Docking, Synthesis, Spectral Characterization, and Evaluation of In Vitro Antifungal Activity of Bis/Monophenyl-1-aryl-1H-tetrazole-5-carboxylate

Article abstract of DOI:10.1002/jhet.3656

Some novel compounds of bis/monophenyl-1-aryl-1H-tetrazole-5-carboxylate were synthesized by the equimolar reaction between bis/mono-1-aryl-1H-tetrazole and phenyl chloroformate in the presence of NaOH in dry tetrahydrofuran. The content was stirred for 4

Full text of DOI:10.1002/jhet.3656

Month 2019
Docking, Synthesis, Spectral Characterization, and Evaluation of In Vitro
Antifungal Activity of Bis/Monophenyl-1-aryl-1H-tetrazole-5-carboxylate
*
Chandrakumari Sambandam, Sivakumar Dhanavel, Manikandan Haridoss, and Gopalakrishnan Mannuthusamy
Department of Chemistry, Annamalai University, Annamalai Nagar, Chidambaram, India
*E-mail: mgkrishnan61@gmail.com
Received September 20, 2018
DOI 10.1002/jhet.3656
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Some novel compounds of bis/monophenyl-1-aryl-1H-tetrazole-5-carboxylate were synthesized by the
equimolar reaction between bis/mono-1-aryl-1H-tetrazole and phenyl chloroformate in the presence of
NaOH in dry tetrahydrofuran. The content was stirred for 4 h at room temperature. Structures of these
1
synthesized compounds were characterized by IR, H-NMR, 13C-NMR, and mass spectrometric methods.
The in vitro antifungal activity study demonstrates that results of compounds 6g and 6h are excellent, 6e a
comparatively good one, and other compounds are moderate. The C docker energy of compounds 6g and
6h were À38.22 and À32.62 kcal/mol and that of compound 6e was À21.26 kcal/mol.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
removal of the 14-methyl group (C-32) of lanosterol to
give 14,15-desaturated intermediates in ergosterol
biosynthesis in different biological kingdoms and serves
the metabolic function such as membrane permeability
and fluidity, enzyme activity, cell morphology, and cell
cycle progression [9–11]. This enzyme is found in all
eukaryotes (including human), because the azoles also
interact with other cytochrome P450-dependent enzymes
Human fungal diseases show a significant, but often
excluded, burden on public health, which is affecting
over 1 million people worldwide [1]. Superficial fungal
infections such as nail, skin, and urogenital infections
affect most people during their lifetimes, but these
can be cured by treating with antifungal drugs. If
not treated with antifungal drugs means surely
will affect the quality of life and burden health services
(CYP3A4),
a selective inhibition of the enzyme
emerging out with increased therapeutic index [12–14].
The active site of CYP51 is divided into four subsites:
(i) coordination bond with iron of the heme group,
(ii) the hydrophobic region, (iii) the hydrophilic
region, and (iv) hydrogen bonding region and the
narrow hydrophobic left formed. The binding
interaction of azole with lanosterol 14α-demethylase is
made by the affinity of coordination binding of N-4
in triazole, N-3 in imidazole of heme iron in the active
site, N-1 substituent of the apoprotein in
the enzyme and remaining part fits like how
lanosterol in the hydrophobic groove of lanosterol
14α-demethylase [15–19]. Based on these special
features of CYP51, a series of new azole derivatives
with the broad antifungal spectrum have less potential
to develop drug resistance. Tetrazoles are an aromatic
heterocyclic compound (CHN4) and seated as important
place in tetrazole chemistry [20,21], explosives
[22], rocket applicants, and chemical applications
[23,24], 1-Substituted 1,2,3,4-tetrazoles are having
antibacterial [25], antifungal [26], antiviral [27],
analgesic [28], anti-inflammatory [29], antiulcer [30],
and antihypertensive [31] activities. The function of
tetrazole is resembled like the function of acid
[2,3].
life-threatening
blood and organs affecting the immune systems.
