Synthesis and antimicrobial activity of some 1,3,4-oxadiazole derivatives.

Article abstract of DOI:10.1016/S0014-827X(02)01245-4

Six new 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione, 2-amino-5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole, 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one derivatives have been synthesized from 1-and/or 2-naphthol. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The antimicrobial properties of the compounds were investigated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, Candida albicans, C. krusei and C. parapsilosis using microbroth dilution method. 2-Amino-5-(2-naphthyloxymethyl)-1,3,4-oxadiazole and 5-(2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one show significantly (32 microg/ml), compounds 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione, 2-amino-5-(1-naphthyloxymethyl)-1,3,4-oxadiazole and 5-(1-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one moderately (64 microg/ml) active against C. krusei. All the compounds were active against S. aureus, E. coli, P. aeruginosa, C. albicans, and C. parapsilosis at 64-256 microg/ml concentration.

Full text of DOI:10.1016/S0014-827X(02)01245-4

Il Farmaco 57 (2002) 539–542
www.elsevier.com/locate/farmac
Synthesis and antimicrobial activity of some 1,3,4-oxadiazole
derivatives
a
a,
b
b
8
Gu¨lay S¸ahin , Erhan Palaska *, Melike Ekizog˘lu , Meral Ozalp
a Hacettepe Uni6ersity Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06100 Ankara, Turkey
b Hacettepe Uni6ersity Faculty of Pharmacy, Department of Pharmaceutical Microbiology, 06100 Ankara, Turkey
Received 21 December 2001; accepted 16 February 2002
Abstract
Six new 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-thione, 2-amino-5-(1-/2-naphthyloxymethyl)-1,3,4-oxadiazole, 5-(1-/
2-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one derivatives have been synthesized from 1-and/or 2-naphthol. The structures of
the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The antimicrobial properties of the
compounds were investigated against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, Candida albicans, C.
krusei and C. parapsilosis using microbroth dilution method. 2-Amino-5-(2-naphthyloxymethyl)-1,3,4-oxadiazole and 5-(2-naph-
thyloxymethyl)-1,3,4-oxadiazole-2(3H)-one show significantly (32 mg/ml), compounds 5-(1-/2-naphthyloxymethyl)-1,3,4-oxadia-
zole-2(3H)-thione, 2-amino-5-(1-naphthyloxymethyl)-1,3,4-oxadiazole and 5-(1-naphthyloxymethyl)-1,3,4-oxadiazole-2(3H)-one
moderately (64 mg/ml) active against C. krusei. All the compounds were active against S. aureus, E. coli, P. aeruginosa, C. albicans,
´
and C. parapsilosis at 64–256 mg/ml concentration. © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 1,3,4-Oxadiazole-2(3H)-thione; 1,3,4-Oxadiazole-2(3H)-one; 2-Amino-1,3,4-oxadiazole; Synthesis; Antimicrobial activity
2. Experimental procedures
1. Introduction
2.1. Chemistry
1,3,4-Oxadiazole ring is associated with many types
of biological properties such as anti-inflammatory [1–
3], hypoglycemic [4], antifungal and antibacterial [5–9]
activities. On the other hand, some 5-[isoxazolo[5,4-
d]pyrimidinyloxymethyl] - 2 - substitutedphenylamino-
1,3,4-oxadiazole and -1,3,4-oxadiazole-2(3H)-thione
derivatives [9] have been reported as significantly active
antimicrobials against Staphylococcus aureus and Can-
dida albicans. Keeping the above facts in view, we
considered it of interest to synthesize some new 5-(1-/2-
naphthyloxymethyl) - 1,3,4 - oxadiazole - 2(3H) - thione
(2a–b), 2-amino-5-(1-/2-naphthyloxymethyl)-1,3,4-oxa-
diazole(3a–b),5-(1-/2-naphthyloxymethyl)-1,3,4-oxadia-
zole-2(3H)-one (4a–b) derivatives and investigate their
antimicrobial properties against S. aureus, Escherichia
coli and Pseudomonas aeruginosa, C. albicans, C. krusei
and C. parapsilosis using microbroth dilution method.
All chemicals were supplied from Aldrich, Merck and
Fluka Co. Melting points were taken in a Thomas
Hoover capillary melting point apparatus and are un-
corrected. IR spectra were recorded in Perkin Elmer
1720x FT-IR Spectrophotometer (KBr disc). H NMR
spectra were run on a Bruker AC 400 MHz FT NMR
1
Spectrometer (DMSO-d6, CDCl3, TMS).
2.1.1. 1-/2-Naphthyloxyacetylhydrazine (1a–b)
1-Naphthyloxyacetylhydrazine and 2-naphthyloxy-
acetylhydrazine were synthesized by using the method
reported earlier [1,4].
2.1.2. 5-(1-/2-Naphthyloxymethyl)-1,3,4-oxa-
diazole-2(3H)thione (2a–b)
To a 0 °C solution of hydrazide (0.65 g, 3 mmol) and
carbon disulfide (0.46 g, 6 mmol) in absolute ethanol
(20 ml), potassium hydroxide (0.2 g) was added in one
portion. The resulting mixture was stirred and refluxed
* Corresponding author
E-mail address: epalaska@hacettepe.edu.tr (E. Palaska).
´
0014-827X/02/$ - see front matter © 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S0014-827X(02)01245-4

