Synthesis and biological activity test of some new five membered heterocycles

Article abstract of DOI:10.1002/cjoc.201190017

A new series of 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,3,4-thiadiazoles were synthesized using alkylhydrazides as the starting materials, and then 1,2,4-triazoles were used to synthesize [1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles. All the compounds were evaluated for in vitro antibacterial activity and antitumor activity. A new series of five membered heterocyclic compounds were synthesized using alkylhydrazides as the starting materials. All the compounds were evaluated for in vitro antibacterial activity and antitumor activity.

Full text of DOI:10.1002/cjoc.201190017

FULL PAPER
Synthesis and Biological Activity Test of Some New Five
Membered Heterocycles
Xia, Qingchun(夏庆春)
Xu, Dongfang(许东芳)
He, Qizhuang*(何其庄)
Li, Xingyu(李兴玉)
Sun, Dazhi(孙大志)
Department of Chemistry, Shanghai Normal University, Shanghai 200234, China
A new series of 1,3,4-oxadiazoles, 1,2,4-triazoles, 1,3,4-thiadiazoles were synthesized using alkylhydrazides as
the starting materials, and then 1,2,4-triazoles were used to synthesize [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles. All
the compounds were evaluated for in vitro antibacterial activity and antitumor activity.
Keywords cyclization, heterocycles, thiadiazole, oxadiazole, triazolam, biological activity
Introduction
triazoles, 1,3,4-thiadiazines, [1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazoles were synthesized using alkylhydrazides
according to Scheme 1. In addition, all the synthesized
compounds were tested for in vitro antimicrobial activ-
ity and antitumour activity.
In recent years, many compounds consisting of five
member heterocyclic rings such as triazoles, oxadia-
zoles and thiadiazoles have been found to possess many
unique properties in synthesis and pharmacology.1 It has
been reported that derivatives of 1,2,4-triazole2 and
1,3,4-thiadiazole3 condensed nucleus systems exert di-
verse pharmacological activities such as anti-inflam-
matory,4 antitumor,5 antifungal6 and antibacterial.7 It is
mentioned that 1,3,4-thiadiazoles exhibit various bio-
logical activities possibly due to the presence of the
＝N—C—S moiety.8 It is also well known that the
N-bridged heterocycles derived from 1,2,4-triazoles find
applications in the field of medicine,9 agriculture10 and
industry.11 The triazolothiadiazole systems may be
viewed as a cyclic analogue of two very important
components, thiosemicarbazide and biguanide,12 which
often display diverse pharmacological properties. Espe-
cially, 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles substi-
tuted in the 3 and 6 positions by aryl, alkyl or hetero-
cyclic moiety have displayed unique properties both in
chemical synthesis and in chemical biology,13 as they
possess broad-spectrum biological activities such as
Experimental
Elemental analyses were performed on Elementar
VarioEL III elemental analyzer. IR spectra were re-
corded on an American Mattson Company’s PK-60000
－1
FT-IR spectrometer (in KBr pellets, 4000—400 cm ).
1H NMR spectra were obtained on Varian VXR 400
MHz NMR-spectrometer (DMSO-d6). Melting points
were determined by WRS-1AB.
RPMI 1640 and tetrazolium salt 3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
were purchased from Sigma; fetal calf serum (FCS) was
purchased from GiBCo, No. 1165723; sodium dodecyl-
sulfate (SDS) was purchased from Sino-American Bio-
technology. All other chemicals were AR or BR, used
as purchased.
Staphylococcus aureus (S. aureus, 8099) and Es-
cherichia coli (E. coli, ATCC6358P) were provided by
Shanghai Drug Institute, the Chinese Academy of Sci-
ences; cell strain: Human leukemia K562 cells were
obtained from Cell Bank of Chinese Academy of Sci-
ences (Shanghai, China).
antibacterial,14
antifungal,15
antitumour,16
anti-inflammatory,17 herbicidal,18 pesticidal19 and insec-
ticidal properties.20
Acylhydrazides and their derivatives have been, in
general, used as the starting materials for the synthesis
of 1,3,4-oxadiazoles,21 1,3,4-thiadiazoles,22 and 1,2,4-
triazoles.23 Furthermore, heterocyclic hydrazines are
generally utilized as intermediates for the synthesis of
several condensed systems containing triazoles and
other ring systems.
Synthesis
Ethylchloroacetate was synthesized according to the
literature.24
1-H-benzimidazole acid hydrazide, 1-H-benzotria-
zole acid hydrazide, 1-H-8-hydroxyquinoline acid hy-
In view of these findings, 1,3,4-oxadiazoles, 1,2,4-
*
E-mail: hqz@shnu.edu.cn; Tel.: 0086-021-64322513
Received January 11, 2010; revised June 4, 2010; accepted June 24, 2010.
Project supported by the National Natrural Science Foundation of China (No. 20671063), Key Laboratory of Resource Chemistry of Ministry of
Education, Shanghai Leading Academic Discipline Project (No. S30406), Shanghai Key Laboratory of Rare Earth Functional Materials (No.
07dz22303), and Key Subject of Shanghai Normal University (No. DZL711).
Chin. J. Chem. 2010, 28, 2433— 2440
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2433

Xia et al.