Invasive fungal infections cause a serious risk to
immune-compromised
Invasive
fungal
opportunistic
infections
infections
are
more
the
of
people
such
as
people
living with human immunodeficiency virus/acquired
immunodeficiency syndrome or receiving chemotherapy
[4]. Fungi commonly causing infections on human
beings (e.g. Candida species) or in the environment
(e.g. Aspergillus, Cryptococcus, and Pneumocystis
species) were normally without harm to healthy people
[5]. The potential scientific challenge is to develop
antifungal drugs to cure these diseases, which involve
huge investment and long duration [6]. There are six
major drugs used for the treatment of systematic
infections, which are amphotericin B, flucytosine,
fluconazole, itraconazole, voriconazole, and caspofungin
[7]. Some antifungal drugs have face limitations, such
as low drug activity, detrimental side effect, negative
interaction with other drugs, and inappropriate for oral
administration [8]. In fungi, lanosterol 14α-demethylase
(CYP51) belongs to a superfamily of monooxygenase
called cytochrome P450, which catalyzes the oxidative
© 2019 Wiley Periodicals, Inc.

C. Sambandam, S. Dhanavel, M. Haridoss, and G. Mannuthusamy
Vol 000
compound of carboxylic acid group, which has inspired
many medicinal chemists to synthesize tetrazoles
derivatives as potential medicinal agents.
obtained was 80%. The chemical structure of
compounds 6a–h was supported by its spectral data.
The presence of stretching frequency at 1761 cmÀ1
reveals the presence of the ester group. The absorption
band appearing at 3061–3136 cmÀ1 attributed to
aromatic rings. In 1H-NMR spectrum recorded,
resonated signals at 7.11–7.28 and 7.45–7.71 ppm
attributed to two phenyl rings in the compound, which
confirmed the presence of phenyl rings in the
compound. 13C-NMR spectrum exhibited resonated
signals at 169.76, 152.15, and 150.94 ppm, which
indicate the presence of carbonyl carbon, phenoxy
carbon, and tetrazole carbon. The aromatic carbons
signals appeared from 121.33 to 133.68 ppm.
RESULTS AND DISCUSSION
Chemistry.
The novel synthetic tactics for the
synthesis of bis/mono title compounds is portrayed in
Scheme 1a–d. Bis/mono-1-aryl-1H-tetrazole (4a–h) was
easily synthesized by the heterocyclic addition reaction
of readily available bis/monosubstituted anilines (1a–h)
reacting with sodium azide 2 and triethyl orthoformate
3 in acetic acid medium. The synthetic pathway for the
synthesis of 4a–h was given in Scheme 1a–d.
Bis/mono-1-aryl-1H-tetrazole was treated with phenyl
chloroformate 5 in dry tetrahydrofuran (THF). The
content was stirred for 4 h at room temperature. To
facilitate the reaction, a catalytic amount of 20% NaOH
solution was added. The solid product was separated,
filtered, and dried. The yield of mono/bisphenyl-(1-aryl-
1H-tetrazole)-5-carboxylate (6a–h) (Scheme 1a–d)
Antifungal activity results.
In present days,
heterocyclic ring-containing systems exhibited excellent
antifungal activities, which make our attention to evaluate
the antifungal activity of the synthesized compounds. The
in vitro antifungal activity was performed for all
synthesized 6a–h compounds, which were treated with
various pathogenic fungi such as Aspergillus fumigalis,
Candida albicans, and Aspergillus niger. The standard
Scheme 1. Synthetic pathway for the synthesis of phenyl-1-aryl-1H-tetrazole-5-carboxylate. (a) Reaction condition: refluxed at 80°C for 24 h. (b)
Reaction condition: stirred for 4 h at room temperature. (c, d) Synthesis of 6g and 6h followed the same pathway of (a, b). Reactants 2, 3, and 5 are
taken as double the mole ratio of the starting compound.
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Bis/Monophenyl-1-aryl-1H-tetrazole-5-carboxylate
drug fluconazole was used as a positive control. The results
of minimum inhibitory concentration are tabulated in
Table 1. The results revealed that compounds 6g and 6h
show excellent activity, compound 6e shows good
activity, and other compounds have moderate activity.
Hence, synthesized compounds 6a–h have good
antifungal activity.
