Convenient synthesis and antimicrobial activity of some novel amino acid coupled triazoles

Article abstract of DOI:10.3390/molecules15106759

This study describes a promising one-pot synthesis of [2-(5-benzyl-4- phenyl- 4H-[1,2,4]triazol-3-thio)-acetyl]-amino acid methyl esters 6a-h and dipeptides 10a-e, which were successfully synthesized starting from amino acid esters 5a-h, 9a-e and azides 4

Full text of DOI:10.3390/molecules15106759

Molecules 2010, 15, 6759-6772; doi:10.3390/molecules15106759
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Convenient Synthesis and Antimicrobial Activity of Some Novel
Amino Acid Coupled Triazoles
S. M. El Rayes
Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia, Egypt;
E-Mail: samir_elrayes@yahoo.com; Tel.: +2127500914; Fax: +2643202381
Received: 19 July 2010; in revised form: 30 August 2010 / Accepted: 1 September 2010 /
Published: 28 September 2010
Abstract: This study describes a promising one-pot synthesis of [2-(5-benzyl-4-phenyl-
4H-[1,2,4]triazol-3-thio)-acetyl]-amino acid methyl esters 6a-h and dipeptides 10a-e,
which were successfully synthesized starting from amino acid esters 5a-h, 9a-e and azides
4, 8a,b, respectively. On the other hand, azide 4 underwent Curtius rearrangement to the
corresponding isocyanate, which subsequently reacted with selected aliphatic amine and/or
aniline derivatives to give the corresponding urea derivatives 11 and 12a,b. Reactions of
the isocyanate with secondary amines gave amide derivatives 13a,b. The structural
elucidation of products is reported and some of the products were also screened for their
antimicrobial activity.
Keywords: triazoles; azide coupling; peptides; Curtius
1. Introduction
The emergence of drug resistance in disease treatment calls for the continuing availability of new
chemotherapeutic agents able to overcome this problem. In the last few decades, the chemistry of
1,2,4-triazoles and their fused heterocyclic derivatives have received considerable attention due to their
synthetic and effective biological importance. Based on the principle of additive activity, we
anticipated obtaining reinforcement of biological activities by means of substitutions at different
positions of amino acid substituted-1,2,4-triazole derivatives. On the other hand; the electronic
structure of sulfur imbues sulfurous organic compounds, including amino acids, with chemical
reactivities beyond those of the corresponding oxygen or nitrogen-containing analogs. Biosulfur
compounds are much more nucleophilic and acidic than their oxygen analogs, allowing thiols (RSH)

Molecules 2010, 15
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and thioethers (R-S-R') to participate in a far greater range of electrophilic substitutions than the
corresponding alcohols [1].
Recently the literature has reported a large number of 1,2,4-triazole-containing ring systems that
have been incorporated into a wide variety of therapeutically interesting drug candidates including
antiseptic, analgesic, anti-convulsant [2-13], antibiotic [2], antiallergic [2], anti-inflammatory [2-11,14],
diuretic [2,6,9], fungicidal [4,5,11-14], insecticidal [4,11,14], herbicidal [4,11,14], antibacterial
[4-7,12,13], antiviral [3-6,8,9,11], antidepressant [3,6,10], antimicrobial [3-6,8,11-13], antitumor
[4,7,10,11], antihypertensive [6,9,10], and antimigraine compounds [8]. In addition there are several
well known drugs, e.g. anastrozole, rizatriptan, nefazodone, vorozole, ribavirin, fluconazole, letrozole
and uniconazole, that contain the 1,2,4-triazole group (Figure 1).
Figure 1. Biologically active triazoles.
N
Cl
CH3
N
NC
N
N
NMe2
CH3
CN
CH3
N
N
H3C
O
N
CH3
N
N
N
N
O
N
N
N
N
Cl
N
N
N
H
Vorozole
Anastrozole
Rizatriptan
Nefazodone
N
O
N
N
N
N
N
N
N
NH2
N
F
O
N
N
OH
N
OH
HO
N
HO
OH
N
F
CN
N
CN
Cl
Ribavirin
Fluconazole
Letrozole
Uniconazole
On the other hand, many triazole derivatives also have industrial applications as precursors for
photosensitive materials (i.e., inks and toners) [15], in polymer chemistry [12], and others [16,17].
Unfortunately, the water solubility of most triazole compounds is too poor for use in a clinical trials as
medicines [18]. In this paper, we describe the development of a new series of 1,2,4-triazole
derivatives, whose chemical modifications include coupled amino acid and dipeptide derivatives.
2. Results and Discussion
2.1. Chemistry
The synthesis of new amino acid derivatives coupled with biologically active heterocyclic moieties
such as triazoloquinazoline [19], quinoline [20], and pyradizinone [21] attracted our attention. In this
work we studied 5-benzyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (1) as a biologically active
heterocyclic precursor which was synthesized according to the established procedure [3].

