Synthesis and antifungal activity of novel 7-O-substituted pyridyl-4-methyl coumarin derivatives

Article abstract of DOI:10.1007/s00044-013-0470-2

A new series of 7-O-substituted pyridyl-4-methyl coumarin derivatives were synthesized and characterized based on their spectral data. All the target compounds were evaluated for their in vitro antifungal activity against eight important fungal pathogens. This study showed that the introduction of the substituted pyridyl moiety at the 7-hydroxy position of coumarin could enhance the antifungal activities. It also indicated that a bulky substituent was not beneficial to the antifungal activity of those coumarin derivatives.

Full text of DOI:10.1007/s00044-013-0470-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0470-2
ORIGINAL RESEARCH
Synthesis and antifungal activity of novel 7-O-substituted
pyridyl-4-methyl coumarin derivatives
•
Xiaoyun Chai Shichong Yu Xiaoyan Wang
•
•
•
Nan Wang Zhanzhou Zhu Dazhi Zhang
•
•
•
Qiuye Wu Yongbing Cao Qingyan Sun
•
Received: 3 September 2012 / Accepted: 3 January 2013
Ó Springer Science+Business Media New York 2013
Abstract A new series of 7-O-substituted pyridyl-4-
methyl coumarin derivatives were synthesized and charac-
terized based on their spectral data. All the target compounds
were evaluated for their in vitro antifungal activity against
eight important fungal pathogens. This study showed that
the introduction of the substituted pyridyl moiety at the
7-hydroxy position of coumarin could enhance the anti-
fungal activities. It also indicated that a bulky substituent was
not beneficial to the antifungal activity of those coumarin
derivatives.
Introduction
Fungi are widely distributed in nature and frequently
appear as pathogens in the animal and plant kingdoms. In
recent decades, the incidence of systemic fungal infections
has been increasing dramatically due to an increasing
number of immunocompromised hosts, such as patients
undergoing organ transplants or anticancer chemotherapy
and patients with AIDS (Fridkin and Jarvis, 1996; Wingard
and Leather, 2004). However, resistance to a number of
antifungal agents among a variety of clinically significant
species of fungi is becoming an increasingly major global
problem and is reaching an alarming level on a global
scale. These issues pose a serious challenge to the scientific
community, and hence emphasis has been laid on the
development of new antifungal agents, including natural
compounds (Jeu et al., 2003; Lepesheva et al., 2006).
A large number of naturally occurring compounds
appear as interesting sources for antifungal compounds and
are also considered a valuable source of knowledge for the
discovery of new antifungal drugs. Among them, couma-
rins and their derivatives have gained great therapeutic
importance in the field of medicinal chemistry because they
display a fascinating array of pharmacological properties,
such as antibacterial (Chopra et al., 2008), antifungal (Xu
et al., 2006; Jeso and Nicolaou, 2009; Alvey et al., 2009),
anti-inflammatory (Emmanuel-Giota et al., 2001; Ghate
et al., 2003), antitumor (Padmaja et al., 2009, 2011), and
anti-HIV activity (Xie et al., 1999). More importantly, an
increasing number of coumarin compounds have displayed
great potency in the treatment of various types of diseases
(Borges et al., 2005; Kulkarni et al., 2006; Wu et al., 2009;
Riveiro et al., 2010).
Keywords Coumarin derivatives ꢀ Synthesis ꢀ
Antifungal activity ꢀ Pechmann reaction
Xiaoyun Chai and Shichong Yu contributed equally to this study.
X. Chai ꢀ S. Yu ꢀ D. Zhang ꢀ Q. Wu ꢀ Q. Sun (&)
Department of Organic Chemistry, School of Pharmacy,
Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
e-mail: sqy_2000@163.com
X. Wang
Center for Laboratory Teaching, School of Pharmacy,
Second Military Medical University, Guohe Road 325,
Shanghai 200433, People’s Republic of China
N. Wang ꢀ Z. Zhu
Pharmacy Team, Administrative Brigade of Postgraduate,
Second Military Medical University, Zhengtong Road 41,
Shanghai 200433, People’s Republic of China
Y. Cao
Drug Research Center, School of Pharmacy, Second Military
Medical University, Guohe Road 325, Shanghai 200433,
People’s Republic of China
Previous studies have shown that combining the coumarin
backbone with some nitrogen-containing heterocyclic
123

Med Chem Res
moieties could significantly broaden the spectrum of activity
of these compounds and increase their antimicrobial or
antifungal efficiency (Keri et al., 2009; Raghu et al., 2009;
Ronad et al., 2010). Moreover, it has been reported in the
literature that coumarin compounds substituted at the
7-hydroxy position are well known as possessing significant
antifungal activity (Shi and Zhou, 2011). In our work, we
would like to introduce a substituted pyridine ring into the
7-hydroxy position of coumarin. We hope the introduction of
the substituted pyridine ring can help us identify potent
systemic antifungal agents with a broad antifungal spectrum
that also displays less potential to develop resistance.
solid was dissolved in 500 mL 5 % sodium hydroxide, and
the solution was filtered again. 10 % sulfuric acid was added
to the solution to adjust the pH value to 3, and the solution
was filtered. The solid was washed with ice water and
recrystallized from ethanol to obtain compound 2 as light
yellow crystals (16.05 g, 91.2 %, mp: 193–195 °C).