14α-demethylase, all synthesized compounds 6a–h were
docked using Discovery Studio software. The crystal
structure of CYP51 was downloaded from the protein
bank (PDB ID: 1EA1). The values of C docker energy for
monosubstituted title compounds 6a–f (Table 2) are from
À8.92 to À21.26 kcal/mol. The values of C docker energy
for bis-substituted title compounds 6g–h (Table 2) are
from À32.62 to À38.22 kcal/mol. Compounds 6g and 6h
are having more docking value of À38.22 and À32.22
Molecular docking results.
To know the interaction
between the title compounds and the protein lanosterol
Table 1
In vitro antifungal activity of compounds (minimum inhibitory concentration, μg/mL).
Compound
Candida albicans
Aspergillus niger
Aspergillus fumigalis
6a
6b
6c
6d
0.625
1.05
0.625
0.625
1.25
1.25
2.0
2.5
2.5
2.5
0.625
1.25
0.625
0.312
2.5
6e
6f
6g
<0.16
2.5
<0.16
5
<0.16
5
6h
2.1
4.5
5
Fluconazole
<0.16
0.625
2.5
Bold emphasis explain that the compounds possess good antifungal property.
Table 2
Molecular docking data of compounds 6a–j.
Compound
–C docker energy (kcal/mol)
–C docker interaction (kcal/mol)
6a
6b
6c
6d
6e
6f
10.47
12.80
8.92
10.38
21.26
9.97
22.51
23.09
24.39
23.84
25.00
23.73
26.53
39.40
6g
6h
38.22
32.62
Bold emphasis explain that the compounds possess good antifungal property.
Figure 1. The three-dimensional interacting mode of compound 6g with lanosterol 14α-demethylase. [Color figure can be viewed at wileyonlinelibrary.
com]
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C. Sambandam, S. Dhanavel, M. Haridoss, and G. Mannuthusamy
Vol 000
kcal/mol, which revealed that the compounds are having
excellent antifungal activity compared with the other
compounds. The docking energy of compound 6e is
À21.26 kcal/mol having good antifungal activity, other
compounds having moderate activity. The three-
dimensional view of compound 6g with protein 1EA1 is
Figure 2. The two-dimensional interacting mode of compound 6g with lanosterol 14α-demethylase. [Color figure can be viewed at wileyonlinelibrary.
com]
Figure 3. The description of bonding interactions in two-dimensional interacting modes of compound 6g with lanosterol 14α-demethylase. [Color figure
can be viewed at wileyonlinelibrary.com]
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Bis/Monophenyl-1-aryl-1H-tetrazole-5-carboxylate
Figure 4. Structures of all synthesized compounds 6a–h.
given in Fig. 1. The compounds interact with the CYP51
through HIS A: 57, PRO C: 30, ARG C: 34, ARG A: 61,
MET C: 32, and HOH C: 74 (Fig. 2). The two-
dimensional view of diagram (Fig. 3) of 6g shows π–π
stacked interaction of HIS A: 57 with O-phenyl ring, π-
alkyl interaction of PRO C: 30 with O-phenyl ring,
carbon–hydrogen bond interaction of ARG A: 61 with
oxygen and tetrazole nitrogen, π-alkyl interaction of MET
C: 32 with tetrazole ring, cation interaction of ARG C: 34
with tetrazole ring, and water hydrogen bond with one of
the nitrogen tetrazole ring.
exhibited excellent –C docking energy, compound 6e
showed good –C docking energy, and the remaining
compounds
have
moderate
energy.
Therefore,
has
bis/monophenyl-1-aryl-1H-tetrazole-5-carboxylate
possessed good CYP51 inhibition; hence, it is
concluded as active biologically novel compound.
EXPERIMENTAL
Materials and methods.
Melting points (°C,
uncorrected) were checked in open capillary tube by
using (Labtronics 110; Labtronics, Panchkula, India) digi-
tal auto melting point apparatus and found uncorrected.
