Design and synthesis of new 1,2,4-triazole deriaties containing morpholine moiety as antimicrobial agents

Article abstract of DOI:10.3906/kim-1106-44

2-Morpholine-4ylethyl-3H -1,2,4-triazole-3-ones (2a, 2b) were obtained from the condensation between the corresponding ethoxycarbonylhydrazones and 2-morpholinoethanamine. 2a was conerted to acetohydrazide (4) ia the formation of an ester deriatie (3). Treatment of 2a and 2b with seeral aryl sulfonyl chlorides afforded the corresponding 2-arylsulfonyl-1,2,4-triazole-3-ones (5a-c and 6). The reaction of hydrazide (4) with benzyl iso-and benzyl isothiocyanate produced the corresponding carboxamide (8a) and carbothioamide (8b). The basic treatment of 8b yielded 5-mercapto-4H-1,2,4-triazol-3-yl)methyl]-2,4-dihydro-3H -1,2,4-triazol-3-one (10). The synthesis of 1,3-thiazol-2(3H) -ylidene-1,2,4-triazol-1-ylacetohydrazide (11) and 1,3-oxazole-2(3H) -ylidene-1,2,4-triazole-1-yl)acetohydrazide (9) deriaties was performed from the reaction of 8a and 8b with substituted phenacyl bromides. All the newly synthesized compounds were screened for their antimicrobial actiities and some of them were found to possess good or moderate antimicrobial actiity. TUeBITAK.

Full text of DOI:10.3906/kim-1106-44

Turk J Chem
36 (2012) , 411 – 426.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1106-44
Design and synthesis of new 1,2,4-triazole derivatives
containing morpholine moiety as antimicrobial agents
1
1
1,∗
1
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˙
˙
Deniz S¸AHIN , Hacer BAYRAK , Ahmet DEMIRBAS¸ , Neslihan DEMIRBAS¸ ,
2
˘
S¸engu¨l ALPAY KARAOGLU
1Department of Chemistry, Faculty of Sciences, Karadeniz Technical University,
61080 Trabzon-TURKEY
e-mail: neslihan@ktu.edu.tr
2Department of Biology, Rize University, 53100 Rize-TURKEY
Received: 11.06.2011
2-Morpholine-4ylethyl-3H -1,2,4-triazole-3-ones (2a, 2b) were obtained from the condensation between
the corresponding ethoxycarbonylhydrazones and 2-morpholinoethanamine. 2a was converted to aceto-
hydrazide (4) via the formation of an ester derivative (3). Treatment of 2a and 2b with several aryl
sulfonyl chlorides afforded the corresponding 2-arylsulfonyl-1,2,4-triazole-3-ones (5a-c and 6). The re-
action of hydrazide (4) with benzyl iso- and benzyl isothiocyanate produced the corresponding carbox-
amide (8a) and carbothioamide (8b). The basic treatment of 8b yielded 5-mercapto-4H -1,2,4-triazol-3-
yl)methyl]-2,4-dihydro-3H -1,2,4-triazol-3-one (10). The synthesis of 1,3-thiazol-2(3H)-ylidene-1,2,4-triazol-
1-ylacetohydrazide (11) and 1,3-oxazole-2(3H)-ylidene-1,2,4-triazole-1-yl)acetohydrazide (9) derivatives was
performed from the reaction of 8a and 8b with substituted phenacyl bromides.
All the newly synthesized compounds were screened for their antimicrobial activities and some of them
were found to possess good or moderate antimicrobial activity.
Key Words: 1,2,4-Triazole, 1,3-oxazole, 1,3-thiazole, morpholine, antimicrobial activity
Introduction
The development of drug resistance towards the clinically used antibacterial agents has increased the demand
for the design and synthesis of new chemical scaffolds possessing antimicrobial activity. The growing number of
immuno-compromised patients as a result of cancer chemotherapy, organ transplantation, and HIV infection are
∗Corresponding author
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Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
the major factors contributing to this increase. Moreover, in some cases, especially in patients with impaired
liver or kidney functions, the use of antimicrobial drugs to treat infections causes several problems. 1,2
Thus, these trends have required the urgent need for new, more effective antibacterial agents with
lack of side effects. For this purpose, 2 attractive approaches have been developed. One of them involved
the development of structurally new classes of antimicrobial agents with novel mechanism of action; the
other contained structural modification or optimization of the existing agents by improving both the binding
affinity and spectrum of activity while retaining bioavailability and safety profile. However, in recent years,
another strategy employing a combination of 2 different active fragments in 1 molecule has emerged.3 In this
strategy, each drug moiety is designed to bind independently to 2 different biological targets and synchronously
accumulate at both target sites. Such dual-action drugs, or hybrid drugs, offer the possibility to overcome the
current resistance and reduce the appearance of new resistant strains.2,4
1,2,4-Triazole derivatives have consistently attracted scientific and practical interest because of their
widely varying chemical properties, synthetic versatility, and pharmacological activities, such as antibacterial,5−11
antifungal,8−12 antitubercular,13−15 analgesic,16,17 anti-inflammatory,17−19 anticancer,20,21 anticonvulsant,22,23
antiviral,24,25 insecticidal,26 and antidepressant27 antiviral properties. Moreover, the 1,2,4-triazole compounds
carrying sulfone moiety or imine bond have been reported as antibacterial and antifungal, antihypertensive,
analgesic, anti-inflammatory, or antitumoral agents.28−36
Another important pharmacophore group is the morpholine nucleus incorporated in a wide variety of
therapeutically important drugs, one of which is linezolid, which belongs to the oxazolidinone class of antibiotics
and is used for the treatment of infections caused by gram-positive bacteria.37−39 In addition, 4-phenyl-
morpholine derivatives have been reported to possess antimicrobial, anti-inflammatory, and central nervous
system activities.40
Oxazolidinones are a new and promising class of synthetic antibiotics that have activity against numerous
multidrug-resistant gram-positive pathogens. Oxazolidinones have been thought to be not cross resistant with
other types of antibiotics due to their different mode of action mechanism that includes the interaction with the
bacterial ribosome to inhibit bacterial growth.41−45 Thiazolidinones, being bioisosters of oxazolidinones, have
been reported to possess diverse pharmacological properties such as antibacterial, antifungal, anticonvulsant,
anticancer, antituberculosis, and anti-human immunodeficiency virus type 1 (HIV-1) activities.46−52
Over 10 years our interest has focused on the synthesis of novel heterocyclic systems that have antimicro-
bial activity. In the present study, as a part of our ongoing research, we designed and synthesized new hybrid
molecules containing different pharmacophores in a single structure.
Experimental
All the chemicals were purchased from Fluka Chemie AG Buchs (Switzerland) and used without further
purification. Melting points of the synthesized compounds were determined in open capillaries on a Bu¨chi B-
540 melting point apparatus and are uncorrected. The reactions were monitored by thin-layer chromatography
(TLC) on silica gel 60 F254 aluminum sheets. The mobile phase was ethyl acetate:ether (1:1) and detection was
performed using UV light. IR spectra were recorded as potassium bromide pellets using a Perkin Elmer 1600
series FTIR spectrometer. 1 H-NMR and 13 C-NMR spectra were recorded on a BRUKER AVENE II 400 MHz
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Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
NMR Spectrometer (chemical shift in ppm downfield from TMS as an internal reference). The elemental analysis
was performed on a Costech Elemental Combustion System CHNS-O elemental analyzer. All the compounds
gave C, H, and N analyses within 0.4% of the theoretical values. The mass spectra (except compound 5)
were obtained on a Quattro LC-MS (70 eV) Instrument. Compounds 1a and 1b were prepared following a
previously reported literature procedure.53
General method for the synthesis of compounds 2a and 2b
Method 1: A mixture of the corresponding compound 1 (10 mmol) and 2-morpholinoethanamine (10 mmol)
was heated at 110-120 ◦ C in an oil bath for 2 h. (The progress of the reaction was monitored by TLC). Then
n-butyl acetate-diethyl ether (1:2) was added and the reaction mixture was kept overnight in cold conditions.