Synthesis of the intermediate 4-methyl-7-((5-
nitropyridin-2-yl)oxy)-2H-chromen-2-one (3)
Compound 2 (1.76 g, 10 mmol), 2-chlorine-5-nitro pyri-
dine (1.89 g, 12 mmol), and 25 mL CH3CN were added to
a 50 mL Wolff bottle, and K2CO3 (2.00 g, 14 mmol) was
then added to the solution. The solution was stirred for
0.5 h at room temperature and then refluxed for 5 h while
the reaction was monitored by TLC. After the reaction,
30 mL water was added to the solution before it was stirred
and filtered. The solid was washed with water and crys-
tallized from dichloromethane to obtain compound 3
(2.60 g, 87.2 %, mp: 194–196 °C). 1H NMR (300 MH,
CDCl3) d: 8.55 (dd, 1H, J1 = 9.0 Hz, J2 = 3.0 Hz, pyri-
dine-H), 7.68 (d, 1H, J = 9.0 Hz, Ar–H), 7.33 (d, 1H,
J = 3.0 Hz, pyridine-H), 7.14 (d, 1H, J = 9.0 Hz, pyri-
dine-H), 7.16–7.20 (m, 2H, Ar–H), 6.30 (s, 1H, =C–H),
2.47 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d: 165.8,
157.8, 155.7, 154.2, 152.2, 145.0, 141.0, 135.4, 133.2,
126.5, 118.8, 116.9, 114.7, 110.6, 21.6; IR (KBr): 3434,
3397, 3109, 3079, 2996, 2923, 2740, 1734, 1603, 1578,
Materials and methods
Melting points were measured on a Yamato MP-21 melting
point apparatus and are uncorrected. Nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker AC-
300P spectrometer with TMS as the internal standard and
CDCl3 as the solvent. Infrared spectra were recorded using
potassium bromide disks on a HITACHI270-50 spectro-
photometer. ESI mass spectra were performed on an API-
3000 LC–MS spectrometer. TLC analysis was carried out
on silica gel plates GF254 (Yantai Huanghai Chemical,
China). The solvents and reagents were purchased from
commercial vendors and were used either as received or
were dried prior to use as needed.
The desired coumarin derivatives 5–22 were prepared
from commercially available phenols, and the synthetic
route is outlined in Scheme 1. The cyclization of resorcinol
with ethyl acetoacetate in the presence of concentrated
sulfuric acid formed the corresponding 7-hydroxy-4-
methyl coumarin 2 (Kumar et al., 2012). The intermediate
2 reacted with 2-chlorine-5-nitro pyridine in acetonitrile,
using potassium carbonate as a base, to produce interme-
diate 3 (Okaniwa et al., 2012). Reduction of compound 3
with H2 gave compound 4, which by reacting with the
corresponding carboxylic acid in the presence of N-(3-
dimethyla-mino-propyl)-N0-ethylcarbodiimide hydrochlo-
ride (EDCI) and 4-dimethyl- aminopyridine (DMAP) at
room temperature for 12 h led to the synthesis of com-
pounds 5–22.
1464, 1388, 1302, 1281, 1139, 1112, 1015, 996, 804 cm-1
;
ESI–MS: m/z Calcd. for C15H10N2O5, 298.0, found
[M?Na]? 321.0, [M-H]- 297.0.
Synthesis of the intermediate 7-(5-aminopyridin-2-
yloxy)-4-methyl-2H-chromen-2-one (4)
Compound 3 (2.60 g, 9 mmol) was dissolved in 50 mL
ethanol and then added to the catalytic hydrogenation bottle
with a little Pd/C. The hydrogenation reaction was carried
out for 2 h and was monitored by TLC. After reaction, the
solution was filtered and concentrated to 20 mL to obtain the
light yellow-colored compound 4 (1.27 g, 52.6 %, mp:
1
171–172 °C). H NMR (300 MH, CDCl3) d: 8.20 (dd, 1H,
J1 = 9.0 Hz, J2 = 2.4 Hz, pyridine-H), 7.76 (d, 1H, J =
3.0 Hz, pyridine-H), 7.56 (d, 1H, J = 8.4 Hz, Ar–H), 7.15
(dd, 1H, J1 = 8.4 Hz, J1 = 3.0 Hz, Ar–H), 6.98–7.06 (m,
2H, pyridine-H, Ar–H), 6.19 (s, 1H, =C–H), 2.41–2.43 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3) d: 161.7, 160.5,
155.6, 154.5, 153.6, 142.6, 134.6, 127.2, 126.8, 116.2, 114.6,
113.6, 107.2, 19.7; IR (KBr): 3456, 3355, 3226, 3052, 2996,
2885, 1899, 1696, 1577, 1479, 1387, 1275, 1068, 984,
873 cm-1, ESI–MS: m/z Calcd. for C15H12N2O3, 268.1,
found [M?Na]? 291.1, [M-H]- 267.0.
Synthesis of the intermediate 7-hydroxy-4-methyl-2H-
chromen-2-one (2)
Resorcinol (11.00 g, 100 mmol) was added to ethyl aceto-
acetate (13.00 g, 100 mmol). The mixed solution was then
added to 100 mL concentrated sulfuric acid and stirred for
8 h in an iced bath. After the reaction, 500 mL iced water
was added to the blue solution. The solution was cooled to
room temperature, filtered and washed with ice water. The
123

Med Chem Res
Scheme 1 Synthesis of the title
compounds. Conditions:
(a) ethyl acetoacetate, H2SO4,
8 h, 91.2 %; (b) 2-chlorine-5-
nitro pyridine, K2CO3, CH3CN,
reflux, 5 h, 87.2 %; (c) H2, Pd/
C, C2H5OH, 52.6 %;
(d) RCOOH, DMAP, EDCI,
CH2Cl2, 12 h, 23.4–88.3 %
for C17H14N2O4, 310.1, found [M?Na]? 333.1, [M-H]-
General procedure for the target compounds (5–22)
309.1.
