September 2011 Synthesis and Antimicrobial Activity of Some Heterocyclic 1103

2,6-Bis(substituted)-1,3,4-thiadiazolo-, Oxadiazolo-, and

Oxathiazolidino-Pyridine Derivatives from 2,6-Pyridine
Dicarboxylic Acid Dihydrazide
Said A. S. Ghozlan,a Mohammed A. Al-Omar,b Abd El-Galil E. Amr,b*
Korany A. Ali,c and Ahmed A. Abd El-Wahabc
a
Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt
b
Department of Pharmaceutical Chemistry, College Pharmacy, King Saud University,
Riyadh 11451, Saudi Arabia
c
Department of Applied Organic Chemistry, National Research Centre, Dokki, Cairo, Egypt
*E-mail: [email protected]
Received May 1, 2010
DOI 10.1002/jhet.690
Published online 27 May 2011 in Wiley Online Library (wileyonlinelibrary.com).

In this work, we report on the synthesis and preliminary biological activity screening of several heter-
ocyclic derivatives 2–15 based on N20 ,N60 -diphenylthiosemi-carbazide pyridine-2,6-dicarbohydrazide 2,
which has been obtained from the corresponding dihydrazide 1. The biological screening showed that
many of these compounds have good antimicrobial activities. The structure of the new compounds has
been established on the bases of chemical and spectroscopic evidences.

J. Heterocyclic Chem., 48, 1103 (2011).

INTRODUCTION tory [26] activities. In particular, 2,6-peptidopyridines

exhibited a general ionophoric potency [27] and were
The considerable pharmacological importance of pyri-
used for inventing novel thiocyanate-selective membrane
dine derivatives has attracted a great deal of attention.
sensors [28]. In view of these observations and in con-
On the other hand, attachment of other heterocyclic
tinuation of our previous work in heterocyclic pyridine
moieties, which are known to possess pharmacological
chemistry, we have herein synthesized of some new
activity, to pyridine ring may enhance their biological
derivatives containing pyridine moiety.
activity. In our previous work, we have reported that
certain of heterocyclic compounds exhibited antitumor
[1], antiparkinsonian [2–4], anti-microbial [5,6], and
RESULTS AND DISCUSSION
anti-inflammatory [7–10] activities. Another an interesting
group of compounds were found to exhibit pharmacologi- In this work, we report on the synthesis and prelimi-
cal properties such as analgesic [11,12] and antiarihyth- nary biological activity screening of several heterocyclic
mic [13] activities. On the other hand, some synthetic derivatives based on compound 2, which has been
thiazoles exhibit a wide range of biological activities, obtained from the corresponding hydrazide 1 according
such as antitumor, antibiotic, antibacterial, antifungal, and to the published procedure in the previous work [29].
antiinflammatory activities [14–17]. Recent studies have Treatment of compound 2 with chloroacetic acid in abso-
shown some new thiazole cand idates as antimicrobial lute ethanol afforded the corresponding derivative 3. On
and anticancer agents [18–21]. In addition, we have the other hand, when 2 treated with phenacyl bromide in
reported a newly substituted heterocyclic compounds as the presence of catalytic amount of triethylamine gave
antitumor [22–24], antimicrobial [25], and anti-inflamma- unexpected product 4 and the expected compound 5 not

V
C 2011 HeteroCorporation
1104 S. A. S. Ghozlan, M. A. Al-Omar, A. E. E. Amr, K. A. Ali, and A. A. A. El-Wahab Vol 48

Scheme 1

formed (Scheme 1). Structure of 4 was identified by ana- The dihydrazide 1 was reacted with carbon disulfide
lytical and spectral data. EI-MS spectrum of 4 showed in ethanolic potassium hydroxide with stirring at room
the molecular ion peak at m/z 531 (43%) corresponding temperature to afford the corresponding potassium salt
to the molecular formula C29H21N7O2S instead of 6, which was cyclized by refluxing with alcoholic potas-
C37H27N7O2S2 (665). As well as, a fragment ion peak at sium hydroxide for 3 h, via elimination of two molecule
160 (18%) was supported to the substituted oxadiazole of potassium hydrogen sulfide to compound 7. The same
ring. Further confirmation for the unsymmetrical structure product 7 has been obtained by carrying the reaction
4 was explained by 1H-NMR. It displayed an ABM spin under reflux with carbon disulphide in alcoholic potas-
coupling system, each one proton, for the pyridine ring sium hydroxide in one step. Treatment of the potassium
protons at d 7.90 and 7.95 ppm (dd) and 8.30 (t). Addi- salt 6 with hydrazine hydrate under reflux afforded the
tionally, only one CH proton was appeared at 6.21 along corresponding compound 8, which was also obtained by
with two singlet signals were assigned at d 8.90 and treating compound 7 with hydrazine hydrate. In addition,
10.35 ppm characteristic for two unequivalent NH pro- treatment of the potassium salt 6 with sulfuric acid under
tons. Accordingly, for the above spectral data, the struc- reflux afforded thiadiazole derivative 9 (Scheme 2).
ture 4 has been established. The compound 1 was treated with acid chloride deriv-
The reasonable suggested mechanism that explains atives, namely, benzoyl or 4-chlorobenzoyl chlorides
formation of compound 4 was illustrated in Figure 1. under stirring in dry pyridine to give the corresponding

