13
14
15
16
17
18
19
20
3.6
2.1
2.6
0.99
0.78
1.6
0.97
3.3
0.96
0.79
0.83
*MIC values are expressed in µg/mL and the letters indicate significant differences (p < 0.05)
Table 7 Interactions of compounds 2a, 2d, and 2e with residues located in the active site of α-glucosidase
Ligand
ΔG (kcal/mol) Ki (μM) Residue involved in ligand recognition
2a
2d
−7.88
−9.37
1.68 Val100, Asp199, Ala200, Glu256, Trp49, Asn324, Gln167, Tyr63, Asp60, His325, Phe144
0.135 Phe280, Phe282, Phe321 Arg197, Trp49, Gln13, Asn324, Phe163, Gln167, Arg407, Asp326, His325,
Tyr63, Asn61
2e
−8.56
0.534 Ala200, Glu256, Arg197, Trp49, Asn324, Phe144, Asp326, His325, Gln167, Asp60, Tyr63
Acarbose −5.45
100.59 Asp199, Arg197, Glu256, Tyr63, Asn61, Asn324, Arg411, Asp60, Asn258, Phe282, Phe144, Arg407,
Asp326
moieties, which may favor the formation of a cluster of
aromatic residues and reach Arg residues. This is a plausible
explanation for the high affinity of 2d on α-glucosidase.
Analog 2d interacts with some of the same residues as 2a
and 2e (Asn324, Gln167, His325, Trp49, and Trp63). It has
two more residues in common with 2e (Arg197 and
Arg326), but no more in common with 2a. However, the
latter compound shares additional residue interactions with
2e (Ala200, Asp60, Glu256, and Phe144). Several residue
interactions found in 2d do not exist in 2a or 2e (Phe280,
Phe282, Phe321, Phe163, Gln13, Arg407, and Asn61),
clearly explaining the differences in stability (ΔG) and
affinity for α-glucosidase. The protein–ligand interactions
for compounds 2a, 2d, and 2e are illustrated in Fig. 3.
Compound 2d adopts a binding orientation in which the 3-
phenyl ring interacts with the phenyl groups of Phe80,
Phe82, and Trp49, further stabilizing the ligand within the
enzyme catalytic pocket.
Conclusions
After the series of chromones 1–3 were efficiently synthe-
sized in good yields, they were evaluated as α-glucosidase
inhibitors as well as antifungal and antioxidant agents. The
biological testing evidenced a different pattern of biological
activity for the synthesized derivatives than the standard
drugs acarbose, BHT and fluconazole. For example, chro-
mone derivatives 2a and 2d–e exhibited good inhibition of
the α-glucosidase enzyme (IC50 range of 0.89–5.38 mM),

Medicinal Chemistry Research
Fig. 3 Binding modes of
compounds 2a, 2d, and 2e in the
α-glucosidase binding pocket
better than that of acarbose (IC50 of 7.73 mM). The current
results suggest that a phenyl group at the C-3 position of the
chromone moiety and a 4-chlorophenyl group in the
enaminone fragment favored the inhibitory effect on α-
glucosidase. On the other hand, no relevant antioxidant
capacity (10–30% at 10 mM) was found for any of the test
compounds, according to the radical-scavenging assay with
DPPH. Additionally, compounds 3c–e displayed a modest
antifungal activity against C. albicans strains (IC50 range =
70.5–83.1 µg/mL). Hence, the antifungal effect was pro-
moted by methoxy groups at the C-6 and C-7 position as
well as of an aliphatic chain at the C-3 position of the
unsaturated γ-pyran ring. Finally, docking studies revealed
that 2d has the best affinity for α-glucosidase, which is in
agreement with the experimental data. Based upon these
findings, compounds 2a–e should certainly be useful as lead
structures for the development of more potent α-glucosidase
inhibitors.
Acknowledgements The authors thank Carlos Espinoza-Hicks for help
in spectrometric measurements and Bruce A. Larsen for proofreading.
J.T. acknowledges financial support from the Secretaría de Investiga-
ción y Posgrado, Instituto Politécnico Nacional (SIP-IPN) (grants
20090326, 20100236, 20110172, 20120830, 20130686, 20140858,
20180198, and 20195228) and CONACYT (grants 83446 and 178319).
