Synthesis, docking and ADMET prediction of novel 5-((5-substituted-1-H-1,2, 4-triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as antifungal agents

Article abstract of DOI:10.1016/j.cclet.2014.04.003

A novel series of 5-((5-substituted-1H-1,2,4-triazol-3-yl)methyl)-4,5,6,7- tetrahydrothieno[3,2-c]pyridines 5(a-i) has been synthesized from thienopyridine hydrazide, substituted aromatic nitriles using 4-dimethylaminopyridine (DMAP) as a catalyst under microwave irradiation and evaluated for their in vitro antifungal activity. Compound 5g is found to be more potent against Candida albicans when compared with miconazole. Docking study of the newly synthesized compounds was performed, and results showed good binding mode in the active site of fungal enzyme P450 cytochrome lanosterol 14α-demethylase. ADMET properties of synthesized compounds were also analyzed and showed good drug like properties. The results of in vitro antifungal activity, docking study and ADMET prediction revealed that the synthesized compounds have potential antifungal activity and can be further optimized and developed as a lead compound.

Full text of DOI:10.1016/j.cclet.2014.04.003

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CCLET 2940 1–6
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
5
Synthesis, docking and ADMET prediction of novel 5-((5-substituted-
1-H-1,2,4-triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-
c]pyridine as antifungal agents
a
a
b
Q1 Jaiprakash N. Sangshetti a, , Firoz A. Kalam Khan , Rashmi S. Chouthe , Manoj G. Damale ,
*
6
7
Devanand B. Shinde c
8
9
10
a Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad 431001, India
b Department of Bioinformatics, MGM Institute of Biosciences and Technology, Aurangabad 431003, India
c Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, India
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel series of 5-((5-substituted-1H-1,2,4-triazol-3-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyr-
idines 5(a–i) has been synthesized from thienopyridine hydrazide, substituted aromatic nitriles using 4-
dimethylaminopyridine (DMAP) as a catalyst under microwave irradiation and evaluated for their in
vitro antifungal activity. Compound 5g is found to be more potent against Candida albicans when
compared with miconazole. Docking study of the newly synthesized compounds was performed, and
Received 20 January 2014
Received in revised form 27 March 2014
Accepted 28 March 2014
Available online xxx
results showed good binding mode in the active site of fungal enzyme P450 cytochrome lanosterol 14a-
Keywords:
demethylase. ADMET properties of synthesized compounds were also analyzed and showed good drug
like properties. The results of in vitro antifungal activity, docking study and ADMET prediction revealed
that the synthesized compounds have potential antifungal activity and can be further optimized and
developed as a lead compound.
1,2,4-Triazole
Microwave irradiation
Antifungal activity
Docking study
ß 2014 Jaiprakash N. Sangshetti. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
rights reserved.
ADMET properties
11
12
1. Introduction
of these antifungal drugs has led to increase in resistance to these 28
drugs [4–6].
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24
25
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27
In recent years, the incidence of systemic fungal infection is
increasing dramatically due to an increase in number of patients
undergoing organ transplants, anticancer chemotherapy and
patients with AIDS. Commonly used antifungal drugs are azoles
(fluconazole, itraconazole, miconazole and voriconazole), polyenes
(amphotericin B and nystatin), echinocandins (caspofungin and
micafungin) and allylamines (naftifine and terbinafine) [1]. Azoles
have broad-spectrum activities against most yeasts and filamen-
tous fungi and are the drug of choice for antifungal chemotherapy
[2]. Azoles, especially triazole, such as fluconazole, voriconazole
and itraconazole, are leading drugs used for the treatment of
invasive fungal infections. These antifungal drugs act by inhibiting
CYP51 in the process of biosynthesis of ergosterols through a
mechanism in which the heterocyclic nitrogen atom (N-4 of
triazole) binds to the heme iron atom [3]. However, increasing use
The sulfur and nitrogen containing heterocycles, such as 30
thiazole and its derivatives like thienopyridine and tetrahydrothie- 31
nopyridine, have attracted continuing interest because of their 32
varied biological activities [7–10]. The triazole ring, difluorophenyl 33
group and hydroxyl group are the pharmacophores of antifungal 34
agents, but the side chains located in the narrow hydrophobic cleft 35
are also important [11–14]. The optimization of these side chains 36
attached to the pharmacophores has attracted current researches 37
for development of new antifungal agents. In this research work, 38
we intended to alter the side chains to find potent and broad 39
spectrum antifungal agents. The most commonly used method for 40
the preparation of 1,2,4-triazole involves dehydrative condensa- 41
tion of hydrazide derivatives; other approaches involve the Pinner 42
reaction and the Pellizzari reaction. However, these conventional 43
methods involve high reaction temperature, long reaction times 44
and also result in low yields of product [15].
