Synthesis, antiviral, and antimicrobial activity of 1,2,4-triazole thioglycoside derivatives

Article abstract of DOI:10.1080/10426507.2012.668990

The reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol with glucosyl, galactosyl, lactosyl bromide, and peracetylated ribose under the conventional and microwave irradiation methods afforded the corresponding S-glycosides. Deacetylation of S-glycos

Full text of DOI:10.1080/10426507.2012.668990

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Synthesis, Antiviral, and Antimicrobial
Activity of 1,2,4-Triazole Thioglycoside
Derivatives
Hassan A. El-Sayed a , Ahmed H. Moustafa a & Abd El-Fattah Z.
Haikal a
a Department of Chemistry, Faculty of Science , Zagazig University ,
Zagazig , Egypt
Accepted author version posted online: 02 Mar 2012.Published
online: 31 May 2013.
To cite this article: Hassan A. El-Sayed , Ahmed H. Moustafa & Abd El-Fattah Z. Haikal (2013):
Synthesis, Antiviral, and Antimicrobial Activity of 1,2,4-Triazole Thioglycoside Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 188:5, 649-662
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Phosphorus, Sulfur, and Silicon, 188:649–662, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.668990
SYNTHESIS, ANTIVIRAL, AND ANTIMICROBIAL ACTIVITY
OF 1,2,4-TRIAZOLE THIOGLYCOSIDE DERIVATIVES
Hassan A. El-Sayed, Ahmed H. Moustafa,
and Abd El-Fattah Z. Haikal
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
GRAPHICAL ABSTRACT
Abstract The reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol with glucosyl, galac-
tosyl, lactosyl bromide, and peracetylated ribose under the conventional and microwave irra-
diation methods afforded the corresponding S-glycosides. Deacetylation of S-glycosides gave
the corresponding deacetylated derivatives. Reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-
3-thiol with 4-acetoxybutyl bromide, 2-acetoxyethoxymethyl bromide, 3-chloropropanol, 1,3-
dichloroopropan-2-ol, epichlorohydrin, allyl bromide, and propargayl bromide gave the corre-
sponding S-acyclonucleosides, which were deacetylated to give the corresponding deacetylated
compounds. All the newly synthesized compounds were characterized by the IR, 1H, 13C NMR,
and elemental analyses. Some of these compounds were screened for their antiviral and an-
timicrobial activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the related elements to view the free supplemental file.
Keywords 1,2,4-triazole; S-glycosides; microwave; antiviral; antimicrobial activity
Received 23 December 2011; accepted 16 February 2012.
We express our thanks to Zagazig University for financial support of this work. Also our thanks for National
Institute of Health (NIH) USA for antiviral activity, and for Microbiology Lab, Faculty of Science, Zagazig
University for antimicrobial activities.
Address correspondence to Hassan A. El-Sayed and Ahmed H. Moustafa, Department of Chem-
istry, Faculty of Science, Zagazig University, Zagazig, Egypt. E-mail: h.abdelfattah30@yahoo.com or
ab hu mostafa@yahoo.com
649

650
H. A. EL-SAYED ET AL.
INTRODUCTION
In the last few decades, the chemistry of 1,2,4-triazole derivatives has received consid-
erable attention owing to their synthetic and effective biological importance, for example, a
large number of 1,2,4-triazole-containing ring systems have been incorporated into a wide
variety of therapeutic agents including those showing antifungal,1 antidepressant,2 anti-
inflammatory,3–8 CNS stimulants sedatives, antianxiety, antimicrobial,8–17 and antimycotic
activities such as fluconazole, intraconazole, voriconazole.18,19 Also, drugs containing the
1,2,4-triazole moiety such as Alprazolam,20 Etizolam,21 and Furacylin22 are known. Tri-
azole derivatives showed promising antiviral23–26 and anticancer activities.27–29 Acyclic
nucleosides of 1,2,4-triazole derivatives have antiviral activity against the hepatitis C virus
(HCV).23 In addition, ribavirin was the first synthetic nucleoside showing a broad spectrum
of antiviral activities against many RNA, DNA viruses.30,31
Moreover, glycoside analogs play an important role in pharmacology, mainly as
antitumor and antiviral drugs.32–36 Due to their outstanding biological activity, various
synthetic strategies toward such compounds were developed and have been highlighted in
review articles.37
In continuation of our studies on the synthesis of glycosylated heterocyclics and
their acyclic analogs,36,38–41 we reported here the synthesis of some glycosides of the
functionalized 1,2,4-triazole ring.
RESULTS AND DISCUSSION
The preparation of new eighteen 1,2,4-triazole glycoside derivatives is described.
The general synthetic pathway and structure of the investigated compounds is given
in Schemes 1–4; the starting compound 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1
was obtained from 2-(methylthio)benzoic acid in reaction with thiocarbohydrazide as
described in literature.41 The reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol
1 with glycosyl, galactosyl, lactosyl bromide, and peracetylated ribose in dry ace-
tone/DMF in the presence of potassium carbonate and the later in MWI for 5 min38–40
gave the corresponding 3-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-β-D-gluco/galactopyranosylmer
capto)-5-(2-(methylthio)phenyl)-4H-1,2,4,-triazole (2 and 3), 3-(2ꢀ,3ꢀ,5ꢀ-tri-O-acetyl-β-D-
ribofuranosylmercapto)-5-(2-(methylthio)phenyl)-4H-1,2,4-triazole-4-amine (6), 3-(2ꢀ,3ꢀ,
4ꢀ,6ꢀ-tetra-O-acetyl-β-D-galactopyranosyl(1→4)-(2ꢀ,3ꢀ,6ꢀ-tri-O-acetyl-β-D-glucopyr
anosylmercapto)-5-(2-(methylthio)phenyl)-4H-1,2,4-triazole-4-amine (8) (Schemes 1 and
2), respectively.
The structures of the synthesized compounds were confirmed by elemental analysis,
1
IR, H, and 13C NMR. Analytical and spectral data are in agreement with the proposed
structure of compounds 2, 3, 6, and 8, particularly the absence of the SH band and the
1
presence of acetoxy groups bands in the IR between 1731 and 1742 cm−1. H NMR
spectrum of compounds 2 and 3 showed doublet signals at δ 6.25 and 6.19 ppm with
coupling constant J = 8.23 and 8.43 Hz, respectively, which characterized the anomeric
protons and confirmed the β-configuration. 13C NMR spectrum of compound 2 showed the
anomeric carbon at δ 92.5 ppm. The 1H NMR spectrum for compound 6 showed a signal
at δ 6.02 ppm with J = 3.2 Hz for the anomeric proton. 1H NMR spectrum of compound 8
showed signals at δ 1.94, 1.95, 1.96, 1.98, 2.00, 2.03, and 2.04 ppm for seven acetoxy groups,
in addition to, the anomeric proton at δ 6.23 ppm with coupling constant J = 8.82 Hz.
Deacetylation of glycosides 2, 3, 6, and 8 in presence of TEA/MeOH and few drops of