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

September 2011 Synthesis and Antimicrobial Activity of Some Heterocyclic 2,6-Bis(substituted)- 1105
1,3,4-thiadiazolo-, Oxadiazolo-, and Oxathiazolidino-Pyridine Derivatives

Figure 1. The suggested mechanism that explains formation of compound 4.

compounds 10a,b. Also, 1 was condensed with aromatic EXPERIMENTAL

aldehydes, namely, 4-chloro- or 4-methoxy-benzaldhyde Melting points were determined on open glass capillaries
in ethanol to give the corresponding Schiff bases 11a,b. using a Electrothermal IA 9000 digital melting point apparatus
The carbohydrazide derivatives 10a,b were heated with and corrected. Elemental analyses were performed on Elemen-
sulfuric acid at 120
C to afford the corresponding oxa- tar, Vario EL, Microanalytical Unit, National Research Center,
diazolyl derivative 12a,b. Also, compounds 10a,b were Cairo Egypt and were found within 60.4% of the theoretical
treated with phosphorus pentasulphide in dry benzene to values. Infrared spectra were recorded on Carlzeise Spectro-
photometer model ‘‘UR 10’’ spectrophotometer using the KBr
afford the corresponding thiadizolylpyridine derivatives
disk technique. 1H-NMR and 13C-NMR spectra were recorded
13a,b. The reaction of the hydrazone derivative 11a on Varian Gemini 270 MHz spectrometer (DMSO-d6) and the
with mercaptoacetic acid in dry benzene, it afforded chemical shifts are given in d (ppm) downfield from tetrame-
oxothiazolidin-pyridine-dicarboxamide 14. Treatment of thylsilane (TMS) as an internal standard. The mass spectra
11a with acetic anhydride under reflux afforded oxadia- were measured using a Finnigan SSQ 7000 mass spectrometer.
zolylpyridine derivative 15 (Scheme 3). Follow-up of the reactions and checking the purity of the com-
pounds was made by TLC on silica gel-aluminum sheets
Antimicrobial activity. The newly synthesized com-
(Type 60 F254, Merck, Darmstadt, Germany).
pounds were tested for their preliminary antimicrobial N20 ,N60 -Bis(4-oxo-3-phenylthiazolidin-2-ylidene)pyridine-
activity against different microorganisms representing 2,6-dicarbohydrazide (3). A mixture of 2 (0.46g, 1 mmol)
Gram-positive bacteria (Bacillus subtilis, Bacillus aureus, and chloroacetic acid (0.19 g, 2 mmol) in 20 mL absolute
and Staphylococcus aureus), Gram-negative bacteria ethanol was refluxed for 20 h. The solvent was concentrated
(Escherichia coli), yeast (Candida albican), and fungi under reduced pressure and the residue was poured onto water,
(Aspergillus niger). The most active compounds were: 4, the separated solid was filtered off, washed with water, dried,
and crystallized from dioxane to give the title compound 3 in
6, 8, 10b, 11a, 12b, and 13b (all organisms), 3, 9, and 70% yield as red crystals, mp 306–308
C; IR (KBr): m ¼
12a (B. aureus), 5, 10a, 14, and 15 (Staph. aureus), 7 3332–3240 (NH), 1710 (C¼ ¼O), 1685 (C¼ ¼O), 1660 (C¼ ¼C)
and 11b (E. coli), 10b and 15 (C. albicans), and 9, 14, cm1; 1H-NMR (270 MHz, DMSO-d6): d ¼ 3.60 (s, 4H,
and 15 (A. niger). The results are summarized in Table 1. 2CH2), 7.25–7.75 (m, 10H, ArAH), 8.14 (d, 2H, J ¼ 8.0 Hz,