FULL PAPER
drazide were synthesized as follow: benzimidazole,
benzotriazole, 8-hydroxyquinoline separately reacted
with ethylchloroacetate in the acetone solution with the
catalyst of PEG-400 and anhyd. K2CO3, then reacted
with hydrazine hydrate in absolute ethanol.25
2a: yield 74%, m.p. 77—79 ℃; 1H NMR (DMSO-d6,
400 MHz) δ: 6.63 (d, J＝12.0 Hz, 1H, ArH), 7.24—7.57
(m, 5H, ArH), －8.14—8.16 (m, 2H, ArH); IR (KBr) ν:
＋
1
3142, 1593 cm ; MS m/z: 213 (M＋H ). Anal. calcd
for C12H8O2N2: C 67.92, H 3.80, N 13.20; found C
67.68, H 3.98, N 13.33.
2b: yield 78%, m.p. 85—87 ℃; 1H NMR (DMSO-d6,
400 MHz) δ: 6.69 (d, J＝11.6 Hz, 1H, ArH), 7.74 (d,
2H, ArH), 8.16 (d, J＝8.8 Hz, 2H, ArH－), 8.56—8.57 (m,
Synthesis of 5-aryl-1,3,4-oxadiazole-2-thiol (1a—1e)
Acid hydrazide (0.003 mol) was dissolved in a solu-
tion of potassium hydroxide (0.006 mol) in ethanol (20
mL). Carbon disulfide (12 mL) was then added while
stirring and the reaction mixture was heated under re-
flux for 8 h. The solvents were removed under reduced
pressure, the residue was treated with water and then
filtered. The filtrate was cooled, neutralized to pH 6
using dilute hydrochloric acid and the separated product
was filtered, washed with water, dried and crystallized.
1a: yield 68%, m.p. 212 — 214 ℃ ; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.23—7.47 (m, 5H, ArH),
14.46 (s, 1H, SH); IR (KBr) ν: 3055, 2348, 1786, 1593
cm － 1; MS m/z: 179 (M ＋ H ＋ ). Anal. calcd for
C8H6ON2S: C 53.92, H 3.39, N 15.72; found C 53.81, H
3.47, N 15.72.
1
2H, ArH); IR (KBr) ν: 3174, 1638 cm ; MS m/z: 214
(M＋H＋). Anal. calcd for C11H7O2N3: C 61.97, H 3.31,
N 19.71; found C 62.03, H 3.40, N 20.02.
2c: yield 56%, m.p. 101 — 103 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.57 (s, 2H, CH2), 6.67 (d, J＝
12.0 Hz, 1H, ArH), 7.19—7.73 (m, 4H, ArH), 8.19—
8.21 (m, 2H, Ar－H), 8.23 (s, 1H, ArH); IR＋(KBr) ν: 3147,
1
2921, 1603 cm ; MS m/z: 267 (M＋H ). Anal. calcd
for C14H10O2N4: C 63.15, H 3.79, N 21.04; found C
63.24, H 3.89, N 21.14.
2d: yield 61%, m.p. 117 — 119 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.23 (s, 2H, CH2), 6.59 (d, J＝
13.2 Hz, 1H, ArH), 7.39—8.03 (m, 4H, ArH), 8.18－—
1b: yield 73%, m.p. 232 — 234 ℃ ; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.79 (d, J＝8.0 Hz, 2H, ArH),
8.79 (d, J＝6.8 Hz, 2H, ArH), 14.89－(s, 1H, SH); IR
1
8.19 (m, 2H, ArH); IR (KBr) ν: 3150, 2885, 1593 cm ;
MS m/z: 268 (M＋H＋). Anal. calcd for C13H9O2N5: C
58.43, H 3.39, N 27.21; found C 58.66, H 3.52, N 27.23.
2e: yield 64%, m.p. 121 — 122 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.36 (s, 2H, CH2), 6.69 (d, J＝
12.0 Hz, 1H, ArH), 7.39—7.59 (m, 4H, ArH), 8.13－—
1
(KBr) ν: 3093, 2362, 1833, 1607 cm ; MS m/z: 180
(M＋H＋). Anal. calcd for C7H5ON3S: C 46.92, H 2.81,
N 23.45; found C 46.63, H 2.59, N 23.66.
1c: yield 81%, m.p. 178 — 181 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.98 (s, 2H, CH2), 7.16—7.64
(m, 4H, ArH), 8.21 (s, 1H, ArH), 14.37 (s, 1H, SH); IR
1
8.82 (m, 4H, ArH); IR (KBr) ν: 3142, 2907, 1609 cm ;
MS m/z: 294 (M＋H＋). Anal. calcd for C16H11O3N3: C
65.53, H 3.78, N 14.33; found C 65.32, H 3.80, N 14.54.
3a: yield 58%, m.p. 165 — 168 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.21—7.94 (m, 15H, ArH),
9.03 (s, 1H, ArH); IR (KBr) ν: 3050, 1583, 763, 684
cm － 1; MS m/z: 365 (M ＋ H ＋ ). Anal. calcd for
C23H16ON4: C 75.81, H 4.43, N 15.38; found C 75.61, H
4.57, N 15.27.
－1
(KBr) ν: 31＋02, 2891, 2461, 1970, 1605 cm ; MS m/z:
233 (M＋H ). Anal. calcd for C10H8ON4S: C 51.71, H
3.47, N 24.12; found C 52.01, H 3.68, N 24.33.
