Ultrasound-assisted, low-solvent and acid/base-free synthesis of 5-substituted 1,3,4-oxadiazole-2-thiols as potent antimicrobial and antioxidant agents

Article abstract of DOI:10.1007/s11030-020-10125-y

Abstract: One of the goals of green chemistry is to use environmentally friendly solvents or remove and reduce the volume of harmful spent solvents. In this study, a novel process for the synthesis of 5-substituted 1,3,4-oxadiazole-2-thiol derivatives was proposed via ultrasound-assisted reaction of aryl hydrazides with CS₂ (1:1 molar ratio) in some drops of DMF in the absence of basic or acidic catalysts. They were produced in good to excellent yields under easy workup and purification conditions. In order to prove the usefulness of the prepared compounds, their antioxidant, antibacterial, and antifungal potentials were screened by DPPH free radical scavenging, serial twofold microdilution and streak plate methods. Acceptable to significant inhibitory activities were observed with synthesized heterocycles. The results showed that 5-(4-fluorophenyl)-1,3,4-oxadiazole-2-thiol (3c) is an broad-spectrum antimicrobial agent. Many of them displayed remarkable antioxidant properties comparable to standard controls (ascorbic acid and α-tocopherol). Synthesized 1,3,4-oxadiazoles are also potent candidates to treat cancer, Parkinson, inflammatory, and diabetes diseases. Graphic Abstract: Eighteen 5-substituted 1,3,4-oxadiazole-2-thiol derivatives as potent antimicrobial and antioxidant agents were prepared via a new, efficient and green procedure.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s11030-020-10125-y

Molecular Diversity
https://doi.org/10.1007/s11030-020-10125-y
ORIGINAL ARTICLE
Ultrasound‑assisted, low‑solvent and acid/base‑free synthesis
of 5‑substituted 1,3,4‑oxadiazole‑2‑thiols as potent antimicrobial
and antioxidant agents
Elahe Yarmohammadi · Hamid Beyzaei1 · Reza Aryan1 · Ashraf Moradi1
1
Received: 19 May 2020 / Accepted: 4 July 2020
©
Springer Nature Switzerland AG 2020
Abstract
One of the goals of green chemistry is to use environmentally friendly solvents or remove and reduce the volume of harm-
ful spent solvents. In this study, a novel process for the synthesis of 5-substituted 1,3,4-oxadiazole-2-thiol derivatives was
proposed via ultrasound-assisted reaction of aryl hydrazides with CS (1:1 molar ratio) in some drops of DMF in the absence
2
of basic or acidic catalysts. They were produced in good to excellent yields under easy workup and puriꢀcation conditions.
In order to prove the usefulness of the prepared compounds, their antioxidant, antibacterial, and antifungal potentials were
screened by DPPH free radical scavenging, serial twofold microdilution and streak plate methods. Acceptable to signiꢀcant
inhibitory activities were observed with synthesized heterocycles. The results showed that 5-(4-ꢁuorophenyl)-1,3,4-oxa-
diazole-2-thiol (3c) is an broad-spectrum antimicrobial agent. Many of them displayed remarkable antioxidant properties
comparable to standard controls (ascorbic acid and α-tocopherol). Synthesized 1,3,4-oxadiazoles are also potent candidates
to treat cancer, Parkinson, inꢁammatory, and diabetes diseases.
Graphic Abstract
Eighteen 5-substituted 1,3,4-oxadiazole-2-thiol derivatives as potent antimicrobial and antioxidant agents were prepared via
a new, eꢂcient and green procedure.
Keywords Antibacterial · Antifungal · Antioxidant · Green synthesis · 1,3,4-Oxadiazole · Ultrasound irradiation
Introduction
New antimicrobial agents must be developed to counteract
the spread of drug-resistant bacterial and fungal strains.
Compounds containing 1,3,4-oxadiazole moiety have
recently received attention for their antiviral, anti-inꢁam-
matory, antitubercular, anticancer, antiparasitic, enzymatic
inhibition, antioxidant, antibacterial, and antifungal poten-
tials [1–9]. Raltegravir as a HIV integrase inhibitor is pre-
scribed together with other antiretroviral drugs to treat AIDS
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11030-020-10125-y) contains
supplementary material, which is available to authorized users.
*
Hamid Beyzaei
hbeyzaei@yahoo.com; hbeyzaei@uoz.ac.ir
1
Department of Chemistry, Faculty of Science, University
of Zabol, Zabol, Iran
Vol.:(0
1
123456789)
3

Molecular Diversity
diseases [10]. Fenadiazole has sedative and hypnotic eꢃects
and is useful in the treatment of insomnia and anxiety [11].
considered as green procedures due to increased reaction
rates, improved product yields and enhanced selectivity
[27]. A series of gaseous microbubbles having pressures
and temperatures up to 1000 bar and 5000 K are formed in
the liquid phase under ultrasonic irradiation. They aꢃect
physicochemical parameters, and provide the conditions
for tacking place the reactions with the high activation
energies.
Tiodazosin as a presynaptic α -adrenoceptor is used to treat
2
hypertension [12]. Zibotentan is recommended for the treat-
ment of colorectal, breast, ovarian, lung and especially pros-
tate cancers [13] (Fig. 1).
