Antifungal activities of new coumarins

Article abstract of DOI:10.3390/molecules17055713

Newly synthesized coumarins 4-((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)- methoxy)-2H-chromen-2-one and 4-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)- methoxy)- 2H-chromen-2-one were tested against selected types of fungi and showed significant activities. DFT calculations of the synthesized coumarins were performed using molecular structures with optimized geometries. Molecular orbital calculations provide a detailed description of the orbitals, including spatial characteristics, nodal patterns, and the contributions of individual atoms.

Full text of DOI:10.3390/molecules17055713

Molecules 2012, 17, 5713-5723; doi:10.3390/molecules17055713
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Antifungal Activities of New Coumarins
Ahmed A. Al-Amiery 1,2,*, Abdul Amir Hassan Kadhum 1 and Abu Bakar Mohamad 1
1
Chemical Engineering Faculty, University of Kabengassan Malaysia (UKM), Selangor 43000,
Malaysia
2
Applied Chemistry division, Applied Science Department, University of Technology (UOT),
Baghdad 10066, Iraq
* Author to whom correspondence should be addressed; E-Mail: dr.ahmed1975@gmail.com;
Tel.: +6-0-192-903-670.
Received: 31 March 2012; in revised form: 12 April 2012 / Accepted: 20 April 2012 /
Published: 14 May 2012
Abstract: Newly synthesized coumarins 4-((5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)-
methoxy)-2H-chromen-2-one and 4-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)-methoxy)-
2H-chromen-2-one were tested against selected types of fungi and showed significant
activities. DFT calculations of the synthesized coumarins were performed using molecular
structures with optimized geometries. Molecular orbital calculations provide a detailed
description of the orbitals, including spatial characteristics, nodal patterns, and the
contributions of individual atoms.
Keywords: antifungal; 4-aminoantipyrine; benzyl bromide; coumarins; DFT; ethyl
bromoacetate; 4-hydroxycoumarin
1. Introduction
The serious medical problem of bacterial and fungal resistance and the rapid rate at which it
develops has led to increasing levels of resistance to classical antibiotics [1–3], and the discovery and
development of effective antibacterial and antifungal drugs with novel mechanisms of action have thus
become urgent tasks for infectious disease research programs [4,5]. Coumarin and its derivatives
represent one of the most active classes of compound possessing a wide spectrum of biological
activity [6–12]. The interesting biological activity of these coumarins made these compounds attractive
targets in organic synthesis. Several synthetic strategies for the synthesis of coumarins have already

Molecules 2012, 17
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been developed. Coumarins can be synthesized by the Perkin reaction, Pechmann reaction or by
Knoevenagel condensation of salicylaldehydes with malonic acid, or Meldrum’s acid [13]. malonic
esters, cyanoacetic esters. Recently, the Wittig reaction in N,N-diethylaniline was also conveniently
applied for the synthesis of coumarins [14]. The preparation of ethyl 2-(2-oxo-2H-chromen-4-yloxy)-
acetate (2), which was used as a starting material for the synthesis of compounds 5 and 7, is presented
in this study. The chemical structures of the synthesized compounds 2–7 were determined and
confirmed. The in vitro antifungal activities of the synthesized compounds 5 and 7 were investigated.
Structure activity relationships of coumarin derivatives have revealed that the presence of
substituted amino derivatives is an essential feature of their pharmacological action. Based on these
findings, we try to describe the synthesis of some compounds featuring different heterocyclic rings fused
onto the coumarin moiety with the aim of obtaining more potent pharmacologically active compounds.
2. Results and Discussion
2.1. Chemistry
For the synthesis of new coumarins 2–7, the reaction sequence is out lined in Scheme 1, started
from 4-hydroxycoumarins 1.
Scheme 1. Reaction sequences of the synthesized compounds.