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

1106 S. A. S. Ghozlan, M. A. Al-Omar, A. E. E. Amr, K. A. Ali, and A. A. A. El-Wahab Vol 48

Scheme 2

pyrid-H), 8.51 (t, 1H, J ¼ 8.0 Hz, pyrid-H), 12.50 (bs, 2H, 126.48, 138.24, 150.88, 155.72 (5C, pyrid-C), 115.56, 116.05,
2NH, exchangeable with D2O); 13C-NMR (67.5 MHz, DMSO- 117.92, 118.16, 125.86, 127.36, 128.15, 128.96, 129.18, 133.68,
d6): d ¼ 29.82 (2CH2), 121.05, 124.01, 128.32, 134.84 (12C, 140.26, 142.90 (18C, 3Ph), 105.78, 147.05, 153.90 (3C, thiazole
2Ph), 124.32, 138.56, 148.60 (5C, pyrid-C), 147.76 (2C¼ ¼N), ring), 150.70, 151.36 (2C, oxadiazole ring), 156.84 (C¼ ¼O, am-
156.74 (2C¼ ¼O, amides), 172.45 (2C¼ ¼O, thiazole); ms: m/z ide); ms: m/z 531 (15), 440 (42), 288 (22), 220 (100), 160 (18),
545 (62), 399 (24), 320 (12), 192 (100), 60 (78); Anal. Calcd. 135 (65); Anal. Calcd. for C29H21N7O2S: C, 65.52; H, 3.98; N,
for C25H19N7O4S2: C, 55.04; H, 3.51; N, 17.97; S, 11.75. 18.44; S, 6.03. Found: C, 65.44; H, 3.92; N, 18.38; S, 5.95.
Found: C, 54.95; H, 3.45; N, 17.93; S, 11.70. Potassium salt of thiosemicarbazid derivative (6). To a
6-(5-(Phenylamino)-1,3,4-oxadiazol-2-yl)-N0 -(3,4-diphenylth- stirred solution of 1 (1.95 g, 10 mmol) in absolute ethanol 10
iazol-2(3H)-ylidene) pyridine-2-carbohydrazide (4). To a mix- mL containing potassium hydroxide (1.68 g, 30 mmol), carbon
ture of 2 (1.40 g, 3 mmol) and phenacyl bromide (0.60 g, disulfide (2.28 g, 30 mmol) was added. The reaction mixture
3 mmol) in 50 mL absolute ethanol, a catalytic amount of was stirred at room temperature for 8 h. After cooling, the
TEA was added. The reaction mixture was heated under reflux product was precipitated with dry ether, filtered off, washed
for 3 h, the obtained precipitate was filtered off, and crystal- with ether to give the corresponding potassium salt 6 in pure
lized from ethanol to give the title compound 4 in 60% yield form (86% yield) as white powder; IR (KBr): m ¼ 3350–3280
as yellow crystals; mp 298–300
C; IR (KBr): m ¼ 3334–3220 (NH), 1688 (C¼ ¼O), 1259 (C¼ ¼S) cm1; Anal. Calcd. for
(NH), 1680 (C¼ ¼O), 1665 (C¼ ¼N), 1660 (C¼ ¼C) cm1; C9H7K2N5O2S4: C, 25.52; H, 1.67; N, 16.53; S, 30.28. Found
1
H-NMR (270 MHz, DMSO-d6): d ¼ 6.21 (s, 1H, thiazole-H), C, 25.46; H, 1.62; N, 16.48; S, 30.24.
7.30–7.80 (m, 15H, ArAH), 7.90 (dd, 2H, J ¼ 8.0, 2.5 Hz, 2,6-Bis(4,5-dihydro-5-thioxo-1H-1,2,4-oxadiazole-
pyrid-H), 7.95 (t, 2H, J ¼ 8.0 Hz, pyrid-H), 8.30 (dd, 1H, J ¼ 3-yl)pyridine (7)
8.0, 2.5 Hz, pyrid-H), 8.90, 10.35 (2s, 2H, 2NH, exchangeable Method A. To a mixture of 1 (1.95 g, 10 mmol) and potas-
with D2O); 13C-NMR (67.5 MHz, DMSO-d6): d ¼ 118.38, sium hydroxide (1.68 g, 30 mmol) in absolute ethanol 100 mL,

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

September 2011 Synthesis and Antimicrobial Activity of Some Heterocyclic 2,6-Bis(substituted)- 1107
1,3,4-thiadiazolo-, Oxadiazolo-, and Oxathiazolidino-Pyridine Derivatives
Scheme 3

carbon disulfide (2.28 g, 30 mmol) was added. The reaction mix- refluxed for 4 h. The reaction mixture was diluted with water
ture was refluxed for 5 h. then diluted with water and acidified and acidified with hydrochloric acid pH  3–4. The formed
with hydrochloric acid pH  3–4. The precipitated solid was fil- solid was collected by filtration, washed with water, dried, and
tered off, washed with water, dried, and crystallized from ethanol crystallized from ethanol to give the title compound 7 in 90%
to give compound 7 in 70% yield as yellow crystals. yield as yellow crystals; mp 211–213
C; IR (KBr): m ¼ 3393
Method B. A mixture of 6 (4.23 g, 10 mmol) and potassium (NH), 1665 (C¼ ¼N), 1660 (C¼ ¼C) cm1; 1H-NMR (270 MHz,
hydroxide (1.68 g, 30 mmol) in absolute ethanol 100 mL was DMSO-d6): d ¼ 7.85–8.25 (m, 3H, pyrid-H), 10.85 (bs, 2H,

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

1108 S. A. S. Ghozlan, M. A. Al-Omar, A. E. E. Amr, K. A. Ali, and A. A. A. El-Wahab Vol 48

Table 1
Antimicrobial activities of newly synthesized compounds 2–15.