1d: yield 71%, m.p. 195 — 197 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.23 (s, 2H, CH2), 7.40—8.04
(m, 4H, ArH), 14.05 (s, 1H, SH); IR (KBr) ν: 3050,
＋
－1
3b: .yield 59%, m.p. 185 — 188 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.37—7.54 (m, 10H, ArH),
7.82 (d, J＝8.2 Hz, 2H, ArH), 7.97 (d, J＝8.0 Hz, 2H,
ArH), 9.－06 (s, 1H, ArH); IR (KBr)＋ν: 3069, 1605, 755,
2913, 2369, 2003, 1597 cm ; MS m/z: 234 (M＋H ).
Anal. calcd for C9H7ON5S: C 46.34, H 3.02, N 30.03;
found C 46.55, H 2.99, N 30.18.
1e: yield 88%, m.p. 224 — 226 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.35 (s, 2H, CH2), 7.38—8.84
(m, 6H, ArH), 14.36 (s, 1H, SH); IR (KBr) ν: 3073,
1
688 cm ; MS m/z: 366 (M＋H ). Anal. calcd for
C22H15ON5: C 72.32, H 4.14, N 19.17; found C 72.47, H
4.15, N 19.26.
＋
－1
2900, 2461, 1992, 1602 cm ; MS m/z: 260 (M＋H ).
Anal. calcd for C12H9O2N3S: C 55.59, H 3.50, N 16.21;
found C 55.34, H 3.61, N 15.99.
3c: yield 64%, m.p. 201 — 204 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.83 (s, 2H, CH2), 7.13—7.69
(m, 14H, ArH), 8.17 (s, 1H, ArH), 9.02 (s, 1H, ArH); IR
Synthesis of 1,5-diaryl-1,3,4-oxadiazole (2a—2e, 3a—
－1
(KBr) ν: 3062, 2847, 1595, 749, 694 cm ; MS m/z: 419
3e)
(M＋H＋). Anal. calcd for C25H18ON6: C 71.67, H 4.34,
A mixture of the hydrazide (1 mmol) and furoic acid
or 1,3-diphenyl-4-pyrazolic acid (1 mmol) in phospho-
rus oxychloride (5 mL) was refluxed for 2 h. The sol-
vent was removed under reduced pressure to remove the
excess of phosphorous oxychloride, and the solid resi-
due formed was poured into ice-water and neutralized
with ammonia solution. The precipitated solid was fil-
tered off, washed with water, and crystallized from
ethanol.
N 20.07; found C 71.77, H 4.50, N 20.19.
3d: yield 66%, m.p. 209 — 210 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.29 (s, 2H, CH2), 7.22—7.84
(m, 14H, ArH), 9.06 (s, 1－H, ArH); IR (KBr) ν: 3050,
＋
1
2904, 1607, 751, 686 cm ; MS m/z: 420 (M＋H ).
Anal. calcd for C24H17ON7: C 68.72, H 4.09, N 23.38;
found C 68.59, H 3.98, N 23.41.
3e: yield 69%, m.p. 173 — 175 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.35 (s, 2H, CH2), 7.20—8.89
2434
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 2433— 2440

Synthesis and Biological Activity Test of Some New Five Membered Heterocycles
(m, 16H, ArH), 9.03 (s, 1－H, ArH); IR (KBr) ν: 3067,
50.07, H 4.30, N 29.31.
＋
1
2916, 1602, 743, 678 cm ; MS m/z: 446 (M＋H ).
Anal. calcd for C27H19O2N5: C 72.80, H 4.30, N 15.72;
found C 72.67, H 4.21, N 15.92.
5b: yield 88%, m.p. 224 — 226 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.85 (s, 2H, NH), 8.01 (d, J＝
11.2 Hz, 2H, ArH), 8.78 (d, J＝8.4 Hz, 2H, ArH), 14.－16
1
(s, 1H, NH); IR (KBr) ν: 3282, 3166, 1607, 937 cm ;
MS m/z: 194 (M＋H＋). Anal. calcd for C7H7N5S: C
43.51, H 3.65, N 36.24; found C 43.67, H 3.47, N 36.38.
5c: yield 81%, m.p. 215 — 217 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.58 (s, 2H, CH2), 5.66 (s, 2H,
NH), 7.20—7.66 (m, 2H, ArH), 8.27 (s, 1H, ArH),
13.67 (s, 1H, NH); IR (KBr) ν: 3251, 3154, 2855, 1583,
Synthesis of 5-aryl-1,3,4-thiadiazole-2-thiol (4a—4e)
To a mixture of potassium hydroxide (2 mmol) and
hydrazide (1 mmol) in absolute ethanol (5 ml), carbon
disulfide (4 mmol) was added and sonicated for 12 h.
The separated solid was filtered and dried.
The potassium dithiocarbazinate (1 mmol) was
added gradually with stirring to ice cold concentrated
sulphuric acid (10 mL) and the reaction mixture was
further stirred for 4 h in an ice bath. It was then poured
over crushed ice and solid thus separated was filtered,
washed with water and recrystallized from DMF-H2O.
4a: yield 63%, m.p. 155 — 157 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.50—7.94 (m, 5H, ArH); IR
－1
＋
946 cm ; MS m/z: 247 (M＋H ). Anal. calcd for
C10H10N6S: C 48.77, H 4.09, N 34.12; found C 48.36, H
3.89, N 34.21.