SYNTHESIS, ANTIVIRAL, AND ANTIMICROBIAL ACTIVITY
651
S
N
N
SMe
R" OAc
O
N
N
SMe
R'
AcO
N
Et3N/H2O
MeOH
AcO
S
N
Br
NH2
OH
NH2
OAc
K2CO 3/DMF
O
O
R"
R'
R"
OH
OA c
HO
R'
AcO
4,5
2,3
4; R' = OH, R" = H
5;
2; R' = OAc, R" = H
3; R' = H, R" = OAc
R' = H, R" = OH
SMe
N
N
SH
N
NH2
N
N
N
N
SMe
SMe
1
S
S
N
N
MWI
Et3N/H2O
MeOH
NH2
NH2
AcO
O
OAc
HO
AcO
O
O
OAcOAc
OH OH
OA c OAc
7
6
Scheme 1 Glycosylated analogs.
water38–40 afforded the corresponding deacetylated glycosides 4, 5, 7, and 9 (Schemes 1
and 2), respectively. The elemental analysis and spectral data are in agreement with the
structures and are presented in the experimental section.
Reaction of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1 with 4-acetoxybutyl bro-
mide, 2-acetoxyethoxymethyl bromide,42 3-chloropropanol, and 1,3-dichloropropan-2-ol
in presence of anhydrous potassium carbonate gave the corresponding S-acyclonucleosides
10, 11, 14, and 15, respectively (Scheme 3).
The IR spectra of compounds 10 and 11 revealed the presence of acetoxy carbonyl
groups bands at 1739 and 1738 cm−1, respectively. While the SCH2 and SCH2O protons
appeared in 1H NMR spectra at δ 4.05 and 5.68 ppm as triplet and singlet, respectively. IR
spectra of 14 and 15 showed bands at 3460 and 3485 cm−1 for OH groups.
The 1H NMR spectra of 14 and 15 showed two triplet signals at δ 4.40 and 4.49 ppm
(exchange with D2O) for OH groups, in addition to the multiplet signals at δ 2.98 and 3.38
ppm characteristic to diastereotopic protons of H-c and H-cꢀ for compound 15, respectively.
Deacetylation of compounds 10 and 11 in presence of TEA/MeOH and few drops of
water gave the corresponding deacetylated derivatives 12 and 13, respectively (Scheme 3).
1
The IR, H, and 13C NMR showed the disappearance of acetoxy groups and presence of
new hydroxyl groups (see Experimental section).

652
H. A. EL-SAYED ET AL.
N
N
SMe
OAc
OA c
OAc
O
S
O
K2CO3/DMF
N
1
+
O
AcO
NH2
AcO
AcO
AcO
OAc
O
Br
OAc
OAc
OA c
O
O
AcO
AcO
AcO
8
N
N
SMe
S
N
Et3N/H2O
NH2
OH
MeOH
O
OH
OH
OH
O
O
HO
HO
HO
9
Scheme 2 Lactosy derivatives.
Alkylation of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1 with epichlorohydrin,
allyl, and propargyl bromide in presence of anhydrous potassium carbonate afforded the
corresponding S-alkylated derivatives 16–18, respectively, in good yields (Scheme 4).
The 1H NMR spectra of 16, 17, and 18 showed multiplet signals at δ 2.38, 2.69, and
3.42–3.63 ppm for protons of the oxiran ring in compound 16, which characterized the
(H-a, H-aꢀ, H-b, and H-c) protons, two doublet and multiplet signals at δ 5.3, 5.42, and 6.09
ppm for the olefinic protons (H-a, H-aꢀ, and H-b) in compound 17. The acetylenic proton
in compound 18 appeared as doublet of doublet at δ 3.86 ppm.
PHARMACOLOGICAL STUDIES
Antiviral Activity
Eight compounds were evaluated in vitro against viruses carried out by Health
Specialist, Virology Branch, Division of Microbiology and Infection Diseases (DMID)/
National Institute of Allergy and Infection Diseases (NIAID) and an institute of the Na-
tional Institute of Health (NIH) USA. Another 12 compounds were evaluated in vitro
against Gram-positive and Gram-negative bacteria and Fungi. Results are presented in the
Supplemental Materials.
The compounds were evaluated for antiviral activity against viruses’ representative
of HCV and HBV, used RNA Hybridization (Replicon) and DNA Hybridization (virion)