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Compound 2, (ethyl 2-(2-oxo-2H-chromen-4-yloxy) acetate) was obtained by the reflux of ethyl
bromoacetate with 4-hydroxycoumarin (1) in the presence of anhydrous potassium carbonate in
anhydrous acetone. Reaction of compound 2, with various amines was very difficult, even when
different solvents (methanol, ethanol and acetone) were used and only hydrazine reacted with
compound 2. Hydrazinolysis of compound 2 with hydrazine hydrate afforded hydrazide 3 in good
yield. The FT-IR spectrum of compound 3 showed absorption bands in the 3297.3, 3211.0 cm−1
(hydrazide NH-NH2), 1671 cm−1 (lactonic-C=O carbonyl stretching), and 1,711.5 cm−1 (esteric-C=O
1
carbonyl stretching). The H-NMR spectrum exhibited a singlet due to the –CO-NH-NH2 proton at δ
8.89 ppm. Compound 3 was allowed to react with isothiocyanatobenzene to yield compound 4 that can
be cyclized either with sodium hydroxide to yield compound 5 that cannot react with benzyl bromide,
or cyclized with sulphuric acid to yield compound 7. For compound 4, the IR spectrum has the
following characteristic absorption bands: νN-H (3368.9, 3371, 3350, 3262 cm−1); νC=O (1760 lactone;
1686 ester cm−1), νC=S (1276 cm−1). In the IR spectrum of compound 7, no absorption band was
detected about 1700 cm−1 indicating the absence of the ester carbonyl group, which is evidence for the
conversion of compound 4 to compound 7. Also, in the IR spectrum of the new heterocyclic compound
7 a stretching band characteristic of the C=N group from heterocyclic nucleus was seen at 1599 cm−1
(from thiadiazole). Although two types of tautomers, thione or thiole (Scheme 2), could be expected
from the cyclization of compound 5, under basic media, only the thione type compound 5 was
observed. Existence of the thione form predominantly in the solid state is demonstrated by the
presence of two absorption bands at 1240 cm−1 and 3408 cm−1 belonging to the νC=S and νNH groups,
respectively, and by absence of νSH [15]. Reaction of compound 2 with 4-aminoantipyrine was not
successful, even when we use dimethyformamide as solvent, moreover no product was formed when
we try to react compound 5 with benzyl bromide.
Scheme 2. Tautomerization of compound 5.
2.2. Computational Studies
2.2.1. Atomic Charges and Stabilities
The theoretical studies for compound 5 revealed that the atomic charges have been affected by the
presence of the ring substituent. The minimized geometry is shown in Figure 1, where the calculated
atomic charges for the compounds 5 and 7 are also indicated. For compound 5 the highest atomic
charge is at [O(3) −0.57)] and the next charge values are at [N(18) −0.512] and [S(19) −0.38]. These
results clearly indicated that these three atoms are the most reactive sites toward the reactions and

Molecules 2012, 17
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bonding with the metals. The calculated bond and twist angles and 3D-geometrical structure, indicated
that this molecule is not planar moreover the stereochemistry is C(5)-C(4): (E) and N(18)-C(14): (Z).
The C(13)-C(14) bond length is 1.4970; O(12)-C(13) is 1.4020 and C(5)-O(12) is 1.3550.
For compound 7 the highest atomic charge is at [O(11) −0.805)] and the next charge value is at
[C(2) −0.433]. These results clearly indicated that these atoms are the most reactive sites toward the
reactions and bonding with the metals. The calculated bond and twist angles and 3d-geometrical
structure, indicated that this molecule is not planar moreover the stereochemistry is C(3)-C(2): (E).
The S(14)-C(18) bond length is 1.7159; S(14)-C(15) is 1.7158; C(18)-C(19) is 1.2660 and C(20)-C(19)
is 1.2660.
Figure 1. 3D-geometrical structures for compounds 5 and 7.
Compound 5
Compound 7
2.2.2. Density Function Theory (DFT)
DFT calculations were performed for compound 5. The optimized molecular structures of the most
stable forms are shown in Figure 1. Molecular orbital calculations provide a detailed description of
orbitals including spatial characteristics, nodal patterns and individual atom contributions. The contour
plots of the frontier orbitals for the ground state of 5 and 7 are shown in Figures 2 and 3, including the
Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital
(LUMO). It is interesting to see that both orbitals are substantially distributed over the conjugation
plane. It can be seen from Figures 2 and 3 that the HOMO orbitals are located on the substituted
molecule while LUMO orbitals resemble those obtained for the unsubstituted molecule and therefore
the substitution has an influence on the electron donation ability, but only a small impact on electron
acceptance ability [16–18]. The orbital energy levels of HOMO and LUMO of compound 5 and 7 are
listed in Table 1. It can be seen that the energy gaps between HOMO and LUMO is about 2.241 eV.
for compound 5, and the lower value in the HOMO and LUMO energy gap explain the eventual charge
transfer interaction taking place within the molecules.
For compound 7, the energy gap between HOMO and LUMO is about −2.570 eV. The lower value
of the HOMO and LUMO energy gap explains the eventual charge transfer interaction taking place
within the molecules.