Substituted carboxylic acids (2 mmol), DMAP (0.012 g,
1 mmol), and EDCI (0.308 g, 2 mmol) were added to a
solution of compound 4 (0.270 g, 1 mmol) in CH2Cl2
(30 mL). The reaction mixture was then stirred at room
temperature for 12 h. After adding saturated sodium
bicarbonate solution to adjust the pH value to 8, the solu-
tion was extracted with ethyl acetate. The combined
organic phases were then washed with acetic acid (10 %),
saturated sodium bicarbonate solution, and water. The
resulting organic phase was dried over anhydrous Na2SO4
and concentrated under reduced pressure. After being
crystallized from ethyl acetate, this yielded title com-
pounds 5–22.
2,2,2-Trifluoro-N-(6-(4-methyl-2-oxo-2H-chromen-7-
yloxy)pyridin-3-yl)acetamide (6)
Light yellow solid; Yield: 88.3 %; Melting point:
1
172–174 °C; H NMR (300 MH, CDCl3) d: 11.50 (s, 1H,
NH), 8.16 (dd, 1H, J1 = 8.7 Hz, J2 = 2.7 Hz, pyridine-H),
8.05 (d, 1H, J = 2.4 Hz, Ar–H), 7.80 (d, 1H, J = 8.7 Hz,
pyridine-H), 7.21–7.24 (m, 2H, pyridine-H, Ar–H), 7.14
(dd, 1H, J1 = 8.7 Hz, J2 = 2.4 Hz, Ar–H), 6.35 (s, 1H,
=C–H), 2.43–2.50 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3) d: 170.4, 161.5, 158.4, 158.1, 155.6, 153.8, 139.7,
133.7, 132.3, 126.6, 118.5, 117.8, 117.3, 114.5, 113.7,
108.4, 19.3; IR (KBr): 3341, 3222, 3064, 2986, 2823, 1701,
1675, 1620, 1565, 1500, 1483, 1385, 1295, 1225, 1162,
1054, 980, 873, 804 cm-1; ESI–MS: m/z Calcd. for
C17H11F3N2O4, 364.1, found [M?Na]? 387.2, [M-H]-
363.0.
N-(6-(4-Methyl-2-oxo-2H-chromen-7-yloxy)pyridin-3-
yl)acetamide (5)
White solid; Yield: 23.4 %; Melting point: 224–226 °C; 1H
NMR (300 MH, CDCl3) d: 10.52 (s, 1H, NH), 8.21 (dd, 1H,
J1 = 9.0 Hz, J2 = 2.4 Hz, pyridine-H), 8.14 (d, 1H,
J = 2.4 Hz, Ar–H), 7.60 (d, 1H, J = 8.4 Hz, pyridine-H),
7.00–7.09 (m, 3H, pyridine-H, Ar–H), 6.23 (s, 1H, =C–H),
2.43 (s, 3H, CH3), 2.22 (s, 3H, COCH3); 13C NMR
(75 MHz, CDCl3) d: 170.0, 161.4, 158.8, 158.5, 155.4,
153.4, 139.5, 134.0, 132.6, 126.8, 117.4, 117.0, 114.0,
113.2, 108.7, 24.8, 19.6; IR (KBr): 3313, 3209, 3068, 2983,
2838, 1703, 1681, 1615, 1542, 1506, 1477, 1386, 1280,
1152, 1068, 987, 873, 853, 743 cm-1; ESI–MS: m/z Calcd.
7-((5-(3,3-Dimethyl-2-oxobutyl)pyridin-2-yl)oxy)-4-
methyl-2H-chromen-2-one (7)
1
Red solid; Yield: 84.3 %; Melting point: 193–195 °C; H
NMR (300 MH, CDCl3) d: 10.72 (s, 1H, NH), 8.23 (dd, 1H,
J1 = 8.4 Hz, J2 = 2.1 Hz, pyridine-H), 8.18 (s, 1H, Ar–
H), 7.59 (d, 1H, pyridine-H, J = 8.4 Hz), 6.99–7.09 (m,
3H, pyridine-H, Ar–H), 6.23 (s, 1H, =C–H), 2.43 (s, 3H,
CH3), 1.34 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3)
123

Med Chem Res
d: 170.3, 162.0, 159.8, 158.8, 155.8, 153.4, 140.2, 134.1,
132.8, 126.8, 117.9, 117.7, 114.8, 113.7, 109.7, 40.8, 18.8,
18.8; IR (KBr): 3320, 3217, 3020, 2975, 2822, 1742, 1655,
1632, 1564, 1520, 1484, 1383, 1245, 1138, 957, 872,
787 cm-1; ESI–MS: m/z Calcd. for C20H20N2O4, 352.1,
found [M?Na]? 375.2, [M–H]- 351.1.
137.1, 134.6, 125.5, 117.7, 117.0, 115.4, 113.4, 110.6,
19.3, 16.5, 12.4; IR (KBr): 3307, 3249, 3054, 2973, 2815,
1715, 1680, 1620, 1542, 1518, 1434, 1382, 1264, 1144,
1002, 957, 834, 810, 733, 704 cm-1; ESI–MS: m/z Calcd.
for C19H16N2O4, 336.1, found [M?Na]? 359.2, [M-H]-
335.1.