1
,3,4-Oxadiazole derivatives were synthesized in diꢃer-
ent procedures. N-acylhydrazones are eꢂcient intermedi-
ate or starting materials to synthesize nitrogen-containing
compounds [14], and usually prepared by condensation of
hydrazides with aldehydes or ketones. Intramolecular cyclo-
condensation of N-acylhydrazones is followed by oxidation
In this study, a new one-pot, ultrasound-assisted, and
acid/base-free procedure for the synthesis of 5-aryl-1,3,4-
oxadiazole-2-thiol derivatives under low-solvent condi-
tions has been proposed. In order to expand potent bio-
logically active compounds, antimicrobial and antioxidant
property of the prepared heterocycles was studied on some
important bacterial and fungal pathogens as well as DPPH.
to aꢃord 1,3,4-oxadiazoles. Oxidizing agents such as I ,
2
Fe(III)/TEMPO, and Cu(OTf) promote cleavage of C–H
2
or C–C bonds [15–18]. One-pot reaction of arylhydrazides
with styrene or phenyl acetylene in the presence of iodine
and potassium carbonate gives 2-aryl 1,3,4-oxadiazoles in
good yields [19]. 2,5-Diaryl 1,3,4-oxadiazoles were prepared
via thermal rearrangement of N-acyl tetrazoles formed from
cross-dehydrogenative coupling reaction of aryl tetrazoles
with aryl aldehydes [20]. In situ symmetrical or unsymmetri-
cal bis-hydrazides formed by reaction of hydrazine hydrate
and 2-acyl-4,5-dichloropyridazin-3-ones cyclocondensed in
polyphosphoric acid or BF ·OEt to produce 2,5-disubsti-
Materials and methods
Chemicals
All chemicals and solvents were purchased from Merck
and Sigma-Aldrich companies, and used without further
puriꢀcation. The melting points were determined with
Kruss KSP1N melting point apparatus, and are uncor-
rected. Bruker Tensor-27 FTIR spectrometer was applied
3
2
tuted 1,3,4-oxadiazoles [21]. Cyclization of the thiosemicar-
bazides using potassium iodate in water leads to 1,3,4-oxa-
diazole derivatives as potent antibacterial agents [22].
Industrial and experimental applications of sonochem-
istry have been proven in nanotechnology, biotechnology
and medicine [23, 24]. Ultrasound-assisted techniques
have been rapidly developed for a variety of chemical
processes [25]. Ultrasonic irradiation is a powerful tool
to synthesize chemical compounds especially heterocy-
cles [26]. Processes under these conditions are usually
1
13
to record the FTIR spectra of compounds. H and
C
NMR spectra were registered using a Bruker 300 MHz-
NMR spectrometer. Elemental analyses for C, H, N and
S atoms were performed on a Thermo Finnigan Flash EA
microanalyzer. Ultrasonic irradiation was supplied by
Backer vCLEAN1-L03 (40 kHz frequency and 100 W
output power).
Fig. 1 Some available marketing drugs containing 1,3,4-oxadiazole moiety
1
3

Molecular Diversity
General procedure for the synthesis
ppm; Anal. Calcd for C H FN OS: C, 48.97; H, 2.57; N,
8 5 2
of 1,3,4‑oxadiazoles 3a–r
14.28; S, 16.34. Found: C, 48.98; H, 2.55; N, 14.33; S,
6.33.
1
1
mmol of carbon disulꢀde (0.076 g) was added dropwise
to a suspension including 1 mmol of aryl hydrazides 1a–r
in DMF (5–10 drops, 0.25–0.50 ml) using a glass medicine
dropper 1 ml (1 drop=0.05 ml) subjected to an ultrasonic
5‑(3‑Bromophenyl)‑1,3,4‑oxadiazole‑2‑thiol (3d)
White powder; FTIR (KBr) ν: 3414 (NH), 3239, 2358 (SH),
bath. Hydrogen sulꢀde emission was checked by Pb(OAc) -
1624 (C=N), 1463, 1392 (C=S), 1173 (C–O), 1120 (N–N),
2
−
1 1
impregnated membrane ꢀlter as the reaction progressed.
616, 473 cm ; H NMR (300 MHz, DMSO-d ) δ: 10.73 (s,
6
Each drop of CS was added when no outꢁow of H S gas
1H, SH), 8.15 (m, 1H, H-6ʹ Ar), 7.93 (d, J=7.7 Hz, 1H, H-4ʹ
2
2
was observed. The reaction content was added to 5 g crushed
ice containing an excess of salt. The solid phase was ꢀltered
out, washed, respectively, with water (5 ml) and ethanol
Ar), 7.80 (d, J=8.0 Hz, 1H, H-2ʹ Ar), 7.50 (t, J=7.9 Hz, 1H,
13
H-5ʹ Ar) ppm; C NMR (75 MHz, DMSO-d ) δ: 122.0 (C-3ʹ
6
Ar), 127.1 (C-6ʹ Ar), 127.4 (C-4ʹ Ar), 130.7 (C-1ʹ), 131.1
(C-5ʹ Ar), 134.9 (C-2ʹ), 164.6 (C-5 oxadiazole), 184.2 (C-2
oxadiazole) ppm; Anal. Calcd for C H BrN OS: C, 37.37;
(
5 ml), and oven-dried at 60 °C to aꢃord 1,3,4-oxadiazoles
3
a–r without the need for further puriꢀcation.
8
5
2
H, 1.96; N, 10.90; S, 12.47. Found: C, 37.37; H, 1.98; N,
1
0.86; S, 12.44.
