N- and S-α-l-Arabinopyranosyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles. First synthesis and biological evaluation

Article abstract of DOI:10.1016/j.ejmech.2007.01.025

First synthesis of N- and S-α-l-arabinopyranosyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles is described. Antimicrobial screening of two selected regioisomeric compounds against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida

Full text of DOI:10.1016/j.ejmech.2007.01.025

European Journal of Medicinal Chemistry 42 (2007) 1193e1199
http://www.elsevier.com/locate/ejmech
Original article
N- and S-a-L-Arabinopyranosyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles.
First synthesis and biological evaluation
*
Nasser S.A.M. Khalil
Regional Center for Food and Feed (RCFF), Agricultural Research Center, 9El Gamaa Street, Giza, Egypt
Received 6 November 2006; received in revised form 21 January 2007; accepted 25 January 2007
Available online 21 February 2007
Abstract
First synthesis of N- and S-a-L-arabinopyranosyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles is described. Antimicrobial screening of two se-
lected regioisomeric compounds against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylo-
coccus aureus, Pseudomonas aeruginosa, Bacillus subtilis and Escherichia coli are compared.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Synthesis; Arabinosidation; 1,2,4-Triazoles; 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole-3-thiones; Antimicrobial activity
1. Introduction
HIV-1 and HBV [25,26] viruses. Biochemically, some L-nucle-
osides are substrates for cellular kinases [27,28] and have
greater stability for catabolizing enzymes such as cytidine
and adenosine deaminase [29], thereby providing higher anti
HIV and anti HBV activities [20].
Many 1,2,4-triazoles [30e49], their ribosides [50e53], and
glucosides [54,55] have been reported to possess antibacterial,
antifungal, antiviral, anti-inflammatory, anticonvulsant, antide-
pressant, antitubercular, antihypertensive, analgesic, hypogly-
cemic, herbicidal and sedative properties.
1,3,4-Thiadiazoles exhibit broad spectrum of biological
activities, possibly due to the presence of toxophoric NeCe
S moiety [56]. They find applications as antibacterials, antitu-
mor, anti-inflammatory agents, pesticides, herbicides, dyes,
lubricants and analytical reagents [57]. The 1,2,4-triazolo
[3,4-b][1,3,4]-thiadiazole derivatives obtained by fusing the bi-
olabile 1,2,4-triazole and 1,3,4-thiadiazole rings together, are
reported to possess antibacterial, antifungal, anti-inflammatory,
CNS depressant, hypocholesteremic, antiviral, analgesic, an-
thelmintic, herbicidal and plant growth regulatory effects [58].
Recently, we reported a simple base induced regioselective
method for the a-arabinopyranosylation of different b-lactams
[59], 1,2,4-triazoles [60] and 1,2,4-triazines [61] which
resulted in the synthesis of many antimicrobial [59,60] and
antitumor [61] a-nucleosides.
Nucleoside analogs act as antitumor and antiviral agents
[1e14] via inhibition of the enzymes, viz. DNA and RNA
polymerases, thymidylate synthetase, adenosine deaminase,
adenosine kinase, SAH hydrolase etc. of nucleoside, nucleo-
tide or nucleic acid metabolism of the tumor cells or
pathogens.
Arabinosides are known to act as good selective antiviral
agents [15] and are probably the most extensively investigated
inhibitors of DNA polymerase [16,17]. Though it has been dif-
ficult to assign a mechanism for their action, these inhibitors
may be said to be rather poor substrates for DNA polymerases,
often leading to chain termination during replication. The
best-known inhibitor belonging to the arabinoside series is
Ara-A or Vidarabin [16e19]. It is an important antiviral and
antitumor agent but its activity is restricted by its deamination
caused by the enzyme adenosine deaminase [2e5]. Several b-
L-nucleosides [20e23] have been synthesized and found to be
more active and less toxic than their D-isomers [23,24] against
* Tel.: þ2 02 8520490/þ2 02 5731989/þ2 02 5732280; Mob. þ2
0106571765; fax: þ2 02 5732280.
E-mail address: nasserkhalil_23@hotmail.com
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.01.025

1194
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 42 (2007) 1193e1199
To date therehas not been a single report of reactions that pro-
The S-a-L-configuration of compounds 4aed and the N-a-
L-configuration of compounds 5aed are supported based on
spectroscopic evidences. Thus, the appearance of the anomeric
protons of compounds 5aed at d 6.17e6.19 more downfield
than those for the S-pyranosides 4aed which appear at
d 5.64e5.67, consistent with similar reported data for N-
[54,55,59e65,67e69] and S-glycosides [54,55], confirms the
N-structure of compounds 5aed and the S-structure com-
pounds 4aed. Such downfield shifts in N-pyranosyl deriva-
tives is readily explained by the anisotropic deshielding by
the C]S (similar downfield shifts of the anomeric proton by
an adjacent C]S was reported for pyrimidine [70e72] and
1,2,4-triazole nucleosides [54,55]). The coupling constant
values of the anomeric proton of compounds 4aed and 5ae
d consistent with similar reported data [54,55,59e65,67e70]
proves that the anomeric proton is in a trans position with re-
spect to the proton in position 2 of the L-arabinopyranosyl
ring, a fact that assigns their a-configuration.
duce the a-nucleosides of the 1,2,4-triazolo[3,4-b][1,3,4]thia-
diazole ring system. Thus, in this article and in continuation of
our ongoing program [54,55,59e68] of research on the synthe-
sis of some biologically active compounds, we report here the
first synthesis, antifungal and antibacterial activities of some
novel unusual N- and S-a-L-arabinopyranosyl[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazoles.