7-((5-(3-(Dimethylamino)-2-oxopropyl)pyridin-2-yl)oxy)-
4-methyl-2H-chromen-2-one (8)
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)cyclohexanecarboxamide (11)
1
Red solid; Yield: 83.5 %; Melting point: 129–130 °C; H
White solid; Yield: 83.4 %; Melting point: 174–176 °C; 1H
NMR (300 MH, CDCl3) d: 10.49 (s, 1H, NH), 8.27 (dd, 1H,
J1 = 9.0 Hz, J2 = 3.0 Hz, pyridine-H), 8.20 (m, 1H, Ar–
H), 7.60 (d, 1H, J = 9.0 Hz, pyridine-H), 7.25 (m, 1H,
Ar–H), 6.98–7.08 (m, 2H, pyridine-H, Ar–H), 6.23 (s, 1H,
=C–H), 2.43 (s, 3H, CH3), 2.24–2.32 (m, 1H, cyclohexyl-
H), 1.18–1.98 (m, 10H, cyclohexyl-H); 13C NMR (75
MHz, CDCl3) d: 172.4, 162.1, 155.4, 155.0, 153.4, 152.4,
141.6, 137.1, 134.5, 125.3, 117.1, 116.2, 113.1, 110.6,
108.4, 41.2, 28.0, 25.6, 25.1, 19.7; IR (KBr): 3324, 3222,
3140, 2954, 2810, 1735, 1680, 1595, 1532, 1500, 1464,
NMR (300 MH, CDCl3) d: 9.56 (br, 1H, NH), 8.26 (dd, 1H,
J1 = 8.4 Hz, J2 = 2.7 Hz pyridine-H), 8.13 (d, 1H, J =
2.7 Hz, Ar–H), 7.59 (d, 1H, J = 8.4 Hz, pyridine-H),
7.00–7.10 (m, 3H, pyridine-H, Ar–H), 6.23 (s, 1H, =C–H),
3.31 (s, 2H, –NCH2), 2.52 (d, 6H, N(CH3)2), 2.43 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3) d: 170.4, 162.0, 159.8,
158.9, 155.9, 153.4, 139.7, 132.9, 132.5, 126.8, 117.9,
117.6, 114.8, 113.8, 109.7, 64.6, 47.2, 18.9, 12.4; IR (KBr):
3267, 3124, 3048, 2981, 2835, 1735, 1686, 1607, 1565,
1498, 1386, 1323, 1275, 1185, 1079, 988, 946, 865,
834 cm-1; ESI–MS: m/z Calcd. for C19H19N3O4, 353.1,
found [M?Na]? 376.2, [M-H]- 352.1.
1383, 1241, 1185, 1127, 987, 936, 859, 805, 744 cm-1
;
ESI–MS: m/z Calcd. for C22H22N2O4, 378.2, found
[M?Na]? 401.2, [M-H]- 377.3.
2-Cyano-N-(6-((4-methyl-2-oxo-2H-chromen-7-
yl)oxy)pyridin-3-yl)acetamide (9)
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)benzamide (12)
1
Gray solid; Yield: 87.4 %; Melting point: 212–215 °C; H
NMR (300 MH, CDCl3) d: 10.50 (s, 1H, NH), 8.34 (dd,
1H, J1 = 9.0 Hz, J2 = 2.4 Hz, pyridine-H), 8.06 (d, 1H,
J = 2.4 Hz, Ar–H), 7.78 (d, 1H, J = 8.4 Hz, pyridine-H),
7.20–7.25 (m, 2H, Ar–H), 7.12 (d, 1H, J = 2.4 Hz, pyri-
dine-H), 6.33 (s, 1H, =C–H), 3.92 (s, 2H, CH2), 2.43 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3) d: 169.5, 162.1,
158.6, 156.1, 155.0, 153.4, 142.7, 137.8, 135.0, 125.3,
124.1, 117.1, 116.5, 115.5, 113.1, 110.1, 24.8, 19.7; IR
(KBr): 3402, 3245, 3122, 2985, 2775, 1780, 1705, 1646,
1610, 1546, 1483, 1405, 1385, 1245, 1163, 1120, 967, 875,
820 cm-1; ESI–MS: m/z Calcd. for C18H13N3O4, 335.1,
found [M?Na]? 358.1, [M-H]- 334.0.
White solid; Yield: 79.5 %; Melting point: 180–185 °C; 1H
NMR (300 MH, CDCl3) d: 9.79 (s, 1H, NH), 8.39 (dd,
1H, J1 = 9.0 Hz, J2 = 3.0 Hz, pyridine-H), 7.92–7.94 (m,
2H, Ar–H), 7.59–7.62 (m, 1H, Ar–H), 7.48–7.56 (m, 3H,
Ar–H), 7.09 (d, 1H, J = 3.0 Hz, pyridine-H), 7.09–7.11
(m, 2H, Ar–H), 7.07 (d, 1H, J = 9.0 Hz, pyridine-H), 6.22
(s, 1H, =C–H), 2.43 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3) d: 171.5, 162.1, 158.3, 155.2, 153.4, 152.4, 141.2,
137.1, 134.0, 133.8, 131.9, 128.6, 128.4, 128.2, 125.3,
117.2, 116.0, 113.1, 110.2, 108.9, 19.4; IR (KBr): 3285,
3160, 3123, 3085, 3030, 1745, 1667, 1622, 1584, 1555,
1476, 1378, 1343, 1265, 1120, 1077, 1032, 985, 867, 808,
745 cm-1; ESI–MS: m/z Calcd. for C22H16N2O4, 372.1,
found [M?Na]? 395.2, [M-H]- 371.1.