5‑Phenyl‑1,3,4‑oxadiazole‑2‑thiol (3a)
5
‑(4‑(Triꢀuoromethyl)phenyl)‑1,3,4‑oxadiazole‑2‑thiol (3e)
White powder; FTIR (KBr) ν: 3414 (NH), 3237, 2358 (SH),
622 (C=N), 1496, 1392 (C=S), 1349, 1180 (C–O), 1068
1
Cream powder; FTIR (KBr) ν: 3414 (NH), 3239, 2361 (SH),
−
1 1
(
N–N), 969, 767, 619, 474 cm ; H NMR (300 MHz,
1
4
624 (C=N), 1389 (C=S), 1165 (C–O), 1074 (N–N), 618,
DMSO-d ) δ: 14.70 (br, 1H, SH), 7.88–7.86 (m, 2H, H-2ʹ,6ʹ
6
−1 1
77 cm ; H NMR (300 MHz, DMSO-d ) δ: 9.69 (br, 1H,
1
3
6
Ph), 7.62–7.56 (m, 3H, H-3ʹ,4ʹ,5ʹ Ph) ppm; C NMR
SH), 8.91 (d, J=6.3 Hz, 2H, H-2ʹ,6ʹ Ar), 7.94 (d, J=6.3 Hz,
(
75 MHz, DMSO-d ) δ: 123.0 (C-1ʹ Ph), 126.4 (C-2ʹ,6ʹ Ph),
6
13
2
1
H, H-3ʹ,5ʹ Ar) ppm; C NMR (75 MHz, DMSO-d ) δ:
6
1
1
29.8 (C-3ʹ,5ʹ Ph), 132.6 (C-4ʹ Ph), 160.9 (C-5 oxadiazole),
58.1 (CF ), 159.0 (C-1ʹ Ar), 160.0 (C-4ʹ Ar), 161.0 (C-3ʹ,5ʹ
3
77.9 (C-2 oxadiazole) ppm; Anal. Calcd for C H N OS:
8
6
2
Ar), 162.9 (C-2ʹ,6ʹ Ar), 163.6 (C-5 oxadiazole), 168.1 (C-2
C, 53.92; H, 3.39; N, 15.72; S, 17.99. Found: C, 53.89; H,
oxadiazole) ppm; Anal. Calcd for C H F N OS: C, 43.91;
9
5
3
2
3
.41; N, 15.74; S, 17.94.
H, 2.05; N, 11.38; S, 13.02. Found: C, 43.96; H, 2.07; N,
1
1.34; S, 13.00.
5‑(4‑Chlorophenyl)‑1,3,4‑oxadiazole‑2‑thiol (3b)
5
‑(4‑Nitrophenyl)‑1,3,4‑oxadiazole‑2‑thiol (3f)
Yellow powder; FTIR (KBr) ν: 3413 (NH), 2927, 2356
(
SH), 1737, 1621 (C=N), 1459, 1402 (C=S), 1267,
Orange powder; FTIR (KBr) ν: 3415 (NH), 2924, 2856,
−
1 1
1
201 (C–O), 1125 (N–N), 908, 617, 475 cm ; H NMR
2358 (SH), 1621 (C=N), 1552 (N–O), 1461, 1392 (C=S),
−
1
(
300 MHz, DMSO-d ) δ: 9.31 (br, 1H, SH), 7.75–7.71 (m,
1347, 1120 (C–O), 1091 (N–N), 860, 776, 617, 476 cm ;
6
1
3
1
4
–
1
H, H-2ʹ,3ʹ,5ʹ,6ʹ Ar) ppm; C NMR (75 MHz, DMSO-d )
H NMR (300 MHz, DMSO-d ) δ: 10.00 (br, 1H, SH), 8.37
6
6
: 122.3 (C-1ʹ Ar), 128.1 (C-3ʹ,5ʹ Ar), 129.4 (C-2ʹ,6ʹ Ar),
(d, J = 8.0 Hz, 2H, H-3ʹ,5ʹ Ar), 8.09 (d, J = 8.0 Hz, 2H,
1
3
37.3 (C-4ʹ Ar), 160.7 (C-5 oxadiazole), 177.6 (C-2 oxa-
H-2ʹ,6ʹ Ar) ppm; C NMR (75 MHz, DMSO-d ) δ: 125.0
6
diazole) ppm; Anal. Calcd for C H ClN OS: C, 45.19; H,
(C-3ʹ,5ʹ Ar), 127.0 (C-2ʹ,6ʹ Ar), 129.5 (C-1ʹ Ar), 149.8 (C-4ʹ
Ar), 162.8 (C-5 oxadiazole), 180.0 (C-2 oxadiazole) ppm;
Anal. Calcd for C H N O S: C, 43.05; H, 2.26; N, 18.83; S,
8
5
2
2
.37; N, 13.17; S, 15.08. Found: C, 45.23; H, 2.38; N, 13.17;
S, 15.05.
8
5
3
3
1
4.36. Found: C, 43.01; H, 2.23; N, 18.88; S, 14.40.
5‑(4‑Fluorophenyl)‑1,3,4‑oxadiazole‑2‑thiol (3c)
4
‑(5‑Mercapto‑1,3,4‑oxadiazol‑2‑yl)phenol (3g)
Brown powder; FTIR (KBr) ν: 3414 (NH), 2358 (SH),
White powder; FTIR (KBr) ν: 3476 (OH), 3413 (NH), 2809,
1
4
623 (C=N), 1393 (C=S), 1163 (C–O), 1089 (N–N), 618,
2
686, 2622, 2360 (SH), 1618 (C=N), 1505, 1467, 1331
−
1 1
74 cm ; H NMR (300 MHz, DMSO-d ) δ: 10.46 (br, 1H,
6
(
C=S), 1267, 1171 (C–O), 1124 (N–N), 988, 900, 845, 762,
SH), 8.87 (d, J=7.3 Hz, 2H, H-2ʹ,6ʹ Ar), 7.32 (d, J=7.3 Hz,
−1 1
6
14, 476 cm ; H NMR (300 MHz, DMSO-d ) δ: 10.16 (br,
1
3
6
2
1
H, H-3ʹ,5ʹ Ar) ppm; C NMR (75 MHz, DMSO-d ) –:
6
1
H, SH), 9.54 (s, 1H, OH), 7.71 (d, J=6.8 Hz, 2H, H-2ʹ,6ʹ
23.5 (C-3ʹ,5ʹ Ar), 130.2 (C-2ʹ,6ʹ Ar), 137.1 (C-1ʹ Ar), 157.2
1
3
Ar), 6.81 (d, J = 6.8 Hz, 2H, H-3ʹ,5ʹ Ar) ppm; C NMR
(
C-4ʹ Ar), 162.7 (C-5 oxadiazole), 167.4 (C-2 oxadiazole)
(
75 MHz, DMSO-d ) δ: 115.3 (C-3ʹ,5ʹ Ar), 124.4 (C-1ʹ Ar),
6
1
3

Molecular Diversity
1
1
29.3 (C-2ʹ,6ʹ Ar), 160.4 (C-4ʹ Ar), 166.4 (C-5 oxadiazole),
(C-2ʹ Ar), 116.3 (C-4ʹ Ar), 118.6 (C-6ʹ Ar), 126.2 (C-1ʹ Ar),
130.9 (C-5ʹ Ar), 159.1 (C-3ʹ Ar), 161.3 (C-5 oxadiazole),
178.1 (C-2 oxadiazole) ppm; Anal. Calcd for C H N O S:
78.0 (C-2 oxadiazole) ppm; Anal. Calcd for C H N O S:
8
6
2
2
C, 49.48; H, 3.11; N, 14.42; S, 16.51. Found: C, 49.45; H,
8
6
2
2
3
.13; N, 14.46; S, 16.47.