2. Results and discussion
2.1. Chemistry
The starting 6-aryl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadia-
zole-3-thiones (2aed) [68] were prepared from 4-amino-4H-
[1,2,4]triazole-3,5-dithiol (1) by its cyclization with the
appropriate carboxylic acid or acid chloride in refluxing
phosphoryl chloride (Scheme 1). Arabinosidation of com-
pounds 2aed with 1.1 mol equiv of 2,3,4-tri-O-acetyl-b-L-ara-
binopyranosyl bromide (3) gave a chromatographically
separable mixture (39e55% overall yield) of two products
namely, 3-(2,3,4-tri-O-acetyl-a-L-arabinopyranosylthio)-6-aryl
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (4aed) and 2-(2,3,4-tri-
O-acetyl-a-L-arabinopyranosyl)-6-aryl-2H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazole-3-thiones (5aed).
Compounds 4aed were alternatively synthesized in excellent
yields (85e90%) via arabinosidation of 4-amino-4H-[1,2,4]
triazole-3,5-dithiol (1) to give 5-(2,3,4-tri-O-acetyl-a-L-arabino-
pyranosylthio)-4-amino-2,4-dihydro[1,2,4]triazole-3-thione (6)
asthe sole product followed byits ringclosure using the appropri-
ate aromatic acid or acid chloride in the presence of phosphoryl
chloride.
Deacetylation of compound 5a proceeded smoothly via
methanolic ammonia treatment to afford the free nucleoside
8. On the other hand, deacetylation of compound 4a gave
a mixture of the corresponding free nucleoside 7 and 6-phe-
nyl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione (2a).
O
OAc
O
OAc
H
N
1
Br
OAc
OAc
OAc
OAc
The H NMR data of the compounds 7 and 8 revealed the
N
O
OAc
absence of the acetyl protons at d 1.95e2.22 and the appear-
ance of the D2O exchangeable OH protons at d 4.21e5.16.
The IR data of compound 8 as a typical example showed
S
S
N
N
N
/ DMF / TEA
S
S
OAc
OAc
N
S
N
S
3
N
N
N
+
R
N
N
2a-d
R
R
4a-d
5a-d
Table 1
Antimicrobial activity as inhibition zones of compounds 4c and 5c compared
to standard antimicrobial agents
RCOOH / POCl3
or RCOCl / POCl3
MeOH/NH3
RCOOH / POCl3
or RCOCl / POCl3
Test organisms
4ca
5ca
St.b
Concentration (mg/mL)
O
OH
Br
O
OAc
O
OAc
1
2.5
5
1
2.5
5
1
2.5
5
OH
OH
/ DMF / TEA
OAc
OAc
N
N
OAc
OAc
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum
þ
0
þ
þ
þ
þ
þ
þ
0
0
0
0
0
0
0
þþ
þþ
þþþ þþþ
þþþ þþþ
3
HS
SH
N
þ
0
S
N
N
S
N
S
HN
S
0
þþþ þþþ þþþ
NH
1
2
N
N
N
racemosum
NH2
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
0
0
0
0
0
0
0
0
0
0
0
0
0
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
6
R
þ
þ
þ
0
þ
þ
þ
þ
þ
þ
þ
þ
þ
0
O
OH
8
(R=C6H5)
þþþ þþþ
þþþ þþþ
0
OH
OH
MeOH/NH3
Escherichia coli
þ
þþ
þþ
4a
2, 4, 5
R
N
S
a
C6H5
Note: The test was done using the diffusion agar technique. Inhibition val-
ues ¼ 0.1e0.5 cm beyond control ¼ þ; inhibition values ¼ 0.6e1.0 cm be-
yond control ¼ þþ; inhibition values ¼ 1.0e1.5 cm beyond control ¼ þþþ;
0 ¼ not detected.
N
S
b
c
d
4-NH2C6H4
4-ClC6H4
4-NO2C6H4
+
2a
N
N
R
a
Hundered microlitres of each conc. was tested (5, 2.5, and 1.0 mg/mL);
(R=C6H5)
7
well diameter ¼ 0.6 cm.
b
Scheme 1. Synthesis of N- and S-a-L-arabinosides of 6-aryl[1,2,4]triazolo
[3,4,b][1,3,4]thiadiazoles.