The chemicals and solvents were purchased from
Sigma-Aldrich (St. Louis, MO) and Merck, India
(Mumbai, India). All the reactions were carried out at
their appropriate conditions, and the products were
checked by TLC silica gel 60 F254 using eluent solvents
such as pet ether and benzene in the ratio 3:7. All the
compounds were characterized by FT-IR spectrometer
(Agilent Cary 650, Santa Clara, USA) using KBr pellets
CONCLUSION
All the newly synthesized compounds are
characterized by IR, 1H-NMR, 13C-NMR, and mass
spectra. All the compounds are having good antifungal
activities. Among these, compounds 6g and 6h
exhibited excellent activity, compound 6e exhibited
good activity, and other compounds have moderate
activity. Molecular docking of compounds 6g and 6h
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C. Sambandam, S. Dhanavel, M. Haridoss, and G. Mannuthusamy
Vol 000
1
and H-NMR spectroscopy in DMSO (400 MHz, Bruker
121.00, 121.71, 123.40, 126.96, 127.38, 129.82,
130.18, 130.46, 133.01, 151.15, 152.12, 160.47, 168.18
ppm; MS (m/z): 297.08 [M + H]+; Anal. Calcd for
C15H12N4O3: C, 60.81; H, 4.08; N, 18.91; Found: C,
60.79; H, 4.11; N, 18.88.
Corp., Billerica, MA) and 13C-NMR spectroscopy in
DMSO (100 MHz, Bruker Corp.) using tetramethylsilane
as an internal standard. Mass–gas chromatography spectra
were measured by Saturn 2200 (CP-3800; Varian, Palo
Alto, California). Antifungal activity of all the
synthesized compounds was determined by the minimum
inhibitory concentration method. Docking studies of all
the compounds were docked using Discovery Studio
software.
Synthesis of phenyl-1-(4-chlorophenyl)-1H-tetrazole-5-
carboxylate (6c).
Brown color solid, mp 68–74°C; IR
ν (cmÀ1): 1767 (ester group), 1658 (C═N), 3062–3125
(aromatic C─H); 1H-NMR (400 MHz, DMSO-d6): δ
7.13–7.34 ppm (m, 5H, O-phenyl ring), 7.62–7.96 ppm
(m, 4H, N-phenyl ring); 13C-NMR (100 MHz,
DMSO-d6): δ 121.17, 121.69, 124.68, 126.62, 126.94,
127.03, 128.70, 128.99, 129.52, 130.16 133.03, 151.13,
152.15, 168.99 ppm; MS (m/z): 301.07 [M + H]+; Anal.
Calcd for C16H9ClN4O2: C, 55.92; H, 3.02; N, 18.63;
Found: C, 55.90; H, 3.05; N, 18.61.
General procedure for the synthesis of monophenyl-1-aryl-1
H-tetrazole-5-carboxylate (6a–f).
tetrazole is followed by the literature method [32,33].
1-Substituted aryl amine 1a–f (10 mmol) was treated
The synthesis of
with sodium azide
2
(10 mmol) and triethyl
orthoformate 3 (10 mmol) in acetic acid (100 mL)
(Scheme 1a). The content was refluxed for 24 h at
80°C. The reaction progress was checked by TLC.
Once the reaction was completed, the reaction mixture
was transferred into a beaker containing ice. The solid
product was separated on cooling, filtered, and dried.
Then 1-aryl-substituted-1H-tetrazole 4a–h (5 mmol) was
treated with phenyl chloroformate 5 (5 mmol) in THF
(100 mL) in the presence of NaOH (20%)
(Scheme 1b). It was stirred for 4 h. Again, the reaction
progress was checked by TLC. Once the reaction was
completed, the reaction mixture was transferred into a
beaker containing ice. The solid product was separated
on cooling, filtered, and dried. The compound is
purified by column chromatography using 7:3 of pet
ether and benzene. The yield of products 6a–f is from
82 to 90%. The structure of all the synthesized
compound given in Fig. 4.
Synthesis of phenyl-1-(4-acetylphenyl)-1H-tetrazole-5-car-
boxylate (6d).
Brown color solid, mp 64–68°C; IR ν
(cmÀ1): 1768 (ester group), 1677 (C═N), 3058–3127
(aromatic C─H); 1H-NMR (400 MHz, DMSO-d6): δ
7.87–8.07 ppm (m, 5H, O-phenyl ring), 8.14–8.23 ppm
(m, 4H, N-phenyl ring), 2.57 ppm (3H, s); 13C-NMR
(100 MHz, DMSO-d6):
δ 26.82, 121.72, 123.43,
123.70, 125.47, 126.96, 129.80, 129.81, 130.13,
130.19, 137.29, 139.95, 151.15, 152.37, 168.71, 196.81
ppm; MS (m/z): 309.01 [M + H]+; Anal. Calcd for
C16H12N4O3: C, 62.33; H, 3.92; N, 18.17; Found: C,
62.30; H, 3.93; N, 18.21.
