Synthesis and evaluation of 4-amino-5-phenyl-4H-[1,2,4]-triazole-3-thiol derivatives as antimicrobial agents

Article abstract of DOI:10.1007/s00044-009-9178-8

A series of novel 1,2,4-triazole derivatives have been synthesized by condensing the methyl benzoate and methyl salicylate with various substituents; their structures were established on the basis of elemental analysis, Fourier transform infrared spectroscopy (FTIR), ¹H nuclear magnetic resonance (NMR), and mass spectral data. All title compounds were subjected to in vitro antibacterial and antifungal screening against four different bacterial and fungal strains. Preliminary results indicate that some of them exhibit promising activities and deserve further consideration as potential antimicrobials. Birkhaeuser Boston 2009.

Full text of DOI:10.1007/s00044-009-9178-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:127–135
DOI 10.1007/s00044-009-9178-8
ORIGINAL RESEARCH
Synthesis and evaluation of 4-amino-5-phenyl-4H-
[1,2,4]-triazole-3-thiol derivatives as antimicrobial
agents
Prasanta K. Sahoo Æ Rajesh Sharma Æ
Priyabrata Pattanayak
Received: 27 December 2008 / Accepted: 10 February 2009 / Published online: 17 March 2009
¨
Ó Birkhauser Boston 2009
Abstract A series of novel 1,2,4-triazole derivatives have been synthesized by
condensing the methyl benzoate and methyl salicylate with various substituents;
their structures were established on the basis of elemental analysis, Fourier trans-
1
form infrared spectroscopy (FTIR), H nuclear magnetic resonance (NMR), and
mass spectral data. All title compounds were subjected to in vitro antibacterial and
antifungal screening against four different bacterial and fungal strains. Preliminary
results indicate that some of them exhibit promising activities and deserve further
consideration as potential antimicrobials.
Keywords 1,2,4-Traizole Á Antibacterial screening Á Antifungal screening
Introduction
The usage of most antimicrobial agents is limited, not only by the rapidly
developing drug resistance, but also by the unsatisfactory status of present
treatments of bacterial and fungal infections and drug side-effects (Fidler, 1998).
Therefore, the development of new and different antimicrobial drugs is a very
important objective and many research programs are directed towards the design of
new antimicrobial agents.
During the last few decades, considerable attention has been devoted to synthesis
of 1,2,4-triazole derivatives possessing such comprehensive bioactivities as
antibacterial, antifungal (Karabasanagouda et al., 2007; Sztanke et al., 2008),
P. K. Sahoo Á R. Sharma
School of Pharmacy, Devi Ahilya Vishwavidyalaya, Takshashila Campus,
Khandwa Road, Indore 452017, Madhya Pradesh, India
P. Pattanayak (&)
Jeypore College of Pharmacy, Jeypore(K), Orissa 764002, India
e-mail: priyabrata2005@gmail.com