5d: yield 83%, m.p. 222 — 224 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.26 (s, 2H, CH2), 6.05 (s, 2H,
NH), 7.39—8.06 (m, 4H, ArH), 13.85 (s, 1H, NH); IR
－1
(KBr) ν: 3290, 3184, 2922, 1632, 956 cm ; MS m/z:
＋
－1
248 (M＋H＋). Anal. calcd for C9H9N7S: C 43.71, H
(KBr) ν: 3296, 1059 cm ; MS m/z: 195 (M＋H ). Anal.
calcd for C8H5N2S2: C 49.46, H 3.11, N 14.42; found C
49.59, H 3.19, N 14.52.
3.67, N 39.65; found C 43.55, H 3.73, N 39.54.
5e: yield 80%, m.p. 243 — 244 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.34 (s, 2H, CH2), 5.75 (s, 2H,
NH), 7.39—7.60 (m, 4H, ArH), 8.32—8.85 (m, 2H,
ArH), 13.84 (s,－1H, NH); IR (KBr) ν: 3294, 3172, 2843,
4b: yield 89%, m.p. 184 — 188 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 8.01 (d, J＝8.2 Hz, 2H, ArH),
8.8－0 (d, J＝8.0 Hz, 2H, ArH); IR (KBr) ν: 3349, 1071
＋
1
＋
1
cm ; MS m/z: 196 (M＋H ). Anal. calcd for C7H6N3S2:
C 43.06, H 2.58, N 21.52; found C 43.29, H 2.76, N
21.47.
1601, 1108 cm ; MS m/z: 274 (M＋H ). Anal. calcd
for C12H11ON5S: C 52.73, H 4.06, N 25.63; found C
52.89, H 3.89, N 25.53.
4c: yield 57%, m.p. 177 — 179 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.87 (s, 2H, CH2), 7.15—7.63
(m, 4H, ArH), －8.23 (s, 1H, ArH); IR (＋KBr) ν: 3332,
Synthesis of 3,6-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thia-
diazoles (6a—6e, 7a—7e)
1
Equimolar proportions of 5a—5e (2 mmol) and
furoic acid or 1,3-diphenyl-4-pyrazolic acid (2 mmol),
were dissolved in 10 mL of dry phosphorous oxychlo-
ride and the resulting solution was refluxed for 10 h.
The solvent was removed under reduced pressure to
remove the excess of phosphorous oxychloride, and the
solid residue formed was poured into ice-water and
neutralized with ammonia solution. The reaction mix-
ture was stood overnight. The solid product was col-
lected by filtration, washed thoroughly with cold water,
dried and recrystallized from aqueous DMF.
2906, 1082 cm ; MS m/z: 249 (M＋H ). Anal. calcd
for C10H8N4S2: C 48.37, H 3.25, N 22.56; found C 48.57,
H 3.41, N 22.72.
4d: yield 62%, m.p. 185 — 188 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.25 (s, 2H, CH2), 7.38—7.99
－1
(m, 4H, ArH); IR (KBr) ν: 3338, 2896, 1037 cm ; MS
m/z: 250 (M＋H＋). Anal. calcd for C9H7N5S2: C 43.36,
H 2.83, N 28.09; found C 43.27, H 2.98, N 23.14.
4e: yield 74%, m.p. 233 — 234 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.34 (s, 2H, CH2), 7.39—7.59
(m, 4H, ArH), 8.35—8.87 (m, 2H, ArH); IR ＋(KBr) ν:
6a: yield 67%, m.p. 192 — 194 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 6.84 (d, J＝11.8 Hz, 1H, ArH),
7.53—7.63 (m, 5H, ArH), 8.25－(d, J＝16.0 Hz, 2H,
－1
3347, 2896, 1056 cm ; MS m/z: 276 (M＋H ). Anal.
calcd for C12H9ON3S2: C 52.34, H 3.29, N 15.26; found
C 52.60, H 3.53, N 15.33.
1
ArH); IR (KBr) ν: 3147, 1598 cm ; MS m/z: 269 (M＋
H＋). Anal. calcd for C13H8ON4S: C 58.20, H 3.01, N
20.88; found C 58.41, H 3.00, N 20.53.
Synthesis of 3-aryl-4-amino-1,2,4-triazoline-5-thiol
(5a—5e)
6b: yield 68%, m.p. 188 — 189 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 6.86 (d, J＝13.8 Hz, 1H, ArH),
8.01 (d, J＝6.4 Hz, 2H, ArH), 8.18—8.20 (m, 2H, ArH),
8.78 (d, J＝7.2 Hz, 2H, ArH); IR＋(KBr) ν: 3130, 1595
cm － 1; MS m/z: 270 (M ＋ H ). Anal. calcd for
C12H7ON5S: C 53.52, H 2.62, N 26.01; found C 53.77,
H 2.77, N 26.17.
To a solution of potassium dithiocarbazinate (1
mmol) in 6 mL of water, hydrazine hydrate (2 mmol)
was added and refluxed for 8—9 h. The contents of the
flask were cooled, diluted with water and acidified with
acetic acid. The separated solid was filtered, dried and
recrystallized.
5a: yield 78%, m.p. 232 — 234 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.79 (s, 2H, NH), 7.46—7.95
(m, 5H, ArH), 13.94 (s, 1H, NH); IR (KBr)＋ν: 3279,
6c: yield 61%, m.p. 207 — 209 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.53 (s, 2H, CH2), 6.87 (d, J＝
13.8 Hz, 1H, ArH), 7.21—7.71 (m, 4H, ArH), 8.14—
8.15 (m, 2H, ArH), 8.29 (s, 1H, ArH); IR (KBr) ν: 3169,
－1
3157, 1608, 949 cm ; MS m/z: 193 (M＋H ). Anal.
calcd for C8H8N4S: C 49.98, H 4.19, N 29.14; found C
Chin. J. Chem. 2010, 28, 2433— 2440
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Xia et al.