C, 49.48; H, 3.11; N, 14.42; S, 16.51. Found: C, 49.51; H,
3
.09; N, 14.46; S, 16.50.
5‑(4‑(Dimethylamino)phenyl)‑1,3,4‑oxadiazole‑2‑thiol (3h)
5
‑(3‑Methoxyphenyl)‑1,3,4‑oxadiazole‑2‑thiol (3l)
White powder; FTIR (KBr) ν: 3417 (NH), 2359 (SH),
685, 1626 (C=N), 1466, 1393 (C=S), 1118 (C–O), 1024
1
White powder; FTIR (KBr) ν: 3414 (NH), 2929, 2358 (SH),
1743, 1622 (C=N), 1575, 1501, 1391 (C=S), 1350, 1287,
1224, 1176 (C–O), 1074 (N–N), 1035, 965, 884, 842, 788,
−
1 1
(
N–N), 614, 475 cm ; H NMR (300 MHz, DMSO-d ) δ:
6
9
.23 (br, 1H, SH), 7.95 (d, J=7.8 Hz, 2H, H-2ʹ,6ʹ Ar), 6.02
−
1 1
(
d, J=7.8 Hz, 2H, H-3ʹ,5ʹ Ar), 3.39 (s, 6H, 2×CH ) ppm;
751, 615, 472 cm ; H NMR (300 MHz, DMSO-d ) δ:
3
6
1
3
C NMR (75 MHz, DMSO-d ) δ: 41.6 (2 × CH ), 114.2
14.78 (br, 1H, SH), 7.52 (s, 1H, H-2ʹ Ar), 7.48 (m, 1H, H-5ʹ
6
3
(
C-3ʹ,5ʹ Ar), 122.7 (C-1ʹ Ar), 128.2 (C-2ʹ,6ʹ Ar), 159.8 (C-4ʹ
Ar), 7.35 (m, 1H, H-6ʹ Ar), 7.22 (m, 1H, H-4ʹ Ar), 3.85 (s,
1
3
Ar), 165.1 (C-5 oxadiazole), 177.4 (C-2 oxadiazole) ppm;
Anal. Calcd for C H N OS: C, 54.28; H, 5.01; N, 18.99; S,
3H, OCH ) ppm; C NMR (75 MHz, DMSO-d ) δ: 55.9
3
6
(OCH ), 111.0 (C-2ʹ Ar), 118.8 (C-4ʹ Ar), 118.9 (C-6ʹ Ar),
10
11
3
3
1
4.49. Found: C, 54.31; H, 5.00; N, 19.01; S, 14.50.
124.1 (C-1ʹ Ar), 131.2 (C-5ʹ Ar), 160.1 (C-3ʹ Ar), 160.7 (C-5
oxadiazole), 177.9 (C-2 oxadiazole) ppm; Anal. Calcd for
C H N O S: C, 51.91; H, 3.87; N, 13.45; S, 15.40. Found:
5‑(p‑Tolyl)‑1,3,4‑oxadiazole‑2‑thiol (3i)
9
8
2
2
C, 51.92; H, 3.88; N, 13.47; S, 15.36.
Yellow powder; FTIR (KBr) ν: 3414 (NH), 2357 (SH),
1
4
622 (C=N), 1399 (C=S), 1158 (C–O), 1082 (N–N), 618,
3‑(5‑Mercapto‑1,3,4‑oxadiazol‑2‑yl)naphthalen‑2‑ol (3m)
−
1 1
74 cm ; H NMR (300 MHz, DMSO-d ) δ: 8.31 (s, 1H,
6
SH), 7.98 (d, J=7.7 Hz, 2H, H-2ʹ,6ʹ Ar), 7.71 (d, J=7.7 Hz,
Yellow powder; FTIR (KBr) ν: 3474 (OH), 3414 (NH),
13
2
H, H-3ʹ,5ʹ Ar), 2.34 (s, 3H, CH ) ppm; C NMR (75 MHz,
3239, 2927, 2358 (SH), 1626 (C=N), 1491, 1393 (C=S),
3
−
1 1
DMSO-d ) δ: 21.3 (CH ), 118.4 (C-3ʹ,5ʹ Ar), 126.8 (C-2ʹ,6ʹ
1162 (C–O), 1092 (N–N), 874, 744, 616, 472 cm ; H
6
3
Ar), 129.9 (C-1ʹ Ar), 141.5 (C-4ʹ Ar), 160.8 (C-5 oxa-
diazole), 178.3 (C-2 oxadiazole) ppm; Anal. Calcd for
C H N OS: C, 56.23; H, 4.19; N, 14.57; S, 16.68. Found:
NMR (300 MHz, DMSO-d ) δ: 14.22 (br, 1H, SH), 11.53
6
(br, 1H, OH), 8.62–7.32 (m, 6H, H-1ʹ,4ʹ,5ʹ,6ʹ,7ʹ,8ʹ Ar) ppm;
1
3
C NMR (75 MHz, DMSO-d ) δ: 111.0 (C-1ʹ Ar), 124.3
9
8
2
6
C, 56.19; H, 4.20; N, 14.53; S, 16.70.