Molecules 2010, 15
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The hydrazide 3 could be prepared from 1 by regioselective S-alkylation [22] with ethyl
chloroactetate to give the corresponding ester 2, which was subsequently hydrazinolyzed by hydrazine
hydrate.
The acyl azide pathway was one of the first peptide coupling methods developed by Curtius [23].
Synthesis of the target amino acid derivatives 6a-h were successfully achieved via the azide coupling
method [19-21,24], which was reported to minimize the degree of racemization in amino acid
coupling. An ethyl acetate solution of the in situ generated azide 4 reacted with the amino acid methyl
ester hydrochlorides 5a-h in the presence of triethylamine to afford [2-(5-benzyl-4-phenyl-4H-
[1,2,4]triazol-3-thio)-acetyl]-amino acid methyl esters 6a-h in good to moderate yields (Scheme 1).
Scheme 1. Synthesis of amino acid monopeptides coupled with triazole
O
O
C
C
N
N
N
N
N
N
ClCH2COOCH3
Et3N, EtOH
N
N
N
N2H4
SH
S
S
NHNH2
OCH3
Ph
Ph
Ph
Ph
Ph
Ph
3
1
2
NaNO2, HCl, 0 oC
O
O
C OCH3
C
N
N
HN
n
NH2(CHR)2COOCH3.HCl 5a- h
S
N3
N
N
R
O
N
S
°
Ph
Et3N, EtOAc, 0 C, 24 h
N
Ph
Ph
Ph
4
n
2
1
1
1
1
1
R
5, 6
6a-h
H
H
a
b
c
d
e
f
(-Ala)
(Gly)
(L-Leu)
(L-Met)
(L-Thr)
(L-Val)
CH2CH(CH3)2
CH2CH2SCH3
CH(OH)CH3
CH(CH3)2
OH
g (L- Tyr)
h (L-Trp)
1
1
N
H
Further development of the azide coupling was achieved by the synthesis of N-substituted dipeptide
derivatives 10a-e. Thus, boiling the amino acid ester derivatives 6a,b (β-Ala, Gly) with hydrazine
hydrate gave the acyl hydrazides 7a, b (Scheme 2). Finally, nitrosation of acyl hydrazides 7a, b by
treatment with a NaNO2 and HCl mixture gave the acyl azides 8a,b. The in situ generated azides 8a, b
reacted with amino acid methyl ester hydrochlorides 9a-e in ethyl acetate in the presence of
triethylamine to produce dipeptide derivatives 10a-e in reasonable yield (Scheme 2).

Molecules 2010, 15
Scheme 2. Synthesis of amino acid dipeptides coupled with triazole
6762
O
O
COOCH3
N2H4
C
C
HN
O
n
NHNH2 NaNO2, HCl, 0 oC
HN
O
HN
N3
n
n
Ar
S
Ar
S
Ar
S
O
6a,b
8a,b
7a,b
n
6,7, 8
NH2(CHR)(CH2)mCOOCH3.HCl 9a-e
1
0
a
b
(-Ala)
°
Et3N, EtOAc, 0 C, 24 h
(Gly)
m
n
R
9, 10
O
R
0
1
0
1
0
0
H
H
H
COOMe
a
b
c
d
e
(Gly, Gly)
N
N
(Gly, -Ala)
(-Ala, Gly)
(-Ala, -Ala)
(-Ala, L-Ser)
0
1
1
1
C
N
m
HN
O
Ar =
HN
n
H
Ph
Ar
S
Ph
CH2OH
10
An extension of this study was achieved by refluxing the azide 4 in a non polar solvent such as
benzene whereupon a Curtius rearrangement occurred to give the corresponding isocyanate. On
treatment in situ of the isocyanate with selected aliphatic amine and/or aniline derivatives urea
derivatives 11 and 12a,b were obtained. The reaction of isocyanate with secondary amines gave amide
derivatives 13a,b, whereas with methanol it gave the carbamic acid derivative 14 (Scheme 3).
Scheme 3. Synthesis of triazole derivatives under Curtius rearrangement condition
NH
Ar`
NH
NH
N
S
Ar
S
Ar
X
O
O
12
1-Reflux 2 h.
1-Reflux 2 h.
2-1.0 mmol X
3-Reflux 2 h.
13
2-1.0 mmol Ar` NH2
3-Reflux 2 h.
NH
Ar`
X
12
13
a
O
a
Cl
b
CH2
O
NO2
b
N3
S
Ar
1-Reflux 2 h.
2-1.0 mmol
4
MeOH
1-Reflux 2 h.
2-1.0 mmol
3-Reflux 2 h.
3-Reflux 2 h.
NH2
NH
O
NH
O
N
N
OCH3
S
Ar
NH
S
Ar
N
Ar =
Ph
11
Ph
14

Molecules 2010, 15
6763
The structural assignment of ester 2, acyl hydrazide 3, N-substituted amino acid esters 6a-h; acyl
hydrazides 7a,b, N-substituted dipeptides 10a-e, urea derivatives 11 and 12a,b, amide derivatives
1
13a,b and carbamic acid derivative 14 is based on H-NMR,13C-NMR, IR, mass spectral and
1
physicochemical analyses. The H-NMR spectrum of the N-substituted dipeptide 10b, for example,
exhibits signals at δ 8.52, 6.61, 4.63, 3.73, 3.54-3.49 and 2.31 ppm corresponding to the
functionalities found at the dipeptide chain; two NH groups, CH2 (glycyl residue), OMe of ester and
two CH2 (β-alanine residue), respectively (Figure 2). The 1H-NMR spectrum of the urea derivative 12b
1
showed two characteristic signals at δ 10.11 and 5.64 ppm for the two NH groups. The H-NMR
spectra of all compounds showed two characteristic signals, one within the range δ 4.37-4.00 ppm for
SCH2 and the other within δ 412- 3.80 ppm for PhCH2 (Figure 2).
Figure 2. Selected 1H-NMR assignments of compounds 10b and 12b.
3.73
COOMe
NO2
3.54-3.49
O
O
2.91
6.61
C
NH
8.52
C
N
HN
4.63
4.21
4.06
H 10.11
NH
N
N
N
N
5.64
S
S
O
N
3.86
N
3.83
Ph
Ph
Ph
Ph
10b
12b
2.2. Antimicrobial studies
The antimicrobial activity of sixteen triazole derivatives was assayed by the agar well diffusion
method [25] against two bacterial colonies (Escherechia coli and Bacillus subtilis) and two fungal
cultures (Phytophthora infestans and Colletotricum gloeosporioides). Five-millimeter diameter wells
were cut out in agar plates using a sterile cork-borer. Fifty µL of 4 mg/mL test solutions were
transferred aseptically to the wells. Plates were incubated at 25 °C for 24 hours and four days for
bacteria and fungi, respectively. The antimicrobial activity was evaluated by measuring the inhibition
zone formed around the wells. Wells containing sterile distilled water or the solvent (ethanol) served as
controls. Results are listed in Table 1.
The results showed that not all derivatives were active against the tested microorganisms.
Derivative 2 inhibited the growth of P. infestans, but it failed against C. gloeosporioides and the two
bacterial organisms (E. coli, B. subtilis.). On the other hand, 12b was effective against C.
gloeosporioides, but not against P. infestans (Table 1). As for bacteria, derivatives 6c and 12b
inhibited the growth of the bacterium B. subtilis, while derivative No. 14 was inhibitory to the growth
of the bacterium E. coli (Table 1). It is worth mention that derivative 12b was effective against both
types of microorganisms (B. subtilis and C. gloeosporioides) (Table 1).

