Synthesis of novel 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-5(4H)-one as antifungal agents

Article abstract of DOI:10.1016/j.bmcl.2009.04.134

A novel series of 1,2,3 triazole compounds possessing 1,2,4 oxadiazole ring were efficiently synthesized. Synthesized compounds were evaluated for their in vitro antifungal activities using standard cup plate method. SAR for the series has been developed by comparing their MIC values with miconazole and fluconazole. Compound 11a from the series was more potent than miconazole against Candida albicans (MIC-20) and Aspergillus flavus (MIC-10) whereas equipotent with miconazole against Fusarium oxysporum (MIC-25) and Aspergillus niger (MIC-12.5). Also compound 11h was more potent than miconazole against Candida albicans (MIC-20) and Aspergillus niger (MIC-10) and equipotent with miconazole against Fusarium oxysporum. Compound 11h was equipotent with fluconazole against Aspergillus niger (MIC-10).

Full text of DOI:10.1016/j.bmcl.2009.04.134

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3564–3567
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Bioorganic & Medicinal Chemistry Letters
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Synthesis of novel 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-
1,2,4-oxadiazol-5(4H)-one as antifungal agents
*
Jaiprakash N. Sangshetti, Rahul R. Nagawade, Devanand B. Shinde
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, Maharashtra, 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 1,2,3 triazole compounds possessing 1,2,4 oxadiazole ring were efficiently synthesized.
Synthesized compounds were evaluated for their in vitro antifungal activities using standard cup plate
method. SAR for the series has been developed by comparing their MIC values with miconazole and fluco-
nazole. Compound 11a from the series was more potent than miconazole against Candida albicans (MIC-
20) and Aspergillus flavus (MIC-10) whereas equipotent with miconazole against Fusarium oxysporum
(MIC-25) and Aspergillus niger (MIC-12.5). Also compound 11h was more potent than miconazole against
Candida albicans (MIC-20) and Aspergillus niger (MIC-10) and equipotent with miconazole against Fusar-
ium oxysporum. Compound 11h was equipotent with fluconazole against Aspergillus niger (MIC-10).
Ó 2009 Elsevier Ltd. All rights reserved.
Received 27 February 2009
Revised 13 April 2009
Accepted 29 April 2009
Available online 3 May 2009
Keywords:
1,2,3-Triazole
Piperidine
1,2,4-Oxadiazole
MIC values
SAR
1,2,3-Triazole and its derivatives have occupied a pivotal posi-
tion in medicinal chemistry in the past few decades due to their
chemotherapeutic value.1 Many 1,2,3-triazoles are found to be po-
tent antineoplastic,2 antimicrobial,3–5 analgesic,6 anti-inflamma-
tory, local anesthetic,7 anticonvulsant,8 antimalarial,9 and anti-
HIVagents,.10 Some 1,2,3-triazole derivatives were used as DNA
cleaving agents,11 and potassium channel activators.12 Very re-
cently disubstituted 1,2,3-triazole analogues have been reported
as cannabinoid CB1 receptor antagonists,13 and antitubercular
agents.14
synthesized from the commercially available starting material N-
Boc piperidone (1) as outlined in Scheme 1. N-Boc piperidone was
reduced using sodium borohydride to give N-Boc piperidinol (2).
It was subjected to O-mesylation using methane sulfonyl chloride
to give the corresponding O-mesyl derivative (3) with 95% yield.
The tert-butyl 4-azidopiperidine-1-carboxylate (4) was prepared
by nucleophilic substitution reaction using sodium azide in DMF
at 80 °C with 84% yield. It was subjected to 1,3-dipolar cycloaddi-
tion reaction using ethyl propiolate and copper iodide as a catalyst
in acetonitrile to get the compound (5) with 86% yield. The catalyst
copper iodide was used in 0.20 equiv to give the better yield. It is
interesting that use of increased quantity of copper iodide is not
affecting the reaction time and on the contrary, it gives the lower
yield (75%). The cyano compound (7) was obtained in 82% yield,
by treating ester compound (5) with liquid ammonia to yield amide
derivative (6) and subsequently dehydration using trifluoroacetic
anhydride (TFAA). The cyano compound thus prepared was treated
with hydroxylamine hydrochloride and sodium bicarbonate to give
corresponding amidoxime compound (8) with 87% yield.
Amidoxime compound (8) was subjected to cyclization as per
reported procedure in literature, using carbonyl diimidazole (CDI)
in presence of pyridine base in dioaxne solvent at 100 °C to give
tert-butyl-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-1,2,3-
triazol-1-yl)piperidine-1-carboxylate (9) as shown in Scheme 2.
Although, the reaction was completed in 50 min, unfortunately,
the yield obtained of expected compound was very low (52%). In
this reaction, formation of unknown impurities was found. To con-
trol the formation of unknown impurities, amidoxime compound
(8) was treated with CDI and tetrahydrofuran under reflux for
1,2,4-Oxadiazole and its derivatives are important pharmaco-
phore with diversified pharmacological activities like antibacterial,
analgesic and anti-inflammatory.15 Piperidine and its analogues
are reported in literature for varied pharmacological activities like
antihistaminics and antibacterial,16 AChE inhibitors,17 antitubercu-
lar agents.18 Piperidine nucleus is important core of many drug
molecules. From the literature survey it is observed that no efforts
have been made for developments of a molecular scaffold contain-
ing these three important cores. In continuation of our work on
synthesis of some pharmacologically important heterocycles,19
here we wish to report synthesis and antifungal activity of novel
series of 3-(1-(1-substituted piperidin-4-yl)-1H-1,2,3-triazol-4-
yl)-1,2,4-oxadiazol-5(4H)-one. From the activity data SAR for the
series is developed.
The amidoxime compound 8, that is, tert-butyl 4-(4-(N0hydroxy-
carbamimidoyl)-1H-1,2,3-triazol-1-piperidine-1-carboxylate was
* Corresponding author. Tel.: +91 240 2403308.
E-mail address: dbshinde.2007@rediffmail.com (D.B. Shinde).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.134