(C-6ʹ Ar), 126.3 (C-3ʹ Ar), 127.2 (C-8ʹ Ar), 127.4 (C-7ʹ Ar),
28.7 (C-4ʹ Ar), 128.9 (C-5ʹ Ar), 129.3 (C-4aʹ Ar), 136.5
(C-8aʹ Ar), 153.0 (C-2ʹ Ar), 162.7 (C-5 oxadiazole), 178.5
1
5‑(4‑(tert‑Butyl)phenyl)‑1,3,4‑oxadiazole‑2‑thiol (3j)
(
C-2 oxadiazole) ppm; Anal. Calcd for C H N O S: C,
12 8 2 2
Yellow powder; FTIR (KBr) ν: 3414 (NH), 2924, 2866, 2358
59.01; H, 3.30; N, 11.47; S, 13.12. Found: C, 58.98; H, 3.27;
N, 11.51; S, 13.11.
(
SH), 1714, 1622 (C=N), 1457, 1396 (C=S), 1121 (C–O),
−
1 1
1
067 (N–N), 615, 472 cm ; H NMR (300 MHz, DMSO-
d ) δ: 7.24 (s, 1H, SH), 7.74 (d, J=7.5 Hz, 2H, H-2ʹ,6ʹ Ar),
5‑(Pyridin‑4‑yl)‑1,3,4‑oxadiazole‑2‑thiol (3n)
6
7
.55 (d, J=7.5 Hz, 2H, H-3ʹ,5ʹ Ar), 1.31 (s, 9H, 3×CH )
3
1
3
ppm; C NMR (75 MHz, DMSO-d ) δ: 31.3 (C(CH ) ),
Yellow powder; FTIR (KBr) ν: 3414 (NH), 2359 (SH), 1614
6
3 3
3
5.1 (C(CH ) ), 122.2 (C-1ʹ Ar), 125.3 (C-3ʹ,5ʹ Ar), 126.4
(C=N), 1365 (C=S), 1220, 1145 (C–O), 1053 (N–N), 1008,
3
3
−
1 1
(
C-2ʹ,6ʹ Ar), 153.5 (C-4ʹ Ar), 157.8 (C-5 oxadiazole), 164.2
888, 828, 616, 551, 475 cm ; H NMR (300 MHz, DMSO-
(
C-2 oxadiazole) ppm; Anal. Calcd for C H N OS: C,
d ) δ: 14.60 (br, 1H, SH), 8.82 (d, J = 7.8 Hz, 2H, H-2ʹ,6ʹ
1
2
14
2
6
1
3
6
1.51; H, 6.02; N, 11.96; S, 13.68. Found: C, 61.47; H, 6.00;
Ar), 7.82 (d, J = 7.8 Hz, 2H, H-3ʹ,5ʹ Ar) ppm; C NMR
N, 11.99; S, 13.72.
(75 MHz, DMSO-d ) δ: 120.0 (C-3ʹ,5ʹ Ar), 130.2 (C-4ʹ Ar),
6
1
51.3 (C-2ʹ,6ʹ Ar), 159.2 (C-5 oxadiazole), 178.3 (C-2 oxa-
3‑(5‑Mercapto‑1,3,4‑oxadiazol‑2‑yl)phenol (3k)
diazole) ppm; Anal. Calcd for C H N OS: C, 46.92; H, 2.81;
7 5 3
N, 23.45; S, 17.89. Found: C, 46.94; H, 2.83; N, 23.46; S,
17.85.
Yellow powder; FTIR (KBr) ν: 3476 (OH), 3413 (NH),
358 (SH), 1623 (C=N), 1391 (C=S), 1127 (C–O), 1065
2
−
1 1
(
N–N), 620, 475 cm ; H NMR (300 MHz, DMSO-d )
5‑(Furan‑2‑yl)‑1,3,4‑oxadiazole‑2‑thiol (3o)
6
δ: 10.07 (s, 1H, SH), 8.12 (s, 1H, OH), 7.42 (m, 1H, H-6ʹ
Ar), 7.32 (m, 1H, H-5ʹ Ar), 7.25 (m, 1H, H-2ʹ Ar), 7.00 (m,
Brown powder; FTIR (KBr) ν: 3415 (NH), 2924, 2856, 2361
1
3
1
H, H-4ʹ Ar) ppm; C NMR (75 MHz, DMSO-d ) δ: 112.7
(SH), 1622 (C=N), 1553, 1463, 1412 (C=S), 1136 (C–O),
6
1
3

Molecular Diversity
−
1
1
−1
1
076 (N–N), 746, 619, 479 cm ; H NMR (300 MHz,
1169 (C–O), 1088 (N–N), 1029, 831, 781, 625, 476 cm ;
1
DMSO-d ) δ: 8.15 (br, 1H, SH), 7.29 (s, 1H, H-5ʹ Ar),
H NMR (300 MHz, DMSO-d ) δ: 14.64 (br, 1H, SH),
6
6
1
3
7
.02 (s, 1H, H-3ʹ Ar), 6.95 (s, 1H, H-4ʹ Ar) ppm; C NMR
8.23–8.20 (m, 2H, H-2ʹʹ,6ʹʹ Ph), 7.99 (s, 1H, H-4ʹ Ar), 7.83
(
75 MHz, DMSO-d ) δ: 107.5 (C-4ʹ Ar), 112.8 (C-3ʹ Ar),
(m, 1H, H-4ʹʹ Ph), 7.79–7.76 (m, 2H, H-3ʹʹ,5ʹʹ Ph) ppm;
6
1
3
1
1
39.3 (C-5ʹ Ar), 149.3 (C-2ʹ Ar), 168.6 (C-5 oxadiazole),
C NMR (75 MHz, DMSO-d ) δ: 114.0 (C-4ʹ Ar), 124.3
6
75.8 (C-2 oxadiazole) ppm; Anal. Calcd for C H N O S:
(C-4ʹʹ Ph), 128.3 (C-2ʹʹ,6ʹʹ Ph), 130.1 (C-3ʹʹ,5ʹʹ Ph), 132.0
(C-1ʹʹ Ar), 132.8 (C-5ʹ Ar), 133.6 (C-3ʹ Ar), 146.9 (C-5
oxadiazole), 150.5 (C-2 oxadiazole) ppm; Anal. Calcd for
C H N O S: C, 53.87; H, 2.88; N, 17.13; S, 13.07. Found:
6
4
2
2
C, 42.85; H, 2.40; N, 16.66; S, 19.06. Found: C, 42.90; H,
2
.37; N, 16.64; S, 19.09.