Molecules 2010, 15
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Table1. Antimicrobial activity of triazole derivatives.
Antifungal
Antibacterial
Comp.
No.
Phytophthora
Colletotricum
Bacillus subtilis Escherichia coli
infestans
gloeosporioides
2
3
6a
6b
6c
6d
6e
6g
6h
6f
11
12a
12b
13a
13b
14
++
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
++
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+
+++
-
-
-
-
-
-
-
+
-
-
-
-
-
3. Experimental
3.1. General
Solvents were purified and dried in the usual way. The boiling range of the petroleum ether used
was 40–60 °C. Thin layer chromatography (TLC): silica gel 60 F254 plastic plates (E. Merck, layer
thickness 0.2 mm) detected by UV absorption. Elemental analyses were performed on a Flash EA-
1112 instrument at the Microanalytical Laboratory, Faculty of Science, Suez Canal University,
Ismailia, Egypt. Melting points were determined on a Buchi 510 melting-point apparatus and the
values are uncorrected. IR spectra measured with Perkin Elmer 1430 ratio recording. NMR spectra
were measured with Bruker spectrometers (200 MHz and 300 MHz) and TMS (0.00 ppm) was used as
internal standard. The mass spectra were measured with a KRATOS Analytical Kompact spectrometer.
The starting compound 1 was prepared according to a described method [3].
3.2. (5-Benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetic acid ethyl ester (2)
A solution of 5-benzyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (1, 0.27 g, 1.0 mmol) in
ethanol (30 mL), Et3N (0.20 mL, 2.0 mmol) and chloroacetic acid ethyl ester (0.12 mL, 1.0 mmol) was
mixed and then refluxed for 24 h while the reaction was monitored via tlc. The reaction mixture was
then cooled and an ice/water mixture was added. The syrup formed was extracted with cold ethyl
acetate (30 mL); washed with 2 N Na2CO3 and dried (Na2SO4). The solvent was evaporated under
vacuum to obtain a pure oily product. Colorless oil (0.31 g, 88%); IR (neat): 3063, 2971, 1732, 1673,
1
1661, 1620, 1510, 1460, 1403 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 7.61-7.52 (4H, m, ArH);
7.29-7.17 (4H, m, ArH); 7.07 (2H, d, J = 8.4 Hz, ArH); 4.31 (2H, s, SCH2); 4.12 (2H, s, PhCH2); 3.97

Molecules 2010, 15
6765
(2H, q, J = 7.2 Hz, OCH2CH3); 1.36 (3H, t, J = 7.2 Hz, OCH2CH3). Anal. Calcd. For C19H19N3O2S
(353.12): C, 64.57; H, 5.42; N, 11.89; S, 9.07; Found: C, 64.36; H, 5.38; N, 11.78; S, 8.99.
3.3. (5-Benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetic acid hydrazide (3)
To a solution of 2 (0.35 g, 1.0 mmol) in ethanol (30 mL), hydrazine hydrate (0.24 mL, 5.0 mmol)
was added. The reaction mixture was refluxed for 4h, afterwards it was stirred overnight at room
temperature; cold water was added, the formed precipitate was filtered off, washed with ethanol and
ether then crystallized from aqueous ethanol to yield the hydrazide 3. Colorless crystals (0.32 g, 94%);
mp 167–168 °C, IR (KBr disk): 3310, 3290, 3205, 3074, 2961, 1676, 1668, 1652, 1604, 1540, 1502,
1
1451, 1400 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 8.42 (1H, bs, D2O exchangeable, NH);
7.63-7.57 (4H, m, ArH); 7.31-7.22 (4H, m, ArH); 7.13 (2H, d, J = 8.2 Hz, ArH); 4.37 (2H, s, SCH2);
4.33 (2H, bs, D2O exchangeable, NH2); 4.08 (2H, s, PhCH2). Anal. Calcd. For C17H17N5OS (339.12):
C, 60.16; H, 5.05; N, 20.63; S, 9.45; Found: C, 60.32; H, 5.19; N, 20.48; S, 9.65.
3.4. General procedure for azide method; preparation of 6a-h
To a cold solution (−5 °C) of hydrazide 3 (0.34 g, 1.0 mmol) in acetic acid (6 mL), 1 N HCl (3 mL),
and water (25 mL) was added a solution of NaNO2 (0.87 g, 1.0 mmol) in cold water (3 mL). The
reaction mixture was stirred at −5 °C for 15 min. The yellow syrup formed was extracted with cold
ethyl acetate (30 mL), washed with cold 3% NaHCO3, H2O and finally dried (Na2SO4). To this
solution amino acid esters 5a-h (1.0 mmol) in ethyl acetate (20 mL) containing 0.2 mL of
triethylamine was added. The reaction mixture was kept at −5 °C for 24 h., then at 25 °C for another
24 h. The solution was evaporated to dryness, and the residue was crystallized from petroleum ether/
ethyl acetate to give the desired product.
Methyl-3-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-propionate (6a). From β-
AlaOCH3·HCl (5a, 0.14 g). Colorless crystals (0.29 g, 71 %); mp 102 °C, IR (KBr disk): 3271, 3061,
2969, 1757, 1695, 1680, 1663, 1607, 1536, 1506, cm-1; 1H-NMR (200 MHz, CDCl3 δ ppm): 8.16 (1H,
bs, D2O exchangeable, NH); 7.54-7.35 (4H, m, ArH); 7.28-7.17 (4H, m, ArH); 7.08 (2H, d, J = 8.2 Hz,
ArH), 4.09 (2H, s, SCH2); 3.88 (2H, s, PhCH2); 3.74 (3H, s, OMe); 3.64-3.59 (2H, m, CH2NH); 2.63
13
(2H, t, J = 7.2 Hz, CH2CO2Me), C-NMR (CDCl3, 75 MHz, δ ppm): δ 32.3, 33.7, 35.5, 38.4, 51.2,
127.9, 128.1, 128.4, 128.8, 129.0, 129.6, 130.5, 137.8, 144.0, 159.0, 171.4, 173.7; Anal. Calcd.
For C21H22N4O3S (410.14): C, 61.44; H, 5.40; N, 13.65; S, 7.81; Found: C, 61.28; H, 5.53; N, 13.87; S,
7.96. Mass spectrum, m/z (%): 411(3), 410(11), 333(19), 319(28), 281(14), 280(43), 266(19), 267(53),
235(38), 234(26), 91(100).
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-acetate
(6b).
From
GlyOCH3·HCl (5b, 0.13 g). Colorless crystals (0.27 g, 68 %); mp 114 °C, IR (KBr disk): 3298, 3081,
2973, 1767, 1695, 1672, 1649, 1622, 1541, 1492, cm-1; 1H-NMR (200 MHz, CDCl3 δ ppm): 8.51 (1H,
bs, D2O exchangeable, NH); 7.55-7.52 (4H, m, ArH); 7.35-7.24 (4H, m, ArH); 7.11 (2H, d, J = 8.2 Hz,
ArH); 4.11 (2H, s, SCH2); 4.01 (2H, d, J = 7.2 Hz, CH2CO2Me); 3.98 (2H, s, PhCH2); 3.81 (3H, s,
OMe). 13C-NMR (CDCl3, 75 MHz, δ ppm): δ 29.7, 37.8, 44.1, 50.6, 127.6, 128.2, 128.5, 128.8, 129.3,

