A novel amalgamation of 1,2,3-triazoles, piperidines and thieno pyridine rings and evaluation of their antifungal activity

Article abstract of DOI:10.1016/j.ejmech.2013.04.045

It is the first report of the novel amalgamation of 1,2,3-triazoles, piperidines, thieno pyridine rings and evaluation of their antifungal activity. The synthesized compounds showed interesting moderate to good antifungal activity, wherein they were able to discriminate between the two species Aspergillus flavus and Aspergillus niger of the same genus. In addition, the main highlight of this series is the sensitivity of the fungal strain Cryptococcus neoformans to the compounds having p-chlorobenzoyl (9h), methane sulfonyl (9i) and p-methylbenzene sulfonyl (9j) attached to the piperazine nitrogen.

Full text of DOI:10.1016/j.ejmech.2013.04.045

Accepted Manuscript
A novel amalgamation of 1,2,3 triazoles, piperidines and thieno pyridine rings and
evaluation of their antifungal activity
Sunil N. Darandale, Nayeem A. Mulla, Dattatraya N. Pansare, Jaiprakash N.
Sangshetti, Devanand B. Shinde
PII:
S0223-5234(13)00277-8
10.1016/j.ejmech.2013.04.045
EJMECH 6155
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 9 February 2013
Revised Date: 15 April 2013
Accepted Date: 23 April 2013
Please cite this article as: S.N. Darandale, N.A. Mulla, D.N. Pansare, J.N. Sangshetti, D.B. Shinde,
A novel amalgamation of 1,2,3 triazoles, piperidines and thieno pyridine rings and evaluation of their
antifungal activity, European Journal of Medicinal Chemistry (2013), doi: 10.1016/j.ejmech.2013.04.045.
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ACCEPTED MANUSCRIPT
A novel amalgamation of 1,2,3 triazoles, piperidines and thieno pyridine rings
and evaluation of their antifungal activity
Sunil N. Darandale, Nayeem A. Mulla, Dattatraya N. Pansare, Jaiprakash N. Sangshetti,
Devanand B. Shinde*
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad-431004 (MS), India
Tel No.: 0240-2403308
Fax No.: 0240-2400413
*Corresponding author E-mail: dbssunil09@rediffmail.com
Graphical abstract
It is the first report for the novel amalgamation of 1,2,3 triazoles, piperidines, thieno pyridine
rings and evaluation of their antifungal activity, revealing specificity towards fungal strains.

ACCEPTED MANUSCRIPT
A novel amalgamation of 1,2,3-triazoles, piperidines and thieno
pyridine rings and evaluation of their antifungal activity
Sunil N. Darandale, Nayeem A. Mulla, Dattatraya N. Pansare, Jaiprakash N.
Sangshetti, Devanand B. Shinde*
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad-431004 (MS), India.
Tel No.: 0240-2403308
Fax No.: 0240-2400413
*Corresponding author E-mail: dbssunil09@rediffmail.com
Abstract
It is the first report of the novel amalgamation of 1,2,3-triazoles, piperidines, thieno
pyridine rings and evaluation of their antifungal activity. The synthesized compounds
showed interesting moderate to good antifungal activity, wherein they were able to
discriminate between the two species A. flavus and A. niger of the same genus. In
addition, the main highlight of this series is the sensitivity of the fungal strain C.
neoformans to the compounds having p-chloro benzoyl (9h), methane sulfonyl (9i)
and p-methylbenzene sulfonyl (9j) attached to the piperazine nitrogen.
Keywords: 1,2,3-triazole, thieno pyridine, piperazine and antifungal activity.
1. Introduction
The eukaryotic microorganism fungi are vital opportunistic pathogens
of humans which are developing drug resistant strains. In recent time several factors
have contributed towards increasing life threatening systemic fungal infections,
mainly due to development of drug resistant fungal strains. The development of drug
resistance in fungal strains is commonly observed in severely ill and immune
compromised patient population, including HIV-infected patients, patient recipients of
transplant and patient suffering of cancer [1]. The other factors that have contributed
to drug resistance are the frequently used more-invasive medical procedures and the
treatment with broad-spectrum antibiotics. The majority of fungal infections are
caused by Candida and Aspergillus species, with Candida albicans being the most
common agent of fungal bloodstream infections. Cryptococcus neoformans has also
become
immunosuppressive treatment [1, 2].
The emergence of drug resistant fungi in the past decades has
a
major opportunistic fungal pathogen in patients receiving
propelled the researchers around the globe to find new and efficacious drugs to solve
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these problems by designing, synthesizing and biologically evaluating the developed
molecules [3, 4]. Therefore, it is necessary to design new molecules which are not yet
developed and to determine their biological activity. The literature survey revealed
that till date the novel fusion of tetrahydrothieno pyridine [5, 6], 1,2,3-triazole[7, 8]
and piperidine [9,10] has skipped through the vigilant eyes of the research groups.