The solid formed was filtered off and recrystallized several times with suitable solvents to afford the target
compounds.
Method 2: A solution of the corresponding compound 1 (10 mmol) in water was refluxed with 2-
morpholinoethanamine (10 mmol) for 5 h (the progress of the reaction was monitored by TLC). The solvent
was evaporated under reduced pressure and an oily product was obtained. n-Butyl acetate-diethyl ether (1:2)
was added to it and it was kept overnight in cold conditions. The solid formed was filtered off and recrystallized
several times from suitable solvents to afford the target compounds.
5-Methyl-4-(2-morpholine-4ylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (2a). Yield 65%, mp
146-148 ◦ C. IR (KBr, υ, cm−1): 3185 (NH), 1693 (C=O), 1589 (C=N); Anal. Calcd (%) for C9 H16 N4 O2 : C,
50.93; H, 7.60; N, 26.40. Found: C, 50.92; H, 7.65; N, 25.75. 1 H-NMR (DMSO-d6 , δ ppm): 2.00 (3H, s, CH3),
2.16-2.51 (6H, m, 3CH2), 3.52-3.65 (6H, m, 3CH2), 11.31 (1H, brs, NH, exch. D2 O); 13 C-NMR (DMSO-d6 , δ
ppm): 16.99 (CH3), 58.73 (2CH2), 62.08 (2CH2), 71.61 (2CH2), 150.17 (triazole C-5), 160.43 (triazole C-3);
EI MS m/z (%): 212.98 ([M]+ , 69), 125.87 (29), 113.92 (100).
5-Benzyl-4-(2-morpholine-4ylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (2b). Yield 55%, mp
124-126 ◦ C. IR (KBr, υ, cm−1): 3167 (NH), 1697 (C=O), 1675 (C=N); Anal. Calcd (%) for C15 H20 N4 O2 :
C, 62.48; H, 6.99; N, 19.43. Found: C, 62.42; H, 7.03; N, 19.92. 1 H-NMR (DMSO-d6 , δ ppm): 2.17-2.49 (6H,
m, 3CH2), 3.35-3.49 (6H, m, 3CH2), 3.95 (2H, s, CH2), 7.26-7.31 (5H, m, arH), 11.52 (1H, s, NH, exch.D2 O);
13 C-NMR (DMSO-d6 , δ ppm): 31.34 (CH2), 53.05 (3CH2), 55.90 (3CH2), 65.97 (3CH2), ar C: [126.76 (CH),
128.48 (2CH), 128.51 (2CH), 135.41 (C)], 146.29 (triazole C-5), 154.98 (triazole C-3); EI MS m/z (%): 311.42
([M+Na]+ , 99), 289.41 ([M+1]+ , 59), 288.40 ([M]+ , 64), 202.23 (97), 114.18 (34), 113.18 (84).
Ethyl [3-methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]acetate
(3). Compound 2a (10 mmol) was refluxed with 1 equiv. of sodium in absolute ethanol for 2 h. Then ethyl
bromoacetate (10 mmol) was added, followed by refluxing for an additional 8 h (the progress of the reaction
was monitored by TLC). After the solvent was evaporated under reduced pressure, a solid appeared. The crude
product was recrystallized from ethanol:water (1:1) to afford the target compound 3.
Yield 43%, mp 94 ◦ C. IR (KBr, υ, cm−1): 1743 and 1713 (2C=O), 1581 (C=N), 1215 (C-O); Anal.
Calcd (%) for C13 H22 N4 O4 : C, 52.34; H, 7.43; N, 18.78. Found: C, 52.38; H, 7.39; N, 18.71. 1 H-NMR
(DMSO-d6 , δ ppm): 1.19 (3H, t, J = 7.2 Hz, CH3), 2.22 (3H, s, CH3), 2.35-2.52 (6H, m, 3CH2), 3.54 (4H,
t, J = 4.2 Hz, 2CH2), 3.68 (2H, t, J = 6.0 Hz, CH2), 4.12 (2H, q, J = 7.2 Hz, CH2), 4.49 (2H, s, CH2);
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Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
13 C-NMR (DMSO-d6 , δ ppm): 11.25 (CH3), 13.90 (CH3), 45.89 (CH2), 53.18 (2CH2), 56.35 (CH2), 60.91
(2CH2), 66.04 (2CH2), 144.21 (triazole C-5), 153.45 (triazole C-3), 167.86 (C=O). EI MS m/z (%): 321.23
([M+Na]+ , 100), 299.22 ([M+1]+ , 69), 211.98 (23), 113.93 (78).
2-[3-Methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl] acetohyd-
razide (4). A solution of compound 3 (10 mmol) in ethanol was allowed to reflux in the presence of hydrazine
hydrate (25 mmol) for 5-8 h (the progress of the reaction was monitored by TLC). After cooling to room
temperature, acetone was added to the mixture and it was kept overnight in cold conditions. The resulting solid
that separated was collected by filtration and recrystallized from ethyl acetate to afford the desired product.
Yield 36%, mp 146-148 ◦ C. IR (KBr, υ, cm−1): 3313 and 3169 (NH+NH2), 1692 and 1654 (C=O),
1585 (C=N), 1112 (C-O); 1 H-NMR (DMSO-d6 , δ ppm): 2.18 (3H, s, CH3), 2.30-2.50 (6H, m, 3CH2 +DMSO),
3.50-3.60 (4H, m, 2CH2), 3.64 (2H, t, J = 6.0 Hz, CH2), 4.17 (2H, s, CH2), 4.50 (2H, brs, NH2), 9.17 (1H, s,
NH); 13 C-NMR (DMSO-d6 , δ ppm): 16.83 (CH3), 43.62 (CH2), 51.39 (CH2), 58.77 (2CH2), 62.04 (CH2),
71.62 (2CH2), 149.42 (triazole C-5), 156.14 (triazole C-3), 171.49 (C=O); EI MS m/z (%): 325.32 ([M+2+K]+
53), 285.26 ([M+1]+ , 69), 114.06 (100).
,
General method for the synthesis of compounds 5a-c and 6. A solution of compound 4 (10
mmol) in dichloromethane was refluxed in the presence of metallic sodium (10 mmol) until the metallic sodium
disappeared completely (about 7-8 h). Then a suitable aryl sulfonylchloride was added, followed by refluxing
for an additional 8 h (the progress of the reaction was monitored by TLC). Water was added to the reaction
mixture, and the organic phase was separated and dried on sodium sulfate. After evaporation of the solvent
under reduced pressure, an oily product was obtained. This crude product was recrystallized from an appropriate
solvent to afford the desired compound.