Molecules 2010, 15
6766
129.9, 130.3, 137.9, 145.3, 158.6, 171.0, 173.4; Anal. Calcd. For C20H20N4O3S (396.13): C, 60.59; H,
5.08; N, 14.13; S, 8.09; Found: C, 60.48; H, 5.22; N, 14.07; S, 8.18. Mass spectrum, m/z (%): 397(5),
396(9), 319(16), 305(23), 281(13), 280(48), 266(23), 267(61), 234(19), 235(49), 91(100).
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-4-methyl-pentanoate
(6c).
From L-LeuOCH3·HCl (5c, 0.18 g). Colorless crystals (0.34 g, 75 %); mp 94 °C, IR (KBr disk): 3256,
1
3043, 2955, 1751, 1700, 1681, 1658, 1600, 1561, 1520, 1500 cm-1; H NMR (200 MHz, CDCl3 δ
ppm): 8.33 (1H, bs, D2O exchangeable, NH); 7.54-7.38 (4H, m, ArH); 7.32-7.23 (2H, m, ArH); 7.10-
7.04 (4H, m, ArH); 4.65-4.62 (1H, m, NHCH); 4.11 (2H, s, SCH2); 3.97 (2H, s, PhCH2); 3.79 (3H, s,
OMe); 1.76-1.72 (2H, m, NHCH2); 1.36-1.34 (1H, m, CH2CH); 1.01 (6H, d, J = 6.8 Hz, (CH3)2CH),
13C-NMR (CDCl3, 75 MHz, δ ppm) 20.4, 21.6, 32.4, 38.5, 39.3, 48.9, 50.4, 128.0, 128.1, 128.3, 128.5,
129.0, 129.9, 130.0, 137.7, 144.2, 158.8, 172.5, 174.6. Anal. Calcd. For C24H28N4O3S (452.19): C,
63.69; H, 6.24; N, 12.38; S, 7.09; Found: C, 63.52; H, 6.11; N, 12.21; S, 6.85. Mass spectrum, m/z
(%): 453(2), 452(6), 375(13), 361(18), 281(19), 280(52), 266(25), 267(71), 234(17), 235(33), 91(100).
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-4-(methylthio)-butyrate (6d).
From L-MetOCH3·HCl (5d, 0.20 g). Colorless crystals (0.29 g, 62%); mp 89 C, IR (KBr disk): 3262,
1
3061, 2973, 1764, 1689, 1677, 1649, 1605, 1554, 1511, 1485cm-1; H-NMR (200 MHz, CDCl3 δ
ppm): 8.51 (1H, bs, D2O exchangeable, NH); 7.55-7.51 (4H, m, ArH); 7.37-7.26 (2H, m, ArH); 7.12-
7.04 (4H, m, ArH); 4.76-4.73 (1H, m, NHCH); 4.11 (2H, s, SCH2); 3.96 (2H, s, PhCH2); 3.81 (3H, s,
13
OMe); 2.59 (2H, t, J = 7.2 Hz, CH2SMe); 2.26-2.24 (2H, m, CHCH2); 2.15 (3H, s, SMe). C-NMR
(CDCl3, 75 MHz, δ ppm): δ 17.2, 27.9, 29.6, 32.7, 38.0, 51.2, 54.0, 127.6, 128.5, 128.7, 128.8, 129.6,
129.8, 131.0, 137.9, 145.2, 159.6, 171.7, 173.1; Anal. Calcd. For C23H26N4O3S2 (470.61): C, 58.70; H,
5.57; N, 11.91; S, 13.63; Found: C, 58.58; H, 5.43; N, 11.78; S, 13.79. Mass spectrum, m/z (%):
471(3), 470(8), 423(16), 409(17), 396(28), 319(19), 305(27), 281(22), 280(56), 266(32), 267(64),
234(23), 235(26), 91(100).
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-3-hydroxy-butyrate (6e). From
L-ThrOCH3·HCl (5e, 0.17 g). Colorless crystals (0.23 g, 52%); mp 101 C, IR (KBr disk): 3522, 3291,
3055, 2967, 1746, 1704, 1680, 1649, 1610, 1544, 1507 cm-1; 1H-NMR (200 MHz, CDCl3 δ ppm): 8.28
(1H, bs, D2O exchangeable, NH); 7.57-7.53 (4H, m, ArH); 7.38-7.28 (2H, m, ArH); 7.13-7.03 (4H, m,
ArH); 4.67-4.63 (1H, m, NHCH); 4.44 (1H, bs, D2O exchangeable, HCOH); 4.32-4.28 (1H, m,
CH3CH); 4.12 (2H, s, SCH2); 4.00 (2H, s, PhCH2); 3.85 (3H, s, OMe); 1.37 (3H, d, J = 6.8 Hz, Me).
13C-NMR (CDCl3, 75 MHz, δ ppm): δ 17.9, 27.6, 38.7, 51.6, 60.9, 66.9. 127.2, 128.3, 128.4, 128.6,
129.2, 129.9, 132.2, 138.0, 145.7, 158.9, 170.9, 172.8; Anal. Calcd. For C22H24N4O4S (440.52): C,
59.98; H, 5.49; N, 12.72; S, 7.28; Found: C, 60.27; H, 5.63; N, 12.56; S, 7.09. Mass spectrum, m/z
(%): 441(5), 440(10), 422(19), 396(34), 319(21), 305(32), 281(25), 280(47), 266(29), 267(71),
234(19), 235(22), 91(100).
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-3-methyl-butyrate (6f). From
L-ValOCH3·HCl (5f, 0.12 g). Colorless crystals (0.33 g, 75%); mp 93 C, IR (KBr disk): 3283, 3072,
2981, 1761, 1707, 1680, 1649, 1610, 1572, 1545, 1523 cm-1; 1H-NMR (200 MHz, CDCl3 δ ppm): 8.25