2-Cyclopropyl-N-(6-((4-methyl-2-oxo-2H-chromen-7-
yl)oxy)pyridin-3-yl)acetamide (10)
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)picolinamide (13)
Crimson solid; Yield: 82.3 %; Melting point: 209–212 °C;
1H NMR (300 MH, CDCl3) d: 10.60 (s, 1H, NH), 8.30 (dd,
1H, J1 = 9.0 Hz, J2 = 3.0 Hz, pyridine-H), 8.23 (d, 1H,
J = 2.4 Hz, Ar–H), 7.63 (d, 1H, J = 9.0 Hz, pyridine-H),
7.07–7.09 (m, 2H, Ar–H), 7.00 (d, 1H, J = 3.0 Hz, pyri-
dine-H), 6.24 (s, 1H, =C–H), 2.44 (s, 3H, CH3), 2.25 (m,
1H, cyclopropyl-H), 1.10–1.12 (m, 2H, cyclopropyl-H),
0.88–0.92 (m, 2H, cyclopropyl-H); 13C NMR (75 MHz,
CDCl3) d: 170.2, 162.7, 158.7, 156.3, 154.8, 153.1, 142.4,
White solid; Yield: 83.4 %; Melting point: 162–163 °C; 1H
NMR (300 MH, CDCl3) d: 10.10 (s, 1H, NH), 7.95–8.65
(m, 4H, pyridine-H), 8.39 (dd, 1H, J1 = 9.0 Hz,
J2 = 3.0 Hz, pyridine-H), 7.54–7.57 (m, 1H, Ar–H), 7.27
(s, 1H, Ar–H), 7.14–7.16 (m, 1H, Ar–H), 7.09 (d, 1H,
J = 3.0 Hz, pyridine-H), 7.08 (d, 1H, J = 9.0 Hz, pyri-
dine-H), 6.24 (s, 1H, =C–H), 2.44 (s, 3H, CH3); 13C NMR
123

Med Chem Res
(75 MHz, CDCl3) d: 170.3, 162.2, 157.4, 155.0, 154.4,
152.3, 151.7, 149.1, 141.2, 137.4, 134.8, 133.2, 129.7,
125.3, 123.8, 117.2, 115.9, 113.1, 110.6, 108.4, 19.5; IR
(KBr): 3305, 3176, 3150, 3138, 3020, 1785, 1666, 1607,
1567, 1495, 1385, 1332, 1255, 1132, 1089, 1074, 965, 834,
810, 798, 745 cm-1; ESI–MS: m/z Calcd. for C21H15N3O4,
373.1, found [M?Na]? 396.2, [M-H]- 372.1.
158.7, 157.7, 155.4, 153.5, 148.5, 145.7, 140.6, 133.5,
133.2, 126.8, 117.6, 117.1, 116.0, 114.1, 113.2, 108.9,
19.6; IR (KBr): 3289, 3145, 3113, 3087, 3031, 1723, 1648,
1618, 1524, 1484, 1388, 1339, 1287, 1151, 1132, 1066,
983, 884, 811, 770 cm-1; ESI–MS: m/z Calcd. for
C20H14N2O5, 362.1, found [M?Na]? 385.2, [M-H]-
361.1.
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)nicotinamide (14)
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)thiophene-2-carboxam-ide (17)
Yellow solid; Yield: 85.6 %; Melting point: 163–165 °C;
1H NMR (300 MH, CDCl3) d: 10.45 (s, 1H, NH), 8.52 (d,
1H, J = 2.4 Hz, pyridine-H), 8.25 (dd, 1H, J1 = 8.7 Hz,
J2 = 2.7 Hz, pyridine-H), 7.95 (d, 1H, pyridine-H), 7.78
(d, 1H, Ar–H), 7.32 (d, 1H, pyridine-H), 7.10–7.19 (m, 3H,
Ar–H, pyridine-H), 6.72 (m, 1H, pyridine-H), 6.34 (s, 1H,
=C–H), 2.43 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d:
170.7, 166.4, 164.7, 164.0, 161.0, 159.2, 158.3, 155.1,
146.2, 142.5, 139.3, 136.6, 132.5, 131.4, 130.0, 123.1,
122.3, 119.7, 118.7, 114.4, 17.7; IR (KBr): 3276, 3182,
3144, 3035, 1745, 1687, 1606, 1542, 1469, 1383, 1362,
1265, 1159, 1107, 1082, 976, 859 cm-1; ESI–MS: m/z
Calcd. for C21H15N3O4, 373.1, found [M?Na]? 396.2,
[M-H]- 372.1.
Brown solid; Yield: 83.9 %; Melting point: 196–197 °C;
1H NMR (300 MH, CDCl3) d: 10.32 (s, 1H, NH),
7.94–8.35 (m, 3H, thiophene-H), 7.73 (d, 1H, J = 9.0 Hz,
pyridine-H), 7.59–7.63 (m, 2H, Ar–H), 7.13 (m, 1H, Ar–
H), 7.08 (d, 1H, J = 3.0 Hz, pyridine-H), 7.09 (d, 1H,
J = 9.0 Hz, pyridine-H), 6.25 (s, 1H, =C–H), 2.45 (s, 3H,
CH3); 13C NMR (75 MHz, CDCl3) d: 170.8, 162.2, 158.3,
157.1, 155.5, 153.1, 148.7, 145.5, 140.2, 133.9, 133.4,
126.5, 117.4, 116.8, 116.2, 114.4, 113.0, 108.6, 20.5; IR
(KBr): 3285, 3131, 3105, 3098, 3012, 1755, 1645, 1607,
1545, 1532, 1507, 1474, 1383, 1327, 1283, 1150, 1108,
1053, 975, 845, 820, 796 cm-1; ESI–MS: m/z Calcd. for
C20H14N2O4S, 378.1, found [M?Na]? 401.1, [M-H]-
377.1.