5-Methyl-4-(2-morpholine-4-ylethyl)-2-[(4-nitrophenyl)sulfonyl]-2,4-dihydro-3H-1,2,4-tria-
zole-3-one (5a). Recrystallized from ethanol:water (1:2). Yield 31%, mp 190-192 ˚C. IR (KBr, υ, cm−1):
1742 (C=O), 1605 (C=N), 1186 (C-O); Anal. Calcd (%) for C15 H19 N5 O6 S: C, 45.33; H, 4.82; N, 17.62. Found:
C, 45.48; H, 4.96; N, 17.47. 1 H-NMR (DMSO-d6 , δ ppm): 2.26 (3H, s, CH3), 3.20-3.37 (12H, m, 6CH2), 7.85
(1H, d, J =8.6 Hz, arH), 8.18 (2H, d, J =8.9 Hz, arH), 8.51 (1H, d, J =8.6 Hz, arH); 13 C-NMR (DMSO-d6 ,
δ ppm): 12.26 (CH3), 38.69-41.17 (DMSO-d6 +4CH2), 50.22 (CH2), arC: [123.91 (CH), 125.66 (CH), 126.20
(C), 127.43 (CH), 129.86 (CH), 130.04 (C)], 140.18 (triazole C-3), 150.22 (triazole C-5); EI MS m/z (%): 436
([M+K]+ , 14), 399 ([M+2]+ , 11), 398 ([M+1]+ , 49), 336 (14), 216 (14), 215 (70), 154 (16), 153 (100), 120
(30), 114 (42).
5-Methyl-4-(2-morpholine-4-ylethyl)-2-[(4-bromophenyl)sulfonyl]-2,4-dihydro-3H-1,2,4-tria-
zole-3-one (5b). Recrystallized from ethyl acetate:petroleum ether (1:1). Yield 35%, mp 179-181 ◦ C. IR (KBr,
υ, cm−1): 1722 (C=O), 1600 (C=N), 1186 (C-O); Anal. Calcd (%) for C15 H19 N4 O4 S: C, 41.77; H, 4.44; N,
12.99. Found: C, 41.77; H, 4.49; N, 12.71. 1 H-NMR (DMSO-d6 , δ ppm): 2.22 (3H, s, CH3), 3.31-3.52 (8H,
m, 4CH2), 3.60 (4H, t, J = 5.6 Hz, 2CH2), 7.87-7.94 (4H, m, arH); 13 C-NMR (DMSO-d6 , δ ppm): 11.63
(CH3), 38.07-40.16 (DMSO-d6 +CH2), 52.94 (CH2), 55.28 (2CH2), 65.91 (2CH2), arC: [129.20 (2CH), 130.42
(C), 132.80 (2CH), 135.52 (C)], 149.59 (triazole C-3), 151.11 (triazole C-5); EI MS m/z (%): 114 (96), 215 (99),
216 (19), 431 ([M]+ , 76), 433 (72), 434 (16), 453 (40), 455 ([M+1+Na]+ , 32).
5-Methyl-4-(2-morpholine-4-ylethyl)-2-[(4-chlorophenyl)sulfonyl]-2,4-dihydro-3H-1,2,4-tria-
zole-3-one (5c). Recrystallized from ethanol. Yield 27%, mp 167-169 ◦ C. IR (KBr, υ, cm−1): 1721 (C=O),
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Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
1599 (C=N), 1186 (C-O). Anal. Calcd (%) for C15 H19 N4 O4 S: C, 46.57; H, 4.95; N, 14.48. Found: C, 46.84;
H, 5.12; N, 14.21. 1 H-NMR (DMSO-d6 , δ ppm): 2.22 (3H, s, CH3), 2.27 (2H, t, J = 4.4 Hz, CH2), 2.40
(2H, t, J =5.6 Hz, CH2), 2.51 (2H, m, CH2), 3.38-3.43 (4H, m, 2CH2 +H2 O), 3.60 (2H, t, J =5.8 Hz , CH2),
7.77 (2H, d, J = 8.6 Hz, arH), 7.94 (2H, d, J = 9.0 Hz, arH); 13 C-NMR (DMSO-d6 , δ ppm): 11.66 (CH3),
52.98 (2CH2), 55.33 (2CH2), 65.95 (2CH2), arC:[129.25 (2CH), 129.88 (2CH), 135.11 (C), 140.01 (C)], 149.60
(triazole C-3), 151.12 (triazole C-5); EI MS m/z (%): 411 (38), 409 ([M+Na]+ , 87), 389 (28), 387 ([M+1]+ ,
100), 229 (61), 114 (91).
5-Benzyl-4-(2-morpholine-4-ylethyl)-2-[(4-nitrophenyl)sulfonyl]-2,4-dihydro-3H-1,2,4-tria-
zole-3-one (6). Recrystallized from ethyl acetate. Yield 53%, mp 144-146 ◦ C. IR (KBr, υ, cm−1): 1743
(C=O), 1604 (C=N), 1186 (C-O); Anal. Calcd (%) for C21 H23 N5 O6 S: C, 53.27; H, 4.90; N, 14.79. Found: C,
53.27; H, 4.89; N, 14.85. 1 H-NMR (DMSO-d6 , δ ppm): 2.12 (4H, brs, 2CH2), 2.49 (2H, brs, CH2), 3.32-3.35
(4H, m, 2CH2 +H2 O), 3.54 (2H, t, J = 6.4 Hz, CH2), 4.03 (2H, s, CH2), 8.18-8.26 (5H, m, arH), 8.46-8.50 (2H,
m, arH), 8.52-8.55 (2H, m, arH); 13 C-NMR (DMSO-d6 , δ ppm): 31.16 (CH2), 52.87 (2CH2), 54.92 (2CH2),
65.92 (2CH2), arC: [125.03 (3CH), 127.22 (CH), 128.63 (3CH), 128.70 (2CH), 133.68 (C), 141.20 (C), 150.96
(C)], 151.29 (triazole C-3), 151.51 (triazole C-5); EI MS m/z (%): 496 (20), 475 (25), 474 ([M+1]+ , 100), 458
(11), 216 (12), 215 (50), 202 (12), 153 (19), 114 (41).
General method for the synthesis of compounds 7a-c. A solution of the corresponding compound
4 (10 mmol) in absolute ethanol was refluxed with appropriate aldehyde (10 mmol) for 3 h. On cooling the
mixture to room temperature, a white solid appeared. This crude product was recrystallized from ethanol to
afford the desired product.
2-[3-Methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]-N ’-[phen-
ylmethylene]acetohydrazide (7a). Yield 84%, mp 190-191 ◦ C. IR (KBr, υ, cm−1): 3126 (NH), 1709 and
1681 (C=O). Anal. Calcd (%) for C18 H24 N6 O3 : C, 57.99; N, 22.55; H, 6.44. Found: C, 57.68; N, 22.33;
H, 6.71. 1 H-NMR (DMSO-d6 , δ ppm): 2.23 (3H, s, CH3), 2.41-2.51 (8H, m, 4CH2 +DMSO-d6), 3.36-3.66
(2H, m, CH2 +H2 O), 3.70 (2H, t, J = 6.2 Hz, CH2), 4.41 and 4.81 (2H, s, CH2, cis/trans amide conformers),
7.40-750 (3H, m, arH), 7.71 (2H, d, J = 3.4 Hz, arH), 7.99 and 8.21 (1H, s, N=CH, cis/trans amide conformers),
11.67 (1H, s, NH); 13 C-NMR (DMSO-d6 , δ ppm): 12.09 (CH3), 39.74 (CH2), 46.66 (CH2), 54.01 (2CH2),
57.23 (CH2), 66.86 (2CH2), arC:[127.64 (CH), 127.82 (2CH), 129.50 (CH), 130.68 (CH), 134.62 (C)], 144.53
(CH), 144.67 (triazole C-5), 154.68 (triazole C-3), 168.83 (C=O); EI MS m/z (%): 373 ([M+1]+ , 100), 395
([M+Na]+ , 50), 374 (24), 114 (56).