SYNTHESIS, ANTIVIRAL, AND ANTIMICROBIAL ACTIVITY
653
N
N
N
N
SMe
SMe
Br
OAc
S
X
Et3N/H2O
MeOH
N
S
N
NH
2
NH
K2CO3/DMF/ref. 1h
2
HO
X
AcO
X
12,13
10,11
10;
12; X = CH
13; X = O
2
X = CH
11; X = O
2
N
N
SMe
c
a
Cl
OH
OH
S
N
1
b
K2CO3/DMF/ref.1h
NH
2
14
N
N
Ha'
Cl
Hc Ha
SMe
Hc'
OH
Cl
Cl
S
N
HO
Hb
NH
K2CO3/DMF/ref.7h
2
15
Scheme 3 Ribavirin analogs.
control assays with Human interferon alpha, 2ꢀC-methylcytidine and Lamivudine as control
drugs (Table S1, Supplemental Materials). Two representatives of DNA virus families were
also included: Herpes Simplex virus Type-1 and Type-2 (HSV-1 and HSV-2) (Herpesviri-
dae) using acyclovir as control drug. Also, the eight compounds were screened against
SARS, Coronavirus, and West Nile Virus using M128533 and infergen as control drugs (vi-
sual/neutral red). The compounds were screened against Influenza Virus type-B and type-A
(H3N2, H5N1, and H1N1) using Ribavirin (visual/neutral red) as control drug and cyto-
pathic effect/toxicoity as control assays (Table S2). The high cytotoxicity of the screened
compounds is reported in Table S3 using acyclovir and cidofovir as drugs control. The
antiviral screening showed that all the tested compounds are not active against HCV, HBV,
and WNV, while some of these are moderate antiviral (HSV-1 and HSV-2) and only one
compound 17 is moderate against SARS Virus (Table S1). In Table S2, the screened com-
pounds against Influenza Virus type-A and type-B showed that all tested compounds are
not active. Compounds 2 and 6 are moderately active against H3N2 and weak active against
H5N1.

654
H. A. EL-SAYED ET AL.
N
N
H
H
c
b
O
SMe
H
c'
O
Cl
Ha
S
N
K2CO3/DMF/ref.1h
NH2
Ha'
16
N
N
SMe
H
b
a
Br
S
N
1
K2CO3/DMF/ref.1h
NH2
Ha'
H
17
N
N
SMe
Br
S
N
NH2
K2CO3/DMF/ref.1h
18
Scheme 4 Alkylation of 1,2,4-triazole.
ANTIMICROBIAL ACTIVITY
Antibacterial Activity
These synthesized compounds were screened for their antimicrobial activities in vitro
against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two
Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli) using a cup plate
agar diffusion method.43
Clinically antimicrobial drug, such as ampicillin, was used as the positive control.
The obtained results, depicted in Table S4, revealed that these prepared nucleosides 3–16
could effectively, to some extent, inhibit the growth of all tested strains in vitro, except
for the thiolactoside 9, which did not give any result. The prepared triazole glycosides
3, 7, 12, 13, 14, and 16 demonstrated excellent antibacterial activities toward the tested
microorganisms comparable to ampicillin, which may be attributed to the introduction of
glycone moiety to triazole ring. Glycosides 6 and 11 showed moderate antibacterial activity,
while compounds 4, 5, and 10 showed antibacterial activity but less than the standard drug.

SYNTHESIS, ANTIVIRAL, AND ANTIMICROBIAL ACTIVITY
655
Antifungal Activity
Compounds 3–16 were also screened for their antifungal activity against Candida
albicans at 100 μg mL−1 concentrations using a cup plate agar diffusion method.43
The antifungal activity was compared with the known antibiotic Clotrimazole and
the results are presented in Table S4. Compounds 4, 5, 10, 13, 14, and 16 indicated
high antifungal activities compared to standard drug, while compounds 6, 7, and 11 have
moderate activity, compounds 3 and 9 showed low activity compared to clotrimazole.
Compound 12 was the only inactive compound.
CONCLUSIONS
The glycosylation of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1 gave the re-
spective nucleosides and acyclo nucleosides. The in vitro growth inhibitory activities of
compounds 2, 6, 8, 10, 13, 16, 17, and 18 against antiviral (HCV, HBV, HSV-1 and HSV-
2, SARS, WNV, and Influenza Type-A and Type-B) revealed moderate potential activity
against HSV-1 and HSV-2, SARS, and Influenza Type-A (H3N2, H5N1). Although, com-
pounds 3, 7, 12, 13, 14, and 16 have significant antibacterial activity compared to ampicillin,
while compounds 4, 5, and 10 have low activity. The tested compound 4, 5, 13, 14, and 16
have a significant antifungal activity compared to standard drug.
EXPERIMENTAL
All melting points are uncorrected and were measured using an Electro thermal IA
9100 apparatus. TLC was performed on Merck Silica Gel 60F254 with detection by UV
light and by charring after separating with 10% EtOH solution of H2SO4. The IR spectra
(KBr disc) were recorded on a Pye Unicam Sp-3-300 or a Shimadzu FTIR 8101 PC infrared
1
spectrophotometer. The H and 13C NMR spectra were determined with JEOL-JNM-LA
300 MHz spectrometer. The chemical shifts are expressed on the δ (ppm) scale using
TMS as the standard reference. Elemental analysis was performed on a Perkin Elmer 240
(microanalysis), Microanalysis Center, Cairo University, Cairo, Egypt.
4-Amino-5-(2-(methylthio)phenyl)-4H-1,2,4-triazole-3-thiol (1)
The thiocarbohydrazide (0.01 mol) was added to a solution of 2-(methylthio)benzoic
acid (0.01 mol) in pyridine (30 mL), and the reaction mixture was refluxed for 6 h. Then,
pouring the reaction mixture into ice water, the white solid formed was collected and
recrystallized from ethanol or acetic acid to give colorless crystals, yield 63%, mp 294–
296 ◦C. IR (KBr, cm−1): 3250 (NH), 2558 (SH). 1H NMR (DMSO-d6, δ ppm): δ = 2.62
(s, 3H, CH3), 6.25 (br, 1H, NH2), 7.33–8.04 (m, 4H, Ar-H), 13.21 (s, 1H, SH). 13C NMR
(DMSO-d6, δ ppm): 16.2 (CH3S), 126.8, 128.8, 131.6, 132.8, 134.1, 138.6, 152.1, and
169.5 (Ar-C and 2C N). Anal. Calcd for C9H10N4S2 (238.33): C, 45.36; H, 4.23; N,
23.51. Found: C, 45.36; H, 4.24; N, 23.52.
General Procedure for Synthesis of Glycosides
A mixture of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1 (0.01 mol) and
(0.01 mol) potassium carbonate was stirred in dry acetone/DMF (15 mL) for 1 h, then