45
Based on the above facts and our interest for search for new 46
antifungal agents [16–21], we have reported a facile method for 47
the synthesis of novel, 5-((5-substituted-1H-1,2,4-triazol-3-yl) 48
*
Corresponding author.
E-mail address: jnsangshetti@rediffmail.com (J.N. Sangshetti).
http://dx.doi.org/10.1016/j.cclet.2014.04.003
1001-8417/ß 2014 Jaiprakash N. Sangshetti. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: J.N. Sangshetti, et al., Synthesis, docking and ADMET prediction of novel 5-((5-substituted-1-H-1,2,4-
triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as antifungal agents, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.04.003

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J.N. Sangshetti et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
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methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridines 5a–i as antifun-
gal agents by using 4-dimethylaminopyridine (DMAP) as a catalyst
under microwave irradiation. In present study, we have also
reported molecular docking and ADMET properties of the
synthesized compounds. The results suggest that the compounds
could be exploited as an antifungal drug.
in Fig. S2 (Supporting information). The molecular docking study of
the synthesized compounds 5a–i was performed against homology
built cytochrome P450 lanosterol 14a-demethylase of C. albicans
to understand the binding interactions using VLife MDS 4.3
package following standard procedures [26].
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111
2.3.2. ADMET properties
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56
2. Experimental
A computational study of synthesized compounds 5a–i was
performed for prediction of ADMET properties. In this study, we
assessed ADMET properties using ADMET predictor FAFDrugs2
which runs on Linux OS. This tool is freely available and used for in
silico ADMET filtering [27]. In particular, we calculated the
compliance of synthesized compounds to the Lipinski’s rule of
five [28]. This approach has been widely used as a filter for
substances that would likely be further developed for drug design
programs. We have also assessed parameters like number of
rotatable bonds (>10) and the number of rigid bonds which signify
that the compound may have good oral bioavailability and good
intestinal absorption [29].
2.1. Chemistry
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68
2.1.1. Synthesis of 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
yl)acetohydrazide (4)
Ethyl-2(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)acetate (3)
was obtained by the reaction of 4,5,6,7-tetrahydrothieno[3,2-
c]pyridine hydrochloride (1) with ethyl-2-bromoacetate (2) using
triethylamine as catalyst [22]. Equimolar quantities of ethyl-2(6,7-
dihydrothieno[3,2-c]pyridine-5(4H)-yl)acetate (3) was refluxed
with hydrazine hydrate in n-butanol using glacial acetic acid as
catalyst to give product 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-
yl)acetohydrazide (4) [23]. The structures were confirmed by
spectral analysis (Mass, 1H NMR and 13C NMR) and in agreement
with published data.
3. Results and discussion
125
126
3.1. Chemistry
69
70
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79
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2.1.2. General procedure for the synthesis of 5-((5-substituted-1H-
1,2,4-triazol-3-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridines
5a–i
The synthetic protocols employed for the synthesis of 5-((5-
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135
136
137
138
139
140
141
142
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145
146
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149
150
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153
154
155
156
157
158
159
substituted-1H-1,2,4-triazol-3-yl)
methyl)-4,5,6,7-tetrahy-
drothieno[3,2-c]pyridine derivatives 5a–i are presented in Scheme
1. For the synthesis of 5-((5-substituted-1H-1,2,4-triazol-3-yl)
methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives 5a–i,
we first optimized the reaction conditions. The reaction of 2-(6,7-
dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide (1.0 mmol)
(4) and benzonitrile (1.0 mmol) in ethanol (15 mL) under
microwave irradiation (700 W) was used as the model reaction.