St. ¼ Reference standard; Chloramphenicol was used as a standard anti-
bacterial agent and Terbinafin was used as a standard antifungal agent.

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 42 (2007) 1193e1199
1195
Table 2
Minimum inhibitory concentrations (MICs) of compounds 4c and 5c com-
pared to standard antimicrobial agents
Egypt. The starting 6-substituted-2H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazole-3-thiones (2aed) [68], 4-amino-4H-[1,2,4]
triazole-3,5-dithiol (1) [75] and 2,3,4-tri-O-acetyl-b-L-arabino-
pyranosyl bromide (3) [76] were prepared as reported. TLC was
performed on Fluka silica gel 60 F254 aluminum sheets, and
products were detected using 254 nm light. Fluka silica gel
60 (70e230 mesh) was used for column chromatography.
Test organisms
4c
5c
Gentamycin Griseofulvin
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum 1600
Candida albicans
25
1600
e
>1600
e
e
e
e
50
50
50
50
e
e
e
e
>1600
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
25
3.12
12.5
1.56
4.1.1. Synthesis of 5-(2,3,4-tri-O-acetyl-a-L-
arabinopyranosylthio)-4-amino-2,4-dihydro[1,2,4]triazole-
3-thione (6)
12.5
25
e
e
e
e
Escherichia coli
1600
>1600 12.5
e
To a solution of compound 1 (500 mg, 3.4 mmol) in N,N-di-
methylformamide (3.0 mL) and triethylamine (1 mL,
7.2 mmol) was added 2,3,4-tri-O-acetyl-b-L-arabinopyranosyl
bromide (3) (900 mg, 2.6 mmol) and the reaction mixture was
stirred overnight. The next day, the reaction mixture was diluted
with iceewater mixture and the formed precipitate was col-
lected by filtration, washed several times with water and dried
at room temperature. The precipitate was extracted with di-
chloromethane, the solution was concentrated and the residue
subjected to silica gel (70e230 mesh) column chromatography.
Compound 6 was eluted with 60% ethyl acetate/petroleum
ether (bp 40e60 ꢁC) / 80% ethyl acetate/petroleum ether
(bp 40e60 ꢁC) and recrystallised from ethanol to give
586 mg (42% based on 1) of colorless crystals, mp 228e
230 ꢁC (Rf ¼ 0.70, determined on TLC aluminum sheets using
ethyl acetate/petroleum ether (bp 40e60 ꢁC) [60:40, v/v] as
a developing system). IR: 3308, 3227, 3156, 2994, 2936,
2798, 1744, 1617, 1510, 1451, 1375, 1299, 1249, 1223, 1161,
1103, 1085, 1059, 1024, 947, 916, 883, 802, 724, 656, 600,
549, 496, 463; 1H NMR (DMSO-d6) d 2.01, 2.06, 2.08
also the absence of the acetyl carbonyl function at
1748 cmꢀ1 and the appearance of the characteristic OH
band at 3380 (br) cmꢀ1
.
2.2. Pharmacology
The in vitro antimicrobial screening of compounds 4c and 5c
were evaluated against selected two Gram-positive bacteria (Ba-
cillus subtilis ATCC 6633 and Staphylococcus aureus ATCC
25923), two Gram-negative bacteria (Pseudomonas aeruginosa
ATCC 10145 and Escherichia coli ATCC 23556), one yeast
(Candida albicans ATCC 14053) and three fungal strains (As-
pergillus fumigatus ATCC 96918, Penicillium italicum ATCC
48114 and Syncephalastrum racemosum ATCC 18192). The in-
hibitory effects of S-a-L-arabinoside 4c was studied in compar-
ison with similar effects due to N-a-L-arabinoside 5c using the
diffusion agar technique [73] (Table 1). The broth dilution
method [74] was used to determine the minimum inhibitory con-
centrations (MICs) of the tested compounds (Table 2). Thus,
compound 4c showed higher inhibitory effect against A. fumiga-
tus, P. italicum, S. racemosum, S. aureus, P. aeruginosa,
B. subtilis and E. coli at MIC values of 12.5e1600 mg/mL, com-
pared to compound 5c.
0
0
(3s, 3H each, CH3CO), 3.88 (dd, 1H, JH-5 eH-4 ¼ 2.2 Hz,
0
00
0
00
00
0
JH-5 eH-5 ¼ 12.7 Hz, H-5 ), 3.95 (dd, 1H, JH-5 eH-4 ¼ 3.7 Hz,
00
0
0
0
JH-5 eH-5 ¼ 12.9 Hz, H-5 ), 5.12 (t, 1H, JH-2 eH-1 ¼ 8.1 Hz,
0
0
0
0
JH-2 eH-3 ¼ 8.4 Hz, H-2 ), 5.18 (m, 1H, H-4 ), 5.26 (dd, 1H,
0
0
0
0
0
JH-3 eH-4 ¼ 3.4 Hz, JH-3 eH-2 ¼ 8.4 Hz, H-3 ), 5.57 (d, 1H,
0
0
0
JH-1 eH-2 ¼ 8.1 Hz, H-1 ), 5.62 (s, 2H, D2O exchangeable NH2).