656
H. A. EL-SAYED ET AL.
glycosyl, galactosyl, and lactosyl bromide (0.011 mol) was added. The reaction mixture
was stirred at room temperature overnight then refluxed for 3–5 h, filtered off, and
the solvent was then evaporated under reduced pressure. The product was dried and
crystallized from the proper solvent.
3-(2’,3’,4’,6’-Tetra-O-acetyl-β-D-glucopyranosylmercapto)-
5-(2-(methylthio)phenyl)-4H-1,2,4-triazole-4-amine (2)
◦
Colorless crystals from ethanol yield 55%, mp 202–204 C. IR (KBr, cm−1): 3280
1
(NH2) and 1739 (C O, acetoxy). H NMR (DMSO-d6, δ ppm): δ = 1.99, 2.0, 2.01, and
ꢀ
ꢀ
ꢀ
ꢀꢀ
2.03 (4s, 12H, 4 CH3CO), 2.59 (s, 3H, SCH3), 4.05 (dd, 1H, J5 ,6 = 4.09, J6 ,6 = 11.67 Hz,
H-6ꢀ), 4.23 (dd, 1H, J5 ,6 = 4.52, J6 ,6 = 11.67 Hz, H-6ꢀꢀ), 4.35 (m, 1 H, H-5ꢀ), 5.06 (dd,
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
1H, J4 ,5 = 9.60, J3 ,4 = 9.69 Hz, H-4ꢀ ), 5.18 (dd, 1H, J1 ,2 = 8.15, J2 ,3 = 9.23 Hz, H-2ꢀ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5.58 (dd, 1H, J2 ,3 = 9.21, J3 ,4 = 9.69 Hz, H-3ꢀ), 6.25 (d, 1H, J1 ,2 = 8.15 Hz, H-1ꢀ), 6.52
(s, 2H, NH2), 7.14–7.94 (m, 4H, Ar-H). 13C NMR (DMSO-d6, δ ppm): δ = 16.26 (SCH3),
207, 20.8, 20.86, 20.9 (4CH3CO), 61.8 (C-6ꢀ), 68.1 (C-4ꢀ), 70.4 (C-3ꢀ), 71.9 (C-2ꢀ), 72.1
(C-5ꢀ), 92.5 (C-1ꢀ), 125.7, 126.0, 127.1, 132.1, 135.2, 149.1, 149.9, 164.0, 169.7, 169.8,
170.0, and 170.5 (Ar-C, 2C N, and 4C O). Anal. Calcd for C23H28N4O9S2 (568.62): C,
48.58; H, 4.96; N, 9.85. Found: C, 48.56; H, 4.96; N, 9.86.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-Tetra-O-acetyl-β-D-galactopyranosylmercapto)-
5-(2-(methylthio)phenyl)-4H-1,2,4-triazole-4-amine (3)
Colorless crystals from ethanol, yield 52%, mp 185–187 ◦C. IR (KBr, cm−1): 3269
(NH2) and 1742 (C O, acetoxy). 1H NMR (DMSO-d6): δ = 1.96, 1.98, 2.01, and 2.09 (4s,
12H, 4 CH3CO), 2.56 (s, 3H, SCH3), 4.55 (dd, 1H, J5 ,6 = 6.12, J6 ,6 = 12.06 Hz, H-6ꢀ),
ꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀ ꢀꢀ
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
ꢀ
ꢀ
4.58 (dd, 1H, J5 ,6 = 6.39, J6 ,6 = 12.06 Hz, H-6 ), 4.73 (m, 1H, H-5 ), 5.26 (t, 1H, J3 ,2
=
10.17, J3 ,4 = 2.98 Hz, H-3ꢀ), 5.32 (t, 1H, J2 ,1 = 8.43, J2 ,3 = 10.18 Hz, H-2ꢀ), 5.45 (t, 1H,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J4 ,3 = 2.98, J4 ,5 = 2.74 Hz, H-4ꢀ), 6.19 (d, 1H, J1 ,2 = 8.43 Hz, H-1ꢀ), 6.57 (s, 2H, NH2),
7.46–8.30 (m, 4H, Ar-H). Anal. Calcd for C23H28N4O9S2 (568.62): C, 48.58; H, 4.96; N,
9.85. Found: C, 48.57; H, 5.00; N, 9.83.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
General Procedure for Deprotection of Thioglycosides
Triethylamine (1 mL) was added to a solution of glycoside (0.01 mol) in MeOH
(20 mL) and three drops of water. The mixture was stirred overnight at room temperature,
evaporated under reduced pressure, and the residue was co-evaporated with MeOH until
the triethylamine was removed. The residue was crystallized from proper solvent, yield
>85%.
3-(β-D-Glucopyranosylmercapto)-5-(2-(methylthio)phenyl)-4H-1,2,
4-triazole-4-amine (4)
Colorless crystals from ethanol, yield 87%, mp 212–214 ◦C. IR (KBr, cm−1): 3412
(4OH) and 3265 (NH2). 1H NMR (DMSO-d6, δ ppm): δ = 2.99 (s, 3H, SCH3), 3.42-3-92
(m, 6H, H-6ꢀ, H-6ꢀꢀ, H-5ꢀ, H-4ꢀ, H-3ꢀ, and H-2ꢀ), 4.37 (t, 1H, J = 5.40 Hz, OH-6ꢀ), 4.47
(d, 1H, J = 3.9 Hz, OH-4ꢀ), 4.64 (d, 1H, J = 4.48 Hz, OH-3ꢀ), 4.90 (d, 1H, J = 3.9 Hz,
OH-2ꢀ), 6.21 (d, 1H, J1 ,2 = 8.23 Hz, H-1ꢀ), 6.23 (s, 2H, NH2), 7.38–8.06 (m, 4H, Ar-H).
ꢀ
ꢀ