1
1
7
3
2
5
‑(5‑Chlorothiophen‑2‑yl)‑1,3,4‑oxadiazole‑2‑thiol (3p)
C, 53.91; H, 2.90; N, 17.09; S, 13.04.
Cream powder; FTIR (KBr) ν: 3415 (NH), 3232, 2927,
Biological evaluation
2
1
4
1
358 (SH), 1635 (C=N), 1549, 1493, 1421 (C=S), 1328,
284, 1144 (C–O), 1043 (N–N), 881, 805, 735, 664, 620,
Microbiological culture media, antibiotic and antifungal
drug were purchased from HiMedia and Sigma-Aldrich
companies. Gram-positive strains including Bacillus cereus
(PTCC 1665), Staphylococcus epidermidis (PTCC 1435),
Streptococcus pneumoniae (PTCC 1240), Gram-negative
strains including Acinetobacter baumannii (PTCC 1855),
Escherichia coli (PTCC 1399), Pseudomonas aeruginosa
(PTCC 1310), and fungal strains including Aspergillus
fumigatus (PTCC 5009), Candida albicans (PTCC 5027),
and Fusarium oxysporum (PTCC 5115) were obtained from
Persian Type Culture Collection. Serial twofold microdilu-
tion, streak plate and DPPH free radical-scavenging methods
were applied in antimicrobial susceptibility tests and antioxi-
dant experiments according to the previous literature [28].
−
1 1
77 cm ; H NMR (300 MHz, DMSO-d ) δ: 14.36 (br,
6
H, SH), 7.78 (m, 1H, H-3ʹ Ar), 7.25 (m, 1H, H-4ʹ Ar) ppm;
1
3
C NMR (75 MHz, DMSO-d ) δ: 124.0 (C-3ʹ Ar), 128.7
6
(
C-4ʹ Ar), 129.4 (C-5ʹ Ar), 131.8 (C-2ʹ Ar), 162.7 (C-5
oxadiazole), 168.3 (C-2 oxadiazole) ppm; Anal. Calcd for
C H ClN OS : C, 32.96; H, 1.38; N, 12.81; S, 29.32. Found:
6
3
2
2
C, 32.91; H, 1.36; N, 12.81; S, 29.35.
5‑(4‑Methyl‑1,2,3‑thiadiazol‑5‑yl)‑1,3,4‑oxadiazole‑2‑thiol
(3q)
Yellow powder; FTIR (KBr) ν: 3414 (NH), 2925, 2858,
359 (SH), 1724, 1624 (C=N), 1461, 1393 (C=S), 1157
2
−
1 1
(
C–O), 1078 (N–N), 614, 473 cm ; H NMR (300 MHz,
DMSO-d ) δ: 11.36 (br, 1H, SH), 2.93 (s, 3H, CH ) ppm;
6
3
1
3
C NMR (75 MHz, DMSO-d ) δ: 16.5 (CH ), 135.6 (C-4ʹ
Results and discussion
6
3
Ar), 157.3 (C-5ʹ Ar), 160.8 (C-5 oxadiazole), 167.8 (C-2
oxadiazole) ppm; Anal. Calcd for C H N OS : C, 29.99;
5-Aryl 1,3,4-oxadiazole-2-thiols 3a–r were synthesized
through one-pot cyclocondensation of aryl/heteroaryl
hydrazides 1a–r with carbon disulꢀde (2) under ultrasonic
irradiation (Scheme 1). Small amounts of N,N-dimeth-
ylformamide (DMF) as solvent were used to progress the
reactions.
5
4
4
2
H, 2.01; N, 27.98; S, 32.02. Found: C, 29.95; H, 1.99; N,
2
8.02; S, 32.03.
5‑(5‑Phenylisoxazol‑3‑yl)‑1,3,4‑oxadiazole‑2‑thiol (3r)
White powder; FTIR (KBr) ν: 3413 (NH), 3239, 2924,
853, 2357 (SH), 1622 (C=N), 1492, 1390 (C=S), 1238,
The progress of reaction 1 mmol of benzhydrazide
2
(1a) and 1 mmol of CS was studied in the presence of
2
Scheme 1 Ultrasound-assisted one-pot synthesis of 5-substituted 1,3,4-oxadiazole-2-thiols 3a–r
1
3

Molecular Diversity
diꢃerent solvents and additives in a temperature range. No
,3,4-oxadiazole was obtained in water, ethanol, acetoni-
Table 1 The results of reaction between aryl hydrazides and CS (1:1
2
molar ratios) under ultrasonic irradiation
1
trile, and diethyl ether solvents at room temperature up to
reꢁuxing temperatures as well as under ultrasonic irradia-
tion. Since these compounds were previously synthesized
in the presence of strong bases such as potash and ethoxide,
it was attempted to produce them using potassium acetate
as a weaker base. 1,3,4-Oxadiazole was not formed in all
above-mentioned solvents with 1, 2 or 3 mmol of potas-
sium acetate under diꢃerent conditions. Small quantities of
products were obtained when a drop of DMF was added
Product DMF
(drops)
Time (h) Yield (%) M.P. (°C)
Observed Reported
[
Ref.]