2-[3-Methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]-N ’-[(4-
nitrophenyl)methylene]acetohydrazide (7b). Yield 94%, mp 200-203 ◦ C. IR (KBr, υ, cm−1): 3193 (NH),
1703 and 1679 (C=O). Anal. Calcd (%) for C18 H23 N7 O5 : C, 53.63; N, 23.45; H, 5.06. Found: C, 53.26; N,
23.18; H, 5.37. 1 H-NMR (DMSO-d6 , δ ppm): 2.23 (3H, s, CH3), 2.40-2.60 (4H, m, 2CH2 +DMSO-d6), 3.55
(4H, t, J = 5.0 Hz, 2CH2), 3.70 (2H, t, J = 6.4 Hz, CH2), 4.86 (2H, s, CH2), 7.94-8.03 (2H, m, arH), ,
8.10 (1H, s, N=CH), 8.24-8.33 (2H, m, arH), 11.94 (1H, s, NH); 13 C-NMR (DMSO-d6 , δ ppm): 11.30 (CH3),
38.92 (CH2), 45.89 (CH2), 53.20 (2CH2), 56.41 (CH2), 66.05 (2CH2), arC: [121.85 (C), 123.89 (2CH), 127.84
(2CH), 140.13 (C)], 141.55 (N=CH), 143.84 (triazole C-5), 158.75 (triazole C-3), 167.07 (C=O); EI MS m/z
(%): 419.27 (21), 418.27 ([M+1]+ , 100), 284.37 (54), 259.59 (22).
N ’-[1H -Indol-3-ylmethylene]-2-[3-methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-
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Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
1,2,4-triazole-1-yl]acetohydrazide (7c). Yield 92%, mp 130 ◦ C. IR (KBr, υ, cm−1): 3217 (NH), 1690
(C=O). Anal. Calcd (%) for C20 H25 N7 O3 : C, 52.28; N, 21.35; H, 5.45. Found: C, 52.41; N, 21.17; H,
5.63. 1 H-NMR (DMSO-d6 , δ ppm): 2.24 (3H, s, CH3), 2.43-2.51 (4H, m, 2CH2 +DMSO-d6), 3.56 (4H, m,
2CH2 +H2 O), 3.67 (2H, t, J =6.2 Hz, CH2), 3.70 (2H, m, CH2), 4.87 (2H, s, CH2), 7.12-7.25 (2H, m, arH),
7.45 (1H, d, J =8.0 Hz, arH), 7.83 (1H, s, arH), 8.20 and 8.38 (1H, s, N=CH, cis/trans amide conformers),
11.60 (1H, s, NH); 13 C-NMR (DMSO-d6 , δ ppm): 11.30 (CH3), 38.92 (CH2), 45.86 (CH2), 53.23 (2CH2),
56.49 (CH2), 60.07 (2CH2), arC: [120.30 (CH), 121.53 (CH), 122.54 (CH), 123.91 (C), 130.53 (CH), 136.88
(C)], 141.34 (N=CH), 143.91 (triazole C-5), 144.38 (N-CH), 153.93 (triazole C-3), 162.22 (indole C-3) 167.07
(C=O); EI MS m/z (%): 434.28 (31), 413.32 (28), 412.32 ([M+1]+ , 100], 284.30 (41), 113.92 (69).
General method for the synthesis of compounds 8a and 8b.
A mixture of compound 4 (10 mmol) and benzylisocyanate (10 mmol) (for 8a) or benzylisothiocyanate (10
mmol) (for 8b) was stirred under reflux in ethanol for 3 h (the progress of the reaction was monitored by TLC).
After evaporating the solvent under reduced pressure an oily product appeared; this was recrystallized from
ethanol to afford the desired products.
N -Benzyl-2-{[3-methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]
acetyl}hydrazinecarboxamide (8a). Yield 70%, mp 178-180 ◦ C. IR (KBr, υ, cm−1): 3278 (2NH), 3020
(NH), 1720 (C=O), 1690 (C=O), 1667 (C=O); 1 H-NMR (DMSO-d6 , δ ppm): 2.19 (3H, s, CH3), 2.30-2.53
(6H, m, 3CH2 +DMSO-d6), 3.40-3.50 (4H, m, 2CH2), 3.66 (2H, t, J = 5.6 Hz, CH2), 4.23 (2H, d, J = 5.6
Hz, CH2), 4.33 (2H, s, CH2), 7.05 (1H, brs, NH), 7.25-7.30 (5H, m, arH),7.99 (1H, s, NH), 9.83 (1H, s, NH);
13 C-NMR (DMSO-d6 , δ ppm): 12.02 (CH3), 38.74 (CH2), 43.07 (CH2), 46.70 (2CH2), 53.93 (2CH2), 57.14
(CH2), 66.77 (CH2), arC: [127.26 (CH), 127.51 (2CH), 128.84 (2CH), 141.04 (C)], 144.85 (triazole C-5), 154.46
(triazole C-3), 158.66 (C=O), 167.52 (C=O); EI MS m/z (%): 456.25 (50), 440.29 (47), 418.27 ([M+1]+ ,59),
246.07 (34), 232.06 (23).
N -Benzyl-2-{[3-methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]
acetyl}-phenylhydrazinecarbothioamide (8b). Yield 57%, mp 180-181 ◦ C. IR (KBr, υ, cm−1): 3371
(3NH), 1734 (C=O), 1681 (C=N), 1180 (C-O). Anal. Calcd (%) for C19 H27 N7 O3 S: C, 52.64; H, 6.28; N,
22.62. Found: C, 53.08; H, 6.35; N, 22.49. 2.19 (3H, s, CH3), 2.42-2.51 (2H, m, CH2 +DMSO-d6), 3.38 (4H,
brs, 2CH2), 3.41 (4H, brs, 2CH2), 3.47 (2H, brs, CH2), 4.36 (2H, s, CH2), 4.72 (2H, brs, CH2), 7.22-7.30
(5H, m, arH), 8.57 (1H, brs, NH), 9.50 (1H, s, NH), 10.13 (1H, s, NH); 13 C-NMR (DMSO-d6 , δ ppm): 12.06
(CH3), 38.92-41.43 (CH2 +DMSO-d6), 46.77 (CH2), 47.31 (CH2), 54.01 (2CH2), 57.21 (CH2), 66.86 (2CH2),
arC:[127.35 (2CH), 127.63 (CH), 128.77 (2CH), 139.85 (C)], 144.80 (triazole C-5), 154.46 (triazole C-3), 167.28
(C=O), 182.48 (C=S); EI MS m/z (%): 472.14 (53), 456.18 (28), 434.22 ([M+1]+ , 53), 285.12 (38), 284.24
(65), 238.06 (91), 113.86 (100).
N ’-[3-Benzyl-4-(4-nitrophenyl)-1,3-oxazole-2(3H)-ylidene]-2-(3-methyl-4-(2-morpholine-4-
ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl)acetohydrazide (9). 4-Nitrophenacyl bromide (10
mmol) was added to the solution of compound 8a (10 mmol) in ethanol and the mixture was refluxed in the
presence of dried sodium acetate (30 mmol) for 11 h (the progress of the reaction was monitored by TLC). Then
the mixture was cooled to room temperature, poured into ice-cold water while stirring, and left overnight in
416

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
cold conditions. The formed solid was filtered off, washed with water 3 times, and recrystallized from dimethyl
sulfoxide to afford the pure compound. Yield 48%, mp 238-240 ◦ C. IR (KBr, υ, cm−1): 3288 (NH), 1661
(C=O), 1572 (C=O); EI MS m/z (%): 134.76 (100), 137.89 (51), 337.06 (41), 423.10 (81), 563.39 ([M+1]+ ,
15).