The main reason for the amalgamation of these rings was the diverse array of
bioactivities possessed individually by them as mentioned below, and to study the
effect of fusion of these rings on the biological activity of a molecule compromising
these three rings on combined scale. The lack of efforts for the fusion of these three
important cores into a single molecule and to study its biological activity propelled us
to carry out this work.
The sulfur containing heterocycles have emerged as an important class
of molecules in past decade due to their biodiversities from the industrial perspective
and thus rise is seen in development of sulfur containing heterocycles. Tetrahydro
thieno pyridine is one of such sulfur containing heterocycles having varied biological
activities like anti-inflammatory, vasodilators and blood platelet aggregation
inhibitory action [11]. The other nucleus, piperidine and its analogues are reported in
literature for varied pharmacological activities like antibacterial [12], AChE inhibitors
[13], antihistaminics [14] and antitubercular agents [15]. The piperidine and its
derivatives are important building blocks in the synthesis of pharmaceuticals drug
molecules like paroxetin, methylphenidate, raloxifene, minoxidil, risperidone and
pethidine. The antifungal activity of the triazole analogues makes it a hot topic of
research, especially in the industries. The research on 1,2,3-triazole and its derivatives
like tazobactam enjoy a central position especially in medicinal chemistry attracting
large number of researchers. The 1,2,3-triazoles analogues are also established as
potent antineoplastic [16], antimicrobial [17], analgesic [18], anti-inflammatory [19],
local anesthetic [20], anticonvulsant [21], antimalarial [22] and anti-HIV agents [23].
More recently there were reports of 1,2,3-triazole derivatives being used as DNA
cleaving agents [24] and as a potential antitubercular agents [25].
2. Chemistry
In continuation of our work [26, 27], on the synthesis and biological
evaluation of new heterocyclic molecules, we herein report the synthesis and
antifungal evaluation of some novel structural scaffolds formed from fusion of 1,2,3-
triazole, piperidine and tetrahydrothieno pyridine rings. The starting material tert-
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butyl 4-azidopiperidine-1-carboxylate (4) was prepared according to our reported
procedure in (Scheme 1) [26]. The reaction sequence for different title compounds is
as outlined in (Scheme 2 and Scheme 3). The compounds (5, 6) were prepared as per
the (Scheme 2). The tert-butyl 4-(4-((4,5-dihydrothieno[2,3-c]pyridin-6(7H)-
yl)methyl)-1H-1,2,3-triazol-1-yl) piperidine-1-carboxylate (8) was prepared by
nucleophilic substitution reaction using O-mesyl derivative (6) and 4,5,6,7-
tetrahydrothieno[2,3-c]pyridine (THTP) (7) in acetonitrile at 60oC for 6 hr. with 85 %
yield (Scheme 2). The compound (8) was then subjected to deprotection to give 5-((1-
(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine
(9a) by using trifluoroacetic acid (TFA) in dichloromethane with 87 % yield. The 5-
((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]
pyridine (9a) was subjected to substitution reaction in dichloromethane by using acyl
chlorides/ alkyl chlorides to get the target derivatives (9b-k) in 82-91 % yield (Table
1, Scheme 3).
3. Pharmacology
3.1 Antifungal activity
All the synthesized compounds were screened for their in-vitro antifungal
activity (Table 2). The antifungal activity was evaluated against different fungal
strains including Candida albicans (NCIM3471), Fusarium oxysporum (NCIM1332),
Aspergillus flavus (NCIM539), Aspergillus niger (NCIM1196) and Cryptococcus
neoformans (NCIM576). Minimum inhibitory concentration (MIC, µg/mL) values of
all compounds were determined using standard agar dilution method as per CLSI
guidelines [28-31]. Miconazole was used as a standard drug for comparison of
antifungal activity while dimethyl sulfoxide was used as solvent control.
4. Results and discussion
The antifungal data (Table 2) shows that all the tested compounds
have moderate to good level of activity against all the tested fungal strain, except C.
neoformans. The C. neoformans shows higher level of resistance to majority of
synthesized compounds and in most cases this resistance was greater than 150 µg/mL.
The compounds (9i) (MIC 25 to 50 µg/mL) and (9h) (MIC 40 to 45 µg/mL) are most
active amongst the series, notably (9i) had promising activity (MIC of 25 µg/mL)
against C. neoformans, but none of these compound is equivalent to miconazole.
Among the synthesized series the compounds (9b, 9e, 9j and 9k) were having the
intermediate activity compared to standard, in which compound (9j) was found to be
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most potent and specific against A. niger with lowest MIC value of 37.5 µg/mL. The
remaining compounds (9a, 9c, 9d, 9f and 9g) were least active showing very low
level of activity.