Anal. Calcd for C13H18N4O7S2 (406.4): C, 38.42; H, 4.46; N,
13.78; S, 15.78. Found: C, 38.33; H, 4.41; N, 13.68; S, 15.84.
3. Conclusion
The present work describes the first access to the N- and S-a-
L-arabinosides of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole ring
system with potential antimicrobial activities. These com-
pounds could serve as possible starting materials for further
synthetic transformations. It also expands the synthesis as
well as the utility of both base-modified and sugar-modified nu-
cleosides of possible application in the chemotherapy of cancer
and viral infections.
4.1.2. General procedures for the synthesis of compounds
4aed and 5aed
(A) To a solution of each of compounds 2aed (2.1 mmol)
in N,N-dimethylformamide (2.5 mL) and triethylamine
(0.36 mL, 2.6 mmol) was added 2,3,4-tri-O-acetyl-b-L-arabi-
nopyranosyl bromide (3) (780 mg, 2.3 mmol) and the reaction
mixture was stirred overnight. The next day, the reaction mix-
ture was diluted with iceewater mixture and the formed pre-
cipitate was collected by filtration, washed several times
with water and dried at room temperature. The precipitate
was extracted with dichloromethane, the solution was concen-
trated and the residue subjected to silica gel (70e230 mesh)
column chromatography. Compounds 5aed were eluted first
with 50% ethyl acetate/petroleum ether (bp 40e60 ꢁC) /
70% ethyl acetate/petroleum ether (bp 40e60 ꢁC), followed
by compounds 4aed with 80% ethyl acetate/petroleum ether
(bp 40e60 ꢁC) / 10% methanol/ethyl acetate. The
4. Experimental
4.1. Chemistry
All melting points are uncorrected. IR spectra were recorded
on a PerkineElmer 1430 spectrometer. NMR spectra were
measured with a Varian Mercury 300 spectrometer (300 MHz
1H NMR, 75 MHz 13C NMR). Elemental analyses were carried
out at the Micro Analytical Center, Cairo University, Giza,

1196
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 42 (2007) 1193e1199
chromatographically separated crude products were recrystal-
lised from dichloromethane/petroleum ether (bp 40e60 ꢁC). Rf
values of the latter compounds were determined on TLC alu-
minum sheets using ethyl acetate/petroleum ether (bp 40e
60 ꢁC) [60:40, v/v] as a developing system.
(CDCl3) d 2.07, 2.10, 2.12 (3s, 3H each, CH3CO), 3.72 (dd,
0
0
0
0
00
1H, JH-5 eH-4 ¼ 3.0 Hz, JH-5 eH-5 ¼ 12.3 Hz, H-5 ), 4.21 (dd,
00
00
0
00
0
1H, JH-5 eH-4 ¼ 6.3 Hz, JH-5 eH-5 ¼ 12.3 Hz, H-5 ), 5.22
0
0
0
0
0
(dd, 1H, JH-3 eH-4 ¼ 3.0 Hz, JH-3 eH-2 ¼ 6.6 Hz, H-3 ), 5.28
(m, 1H, H-40), 5.34 (t, 1H, JH-2 eH-1 ¼ 5.7 Hz, JH-2 eH-3
¼
0
0
0
0
0
6.6 Hz, H-20), 5.64 (d, 1H, JH-1 eH-2 ¼ 5.7 Hz, H-1 ), 7.50
(d, 2H, J ¼ 7.9 Hz, ArH), 7.83 (d, 2H, J ¼ 7.9 Hz, ArH).
Anal. Calcd for C20H19ClN4O7S2 (527.0): C, 45.59; H,
3.63; N, 10.63; S, 12.17. Found: C, 45.61; H, 3.59; N,
10.44; S, 12.08.
0
0
(B) A mixture of compound 6 (406 mg, 1.0 mmol) and the
appropriate carboxylic acid (1 mmol; for the synthesis of com-
pounds 4a, b and d) or acyl chloride (1 mmol for the synthesis
of compound 4c) in phosphoryl chloride (2 mL) was heated at
reflux temperature in an oil bath for 8 h. The excess of phos-
phoryl chloride was removed under reduced pressure and the
formed residue was extracted with dichloromethane, washed
with KOH solution (0.1 M, 2 ꢂ 100 mL) then water
(4 ꢂ 100 mL) and dried (Na2SO4). The solvent was then re-
moved under reduced pressure and the formed residue was re-
crystallised from dichloromethane/petroleum ether (bp 40e
60 ꢁC). Rf values of the latter compounds were determined
on TLC aluminum sheets using ethyl acetate/petroleum ether
(bp 40e60 ꢁC) [60:40, v/v] as a developing system.