FULL PAPER
＋
－1
2916, 1603 cm ; MS m/z: 323 (M＋H ). Anal. calcd
for C15H10ON6S: C 55.89, H 3.13, N 26.07; found C
55.73, H 3.22, N 25.87.
(M＋H＋). Anal. calcd for C10H10O2N4S: C 47.99, H
4.03, N 22.39; found C 47.65, H 4.18, N 22.46.
8b: yield 88%, m.p. 98—99 ℃; 1H NMR (DMSO-d6,
400 MHz) δ: 4.00 (s, 2H, CH2), 6.18 (s, 2H, NH), 8.23
(d, J＝8.0 Hz, 2H, ArH), 8.79 (d, J＝8.2 Hz, 2H, ArH),
12.89 (s,－1H, COOH); IR (KBr) ν: 3294, 3172, 2868,
6d: yield 70%, m.p. 177 — 178 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.29 (s, 2H, CH2), 6.91 (d, 1H,
ArH), 7.36—8.07 (m, 4H, ArH), 8.10－—8.12 (m, 2H,
＋
1
1
ArH); I＋R (KBr) ν: 3173, 2899, 1592 cm ; MS m/z: 324
1729 cm ; MS m/z: 252 (M＋H ). Anal. calcd for
C9H9O2N5S: C 43.02, H 3.61, N 27.87; found C 43.14,
H 3.42, N 27.62.
(M＋H ). Anal. calcd for C14H9ON7S: C 52.01, H 2.81,
N 30.32; found C 52.22, H 2.99, N 30.14.
6e: yield 63%, m.p. 165 — 167 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.38 (s, 2H, CH2), 6.79 (d, J＝
12.4 Hz, 1H, ArH), 7.39—7.60 (m, 4H, ArH), 8.16－—
8c: yield 83%, m.p. 104 — 106 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 3.98 (s, 2H, CH2), 5.53 (s, 2H,
CH2), 6.24 (s, 2H, NH), 7.21—7.71 (m, 4H, ArH), 8.29
(s, 1H, ArH), 12.83 (s, 1H, －COOH); IR (KBr) ν: 3239,
1
8.85 (m, 4H, ArH); I＋R (KBr) ν: 3161, 2913, 1600 cm ;
＋
1
MS m/z: 350 (M＋H ). Anal. calcd for C17H11O2N5S: C
58.44, H 3.17, N 20.05; found C 58.56, H 3.11, N 19.78.
7a: yield 76%, m.p.＞250 ℃; IR (KBr) ν: 3100,
3143, 2989, 2874, 1748 cm ; MS m/z: 305 (M＋H ).
Anal. calcd for C12H12O2N6S: C 47.36, H 3.97, N 27.62;
found C 47.39, H 4.01, N 27.83.
－1
1593, 747, 696 cm ; 1H NMR (DMSO-d6, 400 MHz) δ:
8d: yield 82%, m.p. 82—84 ℃; 1H NMR (DMSO-d6,
400 MHz) δ: 3.83 (s, 2H, CH2), 5.30 (s, 2H, CH2), 6.19
(s, 2H, NH), 7.34—8.15 (m, 4H, ArH), 13.49 (s, 1H,
7.18—7.82 (m, 15H, ArH), 8. 83 (s, 1H, ArH); MS m/z:
421 (M＋H＋). Anal. calcd for C24H16N6S: C 68.55, H
3.84, N 19.94; found C 68.41, H 3.78, N 19.72.
－1
COOH); IR (KBr) ν: 3349, 3282, 2977, 1732 cm ; MS
7b: yield 72%, m.p. 247 — 249 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.18—7.69 (m, 10H, ArH),
8.04 (d, J＝8.8 Hz, 2H, ArH), 8.79 (d, J＝7.6 Hz, 2H,
ArH), 8.－85 (s, 1H, ArH); IR (KBr)＋ν: 3182, 1600, 731,
m/z: 306 (M＋H＋). Anal. calcd for C11H11O2N7S: C
43.27, H 3.63, N 32.11; found C 43.50, H 3.69, N 32.27.
8e: yield 85%, m.p. 111 — 113 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 4.03 (s, 2H, CH2), 5.29 (s, 2H),
6.07 (s, 2H, NH), 7.19—7.48 (m, 4H, ArH), 8.29—8.80
(m, 2H, ArH), 12.83 (－s, 1H, COOH); IR (KBr)＋ν: 3428,
1
694 cm ; MS m/z: 422 (M＋H ). Anal. calcd for
C23H15N7S: C 65.54, H 3.59, N 23.26; found C 65.71, H
3.65, N 23.14.
1
3312, 2916, 1732 cm ; MS m/z: 332 (M＋H ). Anal.
7c: yield 69%, m.p. 243 — 245 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.55 (s, 2H, CH2), 7.21—7.80
(m, 14H, ArH), 8.28 (s, 1H, ArH), 8.79 (s, 1H, ArH); IR
calcd for C14H13O3N5S: C 50.75, H 3.95, N 21.14; found
C 50.44, H 4.11, N 21.32.