4.1 Structure activity relationship
The structure activity relationship reveals some very interesting facts about the
strain specific variation in activity. Interestingly the synthesized compounds did not
follow the same pattern in antifungal activity against different fungal strains and were
able to discriminate the various targets in different strains. The highlights of structure
activity relationship are,
1. Specificity towards the A. flavus: The standard drug (Miconazole) showed
the same degree of activity against A. flavus and A. niger which belongs to the
same genus. But on the other hand the synthesized molecules (9a-k)
irrespective of their side chains attached to the piperazine ring showed more
specificity towards A. flavus compared to A. niger. It verified that the
synthesized molecules (9a-k) were able to discriminate between the two
species A. flavus and A. niger of the same genus.
2. Effect of alkyl group: The compound with unsubstituted piperazine nitrogen
(9a) renders the molecule less active as compared to Miconazole but it showed
activity against all the tested strains. The substitution of hydrogen (9a) on
nitrogen of piperazine ring by methyl group (9b) increases the activity to
intermediate level compared to compound (9a), but the compound was found
to be inactive against A. niger and C. neoformans. The substitution of
hydrogen (9a) on nitrogen of piperazine ring by ethyl group (9c) decreases the
activity compared to (9b). But compound (9c) was found to be active against
all the tested strains unlike that of (9b) and was especially more potent on A.
flavus. It could be thus stated that as the chain length increase the molecule
shows activity against all the tested strains and more specificity towards the
particular strains.
3. Effect of acyl group: The effect of acyl substitution of hydrogen (9a) on
nitrogen of piperazine ring was studied and it revealed some interesting
results. The compound (9d) having an acetyl substitution gave intermediate
active compound compared to miconazole for C. albicans and F. oxysporum,
however it showed less activity for A. Niger and was fairly inactive for A.
flavus and C. neoformans. The compound (9e) having an propionyl
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substitution give intermediate active compound compared to standard,
however unlike that of (9d) it was active against all the tested strains, which
indicated that the increase in chain length plays an important role in antifungal
activity. Lastly the compound (9f) having an isobutyryl substitution, resulted
in less active compound compared to (9d and 9e), but was moderately active
against A. flavus and A. niger. This clearly highlights the crucial role of chain
length and branching of acyl group in activity and strain specificity of
compound. Thus for the antifungal activity the chain length must not be too
short and preferably should avoid its branching.
4. Effect of benzoyl group: The benzoyl substituted compound (9g) lowers the
activity and was fairly inactive for F. oxysporum and A. niger. The p-
chlorobenzoyl compound (9h) gave one of the most active compounds of the
series giving intermediate activity compared to the miconazole. The
compound (9h) gave good activity compared to compound (9g) indicating the
importance of the halogen substitution. The activity data suggest that the
halogen analogues might help in improving the antifungal activity.
5. Effect of sulfonyl group: The methane sulfonyl substituted compound (9i)
gave one of the most active compounds among the series. The introduction of
the sulfonyl group enhanced the activity to great extent compared to (9a) but
the same sulfonation does not work well with p-methylbenzene sulfonyl group
(9j) when compared to (9i) except for A. niger. This could be attributed to the
increase in length of the substituent [p-methylbenzene in case of compound
(9j)]. Thus best antifungal activity could be achieved if the substituent used
has a sulfonyl group.
6. Effect of acyl and sulfonyl group: The acyl substituents (9d, 9e and 9f) gave
improved activity compared with compound (9a). But the sulfonyl substituent
(9i and 9j) made the molecule most potent compounds amongst the series
which could be attributed to the replacement of the carbonyl group by the
sulfonyl group. In short substitution with sulfonyl group is better than acyl
group for superior activity.
7. Effect of benzyl and benzoyl group: The introduction of benzyl group (9k)
gave activity similar to the (9a) i.e. it neither improved nor decreased the
activity of molecule compared to (9a). However the benzyl group was found
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to have somewhat superior activity compared to that of the benzoyl group
(9g).
8. Equipotency against C. neoformans: The main highlight of this series is the
equipotency of compound (9i) and comparable activity by compounds (9h, 9j)
compare to miconazole against C. neoformans. While the rest of the
synthesized molecules were almost inactive against the C. neoformans. In
general it could be stated that the sulfonyl group is making the molecule more
active against the fungal strain C. neoformans.
4.2 Highlight of synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives (9a-k):
The remarkable highlight of synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-
triazol-4-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine analogues is, (i) the first
report for the synthesis of series of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-
yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine analogues; (ii) the first report of 5-
((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]
pyridine analogues, which has been synthesized and evaluated for antifungal activity;
(iii) the main highlight of this series is the equipotency of compound (9i) against C.
neoformans; (iv) the synthesized molecules (9a-k) were able to discriminate between
the two species A. flavus and A. niger belonging to same genus; (v) to increase the
antifungal activity the chain length must not be too short and preferably should avoid
branching; (vi) to increase the antifungal activity the substitution could be having a
sulfonyl group.