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)isonicotinamide (15)
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)pyrazine-2-carboxami-de (18)
Light yellow solid; Yield: 84.7 %; Melting point:
1
Yellow solid; Yield: 82.2 %; Melting point: 233–235 °C;
1H NMR (300 MH, CDCl3) d: 9.71 (s, 1H, NH), 8.44–8.48
(m, 2H, pyridine-H), 8.27–8.45 (m, 3H, pyrazine-H), 7.63
(s, 1H, Ar–H), 7.15 (s, 1H, pyridine-H), 7.10–7.13 (m, 2H,
Ar–H), 6.25 (s, 1H, =C–H), 2.45 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d: 170.4, 162.2, 157.9, 157.2, 155.0,
152.4, 145.9, 142.6, 140.8, 137.1, 133.8, 125.3, 117.1,
116.2, 115.9, 114.4, 113.1, 110.6, 108.4, 20.1; IR (KBr):
3315, 3178, 3145, 3096, 3020, 1743, 1634, 1624, 1575,
1498, 1455, 1396, 1385, 1325, 1287, 1126, 1095, 1045,
967, 852, 802 cm-1; ESI–MS: m/z Calcd. for C20H14N4O4,
374.1, found [M?Na]? 397.2, [M-H]- 373.1.
200–205 °C; H NMR (300 MH, CDCl3) d: 10.67 (s, 1H,
NH), 7.79–8.78 (m, 4H, pyridine-H), 8.30–8.32 (m, 1H,
Ar–H), 8.29 (d, 1H, J = 9.0 Hz, pyridine-H), 7.56–7.60
(m, 1H, Ar–H), 7.11–7.22 (m, 2H, pyridine-H), 7.19 (s, 1H,
Ar–H), 6.33 (s, 1H, =C–H), 2.42 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d: 170.8, 162.4, 157.3, 155.5, 154.1,
152.5, 151.4, 149.3, 142.4, 137.5, 134.4, 133.3, 129.5,
124.9, 123.6, 117.7, 115.8, 113.4, 110.5, 108.7, 19.4; IR
(KBr): 3275, 3203, 3176, 3062, 3021, 1746, 1685, 1622,
1574, 1483, 1384, 1354, 1286, 1133, 1089, 1044, 978, 864,
808, 794, 756 cm-1; ESI–MS: m/z Calcd. for C21H15N3O4,
373.1, found [M?Na]? 396.2, [M-H]- 372.1.
5-Methyl-N-(6-((4-methyl-2-oxo-2H-chromen-7-
yl)oxy)pyridin-3-yl)pyrazine-2-carboxamide (19)
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)furan-2-carboxamide (16)
Yellow solid; Yield: 81.9 %; Melting point: 223–225 °C;
1H NMR (300 MH, CDCl3) d: 9.67 (s, 1H, NH), 8.45 (d,
1H, J = 9.0 Hz, pyridine-H), 8.43–8.44 (m, 1H, pyrazine-
H), 8.25–8.40 (m, 2H, pyrazine-H, Ar–H), 7.62 (d, 1H,
J = 3.0 Hz, pyridine-H), 7.14 (s, 1H, Ar–H), 7.10–7.11
(m, 1H, Ar–H), 7.10 (d, 1H, J = 9.0 Hz, pyridine-H), 6.25
(s, 1H, =C–H), 2.72 (m, 3H, CH3), 2.45 (s, 3H, CH3); 13C
NMR (75 MHz, CDCl3) d: 171.5, 162.4, 157.5, 156.8,
Yellow solid; Yield: 88.1 %; Melting point: 134–136 °C;
1H NMR (300 MH, CDCl3) d: 10.67 (s, 1H, NH), 9.11 (d,
1H, J = 2.1 Hz, furan-H), 8.76–8.78 (m, 1H, Ar–H), 8.55
(m, 1H, furan-H), 8.26–8.32 (m, 1H, pyridine-H), 7.79 (m,
1H, pyridine-H), 7.56–7.60 (m, 1H, Ar–H), 7.11–7.22 (m,
3H, furan-H, pyridine-H, Ar–H), 6.34 (s, 1H, =C–H), 2.43
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3) d: 171.2, 162.4,
123

Med Chem Res
155.2, 152.7, 146.2, 142.4, 140.6, 137.4, 133.5, 125.8,
117.7, 116.6, 115.4, 114.7, 113.9, 110.5, 108.3, 21.4, 19.8;
IR (KBr): 3286, 3155, 3123, 3075, 3024, 1766, 1638, 1604,
1563, 1468, 1396, 1383, 1302, 1264, 1176, 1035, 987, 845,
788 cm-1; ESI–MS: m/z Calcd. for C21H16N4O4, 388.1,
found [M?Na]? 411.2, [M-H]- 387.1.
J = 7.5 Hz, Ar–H), 7.34 (dd, 1H, J1 = 7.2 Hz,
J2 = 0.9 Hz, indole-H), 7.25 (d, 1H, J = 2.4 Hz, Ar–H),
7.13 (d, 1H, J = 2.4 Hz, indole-H), 6.95–7.10 (m, 4H,
indole-H, Ar–H, pyridine-H), 6.32 (s, 1H, =C–H), 3.74 (s,
2H, CH2), 2.42 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d: 171.7, 161.5, 159.2, 158.9, 1557, 154.8, 139.7, 133.1,
128.2, 125.6, 122.7, 120.3, 120.1, 118.2, 114.4, 114.1,
113.1, 109.9, 109.3, 19.8; IR (KBr): 3304, 3278, 3165,
3082, 3017, 1771, 1656, 1613, 1582, 1483, 1464, 1394,
1356, 1302, 1277, 1125, 1054, 958, 920, 878, 812,
775 cm-1; ESI–MS: m/z Calcd. for C25H19N3O4, 425.1,
found [M?Na]? 448.2, [M-H]- 324.2.