2-[(4-Benzyl-5-mercapto-4H-1,2,4-triazol-3-yl)methyl]-5-methyl-4-(2-morpholin-4-ylethyl)-
2,4-dihydro-3H-1,2,4-triazol-3-one (10). A solution of compound 8b (10 mmol) in ethanol:water (1:1)
was refluxed in the presence of 2 N NaOH for 3 h. Then the resulting solution was allowed to cool to room
temperature and acidified to pH 3-4 with 37% HCl. The precipitate formed was filtered off, washed with water,
and recrystallized from ethanol to afford the desired compound. Yield 30%, mp 162-163 ◦ C. IR (KBr, υ,
cm−1): 2854 (SH), 1703 (C=O), 1587 (C=N). Anal. Calcd (%) for C19 H25 N7 O2 S: C, 54.88; N, 23.59; H,
6.01; S, 7.70. Found: C, 54.56; N, 23.19; H, 6.24; S, 7.35. 1 H-NMR (DMSO-d6 , δ ppm): 1.96 (3H, s, CH3),
2.23-2.34 (4H, m, 2CH2), 3.29 (4H, t, J = 6.2 Hz, 2CH2), 3.50 (4H, brs, 2CH2), 4.91 (2H, s, CH2), 5.19
(2H, s, CH2), 6.92-6.99 (2H, m, arH), 7.22-7.27 (2H, m, arH), 13.95 (1H, s, SH); 13 C-NMR (DMSO-d6 , δ
ppm): 11.81 (CH3), 38.80-40.97 (2CH2 +DMSO-d6), 46.50 (CH2), 53.93 (2CH2), 56.97 (CH2), 66.80 (2CH2),
arC:[126.53 (2CH), 127.88 (CH), 128.76 (2CH), 135.38 (C)], 145.14 (triazole C-5), 149.01 (triazole C-3), 153.28
(C=O), 168.89 (C=S); EI MS m/z (%): 229 (81), 438 (38), 416 ([M+1]+ , 100).
N ’-[3-Benzyl-4-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]-2-[3-methyl-4-(2-morpholin-4-
ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide (11). 4-Chlorophenacyl bromide (10
mmol) was added to the solution of compound 8b in ethanol and the mixture was allowed to reflux in the presence
of dried sodium acetate for 8 h (the progress of the reaction was monitored by TLC). Then the mixture was
cooled to room temperature, poured into ice-cold water while stirring, and left overnight in cold conditions. The
formed solid was filtered off, washed with water 3 times, and recrystallized from ethylacetate-ethyl ether (1:2)
to afford the target compound. Yield 33%, mp 138-140 ◦ C. IR (KBr, υ, cm−1): 3386 (NH), 1702 (C=O). 1587
(C=N). 1 H-NMR (DMSO-d6 , δ ppm): 2.02 (3H, s, CH3), 2.08-2.49 (6H, m, 3CH2), 3.39-3.52 (6H, m, 3CH2),
4.88 (2H, s, CH2), 5.02 (2H, s, CH2), 5.25 (1H, s, CH), 6.84 (2H, d, J = 5.4 Hz, arH), 7.28 (3H, d, J = 7.0 Hz,
arH), 7.62 (2H, d, J = 7.0 Hz, arH), 8.0 (2H, d, J = 8.6 Hz, arH), 11.23 (1H, s, NH). 13 C-NMR (DMSO-d6 ,
δ ppm): 11.00 (CH3), 37.29 (CH2), 38.49-40.17 (CH2 +DMSO-d6), 45.72 (CH2), 52.66 (2CH2), 55.52 (CH2),
65.38 (2CH2), 104.36 (thiazole C-5), arC: [125.74 (2CH), 127.14 (CH), 127.99 (2CH), 128.85 (2CH), 130.40
(CH), 131.41 (CH), 134.61 (2C), 136.50 (C)], 144.27 (triazole C-5+thiazole C-4), 148.16 (triazole C-3), 152.57
(thiazole C-2), 164.50 (C=O); EI MS m/z (%): 570.31 (34), 568.29 ([M]+ , 72), 238.17 (44), 152.71 (31), 113.88
(100).
Antimicrobial activity assessment. All test microorganisms were obtained from the Refik Saydam
Hygiene Institute (Ankara, Turkey) and were as follows: E. coli ATCC35218, E. aerogenes ATCC13048, Y.
pseudotuberculosis ATCC911, P. aeruginosa ATCC43288, S. aureus ATCC25923, E. faecalis ATCC29212,
B. cereus 709 Roma, M. smegmatis ATCC607, C. albicans ATCC60193, C. tropicalis ATCC 13803, A.
niger RSKK 4017, and S. cerevisiae RSKK 251. All the newly synthesized compounds were weighed and
dissolved in dimethylsulphoxide to prepare extract stock solution of 5 mg/mL. Agar-well diffusion method
screening test using agar-well diffusion54 as adapted earlier55 was used for all newly synthesized compounds.
Each microorganism was suspended in Mueller Hinton (MH) (Difco Detroit, MI, USA) broth and diluted
approximately to 106 colony forming units (cfu)/mL. They were ”flood-inoculated” onto the surface of MH
417

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
agar and Sabouraud Dextrose Agar (SDA) (Difco, Detriot, MI, USA) and then dried. For C. albicans and C.
tropicalis, SDA were used. Five millimeter diameter wells were cut from the agar using a sterile cork-borer, and
50 mL of the extract substances was delivered into the wells. The plates were incubated for 18 h at 35 ◦ C.
Antimicrobial activity was evaluated by measuring the zone of inhibition against the test organism. Ampicillin
(10 mg), streptomycin (10 mg), and fluconazole (5 mg) were the standard drugs. Dimethyl sulfoxide and ethanol
were used as solvent controls. The antimicrobial activity results are summarized in the Table.
Table. Screening for antimicrobial activity of the compounds.
Comp.
no.
2a
2b
3
Microorganisms and inhibition zone (mm)
Ec Ea
Yp
-
Kp
-
Pa
-
Sa Ef Li Bc Ms Ca Ct
Sc
-
An
-
-
-
-
-
-
20
15
7
8
8
-
7
6
-
15 15
-
-
-
-
-
-
-
-
-
-
-
-
-
-
6
7
6
10
-
-
-
-
-
8
9
-
-
-
6
30 30
15 15
10 10
15 15
25
15
12
12
15
10
15
12
30
10
15
-
40
6
-
10
7
-
-
7a
7b
7c
25 15 10 10 20
15 10 15 20
25 15 20 30 20
-
6
-
-
-
-
-
-
Amp. 10 10 > 18 18 > 18 35 10 10 15
Strep.
Flu.
35
25 25 > 25 ND
Ec: Escherichia coli ATCC 25922, Ea: Enterobacter aeruginosa ATCC 13048, Yp: Yersinia pseudotuberculosis ATCC
911, Kp: Klebsiella pneumoniae ATCC 13883, Pa: Pseudomonas aeruginosa ATCC 43288, Sa: Staphylococcus aureus
ATCC 25923, Ef: Enterococcus faecalis ATCC 29212, Li: Listeria monocytogenes ATCC 43251, Bc: Bacillus cereus 702
Roma, Ms: Mycobacterium smegmatis ATCC607, Ca: Candida albicans ATCC 60193, Ct: Candida tropicalis ATCC
13803, Sc: Saccharomyces cerevisiae RSKK 251, An: Aspergillus niger RSKK 4017, Amp.: Ampicillin, Flu.: Fluconazole,
(-): No activity.
Results and discussion
The synthetic strategies adopted to obtain the target compounds are depicted in Schemes 1 and 2. In the
present study, the synthesis of 5-alkyl-4-(2-morpholine-4ylethyl)-2,4-dihydro-3H-1,2,4-triazole-3-ones (2a, 2b)
was achieved by cyclocondensation of ester ethoxycarbonylhydrazones (1a, 1b) with 2-morpholinoethanamine.