Synthesis of phenyl-1-(2,3-dichlorophenyl)-1H-tetrazole-5-
carboxylate (6e).
Brown color solid, mp 94–98°C; IR
ν (cmÀ1): 1768 (ester group), 1664 (C═N), 3065–3101
(aromatic C─H); 1H-NMR (400 MHz, DMSO-d6): δ
7.00–7.35 ppm (m, 5H, O-phenyl ring), 7.36–7.47 ppm
(m, 3H, N-phenyl ring); 13C-NMR (100 MHz,
DMSO-d6): δ 121.37, 121.68, 125.25, 125.60, 126.97,
128.32, 128.46, 129.84, 130.18, 130.45, 132.27,
151.11, 152.16, 169.41 ppm; MS (m/z): 335.02 [M +
H]+; Anal. Calcd for C14H8Cl2N4O2: C, 50.17; H, 2.41;
N, 16.72; Found: C, 50.15; H, 2.39; N, 16.68.
Synthesis of phenyl-1-phenyl-1H-tetrazole-5-carboxylate
(6a).
Brown color solid, mp 54–64°C; IR ν (cmÀ1):
1761 (ester group), 1659 (C═N), 3061–3136 (aromatic
C─H); 1H-NMR (400 MHz, DMSO-d6): δ 7.11–7.28
ppm (m, 5H, O-phenyl ring), 7.45–7.71 ppm (m, 5H,
N-phenyl ring); 13C-NMR (100 MHz, DMSO-d6): δ
121.33, 121.84, 126.55, 126.79, 128.65, 128.93, 129.05,
129.14, 129.21, 129.49, 133.68, 150.94, 152.15, 169.76
ppm; MS (m/z): 267.02 [M + H]+; Anal. Calcd for
C14H10N4O2: C, 63.15; H, 3.79; N, 21.04; Found: C,
63.12; H, 3.81; N, 21.01.
Synthesis of phenyl-1-(4-bromophenyl)-1H-tetrazole-5-
carboxylate (6f).
Brown color solid, mp 70–75°C; IR
ν (cmÀ1): 1768 (ester group), 1665 (C═N), 3050–3117
(aromatic C─H); 1H-NMR (400 MHz, DMSO-d6): δ
7.32–7.46 ppm (m, 5H, O-phenyl ring), 7.47–7.87 ppm
(m, 4H, N-phenyl ring); 13C-NMR (100 MHz,
DMSO-d6): δ 121.70, 121.95, 122.98, 123.57, 126.98,
129.91, 130.19, 130.46, 131.93, 133.45, 139.07, 151.12,
152.16, 169.06 ppm; MS (m/z): 346.01 [M + H]+; Anal.
Calcd for C14H9BrN4O2: C, 48.72; H, 2.63; N, 16.23;
Found: C, 48.70; H, 2.59; N, 16.21.
Synthesis of phenyl-1-(4-methoxyphenyl)-1H-tetrazole-5-
carboxylate (6b).
Brown color solid, mp 62–64°C;
IR ν (cmÀ1): 1768 (ester group), 1669 (C═N), 3061–
3135 (aromatic C─H); 1H-NMR (400 MHz,
DMSO-d6): δ 7.18–7.39 ppm (m, 5H, O-phenyl ring),
7.46–7.83 ppm (m, 4H, N-phenyl ring), 3.84 (s, 3H);
13C-NMR (100 MHz, DMSO-d6): δ 56.14, 119.25,
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Bis/Monophenyl-1-aryl-1H-tetrazole-5-carboxylate
General procedure for the synthesis of bisphenyl-1-aryl-1H-
tetrazole-5-carboxylate (6g and 6h).
condition. It was incubated for 24 h at 37 1°C. After
incubation, the assay tube concentrations were transferred
into nutrient agar plate to study the inhibition of growth
of the organism. All the experiments were carried in
triplicates.