SYNTHESIS, ANTIVIRAL, AND ANTIMICROBIAL ACTIVITY
657
Anal. Calcd for C15H20N4O5S2 (400.47): C, 44.99; H, 5.03; N, 13.99. Found: C, 45.01; H,
4.98; N, 13.98.
3-(β-D-Galactopyranosylmercapto)-5-(2-(methylthio)phenyl)-4H-1,2,
4-triazole-4-amine (5)
◦
Colorless crystals from ethanol yield 91%, mp 196–197 C. IR (KBr, cm−1): 3443
(4OH) and 3264 (NH2). 1H NMR (DMSO-d6): δ = 2.63 (s, 3H, SCH3), 3.56 (m, 3H, H-3ꢀ,
H-6ꢀ, H-6ꢀꢀ), 3.70 (m, 3H, H-2ꢀ, H-4ꢀ, H-5ꢀ), 4.54 (m, 2H, OH-4ꢀ, OH-6ꢀ), 4.98 (d, 1H, J =
4.87 Hz, OH-3ꢀ), 5.32 (d, 1H, J = 5.12 Hz, OH-2ꢀ), 5.93 (d, 1H, J1 ,2 = 8.31 Hz, H-1ꢀ),
6.03 (s, 2H, NH2), 7.37–7.81 (m, 4H, Ar-H). Anal. Calcd for C15H20N4O5S2 (400.47): C,
44.99; H, 5.03; N, 13.99. Found: C, 44.98; H, 5.02; N, 13.98.
ꢀ
ꢀ
3-(2ꢁ,3ꢁ,5ꢁ-Tri-O-acetyl-β-D-ribofuranosylmercapto)-5-(2-(methylthio)
phenyl)-4H-1,2,4-triazole-4-amine (6)
A mixture of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1 (0.01 mol) and (0.01
mol) of peracetylated ribose was dissolved in ethanol/CHCl3 (70/30) then 1.0 g of silica
gel (200–400 mesh) was added. The solvent was removed by evaporation. The dried
residue was transferred into a glass beaker and irradiated (5 min) in a domestic microwave
oven (220 V-50 Hz, Power: 5.2 Amp. 1200 W, Model: JEI6425DWW). The product was
chromatographed on a silica gel column (CH2Cl2 as eluent) as colorless crystals, yield
67%, mp 154–156 ◦C. IR (KBr, cm−1): 3261 (NH2) and 1731 (C O, acetoxy). 1H NMR
(DMSO-d6): δ = 2.03, 2.04, and 2.07 (3s, 9H, 3CH3CO), 2.50 (s, 3H, SCH3), 4.05, (dd,
1H, J4 ,5 = 4.50, J5 ,5 = 11.02 Hz, H-5ꢀ), 4.15 (dd, 1H, J4 ,5 = 4.23, J5 ,5 = 11.02 Hz,
ꢀ
ꢀ
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
H-5ꢀꢀ), 4.32 (m, 1H, H-4ꢀ), 5.29 (dd, 1H, J2 ,3 = 3.10, J3 ,4 = 6.18 Hz, H-3ꢀ), 5.51 (dd, 1H,
ꢀ
ꢀ
ꢀ
ꢀ
J1 ,2 = 3.80, J2 ,3 = 3.12 Hz, H-2ꢀ), 6.02 (d, 1H, J1 ,2 = 3.82 Hz, H-1ꢀ), 6.36 (s, 2H, NH2),
7.35–8.04 (m, 4H, Ar-H). Anal. Calcd for C20H24N4O7S2 (496.56): C, 48.38; H, 4.87; N,
11.82. Found: C, 48.35; H, 4.88; N, 11.80.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3-(β-D-Ribofuranosylmercapto)-5-(2-(methylthio)phenyl)-4H-1,2,
4-triazole-4-amine (7)
Colorless crystals from ethanol, yield 88%, mp 170–172 ◦C. IR (KBr, cm−1): 3423
(4OH) and 3250 (NH2). 1H NMR (DMSO-d6): δ = 2.48 (s, 3H, SCH3), 3.23 (m, 2H, H-5ꢀ,
H-5ꢀꢀ), 3.30 (m, 1H, H-4ꢀ), 3.54–3.57 (m, 2H, H-3ꢀ and H-2ꢀ), 4.18 (t, 1H, J = 5.35 Hz,
OH-5ꢀ, exchange with D2O), 4.28 (d, 1H, J = 4.65 Hz, OH-3ꢀ, exchange with D2O), 4.84
(d, 1H, J = 4.91 Hz, OH-2ꢀ, exchange with D2O), 5.56 (d, 1H, J1 ,2 = 3.63 Hz, H-1ꢀ), 6.14
(s, 2H, NH2), 7.42–7.84 (m, 4H, Ar-H). Anal. Calcd for C14H18N4O4S2 (370.45): C, 45.39;
H, 4.90; N, 15.12. Found: C, 45.40; H, 4.89; N, 15.11.
ꢀ
ꢀ
3-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-Tetra-O-acetyl-β-D-galactopyranosyl-(1→4)-(2ꢁ,3ꢁ,6ꢁ-tri-O-
acetyl-β-D-glucopyranosylmercapto)-5-(2-(methylthio)phenyl)-4H-1,
2,4-triazole-4-amine (8)
Colorless syrup, yield 55%. IR (KBr, cm−1): 3284 (NH2) and 1736 cm−1 (C O,
acetoxy). 1H NMR (DMSO-d6, δ ppm): δ = 1.94, 1.95, 1.96, 1.98, 2.00, 2.03, and 2.04 (7s,
21H, 7 CH3CO), 2.54 (s, 3H, SCH3), 3.35–3.43 (m, 3H, H-2ꢀb, H-6ꢀa, H-6ꢀb), 3.98 (dd,