In the IR and NMR spectra of compounds 2a and 2b, the absence of any signals pointing to ester functionality
has supported the ring closure. More evidence for cyclization is the presence of [M+ ] or [M+1] ion peak in the
EI-MS spectra.
The reaction of 2a with ethyl bromoacetate in the presence of sodium ethoxide produced ethyl [3-
methyl-4-(2-morpholine-4-ylethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-1-yl]acetate (3). In the 1 H- and 13 C-
NMR spectra of compound 3, additional signals originating from ester moiety were recorded at the related
chemical shift values, while the signal due to ring NH disappeared. The treatment of compound 3 with hydrazine
418

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
O
N NH
NH2
O
N
N
OEt
R
O
O
N
NNH
OEt
N
EtO-, BrCH2CO2Et
R
OEt
CH3
O
N
N
1a: R= -CH3
1b: R= -CH2C6H5
N
O
O
2a: R= -CH3
3
2b: R= -CH2C6H5
ArSO2CI
H2NNH2
NO2
O
Ar
SO2
NHNH2
N
N
O
N
N
SO2
O
CH3
N
N
N
CH3
O
N
N
N
N
N
O
O
O
5a: Ar = -C6H4NO2(p-)
5b: Ar = -C6H4Br(p-)
5c: Ar = -C6H4Cl(p-)
4
6
Scheme 1. Synthetic pathway for the preparation of compounds 2-6.
hydrate in ethanolic solution caused the conversion of the ester group to hydrazide function in good yield. The
IR and NMR spectra of hydrazide compound 4 displayed signals belonging to a -NHNH2 group. Moreover,
compounds 3 and 4 exhibited MS spectral and elemental analysis data consistent with the assigned structures.
The condensation of compounds 2a,b with several aryl sulfonyl chlorides in ethanol in the presence
of metallic sodium generated the corresponding cyclic sulfon amides (5a-c and 6). The structures of these
compounds were confirmed on the basis of IR, NMR, and mass spectroscopic methods and elemental analysis.
The synthesis of arylmethyleneacetohydrazides (7a-c) was achieved from the reaction of compound 4
with several aromatic aldehydes in ethanolic solution in good yields.
The evidence for the formation of compounds 7a-c can be obtained by 1 H-NMR, 13 C-NMR, IR, mass
spectroscopic methods and elemental analysis. In the 1 H-NMR spectra of compounds 7a-c, additional signals
originating from arylidene moiety were observed in the aromatic region, and an additional signal was recorded
at 9.66 ppm derived from –N=CH- bond, whereas the signal due to –NHNH2 amino group disappeared that
had been observed at 4.50 ppm in the 1 H-NMR spectrum of the parent compound, 4.
The compounds having arylidene-hydrazide structure may exist as E/Z geometrical isomers about a
419

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
O
O
7a:
R=
N
N
NHNH2
RCHO
NHN CHR
N
N
CH3
O
NO2
7b: R=
N
CH3
O
N
R=
7c:
N
N
N
H
O
O
4
7a-c
O
NH
PhCH2NCX
N
N
N
N
O
X
CH3
O
O
N
N
N
NHNH
BrCH2COC6H4NO2(p-)
NH
CH3
O
N
N
NO2
O
N
9
8a: X= O
8b: X= S
O
BrCH2COC6H4Cl(p-)
NaOH
N
N
O
SH
N
N
N
N
N
N
N
NH
CH3
O
CH3
O
S
N
N
N
N
CI
O
O
10
11
Scheme 2. Preparation of compounds 7-11.
420

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
–C=N double bond and cis/trans amide conformers.37,56,57 According to the literature, compounds containing
an imine bond are present in higher percentages in dimethyl-d6 sulfoxide solution in the form of geometrical
E isomer about a –C=N double bond.37,56,57 The Z isomer can be stabilized in less polar solvents by an
intramolecular hydrogen bond. In the present study, the spectral data were obtained in dimethyl-d6 sulfoxide
solution and no signal belonging to Z isomer was observed. On the other hand, the cis-trans conformers of E
isomer were present in the dimethyl-d6 sulfoxide solution of compounds 7a and 7b. In the 1 H-NMR spectra
of compounds 7a and 7c, 2 sets of signals each belonging to the N=CH group of cis- and trans- conformers
were observed at 7.99 (for 7a) or 8.20 (for 7c) ppm and 8.21 (for 7a) or 8.38 (for 7c) ppm, respectively. The
upfield lines of N=CH protons were assigned to cis- conformer of the amide structure and downfield lines of
the protons of the same group to trans- conformer of the amide structure.
Iso(thio)cyanates are known as useful tools for the synthesis of nitrogen-, sulfur-, or oxygen-containing
compounds. In the present study, carboxamide (8a) and carbothioamide (8b) were obtained by the nucleophilic
addition of hydrazide (4) to benzyl isocyanate (for 8a) or benzylisothiocyanate (for 8b). In the 13 C-NMR
spectrum of compound 8a, the signal derived from urea carbonyl resonated at 158.66 ppm, while the C=S
function of 8b appeared at a lower field, 182.48 ppm. Their molecular structures were confirmed by mass
spectroscopic method and elemental analysis, as well.
The intramolecular cyclization of compound 8b in the presence of 2 N NaOH resulted in the formation of 2-
[(4-benzyl-5-mercapto-4H -1,2,4-triazol-3-yl)methyl]-5-methyl-4-(2-morpholin-4-ylethyl)-2,4-dihydro-3H-1,2,4-
triazol-3-one (10). On the other hand, the cyclocondenzation of the same intermediate (8b) with 4-chlorophenac-
ylbromide yielded N ’-[3-benzyl-4-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]-2-[3-methyl-4-(2-morpholin-4-yl
ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetohydrazide (11). Similarly, the treatment of 8a with 4-
nitrophenacylbromide led to the formation of the corresponding 1,3-oxazole derivative (9). In the 1 H-NMR
spectrum of compound 10 the absence of any signal pointing to a NH proton confirmed the cyclization at the
side chain of 1,2,4-triazol-3-one ring in compound 8a. It has been reported that type of compounds 10 can be
present in their thioxo-mercapto tautomeric forms. In the 1 H-NMR spectrum of compound 10, the presence of
a singlet peak at 14.00 representing the presence of a –SH proton showed that the dominant form is mercapto
form for compound 10.
So far, several methods have been developed for the preparation of 1,3-thiazole derivatives, the most
commonly applied of which is Hantzsch synthesis, involving the reaction of α-halocarbonyl compounds with
thioamides.58,59 It has been agreed that a Hantzsch reaction starts by the attack of the sulfur atom of thioamide
that is present in its ene-thiol form on the halogene-containing atom of phenacyl bromide, followed by HBr and
H2 O elimination, leading to a 1,3-thiazole ring.58 In the present study, as compounds 8a and 8b possess more
than 1 nucleophilic center and also phenacyl bromide has 2 positions for nucleophilic attacks, there are at least
4 different possibilities leading to the formation of 4 different structural isomers (Scheme 3). In our previous
studies submitted for publication, to identify the exact structure of the products obtained from the reaction
between catbo(thio)amide and phenacyl bromide, full geometric optimizations of the possible products were
obtained by DFT/B3LYP (density functional theory with B3LYP-the hybrid Becke’s 3 parameter functional
and Lee-Yang-Parr exchange-correlation potential)60,61 method with the 6-31G (d, p) basis set and the structure
of the molecules was also investigated in detail. The obtained results (unpublished data) showed that among the
possible Hantzsch products (A-D) the most stable one is A isomer due to its Z geometrical isomer about the
421

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
N=C double bond. Taking into account these data, it can be speculated that the strongly probable structure for
compounds 9 and 11 is structure A. In the present study, contrary to the description in the literature,60−63 the
reaction between carbo(thio)amide (8a, 8b) and substituted phenacyl bromide started by the attack of sulfur
atom on carbonyl carbon of phenacyl bromide instead of halogen bearing carbon atom of acyl component,
because the latter attack leads to the formation of 9 or 11, which is thermodynamically a less favorable isomer
(Scheme 4). The Z rearrangement of groups in these reactions is likely due to the steric hindrance of the bulky
R group and benzyl moiety in the intermediate E. In the reaction media, the presence of dried sodium acetate
is necessary to accelerate the reaction by catching H2 O and HBr furnishing during the reaction.