5. Conclusion
In conclusion, a novel amalgamation of 1,2,3-triazole, piperidine,
tetrahydrothieno pyridine rings and evaluation of their antifungal activity has been
carried out. The synthesized compounds showed interesting activity, wherein they
were able to discriminate between the two species A. flavus and A. niger of the same
genus. In addition the main highlight of this series is the selectivity and specificity for
the fungal strain C. neoformans shown by the compounds (9h), (9i) and (9j).
6. Experimental protocols
6.1 Chemistry
The propargyl alcohol, copper iodide, triethyl amine, trifluoro acetic
acid, substituted alkyl and acyl halides, tetrahydrothieno pyridine used were
commercially available. Melting points were recorded on SRS Optimelt, melting point
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apparatus and are uncorrected. IR spectra were taken on Bruker FT-IR 4000. 1H
NMR spectra were recorded on a 400 MHz Bruker spectrometer and 13C NMR
spectra were recorded on a 100 MHz Bruker spectrometer are reported as parts per
million (ppm) downfield from a tetramethylsilane internal standard. The following
abbreviations are used; singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m)
and broad (br). Mass spectra were taken with Micromass-QUATTRO-II of WATER
mass spectrometer.
6.1.1 Synthesis of tert-butyl 4-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)piperidine-
1-carboxylate (5):
In a 50 mL round bottom flask, propargyl alcohol (10 mmol), triethyl amine (20
mmol) and compound (4) (10 mmol) was added in dimethyl formamide (5 ml),
followed by CuI (2 mmol) and the resulting solution was stirred at room temperature
for 10 hr. After completion of reaction (monitored by TLC, 20 % Ethyl acetate: n-
hexane), solvent was removed in-vacuo and ethyl acetate (10 mL) was added to the
residue and then extracted with 3 portions (3 x 10 mL) of distilled water. The organic
layer was dried over anhydrous Na2SO4 and concentrated in-vacuo to get the desired
compound (5), which was recrystallized using ethanol as solvent.
Pale Yellow Solid, Yield: 92 %, Melting Point: 173-175oC
ES-MS m/z (%): 283 (M+H)
IR (KBr, cm-1): 3400 (-OH), 3020 (C=CH), 2950 (C-CH), 1735 (C=O), 1640 (C=C),
1208 (C-N), 1100 (C-O-C).
1H NMR (400 MHz, CDCl3): δ ppm 1.51 (s, 9H), 2.10-2.20 (m, J =7.0 Hz, 4H), 2.45-
2.55 (m, J =7.0 Hz, 4H), 3.72 (m, 1H), 3.95 (s, 1H), 4.72 (d, J =2.0 Hz, 2H), 7.82 (s,
1H).
13C NMR (100 MHz, CDCl3): δ ppm 27.1, 29.4, 45.7, 55.7, 61.2, 82.3, 124.7, 144.1,
160.8.
6.1.2 Synthesis of tert-butyl 4-(4-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-triazol-1-
yl)piperidine-1-carboxylate (6):
In a 50 mL round bottom flask, compound (5) (10 mmol) and triethyl amine (15
mmol) was added in 10 mL dichloromethane, stirred at room temperature for 5
minutes and then cooled to 0-5°C. Methane sulphonyl chloride (12 mmol) was added
drop wise at 0-5°C, after addition the reaction mixture was allowed to attain room
temperature and then stirred at room temperature for 2 hr. After completion of
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reaction (monitored by TLC, 30 % Ethyl acetate: n-hexane), the reaction mixture was
quenched by addition of distill water (10 mL). The organic layer was extracted with 3
portions (3 x 10 mL) of water and was washed with saturated NaHCO3 (3 x 10 mL),
the organic layer after extraction was separated, dried over anhydrous Na2SO4 and
concentrated in-vacuo to afford compound (6), which was recrystallized using ethanol
as solvent.
Off White Solid, Yield: 95 %, Melting Point: 210-212oC
ES-MS m/z (%): 361 (M+H)
IR (KBr, cm-1): 3025 (C=CH), 2910 (C-CH), 1730 (C=O), 1620 (C=C), 1238 (C-N),
1120 (C-O-C), 1030 (S=O).
1H NMR (400 MHz, CDCl3): δ ppm 1.54 (s, 9H), 2.14-2.27 (m, J =7.0 Hz, 4H), 2.38-
2.51 (m, J =7.0 Hz, 4H), 3.25 (s, 3H), 3.78 (m, J =7.0 Hz, 1H), 4.65 (d, J =7.0 Hz,
2H), 7.80 (s, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 27.8, 29.7, 40.1, 45.3, 61.8, 65.1, 81.6, 123.9,
143.7, 160.1.