Inhibition zones (cm)

Gram-positive bacteria Gram-negative bacteria Yeast Fungi

Comp. No. B. subtilis B. aureus S. aureus E. coli C. albicans A. niger

2 1.65 1.78 1.77 0.50 – 1.50

3 1.65 1.92 1.62 0.48 – 1.45
4 1.98 1.86 1.94 0.86 0.65 1.95
5 1.62 1.60 1.96 – – 1.65
6 1.85 1.96 1.88 0.88 0.64 1.99
7 1.55 1.61 1.56 0.91 – 1.75
8 1.84 1.86 1.94 0.87 0.55 1.85
9 1.66 1.95 1.46 0.57 – 2.05
10a 1.70 1.64 1.98 0.54 – 1.46
10b 1.88 1.94 1.95 0.84 0.75 1.89
11a 1.95 1.96 1.88 0.87 0.55 1.96
11b 1.54 1.64 1.52 0.90 – 1.48
12a 1.56 1.98 1.66 0.74 – 1.54
12b 1.85 1.88 1.90 0.86 0.60 1.95
13b 1.96 1.94 1.92 0.90 0.52 1.92
14 1.66 1.72 1.95 0.67 – 2.0
15 1.71 1.66 1.94 1.56 0.86 2.04
ChloramphinicolV
R
2.0 2.10 2.0 0.95 – 2.10

2NH, exchangeable with D2O); 13C-NMR (67.5 MHz, DMSO- cm1; 1H-NMR (270 MHz, DMSO-d6): d ¼ 7.97 (d, 2H, J ¼
d6): d ¼ 125.48, 135.76, 146.90 (5C, pyrid-C), 149.36, 156.42 8.0 Hz, pyrid-H), 8.01 (t, 1H, J ¼ 8.0 Hz, pyrid-H), 12.10
(4C, oxadiazole ring); ms: m/z 279 (8), 171 (32), 122 (14), 64 (s, 2H, 2NH, exchangeable with D2O); 13C-NMR (67.5 MHz,
(100); Anal. Calcd. for C9H5N5O2S2: C, 38.70; H, 1.80; N, DMSO-d6): d ¼ 125.24, 135.48 145.75 (5C, pyrid-C), 148.85,
25.07; S, 22.96. Found C, 38.64; H, 1.75; N, 24.98; S, 22.90. 179.66 (4C, thiadiazole ring); ms: m/z 311 (45), 204 (100),
2,6-Bis(4-amino-4,5-dihydro-5-thioxo-1H-1,2,4-triazole- 144 (32), 103 (16), 75 (85); Anal. Calcd. for C9H5N5S4: C,
3-yl)pyridine (8) 34.71; H, 1.62; N, 22.49; S, 41.18. Found: C, 34.65; H, 1.58;
Method A. A solution of 6 (4.23 g, 10 mmol) in hydrazine N, 22.43; S, 41.09.
hydrate (5 mL, 70%) was refluxed for 3 h. After cooling, the white N20 ,N60 -Diaroylpyridine-2,6-dicarbohydrazides (10a) and
solid formed was filtered off, dried, and crystallized from DMF/ (10b). A mixture of 1 (1.95 g, 10 mmol) and benzoyl chloride
EtOH to afford compound 8 in 75% yield as brown crystals. or 4-chlorobenzoyl chloride (4 mmol) in dry pyridine 15 mL
Method B. A solution of 7 (2.80 g, 10 mmol) in absolute was stirred for 24 h at room temperature. The reaction mixture
ethanol 20 mL and hydrazine hydrate (5 mL, 70%) was was poured onto crushed ice, the separated solid was filtered
refluxed for 3 h. The reaction mixture was diluted with water off, washed with water, dried, and crystallized from ethanol to