4.1.2.4. 3-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosylthio)-6-(4-
nitrophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4d) Yield
497 mg (44%, A), 484 mg (90%, B); orange yellow crystals,
mp 196e198 ꢁC (Rf ¼ 0.50). IR: 3068, 2927, 1747, 1605,
1531, 1456, 1407, 1373, 1348, 1299, 1225, 1157, 1090,
1063, 1005, 935, 888, 855, 798, 753, 713, 688, 673, 600,
1
509, 457; H NMR (CDCl3) d 2.06, 2.09, 2.11 (3s, 3H each,
0
0
0
00
CH3CO), 3.72 (dd, 1H, JH-5 eH-4 ¼ 3.1 Hz, JH-5 eH-5
¼
¼
¼
¼
¼
12.3 Hz, H-50), 4.20 (dd, 1H, JH-5 eH-4 ¼ 6.3 Hz, JH-5 eH-5
00
0
00
0
12.3 Hz, H-500), 5.22 (dd, 1H, JH-3 eH-4 ¼ 3.1 Hz, JH-3 eH-2
0
0
0
0
4.1.2.1.
3-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosylthio)-6-
6.6 Hz, H-30), 5.26 (m, 1H, H-040), 5.32 (t, 1H, JH-2 eH-1
0
0
phenyl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (4a). Yield 114 mg
(11%, A), 428 mg (87%, B); yellow crystals, mp 206e208 ꢁC
0
0
0
0
5.7 Hz, JH-2 eH-3 ¼ 6.6 Hz, H-2 ), 5.65 (d, 1H, JH-1 eH-2
5.7 Hz, H-10), 8.10 (td, 2H, J ¼ 2.1, 9.0 Hz, ArH), 8.36 (td,
2H, J ¼ 2.1, 9.0 Hz, ArH); 13C NMR (CDCl3) d 18.88, 18.98,
19.06 (CH3), 63.01, 65.08, 67.09, 68.02 (C-20eC-50), 90.63
(C-10), 122.87, 122.92, 127.10, 132.44, 148.18, 158.86,
167.98, 168.04, 168.11 (ArC, triazolothiadiazole C, C]O).
Anal. Calcd for C20H19N5O9S2 (537.5): C, 44.69; H,
3.56; N, 13.03; S, 11.93. Found: C, 44.47; H, 3.51; N, 12.96;
S, 11.87.
1
(Rf ¼ 0.77). H NMR (CDCl3) d, 2.11, 2.15, 2.17 (3s, 3H each,
0
0
0
00
CH3CO), 3.75 (dd, 1H, JH-5 eH-4 ¼ 3.3 Hz, JH-5 eH-5
¼
¼
¼
¼
¼
12.3 Hz, H-50), 4.25 (dd, 1H, JH-5 eH-4 ¼ 6.3 Hz, JH-5 eH-5
00
0
00
0
12.3 Hz, H-500), 5.24 (dd, 1H, JH-3 eH-4 ¼ 3.3 Hz, JH-3 eH-2
0
0
0
0
6.9 Hz, H-30), 5.30 (dd, 1H, JH-4 eH-3 ¼ 3.3 Hz, JH-4 eH-5
0
0
0
00
6.3 Hz, H-40), 5.37 (t, 1H, JH-2 eH-1 ¼ 6.0 Hz, JH-2 eH-3
0
0
0
0
6.9 Hz, H-20), 5.67 (d, 1H, JH-1 eH-2 ¼ 6.0 Hz, H-1 ), 7.52e7.61
(m, 3H, ArH), 7.88e7.97 (m, 2H, ArH). Anal. Calcd for
C20H20N4O7S2 (492.5): C, 48.77; H, 4.09; N, 11.38; S, 13.02.
Found: C, 48.58; H, 4.00; N, 11.46; S, 12.99.
0
0
0
4.1.2.5. 2-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosyl)-6-phenyl-
2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
(5a).
Yield 290 mg (28%, A), pale yellow crystals, mp 142e
144 ꢁC (Rf ¼ 0.85). IR: 3066, 3043, 2924, 2853, 1748, 1557,
1522, 1469, 1371, 1244, 1062, 1002, 948, 764, 687, 602,
4.1.2.2. 3-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosylthio)-6-(4-
aminophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
Yield 149 mg (14%, A), 447 mg (88%, B); yellow crystals,
(4b).