J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3564–3567
3565
OSO2CH3
OH
N3
N
O
N
c
a
b
N
N
Boc
3
Boc
Boc
2
Boc
4
1
d
OH
O
O
N
O
CN
NH2
NH2
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
e
f
g
N
Boc
Boc
Boc
Boc
7
5
6
8
Scheme 1. Reagents and conditions: (a) NaBH4, ethanol, rt, 2 h; (b) Methanesulfonyl chloride, triethylamine, dichloromethane; (c) NaN3, DMF, 80 °C, 8 h; (d) Ethyl Propiolate,
CuI, acetonitrile, rt, 12 h; (e) ammonia, ethanol, rt,12 h; (f) TFAA, dichloromethane, rt, 2 h; (g) Hydroxylamine hydrochloride, sodium bicarbonate, methanol, reflux, 14 h.
O
O
Many of the newly synthesized compounds were found to show
good antifungal activity. From the antifungal activity data (Table
1), it was observed that compound 11a and 11h are the most active
among all tested compounds against all the tested organisms ex-
cept Cryptococcus neoformans. Compound 11h is more potent than
miconazole and comparable to fluconazole as shown by the lower
MIC. Compounds 5–8 are the important intermediates in the syn-
thesis of final compounds. These compounds were also tested for
antifungal activity. Among these compounds compound 8 bearing
amidoxime groups was more active showing moderate activity.
Introduction of 1,2,4 oxadiazole ring in the skeleton (9) enhances
the antifungal activity compared to compound 8 as evidenced by
the decreased MIC. Deprotection of the Boc of nitrogen in piperi-
dine further enhances the antifungal activity against all the tested
organisms except C. neoformans. Substitution of methyl group
(11a) on nitrogen increases the antifungal activity compared with
unsubstituted nitrogen (10). Compound 11a was more potent than
miconazole against Candida albicans (MIC-20) and Aspergillus flavus
(MIC-10) whereas equipotent with miconazole against Fusarium
oxysporum (MIC-25) and Aspergillus niger (MIC-12.5). The further
increase in the alkyl chain decreases antifungal activity resulting
in enhanced MIC. Introduction of acetyl group on nitrogen reduces
the antifungal activity compared with unsubstituted piperidine
against all tested organisms. There was further decrease in anti-
fungal activity if acetyl group replaced by propionyl (11d) and bu-
tyryl (11e). Introduction of benzoyl group on nitrogen shows
marginal enhancement of activity compared with acetyl or propio-
nyl substituent. Introduction of mesyl group on nitrogen gave most
active compound of the series, that is, 11h. Compound 11h was
more potent than miconazole against Candida albicans (MIC-20)
and Aspergillus niger (MIC-10) and equipotent with miconazole
against Fusarium oxysporum. Compound 11h was equipotent with
fluconazole against and Aspergillus niger (MIC-10).
N
N
H
N
N
N
N
a
( 52% yield )
(78 % yield )
8
b
Boc
9
Scheme 2. Reagents and conditions: (a) CDI, 1,4-dioxane, 100 °C, 50 min; (b) CDI,
tetrahydrofuran, reflux, 10 h.
10 h to get target compound with 78% yield. The compound 9 was
treated with trifluoro acetic acid (TFA) in dichloromethane for Boc-
deprotection to yield corresponding amine compound (10). The
compounds 11a-11i were synthesized by treating compound 10
with alkyl halide/acyl halide/mesyl halide to give the correspond-
ing target compounds with 84–89% yield as shown in Scheme 3.
All the synthesized compounds were screened for in vitro anti-
fungal activity. The antifungal activity was evaluated against dif-
ferent fungal strains such as Candida albicans (NCIM3471),
Fusarium oxysporum (NCIM1332), Aspergillus flavus (NCIM539),
Aspergillus niger (NCIM1196) and Cryptococcus neoformans
(NCIM576). Minimum inhibitory concentration (MIC) values were
determined using standard agar plate method.20 Miconazole and
Fluconazole were used as a standard for the comparison of anti-
fungal activity. Dimethyl sulfoxide was used as solvent control.
MIC values of the tested compounds are presented in Table 1.
In conclusion, synthesis and antifungal activity of a novel series
of piperidino-1,2,3 triazoles with 1,2,4 oxadiazole ring at 4 posi-