3
3
a
b
5
10
23
20
76
73
217–218 218 [30]
219–220 199–201
[
31]
3
c
10
23
90
183–184 183–184
[
32]
3d
3e
3f
5
10
5
18
23
20
72
71
77
202–204 212 [33]
211–213
to the mixture including benzhydrazide and CS in ethanol
[34]a
2
and acetonitrile under reꢁux or ultrasound. DMF is applied
as solvent, reactant, catalyst and stabilizer in the chemical
processes [29]. As a result, DMF was used as solvent and
catalyst. A small volume of solvent (5 drops) was applied
to increase the probability of eꢃective interactions between
the reactant molecules. It is predicted that DMF catalyzes
the various steps of the reaction, as illustrated in Scheme 2.
As the reaction proceeded slowly and the volatile carbon
186–187 196–197
[
35]
3
g
5
22
80
231–232 227–228
[35]
3h
3i
10
8
25
24
70
83
204–206 [36]a
167–169 172–174
[
37]
3
3
3
j
k
l
5
5
10
17
24
18
79
75
86
136–137 142 [38]
182–184 [39]a
disulꢀde evaporated during the reaction, 1 mmol of CS was
2
156–157 161–164
added dropwise at 50 °C over several hours. Excess amounts
[
35]
of CS should have been consumed if it was added in one
2
152–154 [40]a
3m
3n
8
5
25
18
85
82
portion or at temperatures above 50 °C without signiꢀcant
improvement in the reaction time and product yield. The
reaction time and product yield were improved by 30 h and
259–260 259–260
[
35]
3
o
5
5
23
24
23
22
79
93
81
92
114–116 109–110
5
9% under classic heating to 23 h and 76% under ultrasonic
[41]
irradiation. In other word, the reaction time and product
yield were improved by about 23% and 29%, respectively.
3p
3q
186–187 195–198
[42]
1
mmol of both hydrazides 3b–r and CS were also
10
137–139 144–146
2
[
43]
reacted together in DMF (5–10 drops) under ultrasonic irra-
diation to aꢃord 5-aryl 1,3,4-oxadiazoles-2-thiols 3b–r. The
results are reported in Table 1. The resulting yields show
that the reactivity of hydrazides is not the only determining
3
r
10
208–209
–
aNo melting point is available
Scheme 2 Probable mecha-
nism of the action of DMF as
catalyst for the reaction between
hydrazides and CS
2
1
3

Molecular Diversity
Table 2 Antibacterial activity
Products
Pseudomonas Escherichia
aeruginosa coli
Acinetobacter Streptococcus Staphylococ- Bacillus
of synthesized 1,3,4-oxadiazoles
baumannii
pneumoniae
cus epider-
midis
cereus
3
a–r as minimum inhibitory
concentration (MIC) and
minimum bactericidal
MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC
concentration (MBC) in μg ml−
1
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
j
k
l
m
n
8
4
8
–
–
2
8
8
4
4
2
4
–
–
1
8
4
4
128
1024 2048
2
–
–
128
–
–
256
–
–
–
–
–
–
–
–
256
–
–
–
–
–
–
4
–
2
–
–
–
–
–
–
2
–
2
–
–
–
–
–
–
512
512
512
–
512
512
512
–
–
–
512
–
–
–
–
–
–
–
–
–
512
–
–
–
–
–
–
–
2
–
–
–
–
2048 2048
512
256
256
64
–
4
–
512
256
256
128
–
4
–
2
8
4
1
4
2
1024 1024 2048 2048 256
256
–
–
1024 1024
1024 1204
–
–
–
512
512
–
–
–
–
–
–
2048 2048 2048 2048
–
4
256
4
256
128
8
128
8
–
–
–
–
–
–
–
–
–
–
–
4
–
2
–
–
–
–
–
–
–
–
32
512
–
64
512
–
3o
3p
3q
3r
2048 2048 256
256
–
4
1024 1024
–
–
–
256
64
–
4
8
–
128
64
–
–
–
–
64
–
64
–
512
8
512
4
–
–
–
–
4
Ampicillin 1024 2048 32
64
64
128
8
16
0.25
2
32
64
No signiꢀcant antibacterial eꢃect at concentration of 2048 μg ml−1
Table 3 Antifungal property of
Products
Candida albicans
Aspergillus fumigatus
Fusarium oxysporum
synthesized 1,3,4-oxadiazoles
3
a–r as MIC and minimum
MIC
MFC
MIC
MFC
MIC
MFC
fungicidal concentration (MFC)
−
1
in μg ml
3a
1024
128
128
64
2048
256
128
512
1024
1024
256
–
1024
256
128
64
2048
512
128
512
2048
1024
256
–
1024
–
8
1024
–
4
–
–
–
–
3
3
3
3
3
3
3
3
3
3
3
3
3
3
b
c
d
e
f
g
h
i
j
k
l
m
n
o
128
–
–
128
–
–
–
–
–
–
2048
–
2048
2048
–
2048
–
2048
2048
–
2048
–
–
2048
–
–
–
–
–
–
–
–
–
–
1024
2048
256
512
–
1024
2048
512
1024
–
2048
2048
256
1024
–
2048
2048
512
1024
–
512
256
128
–
512
256
128
–
3p
3q
3r
–
–
256
2048
32
256
2048
32
128
–
32
128
–
64
2048
32
2048
64
Terbinaꢀne
No signiꢀcant antifungal eꢃect at concentration of 2048 μg ml−1
1
3

Molecular Diversity
factor in the observed differences. Solubility of target
1
,3,4-oxadiazoles-2-thiols in workup stage also plays a key
role in achieving to these yields.