and acidified with diluted hydrochloric acid pH  6. The pre- give the title compounds 10a in 98% yield as colorless powder
cipitated solid was filtered off, dried, and crystallized from and 10b in 93% yield as yellow solid.
DMF/EtOH to give compound 8 in 60% yield as brown crys- N20 ,N60 -Dibenzoylpyridine-2,6-dicarbohydrazide (10a). mp
tals; mp 240–242
C; IR (KBr): m ¼ 3399–3224 (NH2, NH), 268–270
C; IR (KBr): m ¼ 3344–3243 (NH), 1690 (C¼ ¼O),
1664 (C¼ ¼N), 1658 (C¼ ¼C), 1258 (C¼ ¼S) cm1; 1H-NMR (270 1680 (C¼ ¼O), 1660 (C¼ ¼C) cm1; 1H-NMR (270 MHz,
MHz, DMSO-d6): d ¼ 6.30 (bs, 2H, 2NH2 exchangeable with DMSO-d6): d ¼ 7.15–7.70 (m, 10H, ArAH), 8.10 (d, 2H, J ¼
D2O), 7.70 (d, 2H, J ¼ 8.0 Hz, pyrid-H), 8.10 (t, 1H, J ¼ 8.0 8.0 Hz, pyrid-H), 8.40 (t, 1H, J ¼ 8.0 Hz, pyrid-H), 10.10,
Hz, pyrid-H), 8.60 (bs, 2H, 2NH, exchangeable with D2O); 10.90 (2s, 4H, 4NH, exchangeable with D2O); 13C-NMR (67.5
13
C-NMR (67.5 MHz, DMSO-d6): d ¼ 121.68, 135.56, 153.86 MHz, DMSO-d6): d ¼ 124.52, 138.48, 148.86 (5C, pyrid-C),
(5C, pyrid-C), 154.15, 178.10 (4C, triazole ring); ms: m/z 307 126.72, 127.98, 131.78, 133.86 (12C, 2Ph), 160.68, 163.92
(9), 274 (18), 213 (12), 146 (100), 56 (76); Anal. Calcd. for (4C, 4C¼ ¼O, amides); ms: m/z 403 (100), 281 (44), 223 (22),
C9H9N9S2: C, 35.17; H, 2.95; N, 41.01; S, 20.86. Found: C, 105 (43), 77 (68); Anal. Calcd. for C21H17N5O4: C, 62.53; H,
35.08; H, 2.88; N, 40.97; S, 20.80. 4.25; N, 17.36. Found: C, 62.46; H, 4.20; N, 17.30.
2,6-Bis(4,5-dihydro-5-thioxo-1H-1,2,4-thiadiazole-3-yl)- N20 ,N60 -Bis(4-chlorobenzoyl)pyridine-2,6-dicarbohydrazide
pyridine (9). To a stirred ice-cold concentrated sulfuric acid (10b). mp 293–295
C; IR (KBr): m ¼ 3359–3289 (NH), 1700
10 mL, compound 6 (4.23, 10 mmol) was added. The reaction (C¼¼O), 1670 (C¼ ¼O), 1660 (C¼ ¼C) cm1; 1H-NMR (270
mixture was left over night and then gradually added to crush MHz, DMSO-d6): d ¼ 7.50, 7.80 (2d, J ¼ 8.4 Hz, 8H,
ice. The separated precipitate was filtered off, washed with ArAH), 7.95 (d, 2H, J ¼ 8.0 Hz, pyrid-H), 8.30 (t, 1H, J ¼
water, dried, and crystallized from ethanol to give compound 9 8.0 Hz, pyrid-H), 10.80, 11.30 (2s, 4H, 4NH, exchangeable
in 78% yield as colorless powder; mp 196–198
C; IR (KBr): m with D2O); 13C-NMR (67.5 MHz, DMSO-d6): d ¼ 124.55,
¼ 3345–3302 (NH), 1662 (C¼ ¼N), 1660 (C¼ ¼C), 1242 (C¼ ¼S) 138.36, 148.88 (5C, pyrid-C), 128.05, 128.86, 131.78, 137.24