6.1.3 Synthesis of tert-butyl 4-(4-((4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)
methyl)-1H-1,2,3-triazol-1-yl) piperidine-1-carboxylate (8):
In a 50 mL round bottom flask, compound (6) (10 mmol), triethyl amine (20 mmol)
and THTP (7) (10 mmol) was added in acetonitrile (10 mL) at room temperature. The
resulting solution was then heated to 60°C for 6 hr. After completion of reaction
(monitored by TLC, 30 % Ethyl acetate: n-hexane), the solvent was removed in-vacuo
and ethyl acetate (10 mL) was added to the residue and then extracted with 3 portions
(3 x 10 mL) of distilled water. The organic layers was dried over anhydrous Na2SO4
and concentrated in-vacuo to get the desired compound (8), which was recrystallized
using ethanol as solvent.
Pale Yellow Solid, Yield: 85 %, Melting Point: 214-216°C
ES-MS m/z (%): 404 (M+H)
IR (KBr, cm-1): 3038 (C=CH), 2935 (C-CH), 1725 (C=O), 1628 (C=C), 1230 (C-N),
1125 (C-O-C).
1H NMR (400 MHz, CDCl3): δ ppm 1.67 (s, 9H), 2.22-2.35 (m, J =7.0 Hz, 4H), 2.68-
2.80 (m, J =7.0 Hz, 4H), 3.05-3.20 (m, J =7.4 Hz, 4H), 3.54 (d, J =7.4 Hz, 2H), 3.84
(m, J =7.4 Hz, 1H), 4.14 (s, 2H), 6.82 (d, J =9.5 Hz, 1H), 7.42 (s, 1H), 7.65 (d, J =9.5
Hz, 1H).
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13C NMR (100 MHz, CDCl3): δ ppm 22.5, 25.8, 27.1, 28.3, 29.0, 29.7, 42.3, 46.2,
57.6, 59.2, 60.4, 61.3, 81.5, 114.5, 120.9, 124.1, 131.2, 133.6, 134.1, 161.3.
6.1.4 General procedure for synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-
yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9a):
In a 50 mL round bottom flask, compound (8) (10 mmol) and trifluoro acetic acid (2
mmol) was added in dichloromethane (10 mL). The solution was stirred for 2 hr. at
room temperature. After completion (monitored by TLC, 40 % Ethyl acetate: n-
hexane), the mixture was extracted with saturated NaHCO3 (3 x 10 mL). The organic
layer was dried over anhydrous Na2SO4 and on concentration in-vacuo gave the
desired product (9a) in 87 % yield (Table 1, entry 1), which was recrystallized using
ethanol as solvent.
6.1.5 General procedure for synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-
yl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives (9b-k):
In a 50 mL round bottom flask, compound (9a) (10 mmol), triethyl amine (20 mmol)
and CuI (2 mmol) was added in dichloromethane (10 mL) and was stirred at room
temperature for 5 minutes and then cooled to 0-5°C. To this cooled solution, different
substituted alkyl or acyl halides (10 mmol) were added. The resulting solution was
stirred for 2-3 hr. After completion (monitored by TLC, 40 % Ethyl acetate: n-
hexane), was extracted with distilled water (3 x 10mL). The organic layer was dried
over anhydrous Na2SO4 and on concentration in-vacuo gave the desired compounds
(9b-9k) in 82-91 % yield (Table 1, entry 2-11), which were recrystallized using
ethanol as solvent.
6.2 Spectral characterization
6.2.1 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydrothieno
[3,2-c]pyridine (9a):
Pale Yellow Solid, ES-MS m/z (%): 304 (M+H).
IR (KBr, cm-1): 3300 (NH), 3045 (C=CH), 2890 (C-CH), 1660 (C=C), 1243 (C-N),
649 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 1.97 (s, 1H), 2.28-2.42 (m, J =7.0 Hz, 4H), 2.72-
2.85 (m, J =7.0 Hz, 4H), 3.10-3.25 (m, J =7.0 Hz, 4H), 3.65 (s, 2H), 3.74 (m, J =7.0
Hz, 1H), 3.91 (s, 2H), 6.85 (d, J =9.5 Hz, 1H), 7.30 (d, J =9.5 Hz, 1H), 7.82 (s, 1H).
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13C NMR (100 MHz, CDCl3): δ ppm 23.7, 27.1, 28.6, 42.4, 46.3, 54.7, 56.2, 60.1,
61.5, 122.9, 124.2, 125.5, 131.0, 133.9, 135.6.
6.2.2 5-((1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (9b):
Pale Yellow Solid, ES-MS m/z (%): 318 (M+H).