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)-2-phenylacetamide (20)
White solid; Yield: 83.4 %; Melting point: 133–134 °C; 1H
NMR (300 MH, CDCl3) d: 10.11 (s, 1H, NH), 8.15 (dd, 1H,
J1 = 9.0 Hz, J2 = 3.0 Hz, pyridine-H), 7.42–7.44 (m, 2H,
Ar–H), 7.36–7.38 (m, 3H, Ar–H), 7.08–7.10 (m, 1H, Ar–
H), 7.27–7.29 (m, 2H, Ar–H), 7.04 (d, 1H, J = 3.0 Hz,
pyridine-H), 6.98 (d, 1H, J = 9.0 Hz, pyridine-H), 6.23 (s,
1H, =C–H), 3.79 (s, 2H, CH2), 2.43 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d: 170.8, 162.3, 158.5, 155.6, 153.4,
152.6, 141.5, 137.6, 134.2, 133.4, 131.7, 128.5, 127.8,
125.0, 117.6, 116.3, 113.5, 110.7, 108.6, 44.1, 20.4; IR
(KBr): 3302, 3155, 3086, 3034, 1752, 1666, 1620, 1535,
1483, 1432, 1384, 1302, 1275, 1188, 1067, 1022, 955, 814,
782 cm-1; ESI–MS: m/z Calcd. for C23H18N2O4, 386.1,
found [M?Na]? 409.2, [M-H]- 385.1.
Antifungal activity
The in vitro antifungal activities of all the target com-
pounds were evaluated against eight human pathogenic
fungi (Candida albican SC5314 and Y0109, Candida
tropicalis, Candida parapsilosis, Candida kefyr, Crypto-
coccus neoformans, Trichophyton rubrum, and Aspergillus
fumigates), which are frequently encountered in clinic. The
results were compared with positive controls fluconazole
and Amphotericin B. C. alb SC5314 and C. neo, which
were purchased from ATCC, were provided by Shanghai
Changzheng Hospital; C. alb Y0109, C. tro, C. par, C. kef,
T. rub, and A. fum, which are isolated from the clinic, were
provided by Shanghai Changhai Hospital. Fluconazole and
Amphotericin B served as the positive control and were
obtained from their respective manufacturers. The in vitro
minimal inhibitory concentrations (MICs) of the title
compounds were determined by the micro-broth dilution
method in 96-well microtest plates according to the
methods defined by the National Committee for Clinical
Laboratory Standards (NCCLS National Committee for
Clinical Laboratory Standards 2002). The MIC80 was
defined as the first well with an approximate 80 % reduc-
tion in growth compared to the growth of the drug-free
well. For assays, the title compounds to be tested were
dissolved in dimethyl sulfoxide (DMSO), serially diluted in
growth medium, inoculated, and incubated at 35 °C.
Growth MIC was determined at 24 h for C. alb and at 72 h
for C. neo. The results of assays are summarized in
Table 1. These data are the mean of three replicate tests
performed with each antifungal agent.
N-(6-((4-Methyl-2-oxo-2H-chromen-7-yl)oxy)pyridin-3-
yl)cinnamamide (21)
White solid; Yield: 86.5 %; Melting point: 280–285 °C; 1H
NMR (300 MH, CDCl3) d: 10.38 (s, 1H, NH), 8.44 (dd,
1H, J1 = 9.0 Hz, J2 = 3.0 Hz, pyridine-H), 7.78 (d, 1H,
J = 16.0 Hz, =C–H), 7.617.64 (m, 1H, Ar–H), 7.56 (d,
1H, J = 3.0 Hz, pyridine-H), 7.38–7.50 (m, 4H, Ar–H),
7.27–7.30 (m, 1H, Ar–H), 7.09 (d, 1H, J = 9.0 Hz, pyri-
dine-H), 7.04–7.07 (m, 1H, Ar–H), 6.64 (d, 1H, J = 16 Hz,
=C–H), 6.23 (s, 1H, =C–H), 2.44 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d: 171.4, 162.8, 158.3, 155.5, 153.1,
152.4, 141.9, 141.2, 137.4, 134.6, 133.5, 131.1, 128.6,
128.1, 127.9, 125.4, 118.9, 117.2, 116.5, 113.7, 110.5,
108.4, 19.8; IR (KBr): 3286, 3162, 3125, 3088, 3014, 1756,
1665, 1624, 1586, 1498, 1451, 1385, 1346, 1272, 1198,
1068, 1024, 967, 933, 875, 843, 779 cm-1; ESI–MS: m/z
Calcd. for C24H18N2O4, 398.1, found [M?Na]? 421.2,
[M-H]- 397.3.
2-(1H-indol-3-yl)-N-(6-((4-methyl-2-oxo-2H-chromen-7-
yl)oxy)pyridin-3-yl)acetamide (22)
Results and discussion
Light yellow solid; Yield: 76.5 %; Melting point:
1
Many synthetic routes to the coumarin backbones have
been used including the Pechmann, Perkin, Knoevenagel,
Reformatsky, and Wittig reactions. We chose to use the
succinct and efficient Pechmann reaction, which starts from
180–181 °C; H NMR (300 MH, CDCl3) d: 10.92 (s, 1H,
indole-NH), 10.34 (s, 1H, NH), 8.39 (d, 1H, J = 2.7 Hz,
indole-H), 8.14 (dd, 1H, J1 = 8.7 Hz, J1 = 3.0 Hz, pyri-
dine-H), 7.76 (d, 1H, J = 8.7 Hz, pyridine-H), 7.58 (d, 1H,
123

Med Chem Res
Table 1 Antifungal activities of the target compounds in vitro (MIC80, lg/mL)
Compd.