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September 2011 Synthesis and Antimicrobial Activity of Some Heterocyclic 2,6-Bis(substituted)- 1109
1,3,4-thiadiazolo-, Oxadiazolo-, and Oxathiazolidino-Pyridine Derivatives
(12C, 2Ph), 160.55, 164.02 (4C, 4C¼ ¼O, amides); ms: m/z 471 128.55, 129.15, 133.56 (12C, 2Ph), 163.82, 165.45 (4C, oxadia-
(16), 473 (5%), 331 (100), 308 (18), 139 (7), 75 (48); Anal. zoles); ms: m/z 436 (10), 438 (3), 279 (75), 139 (100), 77 (86);
Calcd. for C21H15Cl2N5O4: C, 53.41; H, 3.20; Cl, 15.01; N, Anal. Calcd. for C21H11Cl2N5O2: C, 57.82; H, 2.54; Cl, 16.25;
14.83. Found: C, 53.36; H, 3.14; Cl, 14.88; N, 14.76. N, 16.05. Found: C, 57.75; H, 2.50; Cl, 16.18; N, 15.96.
N20 ,N60 -Bis(4-substituted-benzylidene)pyridine-2,6-dicarbo- 2,6-Bis-(5-aryl-1,3,4-thiadizol-2-y1)pyridines (13a) and
hydrazide (11a) and (11b). A mixture of 1 (1.95 g, 10 mmol) (13b). A mixture of 10a,b (8 mmol) and phosphorus pentasul-
and 4-chloro- or 4-methoxy-benzaldhyde (20 mmol) in abso- fide (1.89 g, 16 mmol) in dry benzene 50 mL was refluxed for
lute ethanol 50 mL was refluxed for 7 h. After cooling, the 7 h. The reaction mixture was filtered off while hot and then
solid precipitate was filtered off, washed with ethanol, dried, the filtrate was concentrated under reduced pressure. The sepa-
and crystallized from ethanol to give compounds 11a in 95% rated yellow solid was filtered off, dried and crystallized from
yield as yellow solid and 11b in 90% yield as red solid. dioxane to give compounds 13a in 60% yield as red powder
N20 ,N60 -Bis(4-chlorobenzylidene)pyridine-2,6-dicarbohydra- and 13b in 75% yield as yellow crystals.
zide (11a). mp 209–211
C; IR (KBr): m ¼ 3385 (NH), 1695 2,6-Bis-(5-phenyl-[1,3,4-thiadizol-2-yl)pyridine (13a). mp
(C¼¼O), 1658 (C¼ ¼N), 1655 (C¼ ¼N) cm1; 1H-NMR (270 304–306
C; IR (KBr): m ¼ 1663 (C¼ ¼N), 1658 (C¼ ¼N) cm1;
MHz, DMSO-d6): d ¼ 7.35 (s, 2H, 2CH¼ ¼N), 7.44, 7.82 (2d, 1
H-NMR (270 MHz, DMSO-d6): d ¼ 7.60–7.80 (m, 10H,
8H, J ¼ 8.5 Hz, ArAH), 7.96 (d, 2H, J ¼ 8.1 Hz, pyrid-H), ArAH), 8.14 (d, 2H, J ¼ 8.1 Hz, pyrid-H), 8.51 (t, 1H, J ¼
8.25 (t, 1H, J ¼ 8.1 Hz, pyrid-H), 11.18 (bs, 2H, 2NH, 8.1 Hz, pyrid-H); 13C-NMR (67.5 MHz, DMSO-d6): d ¼
exchangeable with D2O); 13C-NMR (67.5 MHz, DMSO-d6): ( 121.48, 138.06, 156.88 (5C, pyrid-C), 126.08, 127.14, 128.56,
¼ 124.62, 138.44, 148.94 (5C, pyrid-C), 128.15, 129.10, 133.16 (12C, 2Ph), 172.18, 174.05 (4C, thiadiazoles); ms: m/z
131.68, 137.04 (12C, 2Ph), 142.66 (2C, 2C¼ ¼N), 157.12 (2C, 397 (Mþ 2, 14), 383 (100), 326 (54); Anal. Calcd. for
2C¼ ¼O, amides); ms: m/z 440 (15), 442 (5), 321 (42), 218 C21H13N5S2: C, 63.14; H, 3.28; N, 17.53; S, 16.05. Found: C,
(100), 190 (32), 77 (56); Anal. Calcd. for C21H15Cl2N5O2: C, 63.04; H, 3.18; N, 17.46; S, 15.94.
57.29; H, 3.43; Cl, 16.10; N, 15.91. Found: C, 57.18; H, 3.34; 2,6-Bis[5-(4-chorophenyl)-1,3,4-thiadiazol-2-yl]pyridine
Cl, 16.00; N, 15.84. (13b). mp 310–312
C; IR (KBr): m ¼ 1665 (C¼ ¼N), 1660
N20 ,N60 -Bis(4-methoxybenzylidene)pyridine-2,6-dicarbohy- (C¼ ¼N) cm1; 1H-NMR (270 MHz, DMSO-d6): d ¼ 7.72, 7.84
drazide (11b). mp 203–205
C; IR (KBr): m ¼ 3370 (NH), (2d, 8H, J ¼ 8.4 Hz, ArAH), 8.16 (d, 2H, J ¼ 8.0 Hz, pyrid-
1693 (C¼ ¼O), 1664 (C¼ ¼N), 1659 (C¼ ¼N) cm1; 1H-NMR (270 H), 8.48 (t, 1H, J ¼ 8.0 Hz, pyrid-H); 13C-NMR (67.5 MHz,
MHz, DMSO-d6): d ¼ 3.30 (s, 6H, 2OCH3), 7.18 (s, 2H, DMSO-d6): d ¼ 121.50, 138.12, 156.92 (5C, pyrid-C), 128.38,
2CH¼ ¼N), 7.55, 7.65 (2d, 8H, J ¼ 8.4 Hz, ArAH), 7.80 (d, 129.10, 130.86, 133.46 (12C, 2Ph), 172.24, 174.35 (4C, thia-