The catalysts (30 mol%) like K2CO3, triethylamine and 4-dimethy-
laminopyridine (DMAP) were used to test their efficacy for the
synthesis of model reaction. Among the result, a good yield was
obtained by the use of catalyst DMAP (91% yield) (Table S1,
Supporting information). After deciding upon the catalyst DMAP,
the effect of catalyst load was studied at various loads like 10, 20,
30 and 40 mol%. DMAP with 30 mol% gave good yield (91%) (Table
S2, Supporting information). The effect of various solvents like
acetonotrile, isopropylalcohol, n-butanol and ethanol were also
studied and ethanol was found to be best among the studied
solvents (Table S3, Supporting information). The synthetic protocol
was extended for the synthesis of 5-((5-substituted-1H-1,2,4-
triazol-3-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridines 5a–
i using various substituted aromatic nitrites under microwave
irradiation (700 W) in ethanol with DMAP (30 mol%) as catalyst for
about 20–25 min. The purity of the synthesized compounds was
checked by TLC and melting points were determined in open
capillary tubes melting point apparatus and are uncorrected. The
physical data of the synthesized compounds are presented in
Table 1. The data obtained from 1H NMR, 13C NMR and Mass
Spectrometry confirmed the proposed structures (Spectral data
results are provided in Supporting information). The products were
obtained in good yield (88–91%) and required less reaction time
(20–25 min).
In an Erlenmeyer flask, 2-(6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl)acetohydrazide (4) (1.0 mmol), aromatic nitriles
(1.0 mmol) and DMAP (30 mol%) were taken in ethanol (15 mL).
The reaction mixture was irradiated inside a synthetic microwave
oven (Make-Ethosi Milestone with temperature control) for about
20–25 min (700 W). After completion of reaction (monitored by
TLC), the mixture was concentrated to obtain the solid product. The
solid product formed was filtered, dried and recrystallized from
ethanol.
81
2.2. In vitro antifungal activity
82
83
84
85
86
87
88
89
90
The synthesized compounds 5a–i were screened for their in
vitro antifungal activity. The antifungal activity was evaluated
against five human pathogenic fungal strains, such as Candida
albicans (NCIM3471), Fusarium oxysporum (NCIM1332), Aspergillus
flavus (NCIM539), Aspergillus niger (NCIM1196), Cryptococcus
neoformans (NCIM576), which are often encountered clinically,
and were compared with standard drugs like fluconazole and
miconazole. Minimum inhibitory concentration (MIC) values were
determined using standard agar method [24].
91
2.3. Computational studies
92
93
94
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96
97
98
99
2.3.1. Docking study
The 3D model structure of cytochrome P450 lanosterol 14a-
demethylase of C. albicans was built using homology modeling
with the help of VLifeMDS 4.3 ProModel. Amino acid sequence of
enzyme was obtained from the Universal Protein Resource (http://
www.uniprot.org/) (Accession Code: P10613) and sequence
homologous was obtained from Protein Data Bank (PDB) using
Blast search. Based on the result of blast search, we used the crystal
3.2. In vitro antifungal activity
160
100
101
102
103
104
105
106
structure of human lanosterol 14a-demethylase (CYP51) with
azole as a template for homology modeling (PDB ID: 3LD6). The
alignment of amino acid sequence of CA-CYP51 (P10613) and
human CYP51 (3LD6_B) is given in Fig. S1 (Supporting informa-
tion). The quality of the generated C. albicans lanosterol 14a-
demethylase model was assessed by using the well-validated
program like PROCHECK [25] and its structural validation is shown
The results of in vitro antifungal activity (Table 2) showed that
all the compounds had good to moderate antifungal activity. All
the synthesized compounds 5a–i were less active against C.
albicans, F. oxysporm, A. flavus, A. niger and C. neoformans when
compared with fluconazole. Among the synthesized compounds,
compound 5g showed significant activity against C. albicans, A.
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165
166
Please cite this article in press as: J.N. Sangshetti, et al., Synthesis, docking and ADMET prediction of novel 5-((5-substituted-1-H-1,2,4-
triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as antifungal agents, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.04.003

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3
Scheme 1. Synthetic route for target compounds 5a–i. Reagents and conditions: (a) Acetonitrile, TEA, reflux, 5 h. (b) n-butanol, glacial acetic acid, reflux, 15 h. (c) DMAP,
ethanol, microwave irradiation (700 W), 20–25 min.
167
168
169
170
flavus and A. niger when compared with fluconazole. The compound
5g (MIC = 15 g/mL) showed higher activity against C. albicans than
miconazole (MIC = 25 g/mL). The compounds 5b (MIC = 25 g/mL
g/mL against
F. oxysporm and A. niger, respectively) were equipotent to micona- 171
zole (MIC = 25, 25 and 12.5 g/mL against C. albicans, F. oxysporm 172
and A. niger, respectively). The compounds 5g (MIC = 15 g/mL 173
against A. flavus) and 5h (MIC = 15 g/mL against A. niger) showed 174
m
m
m
m
m
against C. albicans) and 5g (MIC = 25 and 12.5
m
m
Table 1
Physical data for 5-((5-substituted-1H-1,2,4-triazol-3-yl)methyl)-4,5,6,7 tetrahydrothieno[3,2-c]pyridine derivatives 5a–i.a
Compd.