IR (KBr, cm-1): 3060 (C=CH), 2900 (C-CH), 1671 (C=C), 1260 (C-N), 642 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 2.15 (s, 3H), 2.25-2.40 (m, J =7.0 Hz, 4H), 2.64-
2.78 (m, J =7.0 Hz, 4H), 3.10-3.24 (m, J =7.4 Hz, 4H), 3.58 (s, 2H), 3.71 (m, J =7.4
Hz, 1H), 3.86 (s, 2H), 6.83 (d, J =9.5 Hz, 1H), 7.24 (d, J =9.5 Hz, 1H), 7.76 (s, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 24.1, 27.4, 28.3, 47.1, 54.2, 55.8, 57.5, 58.6,
59.8, 61.7, 122.5, 124.5, 125.7, 131.4, 134.3, 135.8.
6.2.3 5-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-tetrahydro
thieno[3,2-c]pyridine (9c):
Pale Yellow Solid, ES-MS m/z (%): 332 (M+H).
IR (KBr, cm-1): 3052 (C=CH), 2914 (C-CH), 1645 (C=C), 1255 (C-N), 650 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 1.30 (s, 3H), 2.08-2.31 (m, J =7.0 Hz, 4H), 2.60-
2.75 (m, J =7.0 Hz, 4H), 2.95 (q, J =7.4 Hz, 2H), 3.17-3.40 (m, J =7.4 Hz, 4H), 3.56
(s, 2H), 3.72 (m, J =7.4 Hz, 1H), 3.81 (s, 2H), 6.87 (d, J =9.5 Hz, 1H), 7.27 (d, J
=9.5 Hz, 1H), 7.82 (s, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 14.1, 23.7, 27.2, 28.0, 49.5, 53.7, 55.1, 56.2,
57.4, 58.6, 61.4, 122.7, 124.8, 126.2, 131.8, 134.5, 135.6.
6.2.4 1-(4-(4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-1H-1,2,3-triazol-
1-yl)piperidin-1-yl)ethanone (9d):
Pale Yellow Solid, ES-MS m/z (%): 346 (M+H).
IR (KBr, cm-1): 3018 (C=CH), 2927 (C-H), 1715 (C=O), 1682 (C=C), 1270 (C-N),
649 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 2.05-2.26 (m, J =7.0 Hz, 4H), 2.40 (s, 3H), 3.25-
3.40 (m, J =7.0 Hz, 4H), 3.45-3.60 (m, J =7.4 Hz, 4H), 3.65 (s, 2H), 3.75 (m, J =7.4
Hz, 1H), 3.86 (s, 2H), 6.80 (d, J =9.5 Hz, 1H), 7.32 (d, J =9.5 Hz, 1H), 7.74 (s, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 22.8, 24.3, 27.5, 28.3, 42.1, 43.2, 55.4, 56.5,
57.4, 61.6, 122.9, 125.0, 126.5, 132.6, 134.1, 135.3, 175.4.
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6.2.5 1-(4-(4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-1H-1,2,3-triazol-
1-yl)piperidin-1-yl)propan-1-one (9e):
Pale Yellow Solid, ES-MS m/z (%): 360 (M+H).
IR (KBr, cm-1): 3035 (C=CH), 2944 (C-H), 1710 (C=O), 1650 (C=C), 1120 (C-N),
620 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 1.30 (s, 3H), 2.15-2.29 (m, J =7.0 Hz, 4H), 2.46
(q, J =7.4 Hz, 2H), 3.05-3.20 (m, J =7.0 Hz, 4H), 3.35-3.54 (m, J =7.4 Hz, 4H), 3.62
(s, 2H), 3.78 (m, 1H), 3.91 (s, 2H), 6.83 (d, J =9.5 Hz, 1H), 7.42 (d, J =9.5 Hz, 1H),
7.68 (s, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 12.1, 24.0, 26.7, 27.6, 28.5, 42.6, 43.7, 55.1,
57.1, 58.2, 62.1, 123.1, 124.6, 125.7, 132.0, 133.5, 134.7, 175.9.
6.2.6 1-(4-(4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-1H-1,2,3-triazol-
1-yl)piperidin-1-yl)-2-methylpropan-1-one (9f):
Pale Yellow Solid, ES-MS m/z (%): 374 (M+H).
IR (KBr, cm-1): 3032 (C=CH), 2942 (C-H), 1705 (C=O), 1680 (C=C), 1228 (C-N),
630 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 1.27 (s, 6H), 2.04-2.21 (m, J =7.0 Hz, 4H), 2.54
(m, J =7.0 Hz, 1H), 2.68-2.80 (m, J =7.4 Hz, 4H), 3.20-3.35 (m, J =7.0 Hz, 4H), 3.67
(s, 2H), 3.74 (s, 2H), 3.84 (m, J =7.0 Hz, 1H), 6.87 (d, J =9.5 Hz, 1H), 7.50 (s, 1H),
7.71 (d, J =9.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 22.4, 24.3, 27.2, 27.9, 36.5, 43.1, 44.3, 55.2,
57.3, 58.5, 61.3, 123.3, 124.5, 125.8, 131.8, 133.7, 135.0, 172.5.