Molecules 2012, 17
Figure 2. HOMO, LUMO, HOMO −1 and LUMO +1 orbitals of 5.
5717
HOMO
LUMO
HOMO −1
LUMO +1
Figure 3. HOMO, LUMO, HOMO −1 and LUMO +1 orbitals of 7.
HOMO
LUMO
HOMO
LUMO
Table 1. HOMO and LUMO energies of 5 and 7 (eV).
HOMO
−2.840
−3.625
LUMO
−0.599
−1.055
∆E
−2.241
2.570
HOMO −1
−6.415
LUMO +1
−0.205
−0.067
∆E
−6.210
8.763
−8.830

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2.3. Antifungal Activity
According to Overtone’s concept of cell permeability, the lipid membrane that surrounds the cell
favors the passage of only lipid-soluble materials, so lipophilicity is an important factor controlling the
antifungal activity. Delocalization of π-electrons over the compounds 5 and 7 increases lipophilicity
which in turn facilitates the penetration of the compounds 5 and 7 into lipid membranes, further
restricting proliferation of the microorganisms. Although the exact biochemical mechanism is not
completely understood, the mode of action of antimicrobials may involve various targets in the
microorganisms:
 Interference with the synthesis of cellular walls, causing damage that can lead to altered cell
permeability characteristics or disorganized lipoprotein arrangements, ultimately resulting in
cell death.
 Deactivation of various cellular enzymes that play a vital role in the metabolic pathways of
these microorganisms.
 Denaturation of one or more cellular proteins, causing the normal cellular processes to be
impaired.
 Formation of a hydrogen bond through the azomethine group with the active centers of various
cellular constituents, resulting in interference with normal cellular processes [19–24].
In vitro antifungal screening effects of the investigated compounds 5 and 7, were tested against
some fungal spices (Aspergillus niger and Candida albicans). Compounds 5 and 7 showed good
activities as antifungals compared to the antifungal ability of fluconazole, which was used as a
standard (Figures 4 and 5).
Figure 4. The effect of compounds 5 and 7 towards the tested organism Aspergillus niger.

Molecules 2012, 17
Figure 5. The effect of compounds 5 and 7 toward the tested organism Candida albicans.
5719
3. Experimental
3.1. General
The chemicals used during synthesis was supplied by Sigma-Aldrich. Purity of the compounds was
checked on thin layer chromatography (TLC) plates (Silica gel G) in the solvent systems benzene-ethyl
acetate-methanol (40:30:30, v/v/v) and toluene-acetone (75:25, v/v). The spots were located under 254
and 365 nm UV light. The IR spectra was obtained on a Thermo Scientific, NICOLET 6700 FTIR
spectrometer (without out KBr or CsI pellets), at the Faculty of Engineering. The NMR spectra was
obtained on a JEOL JNM-ECP 400, FT-NMR system at UKM, Faculty of Science Technology (FST),
Chemistry Department. Elemental microanalysis, was carried out using a model 5500-Carlo Erba
C.H.N elemental analyzer. A Gallenkamp M.F.B.600.010 F melting point apparatus was used to
measure the melting points of all the prepared compounds.
3.1.1. Ethyl 2-((2-oxo-2H-chromen-4-yl)oxy)acetate (2)
A suspension of 4-hydroxycoumarin (1, 6.17 mmol) in acetone (30 mL) was refluxed with ethyl
bromoacetate (9.15 mmol) and K2CO3 (4.69 g, 33.91 mmol) for 12 h. After cooling, the mixture was
evaporated to dryness and the residue was partitioned between CHCl3 (50 mL) and water (50 mL). The
organic phase was dried (Na2SO4), filtered and evaporated to dryness. The residue was recrystallized
from acetone; yield 92%; m.p. 99.0 °C; 1H-NMR (CDCl3): δ 3.22 (t, 3H, CH3), δ 3.85 (m, 2H, CH2), δ
4.91 (s, 2H) and δ 5.20, δ 5.250, δ 5.272 (s, 2H) for CH2), δ 5.78 (s, 1H) for -C=C-H), δ 7.291, δ 7.478,
13
δ 7.80 (s, 1H) for aromatic ring); C-NMR: 167.2; 165.1; 163.4, 155.9; 134.2; 121.8; 121.1; 119.0;
113.8; 100.9; 65.3; 54.7; 22.12; IR: 2987.3 cm−1 (C-H, aliphatic), 3089.5 cm−1 (C-H, aromatic),
1759.3 cm−1 (C=O, lactone), 1717.6 cm−1 (C=O, ester), 1629.2 cm−1 (C=C, alkene), 1577.6 cm−1 (C=C,
aromatic).