－1
Synthesis of 3-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadi-
(KBr) ν: 3129, 2904, 1603, 759, 684 cm ; MS m/z: 475
azole-6-thiols (9a—9e)
(M＋H＋). Anal. calcd for C26H18N8S: C 65.81, H 3.82,
Carbon disulfide (10 cm3) was added to a mixture of
5a—5e (10 mmol) in ethanolic KOH solution (0.56 g,
10 mmol of KOH in 30 cm3 EtOH). The reaction mix-
ture was heated under reflux for 6 h, most of the solvent
was then distilled off under reduced pressure, and the
residue was dissolved after being cooled in 10% KOH
solution and filtered. The cold filtrate was acidified with
conc. HCl and the separated solid was filtered off,
washed with water and recrystallized.
N 23.61; found C 65.89, H 3.88, N 23.82.
1
7d: yield 68%, m.p.＞250 ℃; H NMR (DMSO-d6,
400 MHz) δ: 5.26 (s, 2H, CH2), 7.17—7.63 (m, 14H,
ArH), 8.69 (s, 1H, ArH); IR (KBr) ν:＋3150, 2917, 1596,
－1
749, 695 cm ; MS m/z: 476 (M＋H ). Anal. calcd for
C25H17N9S: C 63.14, H 3.60, N 26.51; found C 63.51, H
3.69, N 26.46.
7e: yield 73%, m.p. 212 — 214 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.40 (s, 2H, CH2), 7.23—8.79
(m,－17H, ArH); IR (KBr) ν: 3147,＋2896, 1598, 742, 681
cm 1; MS m/z: 502 (M ＋ H ). Anal. calcd for
C28H19ON7S: C 67.06, H 3.82, N 19.55; found C 67.22,
H 3.55, N 19.44.
9a: yield 71%, m.p. 240 — 242 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 7.27—7.69 (m, 5H, ArH),
12.－26 (s, 1H, NH); IR (KBr) ν: 3395, 3148, 1597, 1004
＋
1
cm ; MS m/z: 335 (M＋H ). Anal. calcd for C9H6N4S2:
C 46.14, H 2.58, N 23.91; found C 46.36, H 2.91, N
23.81.
Synthesis of (4-amino-3-aryl-1,2,4-triazol-5-ylthio)-
9b: yield 78%, m.p. 229 — 231 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 8.64 (d, J＝8.4 Hz, 2H, ArH),
8.97 (d, J＝7.8 Hz, 2H, ArH), 12.78－(s, 1H, NH); IR
acetic acid (8a—8e)
Equimolar proportions of 5a—5e (2 mmol) and
chloroactic acid (2 mmol) were dissolved in 50 mL po-
tassium hydroxide aqueous solution. The reaction mix-
ture which was slightly acidic by adding HCl was re-
fluxed for 4 h. The solid product was collected by filtra-
tion, washed with water and recrystallized.
1
(KBr) ν: 3434, 3178, 1601, 1010 cm ; MS m/z: 336
(M＋H＋). Anal. calcd for C8H5N5S2: C 40.84, H 2.14, N
29.76; found C 40.61, H 2.66, N 29.56.
1
9c: yield 73%, m.p.＞250 ℃; H NMR (DMSO-d6,
8a: yield 90%, m.p. 137 — 139 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 4.01 (s, 2H, CH2), 6.16 (s, 2H,
NH), 7.53—7.63 (m, 5H, ArH), 13.03 (s, 1H, COOH);
400 MHz) δ: 5.49 (s, 2H, CH2), 7.23—7.83 (m, 4H,
ArH), 8.35 (s, 1H, ArH), 12.76 (s－, 1H, NH); IR (KBr) ν:
1
3383, 3157, 2903, 1603, 989 cm ; MS m/z: 289 (M＋
－1
IR (KBr) ν: 3343, 3270, 2935, 1711 cm ; MS m/z: 251
H＋). Anal. calcd for C11H8N6S2: C 45.82, H 2.80, N
2436
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 2433— 2440

Synthesis and Biological Activity Test of Some New Five Membered Heterocycles
29.15; found C 45.71, H 3.11, N 29.33.
The interaction of alkylhydrazides with carbon di-
9d: yield 68%, m.p. 213 — 215 ℃; 1H NMR
(DMSO-d6, 400 MHz) δ: 5.23 (s, 2H, CH2), 7.44—8.11
(m, 4H, ArH), 12.23 (s, 1H, NH); IR (KBr) ν: 3416,
sulfide in ethanol solution in the presence of potassium
hydroxide led to potassium hydrazinecarbodithionates.
The potassium hydrazinecarbodithionates was dissolved
in water and then neutralized to pH 6 using dilute hy-
drochloric acid, 5-aryl-1,3,4-oxadiazole-2-thiol (1a—1e)
were obtained. The compounds, 2-aryl-5-fural-1,3,4-
oxadiazole (2a—2e) and 2-aryl-5-(1,3-diphenyl-4-
pyrazoly)-1,3,4-oxadiazole (3a—3e) were obtained by
the reaction of alkylhydrazides with furoic acid and
1,3-diphenyl-4-pyrazolic acid in the presence of phos-
phorus oxychloride respectively. The treatment of po-
tassium hydrazinecarbodithionates with concentrated
H2SO4 resulted in an intramolecular cyclization leading
to the formation of the 1,3,4-thiadiazole ring, thus,
compounds 4a—4e were obtained. The 3-aryl-4-amino-
1,2,4-triazoline-5-thiol (5a—5e) which were obtained
by refluxing of potassium hydrazinecarbodithionates
with hydrazine hydrate in water medium, were used as
precursors to synthesize 3-aryl-6-fural-1,2,4-triazolo-
[3,4-b]-1,3,4-thiadiazoles (6a—6e) and 3-aryl-6-(1,3-
diphenyl-4-pyrazoly)-1,2,4-triazolo[3,4-b]-1,3,4-thia-
diazoles (7a—7e) with furoic acid and 1,3-diphenyl-
4-pyrazolic acid in the presence of phosphorus oxychlo-
ride respectively, as well as for the preparation of
3-aryl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole-6-thiols
(9a—9e) with carbon disulfide in ethanol solution in the
presence of potassium hydroxide. 4-Amino-3-aryl-
1,2,4-triazol-5-ylthio-acetic acid (8a — 8e) were ob-
tained by the reaction of 3-aryl-4-amino-1,2,4-tria-
zoline-5-thiol (5a—5e) with chloroactic acid in potas-
sium hydroxide aqueous solution.