The chemical structure of all prepared 5-aryl 1,3,4-oxadi-
azole-2-thiols 3a–r was conꢀrmed by FTIR and NMR spec-
tra as well as elemental analysis. Stretching bands appeared
−
1
around 2358 and 1400 cm are assigned to SH and C=S
groups. It conꢀrms thiol-thione tautomerism of the synthe-
1
3
sized 1,3,4-oxadiazoles. In C NMR spectra, C=S groups
were appeared around 175 ppm as an intermediate of two
tautomers. The type and position of observed signals depend
on diꢃerences of both the chemical shift and the activation
energy between the tautomeric states [44]. The exchange
rates as determining the lifetimes of the states are aꢃected
by factors such as temperature, concentration of targets, the
water content of deuterated solvents, paramagnetic impuri-
ties in solution, the type of deuterated solvent, pH of solution
as well as presence or absence of acidic or basic impuri-
ties, homogeneity of solutions (eꢃective on shimming), the
number of dummy scans and the repetition time of each scan
[
45–47]. Broad or singlet peaks attributed to SH/NH groups
are appeared in the region 7.24–14.78 ppm.
The reaction of hydrazides with CS usually occurs in
2
alkaline media to produce 3-aroyldithiocarbazinate salts
[
48]. Bases such as KOH, K PO and N(Et) have been used
3 4 3
for this purpose [48–50]. 1,3,4-Oxadiazole salts are aꢃorded
via intramolecular ring closure of intermediate 3-aroyl-
dithiocarbazinates under classic heating conditions [39].
1
,3,4-Oxadiazole-2-thiol derivatives are obtained after acidi-
ꢀ
cation and pH regulation [39]. In this study, some 5-aryl
1
,3,4-oxadiazoles-2-thiol derivatives were synthesized via
reaction of equivalent ratio between aryl hydrazides and CS
2
in small volumes of DMF without the presence of any basic
or acidic catalyst. Of course, 1,3,4-oxadiazoles have been
prepared in high volumes of DMF and hydrazide to CS
2
molar ratio of 1:3 at 70–150 °C during the period 3–4 h
[
51, 52].
Inhibitory potential of all prepared 1,3,4-oxadiazoles was
studied against some pathogenic Gram-negative and Gram-
positive bacteria as well as fungi, as reported in Table 2.
Antibiotic ampicillin was used as positive control.
Derivative 3c including 4-fluorophenyl substituent
aꢃected all tested bacteria, it was the only eꢃective oxadia-
zole against Bacillus cereus. Among oxadiazoles 3a–r, the
growth of Acinetobacter baumannii strain was inhibited only
with derivatives 3c and 3j. No antibacterial property was
observed with oxadiazoles 3d, 3e and 3p. Blocking activ-
ity of some synthesized 2,5-disubstituted 1,3,4-oxadiazoles
was assessed on Staphylococcus epidermidis, Escherichia
coli and Staphylococcus aureus; 1,3,4-oxadiazole-2-thiols
bearing 3-pyridinyl and 2-phenylacetic acid substituents
showed the best antibacterial eꢃects [53]. Good antibacterial
properties were exhibited with unsubstituted or S-substituted
1
3

Molecular Diversity
Scheme 3 Possible radicals formed in the reaction DPPH free radical and 1,3,4-oxadiazoles 3a–l
5
-(2,4-dichloro-5-ꢁuorophenyl)-1,3,4-oxadiazole-2-thiol
Conclusion
derivatives on Staphylococcus aureus, Escherichia coli and
Klebsiella pneumonia [54].
In this research project, a novel green procedure for the
preparation of 5-substituted 1,3,4-oxadiazole-2-thiols was
proposed. They were synthesized via reaction of equivalent
1,3,4-Oxadiazoles 3a–r were screened for their antifungal
eꢃects (Table 3). Their results were compared with those
from terbinaꢀne.
molar ratios of aryl hydrazides and CS under ultrasonic
2
Derivatives 3c, 3f, 3m, 3n and 3o could inhibit the
growth of all tested fungal strains. The best fungal activates
was observed with 1,3,4-oxadiazole-2-thiol 3c. Deriva-
tive 3p did not show antifungal eꢃects. Three 5-substituted
irradiation in good to excellent yields and without need for
complex puriꢀcation. No acid or base was used as cata-
lyst or additive. The reactions occurred in some drops of
DMF. Antimicrobial and antioxidant activities of prepared
1,3,4-oxadiazoles were evaluated against bacterial and fun-
gal pathogens and DPPH. Many of them especially deriva-
tive 3c containing 4-ꢁuorophenyl substituent showed high
antimicrobial potentials. Good to signiꢀcant antioxidant
properties were observed with 1,3,4-oxadiazole-2-thiol
derivatives. Accordingly, they are potent anticancer, anti-
diabetic, anti-inꢁammatory, and anti-Alzheimer agents.
2
-(tetradecylthio)-1,3,4-oxadiazoles were synthesized and
introduced as potent anti-Aspergillus ꢀavus, -Aspergillus
niger and -Mucor sp. [55]. The MIC values in the range from
−
1
1
2
2
00 to 1000 μg ml were recorded with some synthesized
-{5-[4-(1-aza-2-(2-thienyl)vinyl)phenyl](1,3,4-oxadiazol-
-ylthio)}-N-arylacetamide derivatives against Aspergillus
niger, Candida albicans and Aspergillus clavatus [56].
There are positive linear correlations between antioxi-
dant capacity of compounds and their anti-proliferative,
anti-neurodegenerative, anti-diabetic, and anti-inꢁammatory
potentials [57–60]. Antioxidant activities of all prepared het-
erocycles were determined by DPPH free radical-scavenging
method, and compared with those of ascorbic acid (vitamin
C) as well as α-tocopherol (vitamin E). The results as IC
Funding Funding was provided by University of Zabol (Grant No.
UOZ-GR-9618-10).
Compliance with ethical standards
5
0
Conflict of interest The authors declare that they have no conꢁict of
values are shown in Table 4.
interest.
According to hydrogen atom donating potentials of
-phenyl- or 5-substituted phenyl-1,3,4-oxadiazole-2-thiols
a–l, they arranged in order 3j (4-tert-Bu)>3d (3-Br)>3 k
5
3
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