Molecules 2010, 15
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(1H, bs, D2O exchangeable, NH); 7.46-7.38 (4H, m, ArH); 7.22-7.16 (2H, m, ArH); 6.97-6.91 (4H, m,
ArH); 4.45-4.41 (1H, m, NHCH); 4.00 (2H, s, SCH2); 3.86 (2H, s, PhCH2); 3.68 (3H, s, OMe); 2.19
(1H, m, CH3CH); 0.92-0.90 (6H, d, J = 6.8 Hz, CH(CH3)2). 13C-NMR (CDCl3, 75 MHz, δ ppm): δ
17.0, 26.9, 28.3, 39.7, 51.0, 62.1, 127.0, 128.5, 128.6, 128.8, 129.5, 130.2, 131.8, 138.2, 145.3, 159.6,
170.4, 172.8; Anal. Calcd. For C23H26N4O3S (438.54): C, 62.99; H, 5.98; N, 12.78; S, 7.31; Found: C,
63.11; H, 6.13; N, 12.59; S, 7.26.
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)acetylamino]-3-(4-hydroxyphenyl)-
propionate (6g). From L-TyrOCH3·HCl (5g, 0.18 g). Colorless crystals (0.32 g, 64%); mp 117 C, IR
1
(KBr disk): 3555, 3281, 3092, 2972, 1738, 1697, 1684, 1667, 1613, 1563, 1507 cm-1; H-NMR (200
MHz, CDCl3 δ ppm): 8.40 (1H, bs, D2O exchangeable, NH); 7.78-7.75 (4H, m, ArH); 7.61-7.49 (4H,
m, ArH); 7.27-7.08 (6H, m, ArH); 5.76-5.59 (1H, bs, D2O exchangeable, OH); 5.12-4.97 (1H, m,
NHCHCH2); 4.37 (2H, s, SCH2); 4.14 (2H, s, PhCH2); 4.03 (3H, s, OMe); 3.41-3.32 (2H, d, J = 6.8
13
Hz, CH2CH), C-NMR (CDCl3, 75 MHz, δ ppm) 31.8, 36.6, 37.8, 51.7, 56.4, 121.3, 127.7, 127.9,
128.5, 128.8, 128.9, 129.0, 129.2, 129.4, 132.8, 136.1, 145.4, 157.3, 160.1, 171.3, 173.4; Anal. Calcd.
For C27H26N4O4S (502.58): C, 64.52; H, 5.21; N, 11.15; S, 6.38; Found: C, 64.37; H, 5.44; N, 11.00; S,
6.49.
Methyl-2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-3-(1H-indol-3-yl)-propionate
(6h). From L-TrpOCH3·HCl (5h, 0.20 g). Colorless crystals (0.36 g, 69%); mp 111 C, IR (KBr disk):
3391, 3265, 3063, 2958, 1742, 1690, 1678, 1647, 1611, 1552, 1507 cm-1; 1H-NMR (200 MHz, CDCl3
δ ppm): 8.70 (1H, bs, D2O exchangeable, NH); 8.31 (1H, bs, D2O exchangeable, NH); 7.85-7.73 (4H,
m, ArH); 7.61-7.53 (6H, m, ArH); 7.46-7.24 (5H, m, ArH); 5.24-5.18 (1H, m, NHCH); 4.33 (2H, s,
SCH2); 4.16 (2H, s, PhCH2); 4.00 (3H, s, OMe); 3.68-3.64 (2H, d, J = 6.8 Hz, CH2CH). Anal. Calcd.
For C29H27N5O3S (525.62): C, 66.27; H, 5.18; N, 13.32; S, 6.10; Found: C, 66.01; H, 4.99; N, 13.53; S,
5.90.
3.5. General procedure for preparation of hydrazides 7a,b
To a solution of esters 6a,b (1.0 mmol) in ethyl alcohol (30 mL), hydrazine hydrate (0.24 mL,
5.0 mmol) were added. The reaction mixture was refluxed for 4h, cooled; the precipitated white
precipitate was filtered and crystallized from aq. EtOH.
N-2-Hydrazinocarbonyl-ethyl-2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetamide (7a). From
ester 6a (0.41 g). Colorless crystals (0.37 g, 90 %); 139–140 C, IR (KBr disk): 3317, 3295, 3223,
1
3209, 3065, 2957, 1683, 1671, 1660, 1648, 1601, 1545, 1513 cm-1; H-NMR (200 MHz, CDCl3 δ
ppm): 8.16 (1H, bs, D2O exchangeable, NH); 7.51-7.33( 4H, m, ArH); 7.27-7.15 (4H, m, ArH); 7.10
(2H, d, J = 8.2 Hz, ArH); 6.58 (1H, bs, D2O exchangeable, NH); 4.49 (2H, m, NHCH2); 4.29 (2H, bs,
D2O exchangeable, NH2); 3.99 (2H, s, SCH2); 3.86 (2H, s, PhCH2); 2.39 (2H, t, J = 6.0 Hz,
NCH2CH2). Anal. Calcd. For C20H22N6O2S (410.49): C, 58.52; H, 5.40; N, 20.47; S, 7.81; Found: C,
58.84; H, 5.18; N, 20.11; S, 7.66.