－1
＋
3288, 2928, 1601, 968 cm ; MS m/z: 290 (M＋H ).
Anal. calcd for C10H7N7S2: C 41.51, H 2.44, N 33.89;
found C 41.59, H 2.53, N 33.45.
1
9e: yield 80%, m.p.＞250 ℃; H NMR (DMSO-d6,
400 MHz) δ: 5.35 (s, 2H, CH2), 7.28—7.57 (m, 4H,
ArH), 8.34—8.79 (m, 2H, ArH), 12.85 (s, 1H, NH); IR
－1
(KBr) ν: 3428, 2825, 1632, 1053 cm ; MS m/z: 316
(M＋H＋). Anal. calcd for C13H9ON5S2: C 49.51, H 2.88,
N 22.21; found C 49.81, H 2.67, N 22.45.
Pharmacology
The antimicrobial activities of the new compounds
were determined by paper disc diffusion and nutrition
broth dilution. The MTT method was used to confirm
all the compounds’ antitumour activities on Leukemia
K562 cells and confocal fluorescence microscopy was
used for morphological observation of apoptosis.26-28
Results and discussion
Chemistry
The product of cyclization depends on the reagent
used. This cyclization leads to the formation of 1,3,4-
oxadiazole, 1,3,4-thiadiazole, 1,2,4-triazole and 1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazoles derivatives according
to Scheme 1. The purity of the synthesized compounds
was checked by elemental analyses. The structures of
the various synthesized compounds were determined on
the basis of spectral analysis of IR and 1H NMR.
Scheme 1 Synthesis of the new five membered heterocyclic compounds
Chin. J. Chem. 2010, 28, 2433— 2440
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2437

Xia et al.
FULL PAPER
and the minimum inhibitory concentrations (MICs) of
these compounds were less than 800 µg/mL. Especially
for 9e which had strong effects against Gram-positive
bacteria, the area of growth inhibition can be as large as
19 mm and the minimum inhibitory concentrations
(MICs) can reach 300 µg/mL. So, in drug discovery,
these compounds have potential utility as antibacterial
agents.
The IR spectra of the cyclize－d products showed ab-
sorption band at 3270—3290 cm 1 due to the NH func-
tional group and the weak absorption band around 2580
－1
cm due to the SH group. An absorption band observed
for all the synthesized compounds in the range of
－ 1
3060 — 3090 cm
may be attributed to aromatic
stretching vibration, while that seen at 1610—1614
－1
cm corresponds to C＝N linkage. C＝S absorption
－1
1
bands could be seen at 960—1200 cm . The H NMR
spectra of all the compounds showed the aromatic pro-
tons in the ranges δ 6.92—9.50 and the compounds
1a—1e showed a singlet at δ 14.89 which was ac-
counted for SH, but 4a—4e and 9a—9e showed no
singlet in this range. Spectra of all compounds c—e also
showed a singlet at δ 5.00—5.60 which were accounted
Antitumour activity
Using an MTT-based growth inhibition assay, the
IC50 values for compounds 1a—9e against a range of
leukemia K562 cells were determined; the cytotoxicity
results reveal that some of the compounds tested had
good activity against leukemia K562 cells, the results
were listed in Table 2. However, some compounds can
promote cells growth, the results were also listed in Ta-
ble 3.
1
for CH2. The singlets at δ 5.60—6.10 in the H NMR
spectra of 5a—5f were attributed to NH2, which were
almost at the same location in the compounds 8a—8e.
Moreover the spectra of the compounds 8a—8e showed
CH2 at δ 4.00—4.10.
The 96-well plates containing experimental and con-
trol K562 tumor cells were analyzed using an inverter
light microscope after 48 h culture. In the control group,
the cells not treated with a compound were of normal
shape and size (about 25 µm; Figure 1). －With the con-
Antibacterial activity
The assessments of the antimicrobial activities of the
synthesized compounds were performed using pa-
per-disc diffusion and nutrition broth dilution methods.
Growth inhibition areas against Staphylococcus aureus
and Escherichia coli were assessed for all compounds.
The results revealed that some of the compounds tested
had good antibacterial activity against S. aureus but
poor activity against Escherichia coli. Most of the
newly synthesized compounds exhibited poor antibacte-
rial activities against Gram-negative bacteria and
Gram-positive bacteria, but some compounds which
were listed in Table 1 had strong effects against
Gram-positive bacteria: the area of growth inhibition
can be as large as 20 mm, the smallest is almost 13 mm,
1
centrations of compound 4d (1 µg•mL ) almost all
cells were killed, whereas at lower concentrations (0.1
－1
µg•mL ), fewer cells died; however, no normal cells
were detected because all cells were small and deformed.