Ar
Mol. formula
C16H16N4S
Time (min)
20
Yield (%)b
91
Mp (8C)
Rf
5a
216–218
0.62
5b
5c
C16H15ClN4S
C23H22N4S
24
22
90
91
192–194
189–190
0.59
0.65
Cl
5d
5e
5f
C16H15ClN4S
C16H15ClN4S
C17H19N5S
25
22
23
90
88
90
184–186
178–180
202–204
0.60
0.59
0.55
Cl
Cl
NH2
5g
5h
C17H17FN4S
C18H20N2OS
C17H18N4S
25
22
25
91
90
91
208–210
200–202
192–194
0.57
0.53
0.55
F
H CO
3
5i
a
Eluants used in TLC were benzene: methanol (8:2) for all compounds.
Isolated yields of two runs. Solvent of recrystallization was ethanol.
b
Please cite this article in press as: J.N. Sangshetti, et al., Synthesis, docking and ADMET prediction of novel 5-((5-substituted-1-H-1,2,4-
triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as antifungal agents, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.04.003

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Table 2
Antifungal activity and results of docking study of compounds.
Compd.
MIC valuesa
(
mg/mL)
Docking score
No. of hydrogen
No. of hydrophilic
bonding interactions
bonding interactions
C. albicans
F. oxysporm
A. flavus
A. niger
C. neoformans
b
b
5a
75
25
100
50
50
50
15
50
100
5
100
37.5
150
62.5
50
150
ꢀ2.4727
ꢀ3.9721
ꢀ4.0792
ꢀ3.0718
ꢀ4.3320
ꢀ3.9214
ꢀ4.8201
ꢀ0.5431
ꢀ3.6561
ꢀ3.3526
ꢀ3.1144
0
0
0
0
0
0
1
0
1
2
0
12
16
10
17
16
14
17
10
12
13
39
5b
75
150
100
100
150
15
100
b
100
b
5c
5d
150
150
150
12.5
125
125
75
5e
5f
62.5
25
5g
37.5
5h
37.5
150
5
37.5
b
15
b
87.5
b
5i
Fluconazole
Miconazole
5
10
5
25
25
12.5
12.5
25
a
Values are the average of three readings.
b
No activity was observed upto 200 mg/mL.
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
moderate activity when compared with miconazole (MIC = 12.5 and
12.5 g/mL against A. flavus and A. niger, respectively). The
compounds 5a and 5i against A. flavus, 5a, 5c and 5i against A.
niger and 5c and 5i against C. neoformans showed no activity up to
data obtained from docking study is presented in Table 3. The
docking results indicated that thienopyridine core of these
compounds 5a–i held in the active pocket by forming the
hydrophobic interactions with amino acid residues ALA343,
THR347, LEU406, LEU412, SER414, MET415, VAL440, SER441,
PRO442, PHE499, GLY500, HIS504, ARG505, CYS506, GLY508,
ALA512, GLU509, CYS506, LEU412, and ALA501. The compounds
5g and 5i had shown hydrogen bonding interaction with amino
acid residues GLU509, CYS506 and LEU412, ALA501, respectively.
The halogen substituted compounds 5b, 5d, 5e and 5g were more
favorable for hydrophobic interactions as compare to other
substituted (H, – NH2, and OCH3) compounds. The 4-F substitu-
ent at benzyl ring of most active compound 5g fitted well into the
hydrophobic pocket. The binding interactions for compound 5g
and fluconazole are shown in Fig. 1. On the basis of activity data
and docking result, it was found that compound 5g had potential
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
m
the concentration of 200
mg/mL.
From the antifungal activity data in Table 2, it is observed that
scaffolds 1,2,4-triazole and 4,5,6,7-tetrahydrothienopyridine are
responsible for antifungal activity. The unsubstituted phenyl
analog 5a shows significant activity against C. albicans and F.
oxysporum than against C. neoforman. Substituted phenyl analogs
are more active than unsubstituted phenyl analogs against almost
all of the tested organisms, except for compounds 5c and 5i where
the activity is reduced due to substitution. Introduction of p-Cl to
phenyl 5b increases the antifungal activity against all of the tested
organisms compared to unsubstituted analog 5a. Replacement of
p-Cl with o-Cl (5e) and m-Cl (5d) decreases the activity.