The synthesis of
tetrazole is followed by the literature method [24,25].
O-Phenylene diamines 1g/4,4-oxydianiline 1h (10
mmol) was treated with sodium azide 2 (20 mmol) and
triethyl orthoformate 3 (20 mmol) in acetic acid (100
mL) (Scheme 1c,d). The reaction mixture was refluxed
for 24 h at 80°C. The reaction progress was monitored
by TLC. Once the reaction was completed, the reaction
mixture was poured into ice. The solid product was
separated on cooling, filtered, and dried. Then 1,2-
di(1H-tetrazolyl)benzene 4g/1,1-(oxybis(4,1-phenylene)
bis(1H-tetrazole) 4h (5 mmol) was treated with phenyl
chloroformate 5 (10 mmol) in THF (100 mL) in the
presence of NaOH (20%). The reaction mixture was
stirred for 4 h. Again, the reaction progress was
monitored by TLC. Once the reaction was completed,
the reaction mixture was poured into ice. The solid
product was separated on cooling, filtered, and dried.
The compound is purified by column chromatography
using 7:3 of pet ether and benzene. The yield of
products 6g and 6h is from 82 to 85%.
Molecular docking studies.
All the title compounds
were docked with protein 1EA1 using Discovery Studio
software. Before the docking process, all the ligand
energies were minimized. The crystal structure of protein
1EA1 was downloaded from the protein bank website
(PDB IB: 1EA1). During the docking process, 10 poses
of –C docker energy were obtained. Among them, one
pose with less –C docker energy was confirmed for the
energy for the respective compounds.
Acknowledgment. One of the authors, S. Chandrakumari, is
thankful to UGC—Rajiv Gandhi National Fellowship (RGNF-
2017-18-SC-TAM-31743) for financial support.
REFERENCES AND NOTES
Synthesis of diphenyl-1,1′-(1,2-phenylene)bis(1H-tetra-
[1] Brown, G. D.; Denning, D. W.; Gow, N. A.; Levitz, S. M.;
Netea, M. G.; White, T. C. Sci Transl Med 2012, 4, 165.
zole-5-carboxylate) (6g).
Brown color solid, mp
56–60°C; IR ν (cmÀ1): 1779 (ester group), 1699 (C═N),
3065–3142 (aromatic C─H); 1H-NMR (400 MHz,
DMSO-d6): δ 7.17–7.50 ppm (m, 10H, O-phenyl ring),
7.76–7.83 ppm (m, 4H, N-phenyl ring); 13C-NMR (100
MHz, DMSO-d6): δ 120.88, 121.58, 125.06, 125.86,
126.82, 127.06, 127.22, 129.37, 129.77, 131.62, 150.90,
152.09, 169.76 ppm; MS (m/z): 455.01 [M + H]+; Anal.
Calcd for C22H14N8O4: C, 58.15; H, 3.11; N, 24.66;
Found: C, 58.13; H, 3.09; N, 24.69.
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Synthesis of diphenyl-1,1′-(oxybis(4,1-phenylene)bis(1H-
tetrazole-5-carboxylate) (6h).
Brown color solid, mp
66–70°C; IR ν (cmÀ1): 1767 (ester group), 1665
(C═N), 3061–3161 (aromatic C─H); 1H-NMR (400
MHz, DMSO-d6): δ 7.07–7.39 (m, 10H, O-phenyl
ring), 7.46–7.98 ppm (m, 8H, N-phenyl ring) ppm;
13C-NMR (100 MHz, DMSO-d6): δ 121.36, 121.72,
122.05, 122.40, 123.76, 129.01, 129.84, 129.92,
135.31, 151.13, 152.81, 157.32, 168.70 ppm; MS (m/z):
547.02 [M + H]+; Anal. Calcd for C28H18N8O5: C,
61.54; H, 3.32; N, 20.50; Found: C, 61.52; H, 3.35; N,
20.49. The spectrum for compounds 6a–h is given in
the Supporting Information.
Antifungal activity. A serial dilution method is used to
determine the in vitro antifungal activity for the title
compounds, and it is measured by the minimum
inhibitory concentration method. Different concentrations
of compounds and standard positive control fluconazole
were taken and dissolved in DMSO under specific
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