497; 1H NMR (CDCl3) d 1.96, 2.04, 2.22 (3s, 3H each,
1
mp 132e134 ꢁC (Rf ¼ 0.42). H NMR (CDCl3) d 2.07, 2.10,
0
0
00
CH3CO), 3.99 (d, 1H, JH-5 eH-5 ¼ 13.5 Hz, H-5 ), 4.20 (dd,
0
2.12 (3s, 3H each, CH3CO), 3.72 (dd, 1H, JH-5 eH-4
0
0
0
¼
¼
¼
00
00
0
00
0
1H, JH-5 eH-4 ¼ 1.9 Hz, JH-5 eH-5 ¼ 13.5 Hz, H-5 ), 5.29
0
0
00
00
7.2 Hz, JH-5 eH-5 ¼ 14.1 Hz, H-5 ), 4.23 (dd, 1H, JH-5 eH-4
0
0
0
0
0
0
(dd, 1H, JH-3 eH-4 ¼ 3.4 Hz, JH-3 eH-2 ¼ 10.2 Hz, H-3 ), 5.43
00
00
0
0
6.0 Hz, JH-5 eH-5 ¼ 14.1 Hz, H-5 ), 5.22 (dd, 1H, JH-3 eH-4
0
00
0
0
0
(d, 1H, JH-4 eH-5 ¼ 1.9 Hz, H-4 ), 5.88 (t, 1H, JH-2 eH-1
¼
¼
0
0
0
0
3.1 Hz, JH-3 eH-2 ¼ 6.6 Hz, H-3 ), 5.28 (m, 1H, H-4 ), 5.35 (t,
0
0
0
0
9.0 Hz, JH-2 eH-3 ¼ 10.2 Hz, H-2 ), 6.19 (d, 1H, JH-1 eH-2
0
0
0
0
0
1H, JH-2 eH-1 ¼ 5.7 Hz, JH-2 eH-3 ¼ 6.6 Hz, H-2 ), 5.20e5.50
9.0 Hz, H-10), 7.48e7.63 (m, 3H, ArH), 7.93 (td, 2H,
J ¼ 1.2, 7.2 Hz, ArH). Anal. Calcd for C20H20N4O7S2
(492.5): C, 48.77; H, 4.09; N, 11.38; S, 13.02. Found: C,
48.80; H, 4.15; N, 11.45; S, 12.98.
0
(br s, 2H, D2O exchangeable NH2), 5.64 (d, 1H, JH-1 eH-
¼ 5.7 Hz, H-10), 6.73 (d, 2H, J ¼ 8.7 Hz, ArH), 7.68 (d,
20
2H, J ¼ 8.7 Hz, ArH). Anal. Calcd for C20H21N5O7S2
(507.5): C, 47.33; H, 4.17; N, 13.80; S, 12.63. Found: C,
47.22; H, 4.12; N, 13.77; S, 12.76.
4.1.2.6. 2-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosyl)-6-(4-ami-
nophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
(5b). Yield 277 mg (26%, A), yellow crystals, mp 154e
156 ꢁC (Rf ¼ 0.75). IR: 3377, 3228, 3016, 2934, 2854, 2360,
1748, 1632, 1582, 1497, 1472, 1456, 1429, 1418, 1377,
1339, 1313, 1266, 1224, 1177, 1121, 1062, 1002, 933, 841,
4.1.2.3. 3-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosylthio)-6-(4-
chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole
(4c).
Yield 509 mg (46%, A), 448 mg (85%, B); pale yellow crys-
tals, mp 186e188 ꢁC (Rf ¼ 0.53). IR: 3062, 3027, 2989,
2934, 2911, 2853, 1747, 1595, 1545, 1521, 1483, 1372,
1
823, 777, 717, 686, 670, 649, 625, 600, 495, 424, 406; H
NMR (CDCl3) d 1.96, 2.04, 2.21 (3s, 3H each, CH3CO),
1
1223, 1090, 1009, 933, 830, 754, 681, 600, 471; H NMR

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 42 (2007) 1193e1199
1197
0
00
0
00
00
0
3.98 (d, 1H, JH-5 eH-5 ¼ 13.5 Hz, H-5 ), 4.20 (dd, 1H, JH-5 eH-4
to afford a solid residue which was washed several times via
boiling in chloroform (100 mL) and decantation. The residue
was dried at room temperature, column chromatographed
(chloroform / 90% methanol/chloroform), and recrystallised
from methanol to give compounds 7 and 8. Rf values of the lat-
ter compounds were determined on TLC aluminum sheets us-
ing chloroform/methanol (95:5, v/v) as a developing system.
Compound 2a (35 mg, 15%) was eluted from the same column
used to separate compound 7 using methanol as an eluent.
Identification of compound 2a was assigned by its mp,
mixed mp, analytical and spectral data compared to reported
data [68].
00
0
¼ 1.8 Hz, JH-5 eH-5 ¼ 13.5 Hz, H-5 ), 4.72 (br s, 2H, D2O
0
0
exchangeable NH2), 50.28 (dd, 1H, JH-3 eH-4 ¼ 3.3 Hz,
0
0
0
0
JH-3 eH-2 ¼ 10.2 Hz, H-3 ), 5.43 (dd, 1H, JH-4 eH-3 ¼ 3.3 Hz,
0
0
00
0
0
JH-4 eH-5 ¼ 1.8 Hz, H-4 ), 5.90 (t, 1H, JH-2 eH-1 ¼ 9.0 Hz,
0
0
0
0
0
JH-2 eH-3 ¼ 10.2 Hz, H-2 ), 6.18 (d, 1H, JH-1 eH-2 ¼ 9.0 Hz,
H-10), 6.74 (d, 2H, J ¼ 8.1 Hz, ArH), 7.71 (d, 2H, J ¼ 8.1 Hz,
ArH). Anal. Calcd for C20H21N5O7S2 (507.5): C, 47.33; H,
4.17; N, 13.80; S, 12.63. Found: C, 47.57; H, 4.07; N, 13.69;
S, 12.55.