Molecules 2010, 15
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N-Hydrazinocarbonylmethyl-2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetamide (7b). From
ester 6b (0.40 g). Colorless crystals (0.37 g, 93%); mp 152–153 C, IR (KBr disk): 3302, 3291, 3218,
3202, 3071, 2962, 1688, 1669, 1671, 1641, 1600 cm-1; 1H-NMR (200 MHz, CDCl3 δ ppm): 8.45 (1H,
bs, D2O exchangeable, NH); 7.53-7.49 (4H, m, ArH); 7.33-7.27 (4H, m, ArH); 7.17 (2H, d, J = 8.2 Hz,
ArH); 6.64 (1H, bs, D2O exchangeable, NH); 4.60 (2H, d, J = 7.4 Hz, NHCH2); 4.30 (2H, bs, D2O
exchangeable, NH2); 4.11 (2H, s, SCH2); 3.98 (2H, s, PhCH2). Anal. Calcd. For C19H20N6O2S
(396.47): C, 57.56; H, 5.08; N, 21.20; S, 8.09; Found: C, 57.33; H, 5.02; N, 21.47; S, 8.44.
3.6. General procedure for preparation of 10a-e.
Dipeptides 10a-e were prepared according to the previously described azide procedure.
Methyl-2-(2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-acetylamino)-acetate (10a).
From hydrazide 7b (0.40 g) and GlyOCH3·HCl (9a, 0.13 g). Colorless crystals (0.22 g, 49 %);
1
mp 78–80 C, IR (KBr disk): 3207, 3198, 3067, 2975, 1701, 1686, 1674, 1665, 1614 cm-1; H-NMR
(200 MHz, CDCl3 δ ppm): 8.47 (1H, bs, D2O exchangeable, NH); 7.55-7.48 (4H, m, ArH); 7.30-7.24
(4H, m, ArH); 7.19 (2H, d, J = 8.2 Hz, ArH); 6.63 (1H, bs, D2O exchangeable, NH); 4.57 (2H, d,
J = 7.4 Hz, NHCH2); 4.52 (2H, d, J = 7.4 Hz, NHCH2); 4.06 (2H, s, SCH2); 3.86 (2H, s, PhCH2); 4.76
13
(3H, s, OMe). C-NMR (CDCl3, 75 MHz, δ ppm) 32.1, 37.2, 45.4, 47.6, 52.4, 128.1, 128.2, 128.5,
128.8, 129.1, 129.8, 130.3, 135.1, 143.9, 157.6, 168.7, 170.0, 172.9; Anal. Calcd. For C22H23N5O4S
(453.51): C, 58.26; H, 5.11; N, 15.44; S, 7.07; Found: C, 58.02; H, 5.45; N, 15.38; S, 6.82.
Methyl-3-(2-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-acetylamino)-propionate
(10b). From hydrazide 7b (0.40 g) and AlaOCH3·HCl (9b, 0.14 g). Colorless crystals (0.26 g, 56
1
%); mp 73–74 C, IR (KBr disk): 3179, 3167, 3061, 2968, 1703, 1690, 1676, 1667, 1610 cm-1; H-
NMR (200 MHz, CDCl3 δ ppm): 8.52 (1H, bs, D2O exchangeable, NH); 7.49-7.45 (4H, m, ArH); 7.29-
7.23 (4H, m, ArH); 7.16 (2H, d, J = 8.0 Hz, ArH); 6.61 (1H, bs, D2O exchangeable, NH); 4.63 (2H, d,
J = 7.4 Hz, NHCH2); 4.06 (2H, s, SCH2); 3.86 (2H, s, PhCH2); 3.73 (3H, s, OMe); 3.54-3.49 (2H, m,
NHCH2); 2.91 (2H, t, J = 7.2 Hz, NCH2CH2). 13C-NMR (CDCl3, 75 MHz, δ ppm): δ 27.5, 33.3, 38.2,
39.6, 45.8, 51.4, 127.3, 128.0, 128.3 128.7, 129.3, 130.7, 132.2, 139.0, 145.6, 160.2, 168.8, 172.6,
173.1; Anal. Calcd. For C23H25N5O4S (467.54): C, 59.08; H, 5.39; N, 14.98; S, 6.86; Found: C, 58.87;
H, 5.18; N, 14.72; S, 6.54. Mass spectrum, m/z (%): 468(2), 467(11), 381(22), 352(27), 281(19),
280(34), 266(26), 267(61), 234(32), 235(41), 91(100).
Methyl-2-(3-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-propionylamino)-acetate
(10c). From hydrazide 7a (0.41 g) and GlyOCH3·HCl (9a, 0.13 g). colorless crystals (0.21 g, 45 %);
77–78 C, IR (KBr disk): 3183, 3177, 3067, 2956, 1699, 1687, 1672, 1651, 1610 cm-1; 1H-NMR (200
MHz, CDCl3 δ ppm): 8.22 (1H, bs, D2O exchangeable, NH); 7.57-7.36 (4H, m, ArH); 7.29-7.19 (4H,
m, ArH); 7.14 (2H, d, J = 8.2 Hz, ArH); 6.51 (1H, bs, D2O exchangeable, NH); 4.62 (2H, m, NHCH2);
4.08 (2H, s, SCH2); 3.97 (2H, s, PhCH2); 3.73 (3H, s, OMe); 3.57 (2H, m, NHCH2); 2.39 (2H, t,
J = 7.0 Hz, NCH2CH2). 13C-NMR (CDCl3, 75 MHz, δ ppm): δ 27.8, 33.9, 36.3, 38.0, 39.5, 45.1, 51.0,
127.1, 128.2, 128.7 128.9, 129.7, 130.3, 132.0, 139.3, 145.1, 159.4, 170.1, 171.9, 172.8; Anal. Calcd.