For financial support, F.D. is grateful to SIP-IPN (grants 20170925,
20181332, and 20195287) and J.C.-B. to CONACyT (CBB-254600
and APN-782). A.M.-M. and C.R.-E. thank CONACYT for the grad-
uate scholarships awarded (178319 and 264517) and SIP-IPN (BEIFI)
for a complementary scholarship. This work was financially supported
by a project from SIP-IPN (20170430, 20181433, 20195786). F.E.J.-
M. (20160247), M.C.C.-L. (20160206), F.D., and J.T. are fellows of
the Estímulos al Desempeño de los Investigadores (EDI-IPN), and M.
C.C.-L., F.D., and J.T. are fellows of the Comisión de Operación y
Fomento de Actividades Académicas (COFAA)-IPN.

Medicinal Chemistry Research
Compliance with ethical standards
Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F (2014) Chro-
mone: a valid scaffold in medicinal chemistry. Chem Rev
114:4960–4992
Goto H, Terao Y, Akai S (2009) Synthesis of various kinds of iso-
flavones, isoflavones, and biphenyl-ketones and their 1,1-diphe-
nyl-2-picrylhydrazyl radical-scavenging activities. Chem Pharm
Bull 57:346–360
Huls R (1958) Synthesis of substituted chromones. Synthesis of 6,7-
dimethoxy-2,2-dimethyl-3-chromene (ageratochromone) Bull
Soc Chim Belg 67:22–32
Jerezano A, Jiménez F, Cruz MC, Montiel LE, Delgado F, Tamariz J
(2011) New approach for the construction of the coumarin frame
and application in the total synthesis of natural products. Helv
Chim Acta 94:185–198
Conflict of interest The authors declare that they have no conflict of
interest.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
References
ACD/ChemSketch (Freeware) version 14. 01 (2012). Advanced
Chemistry Development, Inc., Toronto, ON, Canada
Belov P, Campanella VL, Smith AW, Priefer R (2011) Microwave-
assisted methylation of phenols with DMA-DMF. Tetrahedron
Lett 52:2776–2779
Jha HC, Zilliken F, Offermann W, Breitmaier E (1981) Carbon-13
NMR shifts and C–H coupling constants of deoxybenzoins and
related acetophenones. Can J Chem 59:2266–2281
Berkow EL, Lockhart SR (2017) Fluconazole resistance in Candida
species: a current perspective. Infect Drug Resist 10:237–245
Boonsombat J, Prachyawarakorn V, Pansanit A, Mahidol C, Ruchir-
awat S, Thongnest S (2017) Superbanone, a new 2-aryl-3-
benzofuranone and other bioactive constituents from the tube
roots of Butea superba. Chem Biodivers 14:e1700044
Brunel A-S, Guery B (2017) Multidrug resistant (or antimicrobial-
resistant) pathogens—alternatives to new antibiotics. Swiss Med
Wkly 147:14553–14567
Canno RD, Lamping E, Holmes AR, Niimi K, Tanabe K, Niimi M,
Monk BC (2007) Candida albicans drug resistance—another
way to cope with stress. Microbiology 153:3211–3217
Cevallos-Casals BA, Cisneros-Zevallos L (2003) Stoichiometric and
kinetic studies of phenolic antioxidants from Anden purple corn
and red-fleshed sweetpotato. J Agric Food Chem 51:3313–3319
Chin MR, Zlotkowski K, Han M, Patel S, Eliasen AM, Axelrod A,
Siegel D (2015) Expedited access to vinaxanthone and chemically
edited derivatives possessing neuronal regenerative effects through
ynone coupling reactions. ACS Chem Neurosci 5:542–550
Chohan ZH, Rauf A, Naseer MM, Somra MA, Supuran CT (2006)
Antibacterial, antifungal and cytotoxic properties of some
sulfonamide-derived chromones. J Enzyme Inhib Med Chem
21:173–177
Correa C, Cruz MC, Jiménez F, Zepeda LG, Tamariz J (2008) A new
synthetic route of 2-aryl- and 2-benzyl-benzofurans and their
application in the total synthesis of a metabolite isolated from
Dorstenia gigas. Aust J Chem 61:991–999
Csepanyi E, Szabados-Furjesi P, Kiss-Szikszai A, Frensemeier LM,
Karst U, Lekli I, Haines DD, Tosaki A, Bak I (2017) Antioxidant
properties and oxidative transformation of different chromone
derivatives. Molecules 22:588–599
DeLano WL (2002) PyMOL: an open-source molecular graphics tool.