540
G. S¸ahin et al. / Il Farmaco 57 (2002) 539–542
for 6 h. The solvent was removed in vacuo and the
residue was acidified with 2 M hydrochloric acid and
extracted with ethyl acetate (2×). Organic layers were
washed with water and dried with anhydrous sodium
sulfate. Filtration and concentration in vacuo gave a
solid which was recrystallized from suitable solvents.
nosa (ATCC 27853) by using microbroth dilution
method. The antifungal activities of compounds were
evaluated in vitro against some yeast like fungi such as
Candida albicans (ATCC 90028), C. krusei (ATCC
6258) and C. parapsilosis (ATCC 22018). Ceftazidime
and fluconazole were used as reference compounds in
antibacterial and antifungal activity studies, respec-
tively. The stock solutions of the compounds were
prepared in dimethylsulfoxide. The solutions in the test
medium furnished the required concentration ranging
from 512 to 0.5 mg/ml. The microtiter plates were
incubated at 35 °C and read visually after 24 h, but for
Candida species at 48 h. The MIC values were recorded
as the lowest concentrations of the substances that had
no visible turbidity.
2.1.3. 2-Amino-5-(1-/2-naphthyloxymethyl)-1,3,4-
oxadiazole (3a–b)
0.25 g (3 mmol) Sodium bicarbonate was dissolved in
15 ml of water and added to a solution of hydrazide (1a
or 1b) (0.65 g, 3 mmol) in 15 ml dioxane. Cyanogen
bromide (0.35 g, 3.3 mmol) was added to the resulting
mixture and stirred for 4 h at room temperature, con-
centrated, diluted with water and filtered. The residue
was recrystallized from suitable solvents.
2.1.4. 5-(1-/2-Naphthyloxymethyl)-1,3,4-oxadiazole-
2(3H)one (4a–b)
3. Results and discussion
1,1%-Carbonyldiimidazole (CDI) (0.55 g, 3.4 mmol)
was added to a solution of hydrazide (0.65 g, 3mmol)
and triethylamine (TEA) (0.3 g, 3 mmol) in tetrahydro-
furan (10 ml) at 0 °C. The mixture was stirred for 20 h
at room temperature and concentrated in vacuo. The
residue was dissolved in diethyl ether, washed with 2 M
hydrochloric acid and saturated aqueous sodium bicar-
bonate and dried over sodium sulfate. Filtration and
concentration in vacuo gave a solid which was recrys-
tallized from suitable solvents.
1-/2-Naphthyloxyacetic acid hydrazide was prepared
by esterification of 1-/2-naphthol with ethylbromoa-
cetate and anhydrous potassium carbonate in dry ace-
tone, followed by refluxing with hydrazine hydrate in
absolute ethanol [1,4]. The 1,3,4-oxadiazole-2(3H)-
thiones 2a–b were synthesized by the reaction of acid
hydrazides with carbon disulfide [2,3]. Treatment of
hydrazide with cyanogen bromide under alkaline condi-
tions gave 2-amino-1,3,4-oxadiazole derivatives 3a–b.
1,3,4-Oxadiazol-2(3H)-one derivatives 4a–b were pre-
pared by treating hydrazides with CDI in the presence
of TEA (Scheme 1).
2.2. Microbiology [10]
The structures of the compounds were elucidated by
IR, 1H-NMR and microanalyses. Formula, melting
points, yields%, spectral data and microanalyses of the
compounds are given in Table 1. All spectral data were
The compounds were tested against some Gram-posi-
tive and Gram-negative bacteria such as S. aureus
(ATCC 25923), E. coli (ATCC 25922) and P. aerugi-
Scheme 1. Synthesis of the compounds.