658
H. A. EL-SAYED ET AL.
1H, J6 a,6 a = 11.52, J6 a,5 a = 5.54 Hz, H-6ꢀꢀa), 4.05 (m, 1H, H-5ꢀb), 4.29 (dd, 1H, J6 b,5 b
=
ꢀꢀ
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
ꢀ
6.25 Hz, H-6ꢀꢀb), 4.46 (m, 1H, H-5ꢀa), 4.51 (d, 1H, J1 b,2 b = 7.93 Hz, H-1ꢀb), 4.80 (dd, 1H,
ꢀ
ꢀ
J4 b,3 b = 3.26, J4 b,5 b = 3.57 Hz, H-4ꢀb), 5.0 (dd, 1H, J2 a,1 a = 8.82, J2 a,3 a = 8.39 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
H-2ꢀa), 5.15 (dd, 1H, J4 a,3 a = 9.12, J4 a,5 a = 9.83 Hz, H-4ꢀa), 5.22 (dd, 1H, J3 b,4 b = 3.26,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J3 b,2 b = 8.91 Hz, H-3ꢀb), 5.30 (dd, 1H, J3 a,2 a = 8.38, J3 a,4 a = 9.12 Hz, H-3ꢀa), 6.23 (d,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
1H, J1 a,2 a = 8.82 Hz, H-1ꢀa), 6.30 (s, 2H, NH2), 7.61–8.05 (m, 4H, Ar-H). Anal. Calcd for
ꢀ
ꢀ
C35H44N4O17S2 (856.87): C, 49.06; H, 5.18; N, 6.54. Found: C, 49.05; H, 5.17; N, 6.53.
3-(β-D-Galactopyranosyl-(1→4)-(β-D-glucopyranosyl-5-(2-(methylthio)
phenyl)-4H-1,2,4-triazole-4-amine (9)
Colorless crystals from ethanol/water, mp 165–167 ◦C. IR (KBr, cm−1): 3450 (br, 7
OH), 3278 (NH2). 1H NMR (DMSO-d6, δ ppm): δ = 2.25 (s, 3H, SCH3), 3.80–3.95 (4 m,
12H, H-2ꢀb, H-3ꢀb, H-4ꢀb, H-5ꢀb, H-6ꢀb, H-6ꢀꢀb, H-2ꢀa, H-3ꢀa, H-4ꢀa, H-5ꢀa, H-6ꢀa, H-6ꢀꢀa),
4.42 (d, 1H, OH-4ꢀb), 4.45 (d, 1H, OH-6ꢀb), 4.72 (d, 1H, J = 5.10 Hz, OH-3ꢀb), 4.96 (d,
1H, OH-2ꢀb), 5.02 (d, 1H, OH-6ꢀa), 5.31 (d, 1H, OH-3ꢀa), 5.38 (d, 1H, OH-2ꢀa), 5.10 (d,
1H, J1 b,2 b = 7.88 Hz, H-1ꢀb), 6.33 (d, 1H, J1 a,2 a = 8.93 Hz, H-1ꢀa), 6.67 (s, 2H, NH2),
7.35–8.05 (m, 4H, Ar-H). Anal. Calcd for C21H30N4O10S2 (562.61): C, 44.83; H, 5.37; N,
9.96. Found: C, 44.82; H, 5.36; N, 9.98.
ꢀ
ꢀ
ꢀ
ꢀ
General Procedure for Alkylation of 5-(2-methylthio)phenyl-1,2,4-
triazole-3-thiol (1)
A mixture of 5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol 1 (0.01 mol) and potas-
sium carbonate (0.01 mol) was stirred in dry acetone/DMF (15 mL) for 1 h, then the alkylat-
ing agents (0.011 mol), namely, 4-acetoxybutyl bromide, 2-acetoxyethoxymethyl bromide,
3-chloropropa-nol and 1,3-dichloropropan-2-ol, epichlorhydrin, allyl, and propargyl bro-
mide were added. The reaction mixture was heating under reflux for 1 h, filtered off, and
the solvent was evaporated under reduced pressure. The residue was dried and crystallized
from ethanol.
4-(4-Amino-5-(2-(methylthio)phenyl)-4H-1,2,4-triazol-3-ylthio)butyl
acetate (10)
Colorless crystals from ethanol, yield 85%, mp 102–103 ◦C. IR (KBr, cm−1): 3252
1
(NH2), 1739 (C O, acetoxy). H NMR (DMSO-d6, δ ppm): δ = 1.75–1.98 (m, 4H,
2CH2(b,c)), 1.98 (s, 3H, CH3CO), 2.62 (s, 3H, SCH3), 4.05 (t, 2H, J = 5.7 Hz, SCH2(d)),
4.35 (t, 2H, J = 5.7 Hz, CH2(a)), 6.25 (S, 2H, NH2), 7.35–8.05 (m, 4H, Ar-H). 13C
NMR (DMSO-d6): δ = 16.4 (SCH3), 21.3 (CH3CO), 27.2 (CH2(c)), 28.1 (CH2(b)), 53.4
(SCH2(d)), 67.5 (CH2OCO), 125.8, 126.9, 127.0, 132.0, 134.7, 139.5, 149.2, 149.8, and
170.3 (Ar-C, 2C N and C O). Anal. Calcd for C15H20N4O2S2 (352.47): C, 51.11; H,
5.72; N, 15.90. Found: C, 51.12; H, 5.70; N, 15.90.
2-((4-Amino-5-(2-(methylthio)phenyl)-4H-1,2,4-triazol-
3-ylthio)methoxy)ethyl acetate (11)
◦
Colorless crystals from ethanol, yield 62%, mp 95–97 C. IR (KBr, cm−1): 3280
1
(NH2), 1738 (C O, acetoxy). H NMR (DMSO-d6, δ ppm): δ = 1.99 (s, 3H, CH3CO),