Introduction of –NH2 at 2-position of phenyl 5f shows moderate
activity against C. albicans and F. oxysporum and shows a decrease
in activity against A. flavus, A. niger, C. neoformans compared to the
unsubstituted analog 5a. Introduction of 4-F to benzyl ring 5g leads
to a potent compound against all the tested fungal strains.
Compound 5h with 4-OH to benzyl ring shows enhanced activity
against A. niger, A. flavus and F. oxysporum as compare to
unsubstituted benzyl derivative 5i.
to inhibit cytochrome P450 lanosterol 14a-demethylase of
C. albicans.
3.3.2. ADMET properties
223
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229
230
231
232
233
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235
We had analyzed various physical descriptors and pharmaceu-
tically relevant properties for ADMET prediction by using
FAFDrugs2 and data is summarized in Table 3. All the compounds
showed significant values for the various parameters analyzed and
showed good drug-like characteristics based on Lipinski’s rule of
five. The data obtained for all the synthesized compounds 5a–i was
within the range of accepted values. None of the synthesized
compounds had violated the Lipinski’s rule of five. The value of
polar surface area (PSA) for synthesized compounds 5a–i indicated
good oral bioavailability. The parameters, like number of rotatable
bonds and number of rigid bonds are linked with intestinal
absorption result, showed that all synthesized compounds 5a–i
199
3.3. Computational studies
200
201
202
203
204
3.3.1. Docking study
The synthesized compounds 5a–i and standard drug (flucon-
azole) were docked into the active site of cytochrome P450
lanosterol 14a-demethylase of C. albicans using VLifeMDS 4.3
software package to understand the binding interactions. The
Table 3
Prediction of ADMET properties of compounds.
Compd.
MW
log P
HBA
HBD
PSA
Rigid bond
Rotatable bond
Lipinski violation
Toxicity
5a
296.39
330.83
386.51
330.83
330.83
325.43
328.40
340.44
310.41
306.27
416.12
3.02
3.68
4.54
3.68
3.68
3.11
3.09
2.96
2.95
0.73
6.45
3
3
3
3
3
3
3
4
3
5
2
1
1
1
1
1
2
1
1
1
1
0
73.05
73.05
73.05
73.05
73.05
99.07
73.05
82.28
73.05
81.65
27.05
21
21
27
21
21
21
21
21
21
16
17
3
3
5
3
3
4
4
5
4
5
6
0
0
0
0
0
0
0
0
0
0
1
N
N
N
N
N
N
N
N
N
N
Y
5b
5c
5d
5e
5f
5g
5h
5i
Fluconazole
Miconazole
N: non-toxic.
Y: toxic.
Please cite this article in press as: J.N. Sangshetti, et al., Synthesis, docking and ADMET prediction of novel 5-((5-substituted-1-H-1,2,4-
triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as antifungal agents, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
j.cclet.2014.04.003

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5
Q2
Fig. 1. Docking of compound 5g (Upper left panel), Fluconazole (Upper right panel). Ligands are shown in red color. Hydrogen bonds are shown in green color. Hydrophobic
bonds are shown in sky blue color. (For interpretation of the references to color in figure legend, the reader is referred to the web version of the article.)
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had good absorption. All the synthesized compounds were found
to be nontoxic.
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In conclusion, synthesis and antifungal activity of a novel series
of 5-((5-substituted-1H-1,2,4-triazol-3-yl)methyl)-4,5,6,7-tetra-
hydrothieno[3,2-c]pyridine derivatives 5a–i has been presented.
Use of DMAP as catalyst with ethanol under microwave irradiation
helped in fast conversion of 2-(6,7-dihydrothieno[3,2-c] pyridine-
5(4H)-yl)acetohydrazide to 5-substituted-1,2,4-triazole deriva-
tives in good yields, proving its advantage. Based on the activity
data, structure-activity relationship (SAR) for the series has been
developed and it is observed that compound 5b was equipotent
with miconazole against C. albicans, whereas compound 5g was
equipotent with miconazole against F. oxysporum and A. niger and
more potent than miconazole against C. albicans. Also compounds
5d, 5e, 5f and 5h showed antifungal activity comparable to
miconazole against C. albicans, F. oxysporum, A. flavus and A. niger.
The structure activity relationship study has suggested that the
compound from the present series with 4-Cl or 4-F substituent on
phenyl group on 5-position and 4,5,6,7-tetrahydrothienopyridene
on 3-position of 1,2,4-triazole can serve as an important gateway
for the design and development of new antifungal agent with
potent activity. The docking studies of synthesized compounds
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triazol-3-yl) methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as antifungal agents, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/
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