3566
J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3564–3567
O
O
O
O
N
N
N
H
N
H
N
N
N
N
N
N
N
N
b
a
9
H
R
10
11a-11i
11b R= -CH2CH3
11a R=-CH3
11d R= -COCH2CH3
11c R=-COCH3
11e R=-COC3H7
11f R= -COC6H5
11h R= - SO2CH3
11g R=-COC6H5, 4 Cl
11i R=- SO2C6H5 CH3
Scheme 3. Reagents and conditions: (a) TFA, dichloromethane, rt, 14 h; (b) Triethylamine, R–X or RCOX, tetrahydrofuran, 0–5 °C to rt, 2 h.
Table 1
Supplementary data
Antifungal activity of the synthesized compounds
Compound
MIC Valuesa
(lg/mL)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.134.
C. albicans
F. oxysporum
A. flavus
A. niger
C. neoformans
5
6
7
8
9
10
11a
11b
11c
11d
11e
11f
11g
11h
11i
Miconazole
Fluconazole
40
50
—
44
55
90
35
25
25
25
39
61
90
95
88
55
25
33
25
5
22
27
55
20
15
15
10
19
31
42
19
25
50
20
20
15
12.5
19
31
42
—
42
25
10
20
12.5
10
35
45
—
*
*
References and notes
35
30
27.5
20
37
60
85
90
85
40
20
30
25
5
40
*
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*
No activity was observed up to 200
Values are the average of three readings.
l
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the series has been developed. From SAR it can be said that com-
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Acknowledgements
The authors are thankful to Council for Scientific and Industrial
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(MS), India for providing the laboratory facility.
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