C. alb SC5314
C. alb Y0109
C. tro
C. par
C. kef
C. neo
T. rub
A. fum
2
[64
[64
[64
0.25
0.25
4
[64
64
[64
[64
[64
8
32
32
32
1
[64
[64
[64
16
[64
64
[64
8
32
64
32
16
16
1
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
[64
1
3
4
16
5
1
6
0.25
4
16
1
32
32
32
16
16
32
32
16
32
16
32
[64
32
1
7
32
32
32
4
16
8
32
16
1
32
16
0.25
8
9
0.25
16
16
[64
16
16
10
11
12
13
14
15
16
17
18
19
20
21
22
FCZ
AMB
[64
[64
4
8
32
[64
16
[64
16
4
[64
32
8
1
8
16
16
16
32
32
0.25
[64
32
32
[64
[64
[64
[64
4
16
16
32
32
16
16
0.25
16
[64
4
32
32
32
16
16
16
16
8
32
16
8
16
32
16
16
32
4
4
1
16
16
16
1
4
4
[64
[64
[64
0.25
0.25
[64
[64
64
[64
[64
[64
4
[64
16
[64
[64
8
[64
4
16
1
0.25
0.25
4
1
1
0.25
1
1
C. alb, Candida albicans; C. tro, Candida tropicalis; C. par, Candida parapsilosis; C. kef, Candida kefyr; C. neo, Cryptococcus neoformans;
T. rub, Trichophyton rubrum; A. fum, Aspergillus fumigates; FCZ, fluconazole; AMB, Amphotericin B
commercially available phenols and ethyl acetoacetate in
the presence of H2SO4 to synthesize the backbone of our
title compounds. A series of coumarin derivatives were
successfully synthesized through an easy, convenient, and
economic synthetic procedure of successive cyclization,
substitution, reduction, and acylation. The purity of com-
pounds was checked by thin-layer chromatography, and
their structures were confirmed by 1H NMR, 13C NMR, IR,
and ESI–MS spectroscopy.
peaks at 6.22–6.35 ppm, corresponding to the 3-H of
7-hydroxy coumarin. The 13C NMR spectra of compounds
5–22 showed signals between 161.4 and 162.8 ppm due to
the ester carbonyl carbons. The appearance of signals in the
region between 169.5 and 172.4 ppm, attributed to the
resonance of the amide carbon C=O group, also supports
the expected structures. Characteristic molecular ion peaks
[M?Na] and [M-H] were observed for all the compounds
under investigation.
The assignment of selected characteristic IR bands
provides significant indications for the formation of the
coumarin derivatives 5–22. The appearance of a strong
absorption band around the 1,750 cm-1 region is due to the
stretching vibration of the carbonyl group adjacent to the
unsaturated bond. The IR spectra also show the charac-
teristic amide bond absorption peaks at 1,650–1,690 cm-1
(mc=o) and 3,050–3,500 cm-1 (mN–H). In the 1H NMR
spectra of compounds 5–22, the appearance of doublet–
doublet signals in the region between 8.16 and 8.44 ppm is
attributed to the pyridine ring protons (pyridine-4H,
J1 = 9.0 Hz, J2 = 2.4 Hz). The presence of singlet signals
in the region between 9.56 and 11.50 ppm is due to the
amide protons. The spectra of all the compounds showed
The in vitro antifungal activities of all the target com-
pounds are listed in Table 1. The MIC80 values of all the
targeted compounds against eight important fungal patho-
gens were determined and compared with fluconazole and
Amphotericin B. The intermediates 2, 3, and 4 showed poor
activities against all the tested fungal pathogens, but the
activities of all the title compounds were improved after
reaction with different substituted carboxylic acids. The
antifungal activity screening data revealed that all the syn-
thesized compounds showed moderate to excellent activity
against all the tested fungal pathogens except A. fum (when
compared with that displayed by the lead compound 2).
Compounds 5, 6, 7, 9, and 18 were more active against C.
alb. Among these, compounds 5, 6, and 9 were equipotent
123

Med Chem Res
Chopra I, Schofield C, Everett M, O’Neill A, Miller K, Wilcox M,
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compared to the positive control drug FCZ (with an MIC80
value of 0.25 lg/mL). The antifungal activity may be
improving as the side chain becomes smaller and shorter.
The amide group also appeared to be essential for activity.
Compounds 8, 18, and 19 showed good antifungal activity
(nearly equivalent to that of the positive control drug AMB
against C. tro). Compounds 5, 6, 12, and 15 showed higher
activities against C. par. Compound 15 exhibited especially
excellent activity with an MIC80 value of 0.25 lg/mL
against C. par versus the MIC80 value of FCZ (which is only
4 lg/mL). With the exception of compounds 11, 20, 21, and
22, which contain bigger side chains and showed poorer
activities against most of the tested fungi, the MIC80 value
of the all compounds tested (against nearly all the fungi)
falls in the range of 8–64 lg/mL.
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Acknowledgments This work was supported by the Pharmaceutical
Education research project of Chinese Association of Higher Medical
Education Professional Committee (Grant No. ZD201220), the Cre-
ativity and Innovation Training Program of Second Military Medical
University (Grant No. ZD2008008), and the Shanghai Leading Aca-
demic Discipline Project (No. B906).
Padmaja A, Rajasekhar C, Muralikrishna A, Padmavathi V (2011)
Synthesis and antioxidant activity of oxazolyl/thiazolylsulfonyl-
methyl pyrazoles and isoxazoles. Eur J Med Chem 46(10):5034–
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