Molecules 2010, 15
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For C23H25N5O4S (467.54): C, 59.08; H, 5.39; N, 14.98; S, 6.86; Found: C, 59.31; H, 5.52; N, 14.67; S,
6.90.
Methyl-3-(3-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-propionylamino)-
propionate (10d). From hydrazide 7a (0.41 g) and AlaOCH3·HCl (9b, 0.14 g). Colorless crystals
(0.20 g, 37 %); 71–73 C, IR (KBr disk): 3191, 3180, 3062, 2955, 1704, 1689, 1666, 1647, 1607 cm-1;
1H-NMR (200 MHz, CDCl3 δ ppm): 8.29 (1H, bs, D2O exchangeable, NH); 7.61-7.52 (4H, m, ArH);
7.24-7.08 (4H, m, ArH); 7.01 (2H, d, J = 8.2 Hz, ArH); 6.44 (1H, bs, D2O exchangeable, NH); 4.08
(2H, s, SCH2); 3.97 (2H, s, PhCH2), 3.73 (3H, s, OMe); 3.54 (2H, m, NHCH2); 3.52-3.47 (2H, m,
NHCH2); 2.39-2.32 (4H, m, 2 CH2). Anal. Calcd. For C24H27N5O4S (481.57): C, 59.86; H, 5.65; N,
14.54; S, 6.66; Found: C, 59.58; H, 5.92; N, 14.20; S, 6.97.
Methyl-2-(3-[2-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thio)-acetylamino]-propionylamino)-3-
hydroxy-propionate (10e). From hydrazide 7a (0.41 g) and L-SerOCH3·HCl (9e, 0.16 g). Colorless
crystals (0.24g, 48 %); 79–81 C, IR (KBr disk): 3374, 3207, 3191, 3047, 2976, 1707, 1691, 1683,
1
1664, 1601 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 8.32 (1H, bs, D2O exchangeable, NH);
7.54-7.46 (4H, m, ArH); 7.31-7.27 (4H, m, ArH); 7.13 (2H, d, J = 8.2 Hz, ArH); 6.37 (1H, bs, D2O
exchangeable, NH); 5.04-5.00 (1H, m, NHCH); 4.29-4.26 (2H, m, NHCH2); 4.02 (2H, s, SCH2); 3.95
(2H, s, PhCH2); 3.77 (3H, s, OMe); 3.53-3.50 (2H, m, CHCH2OH); 3.32 (1H, bs, D2O exchangeable,
CH2OH); 2.35-2.32 (2H, m, NCH2CH2). Anal. Calcd. For C24H27N5O5S (497.57): C, 57.93; H, 5.47;
N, 14.08; S, 6.44; Found: C, 57.61; H, 5.42; N, 14.27; S, 6.28.
3.7. General procedure for azide Curtius rearrangement to the corresponding isocyanate; preparation
of 11-14
To a cold solution (−5 °C) of hydrazide 3 (0.34 g, 1.0 mmol) in acetic acid (6 mL), 1 N HCl (3 mL),
and water (25 mL) was added a solution of NaNO2 (0.87 g, 1.0 mmol) in cold water (3 mL). The
reaction mixture was stirred at −5 °C for 15 min. The yellow syrup formed was extracted with cold
benzene (30 mL), washed with cold 3% NaHCO3, H2O and finally dried (Na2SO4); the extract was
filtered off and refluxed for 2 h. To this solution the appropriate amount of amine and/or MeOH
(1.0 mmol) in benzene (20 mL) was added. The reflux was continued for an additional 2 h. The solvent
was evaporated under reduced pressure and the residue was triturated with petroleum ether and
crystallized from petroleum ether/ethyl acetate to give the desired product.
3-Cyclohexyl-1-(5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thiomethyl)-urea (11). From cyclohexylamine
(0.10 g). Colorless crystals (0.35 g, 83%); mp 99 C, IR (KBr disk): 3218, 3201, 3091, 2910, 1710,
1
1676, 1643, 1603, 1571, 1509 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 10.48 (1H, bs, D2O
exchangeable, NH); 7.70-7.61 (4H, m, ArH); 7.47-7.32 (2H, d, J = 8.4 Hz, ArH); 7.21-6.98 (4H, m,
ArH); 6.90 (1H, bs, D2O exchangeable, NH); 3.87 (2H, s, SCH2); 3.80 (2H, s, PhCH2); 2.40 (1H, m,
NHCH); 1.73-1.62 (4H, m, 2 CH2); 1.33-1.27 (2H, m, (CH2)2CH2); 0.96-0.84 (4H, m, 2 CH2) Anal.
Calcd. For C23H27N5OS (421.56): C, 65.53; H, 6.46; N, 16.61; S, 7.61; Found: C, 65.31; H, 6.71; N,