SYNTHESIS, ANTIVIRAL, AND ANTIMICROBIAL ACTIVITY
659
2.62 (s, 3H, SCH3), 3.92 (t, 2H, OCH2), 4.48 (t, 2H, CH2OCO), 5.68 (s, 2H, SCH2O), 6.32
(s, 2H, NH2), 7.35–8.04 (m, 4H, Ar-H). 13C NMR (DMSO-d6): δ = 16.38 (SCH3), 21.32
(CH3CO), 65.8 (CH2OCO), 69.2 (OCH2), 75.2 (SCH2O), 124.8, 126.5, 126.8, 127.3, 131.6,
134.5, 149.2, 149.8, and 171.6 (Ar-C, 2C N, and C O). Anal. Calcd for C14H18N4O3S2
(354.45): C, 47.44; H, 5.12; N, 15.81. Found: C, 47.45; H, 5.13; N, 15.80.
4-(4-Amino-5-(2-meltylthio)phenyl)-4H-1,2,4-triazol-3-ylthio)butan-1-ol
(12)
Triethylamine (0.5 mL) was added to a solution of 10 (0.01 mol) in MeOH (20 mL)
and few drops of water. The mixture was stirred overnight at room temperature, evaporated
under reduced pressure, and the residue was co-evaporated with MeOH until the triethy-
lamine was removed. The residue was crystallized from ethanol to give colorless crystals,
yield 90%, mp 122–124 ◦C. IR (KBr, cm−1): 3458 (OH), 3258 (NH2). 1H NMR (DMSO-d6,
δ ppm): δ = 1.76–1.96 (m, 4H, 2CH2(b,c)), 2.63 (5, 3H, SCH3), 3.98 (t, 2H, J = 5.7 Hz,
SCH2(d)), 4.36 (t, 2H, J = 5.7 Hz, CH2O ), 4.56 (t, 1H, OH, exchange with D2O), 6.36 (s,
2H, NH2, exchange with D2O), 7.36-8-08 (m, 4H, Ar-H). Anal. Calcd for C13 H18N4OS2
(310.44): C, 50.30; H, 5.84; N, 18.05. Found: C, 50.31, H, 5.85, N, 18.06.
2-((4-Amino-5-(methylthio)phenyl)-4H-1,2,4-triazol-3-
ylthio)methoxy)ethanol (13)
Triethylamine (0.5 mL) was added to a solution of 11 (0.01 mol) in MeOH (20 mL)
and few drops of water. The mixture was stirred for overnight at room temperature, evap-
orated under reduced pressure, and the residue was co-evaporated with MeOH until the
triethylamine was removed. The residue was crystallized from ethanol to give colorless
crystals, yield 85%, mp 117–119 ◦C. IR (KBr, cm−1): 3480 (OH), 3265 (NH2). 1H NMR
(DMSO-d6, δ ppm): δ = 2.63 (s, 3H, SCH3), 3.85 (t, 2H, CH2OH), 4.38 (t, 2H, OCH2),
4.59 (t, 1H, OH, exchange with D2O), 5.63 (s, 2H, SCH2O), 6.32 (s, 2H, NH2, exchange
with D2O), 7.36–8.05 (m, 4H, Ar-H). Anal. Calcd for C12H16N4O2S2 (312.41): C, 46.13;
H, 5.16; N, 17.93. Found: C, 46.13, H, 5.17, N, 17.95.
3-(4-Amino-5-(2-meltylthio)phenyl)-4H-1,2,4-triazol-3-ylthio)propan-1-ol (14)
Colorless crystals from ethanol, yield 65%, mp 120–122 ◦C. IR (KBr, cm−1): 3460
(OH), 3285 (NH2). 1H NMR (DMSO-d6, δ ppm): δ = 1.83 (m, 2H, CH2(b)), 2.63 (5, 3H,
SCH3), 3.46 (t, 2H, CH2(c)), 4.26 (t, 2H, CH2(a)), 4.40 (t, 1H, OH), 6.28 (s, 2H, NH2),
7.20–7.84 (m, 4H, Ar-H). 13C NMR (DMSO-d6, δ ppm): δ = 16.4 (SCH3), 29.8 (CH2(b)),
32.8 (CH2(c)), 61.9 (CH2(a)), 124.8, 126.6, 126.8, 127.4, 131.6, 134.5, 148.8, and 149.1
(Ar-C and 2C N). Anal. Calcd for C12 H16N4OS2 (296.41): C, 48.62; H, 5.44; N, 18.90.
Found: C, 48.61, H, 5.43, N, 18.90.
1-(4-Amino-5-(2-meltylthio)phenyl)-4H-1,2,4-triazol-3-ylthio)-3-
chloropropan-2-ol (15)
◦
Colorless crystals from ethanol, yield 80%, mp 80–82 C. IR (KBr, cm−1): 3485
1
(OH), 3280 (NH2). H NMR (DMSO-d6, δ ppm): δ = 2.63 (s, 3H, SCH3), 2.98 (m, 1H,