CCP4 Newsletter on Protein. Crystallography 40:82–92
Dennington R, Keith T, Millan J (2012) GaussView, Version 5.
Semichem, Inc., Shawnee Mission, KS
Dofe VS, Sarkate AP, Lokwani DK, Shinde DB, Kathwate SH, Gill
CH (2017a) Novel o-alkylated chromones as antimicrobial
agents: ultrasound mediated synthesis, molecular docking and
ADME prediction. J Heterocycl Chem 54:2678–2685
Dofe VS, Sarkate AP, Lokwani DK, Kathwate SH, Gill CH (2017b)
Synthesis, antimicrobial evaluation, and molecular docking stu-
dies of novel chromone based 1,2,3-triazoles. Res Chem Intermed
43:15–28
Jiménez F, Cruz MC, Zúñiga C, Martínez MA, Chamorro G, Díaz F,
Tamariz J (2010) Aryloxyacetic ester structurally related to α-
asarone as potential antifungal agents. Med Chem Res 19:33–57
Jhon CH, Riyaphan J, Lin SH, Chia YC, Weng CF (2015) Screening
alpha-glucosidase and alpha-amylase inhibitors from natural com-
pounds by molecular docking in silico. Biofactors 41:242–251
Jose ES, Philip JE, Shanty AA, Kurup MRP, Mohanan PV (2018)
Novel class of mononuclear 2-methoxy-4-chromanones ligated
Cu (II), Zn (II), Ni (II) complexes: synthesis, characterization and
biological studies. Inorg Chim Acta 478:155–165
Keri RS, Budagumpi S, Krishna R, Balakrishna RG (2014) Chro-
mones as a privileged scaffold in drug discovery: a review. Eur J
Med Chem 78:340–374
Kerru N, Singh-Pillay A, Awolade P, Singh P (2018) Current anti-
diabetic agents and their molecular targets: a review. Eur J Med
Chem 152:436–488
Kim MK, Yoon H, Barnard DL, Chong Y (2013) Design, synthesis
and antiviral activity of 2-(3-amino-4-piperazinylphenyl)chro-
mone derivatives. Chem Pharm Bull 61:486–488
Labarrios E, Jerezano A, Jiménez F, Cruz MC, Delgado F, Zepeda JG,
Tamariz J (2014) Efficient synthetic approach to substituted
benzo[b]furans and benzo[b]thiophenenes by iodine-promoted
cyclization of enaminones. J Heterocycl Chem 51:954–971
Lu M, Li T, Wan J, Li X, Yuan L, Sun S (2017) Antifungal effects of
phytocompounds on Candida species alone and in combination
with fluconazole. Int J Antimicrob Agents 49:125–136
Mendieta A, Jiménez F, Garduño-Siciliano L, Mojica-Villegas A,
Rosales-Acosta B, Villa-Tanaca L, Chamorro-Cevallos G, Medina-
Franco JL, Meurice N, Gutiérrez RU, Montiel LE, Cruz MC,
Tamariz J (2014) Synthesis and highly potent hypolipidemic activity
of alpha-asarone- and fibrate-based 2-acyl and 2-alkyl phenols as
HMG-CoA reductase inhibitors. Bioorg Med Chem 22:5871–5882
Moore ML, Day AA, Suter CM (1934) The preparation and germicidal
properties of some derivatives of 4-n-butylresorcinol. J Am Chem
Soc 56:2456–2459
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell
DS, Olson AJ (2009) AutoDock4 and AutoDock Tools4: auto-
mated docking with selective receptor flexibility. J Comput Chem
30:2785–2791
Musso L, Dallavalle S, Merlini L, Farina G (2010) Synthesis and
antifungal activity of 2-hydroxy-4,4-methylenedioxyaryl ketones
as analogues of kakuol. Chem Biodivers 7:887–897
Nohara A, Umetani T, Sanno Y (1974) Studies on antianaphylactic
agents. I. Facile synthesis of 4-oxo-4H-1-benzopyran-3-carbal-
dehydes by Vilsmeier reagents. Tetrahedron 30:3553–3561
Philip JE, Shahid M, Prathapachandra Kurup MR, Velayudhan MP
(2017) Metal based biologically active compounds: design,
synthesis, DNA binding and antidiabetic activity of 6-methyl-3-
Farrugia LJ (1997) ORTEP-3 for Windows—a version of ORTEP-III