2H, J ¼ 8.0 Hz, pyrid-H), 8.30 (t, 1H, J ¼ 8.0 Hz, pyrid-H), diazoles); ms: m/z 467 (Mþ 1, 100), 469 (30), 411 (65), 356
12.30 (bs, 2H, 2NH, exchangeable with D2O); 13C-NMR (67.5 (78), 279 (32); Anal. Calcd. for C21H11Cl2N5S2: C, 53.85; H,
MHz, DMSO-d6): d ¼ 55.55 (2C, OCH3), 124.58, 138.50, 2.37; Cl, 15.14; N, 14.95; S, 13.69. Found: C, 53.80; H, 2.30;
149.04 (5C, pyrid-C), 114.20, 125.74, 129.38, 163.18 (12C, Cl, 15.10; N, 14.90; S, 13.62.
2Ph), 142.72 (2C, 2C¼ ¼N), 157.18 (2C, 2C¼ ¼O, amides); ms: N20 ,N60 -Bis(2-(4-chlorophenyl)-4-oxothiazolidin-3-yl)pyri-
m/z 431 (100), 400 (75), 254 (24), 77 (38); Anal. Calcd. for dine-2,6-dicarboxamide (14). To a suspension of 11a (0.44 g,
C23H21N5O4: C, 64.03; H, 4.91; N, 16.23. Found: C, 63.88; H, 1 mmol) in dry benzene 50 mL, mercaptoacetic acid (0.84 g, 2
4.85; N, 16.16. mmol) in dry benzene 5 mL was added with stirring. The reac-
2,6-Bis-(5-aryl-1,3,4-oxadiazol-2-yl)pyridines (12a) and tion mixture was refluxed for 18 h. Then solvent was evapo-
(12b). An appropriate amount of 10a,b (1 mmol) was dis- rated under reduced pressure. The residue was triturated with
solved in concentrated sulfuric acid 5 mL and heated at 120
C boiling water and left overnight; the formed solid was filtered
for 3 h. The reaction mixture was cooled, poured onto crushed off, washed with water, dried, and crystallized from ethanol/
ice, and left for 1 h. The formed solid was filtered off, dried, dioxane to afford the brown powder of compound 14 in 75%
and crystallized from dioxane to give the title compounds 12a yield; mp 224–226
C; IR (KBr): m ¼ 3363 (NH), 1720
in 90% yield as yellow powder and 12b in 86% yield as (C¼ ¼O), 1680 (C¼ ¼O) cm1; 1H-NMR (270 MHz, DMSO-d6):
brown powder. d ¼ 3.23, 3.34 (2d, 4H, J ¼ 2.5 Hz, AB 2CH2), 5.95 (s, 2H,
2,6-Bis-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridine (12a). mp 2CH), 7.35, 7.65 (2d, 8H, J ¼ 8.5 Hz, ArAH), 8.10–8.30 (m,
274–276
C; IR (KBr): m ¼ 1665 (C¼ ¼N), 1662 (C¼ ¼N) cm1; 3H, pyrid-H), 11.20 (bs, 2H, 2NH, exchangeable with D2O);
1
H-NMR (270 MHz, DMSO-d6): d ¼ 7.36–7.72 (m, 10H, 13
C-NMR (67.5 MHz, DMSO-d6): d ¼ 124.50, 138.38, 149.70
ArAH), 8.18 (d, 2H, J ¼ 7.9 Hz, pyrid-H), 8.68 (t, 1H, J ¼ (5C, pyrid-C), 128.62, 129.85, 132.05, 136.90 (12C, 2Ph),
7.9 Hz, pyrid-H); 13C-NMR (67.5 MHz, DMSO-d6): d ¼ 35.10, 56.98, 168.36 (6C, thiazoles), 160.92 (2C, 2C¼ ¼O,
120.66, 137.98, 157.01 (5C, pyrid-C), 125.80, 126.85, 128.24, amides); ms: m/z 588 (34), 590 (11), 334 (85), 212 (100), 176
129.04 (12C, 2Ph), 163.78, 165.32 (4C, oxadiazoles); ms: m/z (54), 105 (62); Anal. Calcd. for C25H19Cl2N5O4S2: C, 51.02;
367 (12), 186 (28), 139 (100), 111 (15); Anal. Calcd. for H, 3.25; Cl, 12.05; N, 11.90; S, 10.90. Found: C, 50.95; H,
C21H13N5O2: C, 68.66; H, 3.57; N, 19.06. Found: C, 68.58; H, 3.20; Cl, 11.98; N, 11.83; S, 10.85.
3.50; N, 18.96. 2,6-Bis(4-acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4-oxa-
2,6-Bis-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-y1]pyridine diazol-2-yl)pyridine (15). A solution of 11a (0.44 g, 1 mmol)
(12b). mp 284–386
C; IR (KBr): m ¼ 1668 (C¼ ¼N), 1660 in acetic anhydride 15 mL was refluxed for 6–10 h. The sol-
(C¼¼N) cm1; 1H-NMR (270 MHz, DMSO-d6): d ¼ 7.40, 7.75 vent was removed under reduced pressure to dryness and the
(2d, 8H, J ¼ 8.5 Hz, ArAH), 8.21 (d, 2H, J ¼ 8.0 Hz, pyrid- residue was solidified with ether. The obtained solid was fil-
H), 8.75 (t, 1H, J ¼ 8.0 Hz, pyrid-H); 13C-NMR (67.5 MHz, tered off, washed with ether, dried, and crystallized from diox-
DMSO-d6): d ¼ 121.58, 138.18, 156.96 (5C, pyrid-C), 123.98, ane to give yellow crystals of compound 15 in 76% yield; mp