These results are in agreement with the characteristics
of apoptosis. Figure 2 shows acridine-orange-stained
leukemia K562 cells that were pretreated with com-
pound 4d (0.1 µg/mL) for 48 h. The results indicate that
the compound induced apoptosis of the K562 cells,
which was seen as nuclear condensation and/or frag-
mentation. Some apoptotic cells could be seen to have
two nuclei, or nuclear fragments, and single apoptotic
bodies could also be seen.
Table 1 Antibacterial in vitro activity expressed as diameter of growth inhibition area and MICa
－
1
Diameter/mm
No.
MIC/(µg•mL )
Escherichia coli
Staphylococcus aureus
Escherichia coli Staphylococcus aureus
2e
3a
3d
4c
4d
5e
6a
6c
6d
6e
7e
9b
9e
No
No
No
No
No
No
No
No
No
No
No
No
No
13
13
15
13
13
15
14
13
14
15
14
15
19
＞
＞
＞
＞
＞
＞
＞
＞
＞
＞
＞
＞
＞
800
800
800
800
800
800
800
800
800
800
800
800
800
650
600
650
650
650
450
500
700
650
600
650
500
300
a The concentration of all the compounds were 0.005 mol/L.
2438
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 2433— 2440

Synthesis and Biological Activity Test of Some New Five Membered Heterocycles
Table 2 Inhibiting percentage of K562 tumor cell’s growth cycle detected by MTT reduction assay
Control
－
1
Concentration/(µg•mL )
0.1
0.5
1
5
10
25
50
75
100
Black
2b
2e
0
0
0
0
0
0
0
0
0
0.158
0.334
0.414
0.303
0.069
0.035
0.218
0.223
0.094
0.091
0.031
0.428
0.437
0.262
0.204
0.486
0.361
0.264
0.549
0.642
0.118
0.508
0.221
0.102
0.003
0.063
0.374
0.274
0.292
0.167
0.333
0.321
0.252
0.366
0.089
0.101
0.341
0.200
0.199
0.021
0.043
0.111
0.346
0.317
0.044
0.425
0.242
0.520
0.342
0.283
0.044
0.477
0.310
0.196
0.063
0.145
0.412
0.257
0.426
0.031
0.439
0.249
0.397
0.435
0.089
0.036
0.646
0.303
0.325
0.004
0.154
0.425
0.222
0.365
0.221
0.175
0.282
0.097
0.423
0.098
0.171
0.116
0.327
0.374
0.150
0.119
0.109
0.169
0.356
0.474
0.149
0.129
0.112
0.517
0.080
0.159
0.133
0.214
0.427
0.161
0.220
0.096
0.091
0.421
0.686
0.136
0.100
0.153
0.560
0.105
0.470
0.049
0.312
0.503
0.201
0.430
0.107
0.263
0.414
0.621
0.093
0.296
0.127
0.544
0.118
0.446
0.071
0.235
0.587
0.347
0.521
0.106
0.402
0.566
0.657
3b
4d
5c
5e
6b
6d
7b
7c
－
－
7d
8b
9a
9b
9e
Table 3 Promotion percentage of K562 tumor cell’s growth cycle detected by MTT reduction assay
Control
－
1
Concentration/(µg•mL )
0.1
0.5
1
5
10
25
50
75
100
Black
0
0
0
0
0
0
0
0
0
1b
2a
3a
4a
4e
6a
－
－
0.088
0.020
0.006
0.004
0.087
0.205
－
－
－
0.169
0.044
0.064
0.001
0.003
0.135
0.176
0.072
0.061
0.182
0.026
0.066
－
－
－
－
－
－
0.160
0.038
0.013
0.175
0.294
0.202
－
0.181
0.008
0.091
0.343
0.118
0.073
0.158
0.100
0.020
0.114
0.037
0.051
0.093
0.091
0.044
0.012
0.060
0.034
0.139
0.200
0.072
0.058
0.027
0.128
0.102
0.219
0.038
0.108
0.078
0.068
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
－
Figure 1 Influence of 4d on K562 tumor cell’s growth. (A) Normal cells; (B) The cells treated with compound.
1,2,4-triazoles rings (5a—5e, 8a—8e), 1,3,4-thiadia-
zoles rings (4a—4e) and [1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazoles using alkylhydrazides as precursors, and all
Conclusion
We have synthesized some five menbered heterocy-
cles, 1,3,4-oxadiazoles rings (1a—1e, 2a—2e, 3a—3e),
Chin. J. Chem. 2010, 28, 2433— 2440
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2439

Xia et al.
FULL PAPER
Figure 2 Acridine orange stained K562 cells pretreated with 4d. (A) Normal cells; (B) Apoptotic cells.
the synthesized compounds were tested for in vitro an-
timicrobial and antitumor activities. The antimicrobial
activity was assessed using a paper disc diffusion
method and nutrition broth dilution method, and the
results indicate that compounds have strong effects
against Gram-positive bacteria and are potential new
therapeutic agents. The antitumor activity was assessed
using the MTT method and morphological observation
of apoptosis. The results show that some compounds
had strong effects on human K562 cells, so these com-
pounds have potential therapeutic use against leukemia
K562 cells and other cancer cells. However, some
compounds had no effects on them, and even can pro-
mote cell growth. The mechanisms that underlie these
observations are currently under investigation.
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