Molecules 2010, 15
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16.49; S, 7.81. Mass spectrum, m/z (%): 422(4), 421(13), 393(18), 344(21), 330(31), 322(21), 281(16),
280(37), 266(24), 267(55), 234(29), 235(44), 91(100).
1-(5-Benzyl-4-phenyl-4H-[1,2,4]triazol-3-thiomethyl)-3-(4-chlorophenyl)-urea (12a). From p-chloro-
aniline (0.13 g). Colorless crystals (0.34 g, 76%); mp 113 C, IR (KBr disk): 3212, 3145, 3042, 2960,
1
1721, 1682, 1644, 1606, 1543, 1503 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 10.29 (1H, bs, D2O
exchangeable, NH); 7.41-7.31 (4H, m, ArH); 7.18-7.09 (2H, d, J = 8.4 Hz, ArH); 7.10-6.77 (8H, m,
ArH); 5.64 (1H, bs, D2O exchangeable, NH); 4.03 (2H, s, SCH2); 3.80 (2H, s, PhCH2). Anal. Calcd.
For C23H20ClN5OS (449.96): C, 61.39; H, 4.48; N, 15.56; S, 7.13; Found: C, 61.11; H, 4.62; N, 15.41;
S, 7.39.
1-(5-Benzyl-4-phenyl-4H-[1,2,4]triazol-3-thiomethyl)-3-(4-nitrophenyl)-urea (12b). From p-nitro-
aniline (0.14 g). Yellow crystals (0.31 g, 67%); mp 127 C, IR (KBr disk): 3233, 3164, 3049, 2953,
1
1715, 1673, 1652, 1613, 1552, 1523, 1500 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 10.11 (1H, bs,
D2O exchangeable, NH); 7.66 (2H, d, 8.0, ArH); 7.46-7.41 (4H, m, ArH); 7.31-7.27 (2H, d,
J = 8.0 Hz, ArH); 7.11-6.87 (6H, m, ArH); 5.64 (1H, bs, D2O exchangeable, NH); 4.21 (2H, s, SCH2);
3.83 (2H, s, PhCH2). Anal. Calcd. For C23H20N6O3S (460.51): C, 59.99; H, 4.38; N, 18.25; S, 6.96;
Found: C, 59.81; H, 4.02; N, 18.47; S, 6.89.
Morpholine-4-carboxylic acid (5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thiomethyl)-amide (13a). From
morpholine (0.09 g). Colorless crystals (0.30 g, 73%); mp 91 C, IR (KBr disk): 3242, 3081, 2968,
1
1706, 1678, 1646, 1605, 1556, 1511 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 10.36 (1H, bs, D2O
exchangeable, NH); 7.47-7.31 (4H, m, ArH); 7.20-7.01 (2H, d, J = 8.4 Hz, ArH); 6.97-6.87 (4H, m,
ArH), 4.06 (2H, s, SCH2); 3.84 (2H, s, PhCH2); 3.72-3.66 (4H, m, O(CH2)2); 3.5-3.43 (4H, m,
13
NH(CH2)2), C-NMR (CDCl3, 75 MHz, δ ppm) 34.5, 46.8, 47.4, 68.1, 127.4, 127.7, 127.9, 128.5,
128.7, 128.8, 129.1, 136.1, 146.2, 155.7, 159.4; Anal. Calcd. For C21H23N5O2S (409.50): C, 61.59; H,
5.66; N, 17.10; S, 7.83; Found: C, 61.42; H, 5.49; N, 17.28; S, 7.97.
Piperidine-1-carboxylic acid (5-benzyl-4-phenyl-4H-[1,2,4]triazol-3-thiomethyl)-amide (13b). From
piperdine (0.09 g). Colorless crystals (0.35 g, 83%); mp 109 C, IR (KBr disk): 3214, 3174, 2959,
1
1705, 1681, 1640, 1624, 1545, 1501 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 10.59 (1H, bs, D2O
exchangeable, NH); 7.45-7.41 (4H, m, ArH); 7.19 (2H, d, J = 8.4 Hz, ArH); 7.09-6.90 (4H, m, ArH);
4.04 (2H, s, SCH2); 3.80 (2H, s, PhCH2); 3.6-3.53 (4H, m, N(CH2)2); 2.07 (2H, m, (CH2)2(CH2));
1.61-1.43 (4H, m, 2 CH2|). Anal. Calcd. For C22H25N5OS (407.53): C, 64.84; H, 6.18; N, 17.18; S,
7.87; Found: C, 64.99; H, 6.31; N, 17.01; S, 7.63. Mass spectrum, m/z (%): 408(3), 407(11), 379(29),
322(34), 281(21), 280(32), 266(17), 267(58), 234(27), 235(36), 91(100).
(5-Benzyl-4-phenyl-4H-[1,2,4]triazol-3-thiomethyl)-carbamic acid methyl ester (14). From MeOH
(0.04 g). Colourless crystals (0.22 g, 62%); mp 54 C, IR (KBr disk): 3178, 3065, 2942, 1713, 1667,
1
1639, 1604, 1531, 1500 cm-1; H-NMR (200 MHz, CDCl3 δ ppm): 10.05 (1H, bs, D2O exchangeable,
NH); 7.44-7.39 (4H, m, ArH); 7.30-7.26 (2H, d, J = 8.0 Hz, ArH); 7.11-6.86 (4H, m, ArH); 4.05 (2H,
13
s, SCH2); 3.87 (2H, s, PhCH2); 3.77 (3H, s, OMe). C-NMR (CDCl3, 75 MHz, δ ppm): δ 29.1, 48.4,

Molecules 2010, 15
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50.2, 127.6, 128.4, 128.8, 129.1, 129.6, 131.0, 132.6, 139.2, 146.0, 159.9, 160.4; Anal. Calcd. For
C18H18N4O2S (354.43): C, 61.00; H, 5.12; N, 15.81; S, 9.05; Found: C, 59.68; H, 5.18; N, 15.69; S,
9.37.
4. Conclusions
In summary; twenty three newly triazoles derivatives were synthesized and their chemical structure
were elucidated via different analytical and spectroscopic methods. The antimicrobial activities of
some of these compounds against two bacterial colonies (Escherechia coli and Bacillus subtilis) and
two fungal cultures (Phytophthora infestans and Colletotricum gloeosporioides) were studied. The
synthesized compounds 12b, 6c, 2 and 14 showed important biological activity.
Acknowledgements
My deep thanks to Omar Abd El-Wahid Botany Department Faculty of Science SCU for his
technical support to achieving and characterization of antimicrobial studies.
References and Notes
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Sample Availability: Samples of compounds 1 to 7 and 11 to14 are available from the author.
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