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3.1.2. 2-(2-Oxo-2H-chromen-4-yloxy)acetohydrazide (3)
A solution of compound 2 (10 mmol) in ethanol (25 mL) was refluxed with hydrazine hydrate
(15 mmol) for 4 h. After concentrating the reaction mixture a solid mass separated out and
recrystallized using ethanol, yield 51%, m.p. 228 °C; 1H-NMR (CDCl3): δ 4.48 (s, 2H, CH2), δ 4.65 (s,
2H, NH2), δ 8.89 (s, 1H, NH), δ 4.92 (s, 2H) and δ 5.210 (s, 2H) for (O-CH2), δ 5.72 (s, 1H) for
(-C=C-H), δ 7.410, δ 7.521, δ 8.10 (s, 1H) for aromatic ring; IR: 3297.3, 3211 cm−1 (N-H),
2906.0 cm−1 (C-H, aliphatic), 3072.7 cm−1 (C-H, aromatic), 1711.5 cm−1 (C=O), 1671.2 cm−1 (C=O,
amide); Anal. Calc. for C11H10N2O4: C 56.41%, H 4.30%, N 11.96%. Found: C 57.13% H 4.01%,
N 10.52%.
3.1.3. 2-(2-(2-Oxo-2H-chromen-4-yloxy)acetyl)-N-phenylhydrazinecarbothioamide (4)
A mixture of hydrazide 3 (2 mmol) and phenyl isothiocyanate (2 mmol) in ethanol (15 mL) was
refluxed for 12 h. The reaction mixture was cooled and the separated product was filtered off, dried
and recrystallized, using ethanol, yield 88%, m.p. 189–192 °C; 1H-NMR (CDCl3): δ 4.48 (s, 2H, CH2),
δ 5.12 (s, 2H, NH2), δ 8.64 (s, 1H, NH), δ 4.80 (s, 2H) and δ 5.35 (s, 2H) for (O-CH2), δ 5.71 (s, 1H)
for (-C=C-H), δ 7.41, δ 7.32, δ 7.92 (s, 1H) for aromatic ring; IR: 3368.9, 3371, 3350, 3262 cm−1
(N-H), 2929.0 cm−1 (C-H, aliphatic), 3074.6 cm−1 (C-H, aromatic), 1760.5 cm−1 (C=O, lactone),
1686.5 cm−1 (C=O), 1276.7 (C=S); Anal. Calc. for C15H18N3O4S: C 58.53%, H 4.09%, N 11.38%.
Found: C 57.98% H 4.36%, N 10.93%.
3.1.4. 4-((5-Mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy)-2H-chromen-2-one (5)
Compound 4 (0.5 mmol) was added to 8% NaOH solution (4 mL) and the reaction mixture was
heated under reflux for 4 h. After cooling, the solution was acidified with a diluted solution of HCl.
Crude product was precipitated, filtered off and washed with water. The solid thus separated was dried
and recrystallized using chloroform-ether (1:1, v/v), yield 55%, m.p. 247–251 °C; 1H-NMR (CDCl3): δ
4.77 and 5.40 (d, 2H, OCH2), δ 5.81 (s, 1H) for (-C=C-H), δ 7.221–7.71 (m, 1H) for aromatic ring; IR:
3408 cm−1 (N-H), 2892.3 cm−1 (C-H, aliphatic), 3076.3 cm−1 (C-H, aromatic), 1758.29 cm−1 (C=O,
lactone), 1577.8 cm−1 (C=N), 1634.2 cm−1 (C=C) and 1240 cm−1 (C=S). Anal Calc.for C18H13N3O3S:
C 61.53%, H 3.73%, N 11.96%. Found: C 60.91% H .3.98%, N 11.14%.
3.1.5. 4-((5-(Phenylamino)-1,3,4-thiadiazol-2-yl)methoxy)-2H-chromen-2-one (7)
A mixture of compound 4 (0.15 mmol) and concentrated H2SO4 (5 mL) was stirred in an ice bath
for 5 h and then at room temperature for another 5 h. The reaction mixture was neutralized with a
diluted solution of ammonium hydroxide, in an ice bath. The precipitate was filtered off, washed with
water, dried and recrystallized. using chloroform-ether (1:1, v/v), yield 65%, m.p. 240–242 °C;
1H-NMR (CDCl3): δ 4.96 and 5.35 (d, 2H, OCH2), δ 5.80 (s, 1H) for (-C=C-H), δ 7.21–8.02 (m, 1H)
for aromatic ring; IR: 2900.1 cm−1 (C-H, aliphatic), 3079.7 cm−1 (C-H, aromatic), 1761.7 cm−1 (C=O,
lactone), 1626.0 cm−1 (C=C), 1599.7 cm−1 (C=N) cm−1 Anal. Calc. for C18H13N3O3S: C 61.53%, H
3.73%, N 11.96%. Found: C 61.01% H 4.02%, N 11.13%.