6.2.7 (4-(4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-1H-1,2,3-triazol-1-
yl) piperidin-1- yl) (phenyl)methanone (9g):
Pale Yellow Solid, ES-MS m/z (%): 408 (M+H).
IR (KBr, cm-1): 3020 (C=CH), 2925 (C-H), 1712 (C=O), 1667 (C=C), 1250 (C-N),
642 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 2.12 -2.28 (m, J =7.0 Hz, 4H), 2.72-2.85 (m, J
=7.0 Hz, 4H), 3.24-3.40 (m, J =7.4 Hz, 4H), 3.60 (s, 2H), 3.72 (s, 2H), 3.87 (m, J
=7.4 Hz, 1H), 6.81 (d, J =9.5 Hz, 1H), 7.42-7.58 (m, J =7.0 Hz, 5H), 7.68 (s, 1H),
7.78 (d, J =9.5 Hz, 1H).
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13C NMR (100 MHz, CDCl3): δ ppm 24.3, 27.0, 28.1, 43.2, 44.0, 55.5, 57.3, 58.4,
61.0, 123.1, 124.2, 125.4, 126.2, 127.0, 128.4, 130.4, 132.5, 134.2, 135.6, 174.7.
6.2.8 (4-chlorophenyl)(4-(4-((6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)methyl)-
1H-1,2,3-triazol-1-yl)piperidin-1-yl)methanone (9h):
Pale Yellow Solid, ES-MS m/z (%): 443 (M+H).
IR (KBr, cm-1): 3055(C=CH), 2962 (C-H), 1684 (C=O), 1654 (C=C), 1262 (C-N),
639 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 2.15-2.30 (m, J =7.0 Hz, 4H), 2.65-2.80 (m, J
=7.0 Hz, 4H), 3.34-3.48 (m, J =7.4 Hz, 4H), 3.63 (s, 2H), 3.77 (s, 2H), 3.87 (m, J
=7.4 Hz, 1H), 6.78 (d, J =9.5 Hz, 1H), 7.22-7.40 (m, J =7.0 Hz, 4H), 7.65 (s, 1H),
7.80 (d, J =9.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 24.5, 27.4, 28.1, 43.0, 43.8, 55.2, 56.3, 57.1,
61.0, 123.2, 124.0, 125.1, 128.1, 129.4, 130.4, 131.2, 132.6, 134.3, 135.4, 171.2.
6.2.9 5-((1-(1-(methylsulfonyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine (9i):
Pale Yellow Solid, ES-MS m/z (%): 382 (M+H).
IR (KBr, cm-1): 3012 (C=CH), 2937 (C-H), 1642 (C=C), 1230 (C-N), 1042 (S=O),
648 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 1.98 (s, 3H), 2.14-2.32 (m, J =7.0 Hz, 4H), 2.65-
2.77 (m, J =7.0 Hz, 4H), 3.05-3.20 (m, J =7.4 Hz, 4H), 3.50 (s, 2H), 3.75 (m, J =7.4
Hz, 1H), 4.05 (s, 2H), 6.90 (d, J =9.5 Hz, 1H), 7.46 (s, 1H), 7.72 (d, J =9.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 23.1, 26.0, 27.3, 40.3, 45.7, 46.2, 56.4, 57.2,
58.0, 61.5, 121.7, 123.6, 126.4, 131.2, 133.6, 134.1.
6.2.10 5-((1-(1-tosylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-
tetrahydrothieno[3,2-c] pyridine (9j):
Pale Yellow Solid, ES-MS m/z (%): 458 (M+H).
IR (KBr, cm-1): 3025 (C=CH), 2917 (C-H), 1635 (C=C), 1248 (C-N), 1035 (S=O),
641 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 1.97 (s, 3H), 2.12 -2.30 (m, J =7.0 Hz, 4H), 2.55-
2.70 (m, J =7.0 Hz, 4H), 3.05-3.20 (m, J =7.4 Hz, 4H), 3.47 (s, 2H), 3.71 (m, J =7.4
Hz, 1H), 4.12 (s, 2H), 6.87 (d, J =9.5 Hz, 1H), 7.34 (s, 1H), 7.49-7.60 (m, J =7.0 Hz,
4H), 7.65 (d, J =9.5 Hz, 1H).
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13C NMR (100 MHz, CDCl3): δ ppm 21.7, 23.4, 25.6, 26.3, 43.9, 44.7, 56.1, 57.4,
58.3, 60.7, 122.9, 123.8, 126.1, 127.0, 128.6, 129.8, 131.2, 133.6, 134.5, 138.2, 145.2.
6.2.11 5-((1-(1-benzylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine (9k):
Pale Yellow Solid, ES-MS m/z (%): 394 (M+H).