4.1.2.7.
2-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosyl)-6-(4-
chlorophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-
thione (5c). Yield 77 mg (7%, A), pale yellow crystals, mp
210e212 ꢁC (Rf ¼ 0.81). IR: 3024, 2968, 2360, 1748, 1580,
1553, 1522, 1470, 1391, 1340, 1311, 1263, 1223, 1120,
1089, 1061, 1000, 950, 875, 835, 794, 726, 651, 624, 599,
496, 459, 444, 433, 428, 417; 1H NMR (CDCl3) d 1.95,
4.1.3.1.
3-(a-L-Arabinopyranosylthio)-6-phenyl[1,2,4]tria-
zolo[3,4-b][1,3,4]thiadiazole (7). Yield 187 mg (51%); pale
yellow crystals, mp 178e180 ꢁC (Rf ¼ 0.05). 1H NMR
(DMSO-d6) d 4.10e3.10 (m, 5H, H-20, H-30, H-40, H-50, H-
500), 4.21 (d, 1H, J ¼ 6.0 Hz, D2O exchangeable OH), 4.57
(d, 1H, J ¼ 6.0 Hz, D2O exchangeable OH), 4.91 (br s, 1H,
0
0
2.03, 2.21 (3s, 3H each, CH3CO), 3.98 (dd, 1H, JH-5 eH-4
0
0
00
00
0
0
0
¼ 0.9 Hz, JH-5 eH-5 ¼ 13.3 Hz, H-5 ), 4.19 (dd, 1H, JH-5 eH-4
D2O exchangeable OH), 5.46 (d, 1H, JH-1 eH-2 ¼ 8.7 Hz, H-
10), 7.55 (m, 3H, ArH), 7.89 (d, 1H, J ¼ 7.8 Hz, ArH), 7.95
(d, 1H, J ¼ 7.8 Hz, ArH). Anal. Calcd for C14H14N4O4S2
(366.4): C, 45.89; H, 3.85; N, 15.29; S, 17.50. Found: C,
45.79; H, 3.69; N, 15.24; S, 17.41.
00
00
0
0
0
¼ 1.8 Hz, JH-5 eH-5 ¼ 13.3 Hz, H-5 ), 5.29 (dd, 1H, JH-3 eH-4
¼
¼
0
0
0
0
0
3.3 Hz, JH-3 eH-2 ¼ 10.2 Hz, H-3 ), 5.43 (dd, 1H, JH-4 eH-3
0
0
00
0
0
3.3 Hz, JH-4 eH-5 ¼ 1.8 Hz, H-4 ), 5.85 (t, 1H, JH-2 eH-1 ¼ 9.3 Hz,
0
0
0
0
0
0
JH-2 eH-3 ¼ 10.2 Hz, H-2 ), 6.17 (d, 1H, JH-1 eH-2 ¼ 9.3 Hz, H-1 ),
7.51 (td, 2H, J ¼ 2.1, 8.7 Hz, ArH), 7.86 (td, 2H, J ¼ 2.1, 8.7 Hz,
ArH). Anal. Calcd for C20H19ClN4O7S2 (527.0): C, 45.59; H,
3.63; N, 10.63; S, 12.17. Found: C, 45.63; H, 3.71; N, 10.42;
S, 12.09.
4.1.3.2. 2-a-L-Arabinopyranosyl-6-phenyl-2H-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazole-3-thione (8). Yield 308 mg (84%),
pale yellow crystals, mp 170e172 ꢁC (Rf ¼ 0.11). IR: 3380
(br), 3053, 2924, 1648, 1595, 1557, 1445, 1420, 1365, 1277,
1
4.1.2.8.
2-(2,3,4-Tri-O-acetyl-a-L-arabinopyranosyl)-6-(4-
1149, 1081, 1000, 854, 769, 694, 633; H NMR (DMSO-d6)
nitrophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thi-
one (5d). Yield 124 mg (11%, A); pale yellow crystals, mp
170e172 ꢁC (Rf ¼ 0.88). IR: 3071, 2928, 2849, 1748, 1605,
1532, 1487, 1394, 1372, 1347, 1245, 1118, 1087, 1063, 1001,
936, 854, 795, 752, 716, 687, 598, 501, 453; 1H NMR
d 4.40e3.12 (m, 5H, H-20, H-30, H-40, H-50, H-500), 4.72
(br s, 1H, D2O exchangeable OH), 5.00 (br s, 1H, D2O
exchangeable OH), 5.16 (br s, 1H, D2O exchangeable OH),
0
0
0
5.49 (d, 1H, JH-1 eH-2 ¼ 9.0 Hz, H-1 ), 7.56 (m, 3H, ArH),
7.91 (d, 1H, J ¼ 7.5 Hz, ArH), 7.97 (d, 1H, J ¼ 7.5 Hz,
ArH). Anal. Calcd for C14H14N4O4S2 (366.4): C, 45.89; H,
3.85; N, 15.29; S, 17.50. Found: C, 45.93; H, 3.79; N,
15.42; S, 17.38.