O
O
N
N
N
N
NH
N
NH
N
N
N
X
X
CH3
O
CH3
O
N
N
G
N
N
G
O
O
B
A
N
O
N
O
X
X
N
N
NH
N
N
N
NH
N
CH3
O
CH3
O
N
N
N
G
N
G
O
O
D
C
Scheme 3. Possible structural isomers for compounds 9 and 11.
422

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
a
O
X
X
Br
R
N
NH
R
NH NH
G
8a, 8b
b
-HBr
b
a
G
O
HO
X
X
R
N C
Br
NH
R
N
NH
G
-HBr
-H2O
-H2O
G
G
X
R
X
R
X
X
N
N
R
N
N
N
N
R
N
N
G
G
O
B (E)
B (Z)
A (E)
A (Z)
NH
N
N
for 9: X= O, G= NO2; for 11: X= S, G= Cl
R= CH3
O
N
N
O
Scheme 4. The mechanism leading to the formation of compounds 9 and 11.
The IR and 1 H-NMR spectra of compounds 9 and 11 showed no signal representing the –SH group.
Instead, the signals derived from phenacyl moiety were observed in the aromatic region in the 1 H- and 13 C-NMR
spectra of compound 11. Due to the slight solubility in any NMR solvent, a satisfactory NMR spectrum could
not be obtained for compound 9. In addition, elemental analyses are consistent with the assigned structures for
compounds 9, 10, and 11, and the mass spectra of the cyclization products (9-11) showed [M]+ or [M+1]+
423

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
ion peaks consistent with their molecular formulae.
The antimicrobial activity results are presented in Table 1. The compounds displaying no activity are
not incorporated in this table. Among the newly synthesized compounds, compound 6, a cyclic sulfonamide
derivative containing 4-nitrophenyl sulfonyl moiety in position 2 beside a benzyl group at position 5 of the 1,2,4-
triazole skeleton, was the most active against most of the test microorganisms, whereas other sulfonamides (5a-c)
containing a methyl group instead of a benzyl group showed no activity towards the test microorganisms. Com-
pounds 2a and 2b, which are unsubstituted 1,2,4-triazole compounds at position 2, exhibited activity against
the gram-positive bacteria Staphylococcus aureus (Sa), Enterococcus faecalis (Ef), Listeria monocytogenes (Li),
and Bacillus cereus (Bc), and one nonpigmented rapidly growing mycobacterium leading to morbidity and
mortality, Mycobacterium smegmatis (Ms). Arylidenehydrazides (7a-c) are the other most potent group syn-
thesized in this study. They displayed good antibacterial activity against gram-positive and gram-negative
bacterial strains and Mycobacterium smegmatis.
Acknowledgements
¨
˙
This project was supported by the Scientific and Technological Research Council of Turkey (TUBITAK, Project
no: 107T333) and Karadeniz Technical University, BAP, Turkey (Ref. No. 2007.111.002.5). The support is
gratefully acknowledged.
References
1. Patil, B. S.; Krishnamurthy, G.; Naik, H. S. B.; Latthe, P. R.; Ghate, M. Eur. J. Med. Chem. 2010, 45, 3329-3334.
2. Wang, X. L.; Wan, K.; Zhou, C. H. Eur. J. Med. Chem. 2010, 45, 4631-4639.
3. Bremner, J. B.; Ambrus, J. I.; Samosorn, S. Curr. Med. Chem. 2007, 14, 1459-1477.
4. Hubschwerlen, C.; Specklin, J. L.; Sigwalt, C.; Schroeder, S.; Locher, H. H. Bioorg. Med. Chem. 2003, 11, 2313-
2319.
5. Bayrak, H.; Demirbas, A.; Demirbas, N.; Alpay-Karaoglu, S. Eur. J. Med. Chem. 2009, 44, 4362-4366.
6. Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35, 267-271.
7. Shafiee, A.; Sayadi, A.; Roozbahani, M. H.; Foroumadi, A.; Kamal, F. Arch. Pharm. Med. Chem. 2002, 10,
495-499.
8. Sharma, S.; Gangal, S.; Rauf, A.; Zahin, M. Arch. Pharm. Chem. Life. Sci. 2008, 341, 714-720.
9. Gulerman, N. N.; Dogan, H. N.; Rollas, S.; Johansson, C.; Celik, C. Il Farmaco 2001, 56, 953-958.
10. Papakonstantinou-Garoufalias, S.; Pouli, N.; Marakos, P.; Chytyroglou-Ladas, A. Il Farmaco 2002, 57, 973-977.
11. Turan-Zitouni, G.; Kaplacikli, Z. A.; Yildiz, M. T.; Chevallet, P.; Kaya, D. Eur. J. Med. Chem. 2005, 40, 607-613.
12. Jalilian, A. R.; Sattari, S.; Bineshmarevasti, M.; Shafiee, A.; Daneshtalab, M. Arch. Pharm. Pharm. Med. Chem.
2000, 333, 347-354.
13. Ku¨¸cu¨kgu¨zel, I.; Ku¨¸cu¨kgu¨zel, S. G.; Rollas, S.; Kiraz, M. Bioorg. Med. Chem. Lett. 2001, 11, 1703-1707.
424

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
14. Zahajska, L.; Klimesova, V.; Koci, J.; Waisser, K.; Kaustova, J. Arch. Pharm. Pharm. Med. Chem. 2004, 337,
549-555.
15. Foroumadi, A.; Kiani, Z.; Soltani, F. Il Farmaco 2003, 58, 1073-1076.
16. Turan-Zitouni, G.; Sivaci, M.; Kilic¸, F. S. Erol, K. Eur. J. Med. Chem. 2001, 36, 685-689.
17. Tozkoparan, B.; Ku¨peli, E. Ye¸silada, E.; Ertan, M. Bioorg. Med. Chem. 2007, 15, 1808-1814.
18. Rabea, S. M.; El-Koussi, N. A.; Hassan, H. Y.; Aboul-Fadl, T. Arch. Pharm. Chem. Life Sci. 2006, 339, 32-40.
19. Labanauskas, L.; Udrenaite, E.; Gaidelis, P.; Brukstus, A. Il Farmaco 2004, 59, 255-259.
20. Holla, B. S.; Veerendra, B.; Shivananda, M. K.; Poojary, B. Eur. J. Med. Chem. 2003, 38, 759-767.
21. Duran, A.; Dogan, H. N.; Rollas, S. Il Farmaco 2002, 57, 559-564.
22. Almasirad, A. S. A.; Tabatabai, M.; Faizi, A.; Kebriaeezadeh, N.; Mehrabi, A.; Dalvandi, A.; Shafiee, A. Bioorg.
Med. Chem. Lett. 2004, 14, 6057-6059.