Molecules 2012, 17
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3.2. DFT
Gaussian 03, Revision C.01 was used for the calculation of ground-state geometry that was
optimized to a local minimum without any symmetry restrictions using the 3-21G basis set. The Becke
three-parameter hybrid (B3) exchange functional in combination with the Lee-Yang-Parr (LYP)
correction functional (B3LYP) was used for all geometry optimizations, thermodynamic functions
at standard conditions (temperature = 298.150 Kelvin, and pressure = 1.0 Atm), High Occupied
Molecular Orbital (HOMO) and Low Unoccupied Molecular Orbital (LUMO) distribution, and some
physical properties for all molecules.
3.3. Evaluation of Antifungal Assay
Antifungal activity [25,26], was determined based on the growth inhibition rates of the mycelia of
strains (Aspergillus niger and Candida albicans) in Potato Dextrose Broth medium (PDB). Under
aseptic conditions, one mL of spore suspension (5 × 106 cfu/mL) of tested fungi was added to 50 mL
PDB medium in a 100 mL Erlenmeyer flask. Appropriate volumes of tested compounds 5 and 7 were
added to produce concentrations ranging from 10 to 100 μg mL−1. Flasks were incubated at 27 ± 1 °C
in the dark for 5 days and then the mycelium was collected on filter papers. The filter papers were
dried to constant weight and the level of inhibition, relative to the control flasks was calculated from
the following formula:
where T = weight of mycelium from test flasks and C = weight of mycelium from control flasks.
4. Conclusions
In this study, the compounds 2–7 were synthesized, and characterized using various spectroscopic
methods and elemental analysis. The synthesized compounds 5 and 7 were studied theoretically and
their atomic charges, heat of formation and stereochemistry were estimated, and it was found that they
are not planar. The synthesized compounds 5 and 7 were tested for antifungal activities and indicated
significant antifungal activities as compared with fluconazole.
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Sample Availability: Samples of the compounds . Ethyl 2-((2-oxo-2H-chromen-4-yl)oxy)acetate (2),
2-(2-Oxo-2H-chromen-4-yloxy)acetohydrazide
(3),
2-(2-(2-Oxo-2H-chromen-4-yloxy)acetyl)-N-
phenylhydrazinecarbothioamide (4), 4-((5-Mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy)-2H-
chromen-2-one (5) and 4-((5-(Phenylamino)-1,3,4-thiadiazol-2-yl)methoxy)-2H-chromen-2-one (7),
are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).