with a Graphical User Interface (GUI). J Appl Cryst 30:565
Farrugia LJ (1999) WinGX suite for small-molecule single-crystal
crystallography. J Appl Cryst 32:837–838
Farrugia LJ (2012) WinGX and ORTEP for Windows: an update. J
Appl Cryst 45:849–854

Medicinal Chemistry Research
formyl chromone derived. J Photochem Photobiol B 175:178–
191
Rao YJ, Krupadanam GLD (1994) Facile synthesis of linear and
angular 2-methylfurobenzopyranone. Bull Chem Soc Jpn
67:1972–1975
Reis J, Gaspar A, Milhazes N, Borges F (2017) Chromones as a pri-
vileged scaffold in drug discovery: recent advances. J Med Chem
60:7941–7957
Takao K, Ishikawa R, Sugita Y (2014) Synthesis and biological eva-
luation of 3-styrylchromones derivatives as free radical sca-
vengers and α-glucosidase inhibitors. Chem Pharm Bull 62:810–
815
Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou SA,
Katsiki N, Underwood P, Park KH, Seufert J, Kang ES, Sternthal
E, Karagiannis A, Mantzoros CS (2018) Pharmacotherapy of type
2 diabetes: an update. Metabolism 78:13–42
Salehi P, Asghari B, Esmaeili MA, Dehghan H, Ghazi I (2013) α-
Glucosidase and α-amylase inhibitory effect and antioxidant of
ten plant extracts traditionally used in Iran for diabetes. J Med
Plants Res 7:257–266
Wang G, Chen M, Wang J, Peng Y, Li L, Xie Z, Deng B, Chen S, Li
W (2017) Synthesis, biological evaluation and molecular docking
studies of chromone hydrazine derivatives as α-glucosidase
inhibitors. Bioorg Med Chem Lett 27:2957–2961
Sarker SD, Nahar L, kumarasamy Y (2007) Microtitre plate-based
antibacterial assay incorporating resazurin as an indicator of cell
growth, and its application in the in vitro antibacterial screening
of phytochemicals. Methods 42:321–324
Wang G, Chen M, Qiu J, Xie Z, Cao A (2018) Synthesis, in vitro α-
glucosidase inhibitory activity and docking studies of novel
chromone-isatin derivatives. Bioorg Med Chem Lett 28:
113–116
Seleem D, Pardi V, Murata RM (2017) Review of flavonoids: a diverse
group of natural compounds with anti-Candida albicans activity
in vitro. Arch Oral Biol 76:76–83
Sheldrick GM (2008) A short history of SHELX. Acta Cryst Sect A
64:112–122
Sheldrick GM (2015) SHELXT—integrated space-group and crystal-
structure determination. Acta Cryst Sect A 71:3–8
Soengas RG, Silva VLM, Ide D, Kato A, Cardoso SM, Almeida FAP,
Silva AMS (2016) Synthesis of 3-(2-nitrovinyl)-4H-chromones:
useful scaffolds for the construction of biological relevant 3-
(pyrazol-5-yl)chromones. Tetrahedron 72:3198–3203
Sun YL, Bao J, Liu KS, Zhang XY, He F, Wang YF, Nong XH, Qi SH
(2013) Cytotoxic dihydrothiophene-condensed chromones from
the marine-derived fungus Penicillium oxacilum. Planta Med
79:1474–1479
Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS,
Rogers PD (2017) Azole antifungal resistance in Candida albi-
cans and emerging non-albicans Candida species. Front Micro-
biol 7:2173–2184
Xiu C, Hua Z, Xiao BS, Tang WJ, Zhou HP, Liu XH (2017) Novel
benzopyran derivatives and their therapeutic applications: a
patent review (2009–2016). Expert Opin Ther Pat 27:
1031–1045
Zhen J, Dai Y, Villani T, Giurleo D, Simon JE, Wu Q (2017)
Synthesis of novel flavonoid alkaloids as α-glucosidase inhibi-
tors. Bioorg Med Chem 25:5355–5364
Zou H, Jiang H, Zhou JY, Zhu Y, Cao L, Xia P, Zhang Q (2010)
Synthesis of 3-(4-hydroxyphenyl)-4-methyl-6-methoxy-7-hydro-
xycoumarin and its analogous as angiogenesis inhibitors. J Chin
Pharm Sci 19:136–140