¨
23. Ku¨¸cu¨kgu¨zel, I.; Ku¨¸cu¨kgu¨zel, S. G.; Rollas, S.; Otu¨k-Sanis, G.; Ozdemir, O.; Bayrak, I.; Altug, T. Stables, J. P. Il
¨
Farmaco 2004, 59, 893-901.
24. Kritsanida, M.; Mouroutsou, A.; Marakos, P.; Pouli, N.; Papakonstantinou- Garoufalias, S.; Pannecouque, C.;
Witvrouw, M.; De Clercq, E. Il Farmaco 2002, 57, 253-257.
25. Abdel-Aal, M. T.; El-Sayed, W. A.; El-Kosy, S. M.; El-Ashry, E. S. H. Arch. Pharm. Chem. Life Sci. 2008, 341,
307-313.
26. Chai, B.; Qian, X.; Cao, S.; Liu, H.; Song, G. Arkivoc 2003, (i), 141-145.
27. Varvaresou, A.; Tsotinis, T., A.; Tsantili-Kakoulidou, A.; Vamvakides, A. Il Farmaco 1998, 53, 320-326.
28. Padmavathi, V.; Thriveni, P.; Reddy, S. G.; Deepti, D. Eur. J. Med. Chem. 2008, 43, 917-924.
29. Ashton, W. T.; Cantone, C. L.; Chang, L. L.; Hutchine, S. M.; Strelitz, R. A.; Mac Coea, M.; Chang, R. S. L.;
Lotti, V. J.; Faust, K. A.; Tsing-Chen, B.; Bunting, P.; Schorn, T. W.; Kivlighn, S. D.; Sieglt, P. K. S. J. Med.
Chem. 1993, 36, 591-609.
30. Tozkoparan, B.; Kupeli, E.; Yesilada, E.; Ertan, M. Bioorg. Med. Chem. 2007, 15, 1808-1814.
31. Demirbas, N.; Karaoglu-Alpay, S.; Demirbas, A.; Sancak, K. Eur. J. Med. Chem. 2004, 39, 793-804.
32. Demirba¸s, N.; U˘gurluog˘lu, R.; Demirba¸s, A. Bioorg. Med. Chem. 2002, 10, 3717-3723.
33. Bektas, H.; Karaali, N.; Sahin, D.; Demirbas, A.; Alpay-Karaoglu S.; Demirbas, N.; Molecules 2010, 15, 2427-2438.
34. Bekta¸s, H.; Demirba¸s, A.; Demirba¸s, N.; Alpay-Karao˘glu S¸. Medicinal Chemistry Research 2011, 21, 212-223.
35. Demirbas, N.; Demirbas, A.; Alpay-Karao˘glu, S. Russian J. Bioorg. Chem. 2005, 31, 387-397.
36. Bekta¸s, H.; Demirba¸s, A.; Demirba¸s, N., Alpay-Karao˘glu, S. Turk. J. Chem. 2010, 34, 165-180.
37. Wyrzykiewicz, E.; Wendzonka, M.; Kedzia, B. Eur. J. Med. Chem. 2006, 41, 519-525.
38. Dixit, P. P.; Nair, P. S.; Patil, V. J.; Jain, S.; Arora, S. K.; Sinha, N. Bioorg. Med. Chem. Lett. 2005, 15, 3002-05.
39. Panneerselvam, P.; Nair, R. R.; Vijayalakshimi, G.; Subramanian, E. H.; Sridhar, S. K. Eur. J. Med. Chem. 2005,
40, 225-9.
40. Dixit, P. P.; Patil, V. J.; Nair, P. S.; Jain, S.; Sinha, N.; Arora, S. K. Eur. J. Med. Chem. 2006, 41, 423-428.
41. Giera, R.; Cantos-Llopart, C.; Amat, M.; Bosch, J.; del Castillo, J. C.; Huguet, J. Bioorg. Med. Chem. 2006, 16,
529-531.
425

˙
Design and synthesis of new 1,2,4-triazole derivatives..., D. S¸AHIN, et al.
42. Das, B.; Rudra, S.; Yadav, A.; Ray, A.; Rao, A. V. S. R.; Srinivas, A. S. S. V.; Saini, S.; Shukla, S.; Pandya,
M.; Bhateja, P.; Malhotra, S.; Mathur, T.; Arora, S. K.; Rattan, A.; Metha, A. Bioorg. Med. Chem. 2005, 15,
4261-4267.
43. Gage, J. G.; Perrault, W. P.; Poel, T. J.; Thomas, R. C. Tetrahedron Lett. 2000, 41, 4301-4305.
44. Cui, Y.; Dang, Y.; Yang, Y.; Zhang, S.; Ji, R. Eur. J. Med. Chem. 2005, 40, 209-214.
¨
45. Ku¨¸cu¨kgu¨zel, S. G.; Oruc, E. E.; Rollas, S.; Sahin, F.; Ozbek, A. Eur. J. Med. Chem. 2002,37, 197-206.
46. Capan, G.; Ulusoy, N.; Ergenc, N.; Kiraz, M. Monatsh. Chem. 1999, 130, 1399-1407.
47. Ergenc, N.; Capan, G. Il Farmaco 1994, 49,133-135.
48. Bhatt, J. J.; Shah, B. R.; Shah, H. P.; Trivedi, P. B.; Undavia, N. K.; Desai, N. C. Indian J. Chem. 1994, 33B ,
189-192.
49. Bukowski, L.; Janowiec, M.; Zwolska-Kwiek, Z.; Andrezejczyk, Z. Pharmazie 1998, 53, 373-376.
50. Barreca, M. L.; Chimirri, A.; Luca, L. D.; Monforte, A.; Monforte, P.; Rao, A.; Zappala, M.; Balzarini, J.; De
Clercq, E.; Pannecouque, C.; Witvrouw, M. Bioorg. Med. Chem. Lett. 2001, 11, 1793-1796.
51. Andres, C. J.; Bronson, J. J.; Andrea, S. V. D.; Deshpande, M. S.; Falk, P. J.; Grant-Young, K. A.; Harte, W. E.;
Ho, H. T.; Misco, P. F.; Robertson, J. G.; Stock, D.; Sun, Y.; Walsh, A. W. Bioorg. Med. Chem. Lett. 2000, 10,
715-717.
52. El-Gaby, M. S. A.; El-Hag Ali, G. A. M. A.; El-Maghraby, A.; Abd El-Rahman, M. T.; Helal, M. H. M. Eur. J.
Med. Chem. 2009, 44, 4148-4152.
53. Milcent, R.; Redeuilh, C. J. Heteteroc. Chem. 1979, 16, 403-407.
54. Perez, C.; Pauli, M.; Bazerque, P. Acta Biologia Med. Experimentalis 1990, 15, 113-115.
55. Ahmad, I.; Mehmood, Z.; Mohammed, F. J. Ethnopharmacology 1998, 62, 183-193.
56. Mamolo, M. G.; Falagiani, V.; Zampieri, D.; Vio, L.; Banfi, E. Il Farmaco 2001, 56, 587-592.
57. Galic, N.; Peric, B.; Kojic-Prodic, B.; Cimerman, Z. J. Mol. Stuc. 2001, 559, 187-194.
58. Amin, K. M.; Abdel Rahman, D. E.; Al-Eryani, Y. A. Bioorg. Med. Chem., 2008, 16, 5377-5888.
59. Egan, R. S.; Tadanier, J. J. Org. Chem. 1968, 4422-4426.
60. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, B37, 785-789.
61. Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
62. Manaka, A.; Ishii, T.; Ashi, T. K.; Sato, M. Tetrahedron Lett. 2005, 46, 419-422.
63. Bonde, C.; Gaikwad, N. J. Bioorg. Med. Chem. 2004, 12, 2151-2161.
426