660
H. A. EL-SAYED ET AL.
H-c), 3.38 (m, 1H, H-cꢀ), 3.62 (m, 1H, H-a), 3.78 (m, 1H, H-aꢀ), 3.92 (m, 1H, H-b), 4.49 (t,
1H, OH), 6.33 (s, 2H, NH2), 7.48–7.81 (m, 4H, Ar-H). 13C NMR (DMSO-d6, δ ppm): δ =
16.39 (SCH3), 43.2 (SCH2), 48.8 (CH2Cl), 69.6 (CHOH), 124.7, 126.8, 126.9, 127.5, 132.2,
135.5, 148.9, and 149.2 (Ar-C and 2C N). Anal. Calcd for C15 H15ClN4OS2 (330.86): C,
43.56; H, 4.57; N, 16.93. Found: C, 43.58, H, 4.58, N, 16.92.
3-(2-(Methylthio)phenyl)-5-(oxiran-2-ylmethylthio)-4H-1,2,4-triazole-
4-amine (16)
◦
Colorless crystals from ethanol, yield 60%, mp 94–96 C. IR (KBr, cm−1): 3268
(NH2). 1H NMR (DMSO-d6, δ ppm): δ = 2.38 (m, 1H, Ha), 2.63 (s, 3H, SCH3), 2.69 (m,
1H, H-aꢀ), 3.42–3.63 (m, 2H, H-b & H-c), 4.65 (m, 1H, H-cꢀ), 6.28 (S, 2H, NH2), 7.41–8.02
(m, 4H, Ar-H). 13C NMR (DMSO-d6, δ ppm): δ = 16.3 (SCH3), 41.8 (SCH2), 48.6 (CH2O,
oxiran), 53.0 (CHO, oxiran), 125.6, 126.7, 127.4, 131.8, 134.2, 139.1, 149.2, and 149.5
(Ar-C and 2C N). Anal. Calcd for C12 H14N4OS2 (294.40): C, 48.96; H, 4.79; N, 19.03.
Found: C, 48.96, H, 4.78, N, 19.04.
3-(Allylthio)-5-(2-(methylthio)phenyl)-4H-1,2,4-triazol-4-amine (17)
◦
Colorless crystals from ethanol, yield 80%, mp 110–112 C. IR(KBr, cm−1): 3256
1
(NH2). H NMR (DMSO-d6, δ ppm): δ = 2.62 (s, 3H, CH3), 4.86 (d, 2H, J = 5.1 Hz,
SCH2), 5.30 (d, 1H, J = 10.5 Hz, H-a), 5.42 (d, 1H, J = 17.2 Hz, H-aꢀ), 6.09 (m, 1H,
H-b), 6.23 (s, 2H, NH2), 7.36–8.08 (m, 4H, Ar-H). 13C NMR (DMSO-d6, δ ppm): δ = 16.2
(SCH3), 66.18 (SCH2), 118.8, 125.7, 126.8, 127.3, 131.9, 132.7, 134.2, 139.3, 149.2, and
149.7 (Ar-C, C C and 2C N). Anal. Calcd for C12H14N4S2 (278.40): C, 51.77; H, 5.07;
N, 20.12. Found: C, 51.78; H, 5.08; N, 20.12.
3-(2-(Methylthio)phenyl)-5-(prop-2-ynylthio)-4H-1,2,4-triazol-4-amine
(18)
Colorless crystals from ethanol, yield 82%, mp 114–116 ◦C. IR (KBr, cm−1): 3280
1
(NH2). H NMR (DMSO-d6, δ ppm): δ = 2.63 (s, 3H, CH3), 3.86 (dd, 1H, J = 2.3 Hz,
CH), 5.03 (t, 2H, J = 2.3 Hz, SCH2), 6.27 (s, 2H, NH2), 7.37–8.07 (m, 4H, Ar-H).
13C NMR (DMSO-d6, δ ppm): δ = 16.3 (SCH3), 53.5 (SCH2), 78.5, 78.8 (C C), 125.8,
126.7, 126.9, 132.0, 134.6, 139.4, 149.2, and 149.8 (Ar-C and 2C N). Anal. Calcd for
C12H12N4S2 (276.38): C, 52.15; H, 4.38; H, 20.27. Found: C, 52.15; H, 4.37; N, 20.27.
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