IR (KBr, cm-1): 3018 (C=CH), 2925 (C-H), 1626 (C=C), 1272 (C-N), 639 (C-S).
1H NMR (400 MHz, CDCl3): δ ppm 2.08-2.21 (m, J =7.0 Hz, 4H), 2.51-2.65 (m, J
=7.0 Hz, 4H), 3.05-3.22 (m, J =7.4 Hz, 4H), 3.44 (s, 2H), 3.61 (s, 2H), 3.75 (m, J
=7.4 Hz, 1H), 4.12 (s, 2H), 6.81 (d, J =9.5 Hz, 1H), 7.37 (s, 1H), 7.50-7.65 (m, J =7.0
Hz, 5H), 7.71 (d, J =9.5 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ ppm 22.7, 27.3, 28.5, 51.2, 52.1, 54.3, 57.6, 58.7,
60.3, 64.8, 122.7, 124.1, 125.0, 126.7, 127.6, 128.5, 129.4, 130.5, 131.2, 133.4, 135.1,
138.2.
Acknowledgement
The authors are thankful to the Head, Department of Chemical Technology, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad- 431004 (MS), India for
providing the laboratory facility.
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Table 1. Synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine derivatives (9a-k).a,b
Compound
Substituent (-R)
Time
(min)
Yieldc
( %)
Melting
point (°C)
Hydrogen
Methyl
60
120
100
80
87
89
85
87
86
89
90
84
91
85
185-187
178-180
184-186
156-158
191-193
179-181
164-166
170-172
189-191
192-194
9a
9b
9c
9d
9e
9f
Ethyl
Acetyl
Propionyl
Isobutyryl
Benzoyl
150
100
100
150
60
9g
9h
9i
p- chlorobenzoyl
Methane sulfonyl
p-methylbenzene
sulfonyl
60
9j
Benzyl
180
82
174-176
9k
a.
Reaction condition (9a): Compound (8) (10 mmol), TFA (2
mmol) in (10 mL) of dichloromethane at room temperature.
b.
c.
Reaction condition (9b-k): Compound (9a) (10 mmol), alkyl or
acyl halides (10 mmol) in 10 mL of dichloromethane, triethyl
amine (20 mmol) and CuI (2 mmol) at 0-5°C.
Isolated yields.
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Table 2. Antifungal activity of the synthesized compounds (9a-k).
Compound
MIC Values (µg/mL)a
C.
albicans
F.
A.
A.
flavus niger
C.
oxysporum
neoformans
50
40
90
40
50
100
90
45
50
60
50
25
90
70
100
45
60
100
*
60
40
35
*
100
*
100
*
9a
9b
47.5
100
*
150
*
9c
9d
30
35
65
40
40
45
60
12.5
*
9e
47.5
*
150
100
45
25
40
90
25
9f
9g
40
30
70
75
25
42.5
40
9h
9i
37.5
100
12.5
9j
9k
Miconazole
* - Activity not reported up to 200 µg/mL.
a - Values are average of three readings.
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Scheme 1. Synthesis of tert-butyl 4-azidopiperidine-1-carboxylate [20].
Scheme 2. Synthesis of tert-butyl 4-(4-(((methylsulfonyl)oxy)methyl)-1H-1,2,3-
triazol-1-yl)piperidine-1-carboxylate.
N
OH
N
OSO2CH3
N
N
N
N
N3
Propargyl
alcohol
Methanesulphonyl
chloride
TEA
CuI, DMF
N
boc
N
boc
N
boc
TEA,DCM
6
5
4
N
N
N
OSO2CH3
N
S
N
N
N
N
boc
6
TEA
HN
+
S
Acetonitrile
N
boc
7
8
Mesyl compound
4,5,6,7-tetrahydrothieno
[3,2-c]pyridine
Scheme 3. Synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine derivatives.
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A novel amalgamation of 1,2,3 triazoles, piperidines and thieno pyridine rings
and evaluation of their antifungal activity
Sunil N. Darandale, Nayeem A. Mulla, Dattatraya N. Pansare, Jaiprakash N. Sangshetti,
Devanand B. Shinde*
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada
University, Aurangabad-431004 (MS), India
Tel No.: 0240-2403308
Fax No.: 0240-2400413
*Corresponding author E-mail: dbssunil09@rediffmail.com
Highlight of synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-4,5,6,7-
tetrahydrothieno[3,2-c]pyridine derivatives (9a-k):
The remarkable highlight of synthesis of 5-((1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-
4,5,6,7-tetrahydrothieno[3,2-c]pyridine analogues is,
(i) Successful novel amalgamation of piperidine, triazole and thienopyridine;
(ii) Evaluation of antifungal activity which revealed interesting data;
(iii) Specificity of compounds towards fungal strains;
(iv) Role of chain length and sulphonyl group.