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

1110 S. A. S. Ghozlan, M. A. Al-Omar, A. E. E. Amr, K. A. Ali, and A. A. A. El-Wahab Vol 48

250–252
C; IR (KBr): m ¼ 1715 (C¼ ¼O), 1660 (C¼ ¼N), 1600 [4] Abd El-Latif, N. A.; Amr, A. E.; Ibrahiem, A. A. Monatsh
(C¼¼C) cm1; 1H-NMR (270 MHz, DMSO-d6): d ¼ 2.55 (s, Chem 2007, 138, 559.
6H, 2CH3), 5.10 (s, 2H, 2CH), 7.60, 7.80 (2d, 8H, J ¼ 8.5 Hz, [5] Amr, A. E. Indian J Heterocycl Chem 2000, 10, 49.
ArAH), 7.95 (d, 2H, pyrid-H), 8.30 (t, 1H, pyrid-H); 13C- [6] Amr, A. E.; Abo-Ghalia, M. H.; Abdalla, M. M. Z Natur-
NMR (67.5 MHz, DMSO-d6): d ¼ 23.08 (2C, 2CH3), 125.68, forsch 2006, 61b, 1335.
135.86, 146.78 (5C, pyrid-C), 127.92, 128.15, 132.00, 137.88 [7] Ouf, N. H.; Amr, A. E. Monatsh Chem 2008, 139, 579.
(12C, 2Ph), 74.05, 155.18 (4C, oxadiazoles), 168.16 (2C, [8] Amr, A. E.; Sabry, N. M.; Abdulla, M. M. Monatsh Chem
2C¼ ¼O, COCH3); ms: m/z 523 (Mþ 1, 22), 525 (7), 439 (43), 2007, 138, 699.
359 (100), 258 (37); Anal. Calcd. for C25H19Cl2N5O4: C, [9] Amr, A. E.; Abo-Ghalia, M. H.; Abdulla, M. M. Arch
Pharm Chem Life Sci 2007, 340, 304.
57.26; H, 3.65; Cl, 13.52; N, 13.36. Found: C, 57.20; H, 3.60;
[10] Abo-Ghalia, M. H.; Amr, A. E.; Abdulla, M. M. Z Natur-
Cl, 13.46; N, 13.30.
forsch 2003, 58b, 903.
Antimicrobial assay. The newly synthesized compounds
[11] Ouf, N. H.; Amr, A. E.; Fayed, A. A. Monatsh Chem 2008,
were tested for their preliminary antimicrobial activity against
139, 281.
different microorganisms representing Gram-positive bacteria [12] Amr, A. E. Z Naturforsch 2005, 60b, 990.
(Bacillus subtilis, Bacillus aureus, and Staphylococcus aureus), [13] Shalaby, A. F. A.; Abdulla, M. M.; Amr, A. E. Monatsh
Gram-negative bacteria (Escherichia coli), yeast (Candida Chem 2007, 138, 1019.
albican), and fungi (Aspergillus niger). [14] Kumar, Y.; Green, R.; Boryska, K. Z.; Wise, D. D.;
Agar diffusion medium. Nine compounds were screened in Wotring, L. L.; Townsend, L. B. J Med Chem 1993, 36, 3843.
vitro for their antimicrobial activity against, by agar diffusion [15] Michael, L. G.; Tachel, M. L.; Susan, L. M.; John, H. B.;
method [30]. A suspension of the organisms were added to Milton, L. B. Bioorg Med Chem 2004, 12, 1029.
sterile nutrient agar media at 45
C and the mixture was trans- [16] Robert, A. F. Clin Microbiol Rev 1983, 1, 187.
ferred to sterile Petri dishes and allowed to solidify. Holes of [17] Jung, K. Y.; Kim, S. K.; Gao, Z. G.; Ariel, S. G.; Neli, M.;
10 mm in diameter were made using a cork borer. Amounts of Denneth, A. J.; Kim, Y. C. Bioorg Med Chem 2004, 12, 613.
0.1 mL of the synthesized compounds were poured inside the [18] Bonde, C. G.; Gaikwad, N. J Bioorg Med Chem 2004,
holes. A hole filled with DMSO was also used as control. The 12, 2151.
plates were left for 1 h at room temperature as a period of pre- [19] Kucukguzel, G.; Kocatepe, A.; DeClercq, E.; Sahin, F.;
incubation diffusion to minimize the effects to variation in Gulluce, M. Eur J Med Chem 2006, 41, 353.
time between the applications of the different solutions. The [20] Vicini, P.; Geroniki, A.; Anastasia, K.; Incerti, M.; Zani, F.
plates were then incubated at 37
C for 24 h and observed for Bioorg Med Chem 2006, 14, 3859.
antibacterial activity. The diameters of zone of inhibition were [21] Zhou, X.; Shao, L.; Jin, Z.; Liu, J. B.; Dai, H.; Fang, J. X.
measured and compared with that of the standard, the values Heteroatom Chem 2007, 18, 55.
were tabulated. ChloramphinicolV (50 lg/mL) was used as [22] Abou-Ghalia, M. H.; Amr, A. E. Amino Acids 2004, 26, 283.
R

standard for antibiotic drug. The observed zone of inhibition is [23] Hammam, A. G.; Fahmy, A. F. M.; Amr, A. E.; Mohamed,
presented in Table 1. A.M. Indian J Chem 2003, 42B, 1985.
[24] Hammam, A. G.; Sharaf, M. A.; Abdel Hafez, N. A. Indian
J Chem 2001, 40B, 213.
Acknowledgments. The kind help of Dr. El-Sayed E. Mostafa,
[25] Attia, A.; Abdel-Salam, O. I.; Amr, A. E.; Stibor, I.; Bude-
Department of Microbial Chemistry, National Research Center,
sinsky, M. Egypt J Chem 2000, 43, 187.
Cairo, Egypt, for carrying out the antimicrobial screening is [26] Amr, A. E.; Abdulla, M. M. Indian J Heterocycl Chem
highly appreciated. 2002, 12, 129.
[27] Hassan, S. S. M.; Abou-Ghalia, M. H.; Amr, A. E.;
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Journal of Heterocyclic Chemistry DOI 10.1002/jhet