G. S¸ahin et al. / Il Farmaco 57 (2002) 539–542
541
Table 1
Formula, melting points, yields%, IR and 1H NMR spectral data of the compounds
naphthyloxymethyl groups were seen at 4.55–5.35 and
6.80-8.45 ppm. The NꢁH protons of 1,3,4-oxadiazole
ring (2a–b, 4a–b) were seen at about 8.95–12.60 ppm,
respectively. The amino protons of 2-amino-1,3,4-oxa-
diazole derivatives 3a–b were not seen in spectra be-
cause of deuterium exchange (Table 1). The results of
microanalyses were within 90.4% theoretical values.
The compounds were tested against some Gram (+)
and Gram (−) bacteria such as S. aureus (ATCC
25923), E. coli (ATCC 25922) and P. aeruginosa
(ATCC 27853) by using microbroth dilution method.
The antifungal activities of compounds were evaluated
in vitro against some yeast like fungi such as C. albicans
(ATCC 90028), C. krusei (ATCC 6258) and C. parap-
silosis (ATCC 22018). Compounds 3b, 4b showed si-
gnificantly (32 mg/ml) and compounds 2a, 2b, 3a, 4a
in accordance with the assumed structures. In IR spec-
tra, the disappearance of CꢀO stretching bands of the
acylthiosemicarbazides and detection of strong CꢀN
stretching band at 1660–1626 cm−1 are evidence for
ring closure of 1,3,4-oxadiazol ring. The 1,3,4-oxadia-
zol-2(3H)-thiones 2a–b and 1,3,4-oxadiazol-2(3H)-ones
4a–b showed one NꢁH stretching band at 3358–3312
cm−1 and 2-amino-1,3,4-oxadiazole derivatives 3a–b
showed two NꢁH stretching bands at 3317–3102 cm−1
,
respectively. The IR spectra of 1,3,4-oxadiazole-2(3H)-
thiones 2a–b showed NꢁH bands in the region of
3106–3030 cm−1 and CꢀS absorption bands at 1255
and 1244 cm−1 instead of SꢁH bands at around 2600–
1
2550 cm−1. In the H NMR spectra, all protons were
seen according to the expected chemical shift and inte-
gral values. Methylenic and aromatic protons of 1-/2-

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G. S¸ahin et al. / Il Farmaco 57 (2002) 539–542
Table 2
Antibacterial and antifungal activities of the compounds
Comp. (10
S. aureus
E. coli (ATCC P. aeruginosa
C. albicans
C. krusei (ATCC C. parapsilosis (ATCC
mg/kg)
(ATCC 25923) 25922)
(ATCC 27853)
(ATCC 90028)
6258)
22018)
2a
2b
3a
3b
4a
4b
64
64
256
256
128
64
128
256
128
256
256
128
256
128
128
128
128
128
2
64
64
64
64
64
32
64
64
64
32
64
32
64
64
64
64
64
32
Ceftazidime
Fluconazole
2
1–0.5
0.25
32
0.5
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anti-inflammatory activities, Arzneim. Forsch./Drug Res. 51
(2001) 478–484.
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All the compounds were active against S. aureus, E.
coli, P. aeruginosa, C. albicans, and C. parapsilosis at
64–256 mg/ml MIC values (Table 2).
[5] M.I. Husain, A. Kumar, R.C. Srivastava, Synthesis of N-(2-
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