(CDCl3) d 1.95, 2.03, 2.21 (3s, 3H each, CH3CO), 3.99 (d, 1H,
0
0
00
00
0
JH-5 eH-5 ¼ 13.4 Hz, H-5 ), 4.20 (dd, 1H, JH-5 eH-4 ¼ 1.5 Hz,
00
00
0
0
0
JH-5 eH-5 ¼ 13.4 Hz, H-5 ), 5.29 (dd, 1H, JH-3 eH-4 ¼ 3.0 Hz,
0
0
0
0
00
JH-3 eH-2 ¼ 10.2 Hz, H-3 ), 5.43 (dd, 1H, JH-4 eH-5 ¼ 1.5 Hz,
0
0
0
0
0
JH-4 eH-3 ¼ 3.0 Hz, H-4 ), 5.84 (t, 1H, JH-2 eH-1 ¼ 9.0 Hz,
0
0
0
0
0
JH-2 eH-3 ¼ 10.2 Hz, H-2 ), 6.17 (d, 1H, JH-1 eH-2 ¼ 9.0 Hz,
H-10), 8.12 (td, 2H, J ¼ 2.1, 8.7 Hz, ArH), 8.39 (td, 2H,
J ¼ 2.1, 8.1 Hz, ArH); 13C NMR (CDCl3) d 20.54, 20.71,
20.91 (CH3), 67.25, 67.59, 67.81, 71.12 (C-20eC-50), 83.63
(C-10), 124.65, 128.67, 133.66, 149.68, 150.35, 161.90,
162.53, 169.34, 169.84, 170.23 (ArC, triazolothiadiazole C,
C]O). Anal. Calcd for C20H19N5O9S2 (537.5): C, 44.69; H,
3.56; N, 13.03; S, 11.93. Found: C, 44.61; H, 3.38; N, 13.14;
S, 11.99.
4.2. Pharamacology
For the antimicrobial screening using the diffusion agar
technique [73], compounds 4c and 5c were dissolved in di-
methyl sulfoxide (DMSO) (5 mg/mL). Further dilutions of
the compounds and standard drugs were prepared at the re-
quired quantities of 5, 2.5, 1 mg/mL concentrations. All the
compounds were tested for their in vitro growth inhibitory ac-
tivity against different bacteria, yeasts and fungi. Origin of mi-
crobial strains are S. aureus ATCC 25923 and B. subtilis
ATCC 6633 as Gram-positive, E. coli ATCC 23556 and P. aer-
uginosa ATCC 10145 as Gram-negative bacteria, C. albicans
ATCC 14053 as yeast, and, A. fumigatus ATCC 96918, P. ita-
licum ATCC 48114 and S. racemosum ATCC 18192) as fungi.
Chloramphenicol and Terbinafin were used as control drugs.
The antimicrobial activities were expressed as the diameter
of the inhibition zones (Table 1).
4.1.3. Deacetylation of compounds 4a and 5a. General
procedure
Dry gaseous ammonia was passed through a solution of
each of compounds 4a and 5a (1 mmol) in dry methanol
(10 mL) for about 1 h with cooling and stirring then the reac-
tion mixture was stirred at room temperature over night. The
resulting mixture was then concentrated at reduced pressure

1198
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 42 (2007) 1193e1199
[24] J.A.V. Coates, N. Cammack, H.J. Jenkinson, A.J. Jowett, M.I. Jowett,
For the determination of the minimum inhibitory concen-
B.A. Pearson, C.R. Penn, P.L. Rouse, K.C. Viner, J.M. Cameron, Antimi-
crob. Agents Chemother. 36 (1992) 733e739.
trations (MICs), compounds 4c and 5c were dissolved in di-
methyl sulfoxide (DMSO) (1.6 mg/mL). Further dilutions of
the tested compounds and standard drugs in the test medium
were prepared at the required quantities of 800, 400, 200,
100, 50, 25, 12.5, 6.25, 3.12, 1.56, 0.78 mg/mL concentrations
with MuellereHinton broth and Sabouraud dextrose broth.
The minimum inhibitory concentrations (MICs) were deter-
mined using the twofold serial dilution technique [74].
A control test was also performed containing inoculated broth
supplemented with only dimethyl sulfoxide (DMSO) at the
same dilutions used in our experiments. Gentamycin and Gris-
eofulvin were used as control drugs. The data on the antifungal
and antibacterial activities of the compounds and the control
drugs as MIC, mg/mL, values are given in Table 2.
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