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Med Chem Res (2010) 19:127–135
´
antimycobacterial (Klimesova et al., 2004), anti-inflammatory (Mullican et al.,
1993), analgesic (Tozkoparan et al., 2005), anticancer (Demirba et al., 2002),
antihypertensive (Kakefuda et al., 2002), anticonvulsant (Ku¨c¸u¨kgu¨zel et al., 2004),
antiviral (El-Essawy et al., 2008), antidepressant (Kane et al., 1988), antiasthmatic
(Youichiro et al., 1996), diuretic (Mhasalkar et al., 1970) and hypoglycemic (Blank
et al., 1972) activities.
Regarding antimicrobial activity, triazole is structurally similar to imidazole
molecule. Although triazole and imidazole act by the same mechanism of action,
triazoles possess advantages over imidazoles, which have slow metabolic rate, oral
bioavailability, and less effect on human sterol synthesis. For these reasons
imidazoles are slowly being replaced by triazole molecules. It was reported that
incorporation of various halo substituents into the heterocyclic ring systems
augments biological activities considerably (Wang and Shi, 2001) and substitutions
at 3-position by chloro-substituted benzene and at 4-position by free -NH2 group
give a broad spectrum of antimicrobial activity due to the ability of halogen to act as
polar hydrogen or hydroxy mimic. Substitution of hydrogen by halogen has been a
strategy in designing molecules for biological studies (Clerici and Donato, 2001). In
view of the above findings, it was thought worthwhile to synthesize a series of eight
compounds containing the 1,2,4-triazole moiety with different halogenated and
nonhalogenated substituents and study their antimicrobial activities.
Materials and methods
Chemistry
Reaction sequence employed for the synthesis of title compounds is shown in
Schemes 1, 2.
Step 1 (Wang and Shi, 2001)
The esters of substituted aromatic acid (0.1 M) (1 and 5) were dissolved in 30 ml
ethanol, and hydrazine hydrate (0.1 M) was added dropwise to the mixture with
stirring. The resulting mixture was allowed to reflux for 6 h. Excess ethanol was
distilled out and the contents were allowed to cool. The crystals formed were
filtered, washed thoroughly with water, and dried. The completion of the reaction
was monitored by thin layer chromatography (TLC) by using silica gel-G coated
plates by using ethyl acetate and petroleum ether (1:1) as the eluent and observed
with ultraviolet (UV) light.
Step 2
KOH (0.15 M) was dissolved in absolute ethanol (200 ml). To the above solution,
aryl acid hydrazide (0.1 M) (2 and 6) was added and the solution cooled on ice. To
this, carbon disulfide (0.15 M) was added in small portions with constant stirring.
The reaction mixture was agitated continuously for a period of 15 h. It was then

Med Chem Res (2010) 19:127–135
129
O
O
C
C
O
N2H4.H2O
NHNH2
CH3
Step -1
2
1
CS2
Step -2
KOH/C2H5OH
N
N
O
C
S
C
N2H4.H2O
SH
N
NHNH
SK
NH2
Step -3
3
4
Step -4
PS-01
KOH 85%, H2O
Glacial
Acetic acid
Step - 5
RCl
Acetic anhydride
N
N
N
SR
N
N
NH2
SH
N
NH
COCH3
PS-02, PS-03, PS-04, PS-05 & PS-08
PS-07
Scheme 1 Synthesis of substituted 1,2,4-triazole (PS01, PS02, PS03, PS04, PS05, PS07, and 08)
O
O
C
N2H4.H2O
O
C
NHNH2
CH3
OH
Step -1
OH
6
5
CS2
Step- 2
KOH/C2H5OH
N
N
O
C
S
C
N2H4.H2O
Step -3
SH
N
NH2
NHNH
SK
OH
PS-06
Scheme 2 Synthesis of 2-(4-amino-5-mercapto-4H-[1,2,4]triazol-3-yl)-phenol (PS06)
OH
8
7
diluted with anhydrous ether. The precipitated potassium dithiocarbazinate was
collected by filtration. The precipitate was further washed with anhydrous ether
(100 ml) and dried under vacuum. The potassium salt thus obtained was in
quantitative yield and was used in the next step without further purification.

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Med Chem Res (2010) 19:127–135
Step 3
A suspension of potassium dithiocarbazinate (0.1 M) (3 and 7) in water (5 ml) and
hydrazine hydrate (15 ml, 0.3 M) was refluxed for 30 min with occasional shaking.
The color of the reaction mixture changed to green with the evolution of hydrogen
sulfide gas (lead acetate paper and odor). A homogeneous reaction mixture was
obtained during the reaction process. The reaction mixture was cooled to room
temperature and diluted with water (100 ml). On acidification with concentrated
hydrochloric acid, the required triazole 4 (PS01) and 8 (PS06) was precipitated out.
It was filtered, washed thoroughly with cold water, and recrystallized from ethanol.
The completion of the reaction was monitored with TLC by using silica gel-G
coated plates by using ethyl acetate and petroleum ether (1:1) as eluent and
observed with UV light.
Step 4
The appropriate (Clerici and Donato, 2001) triazole (0.1 mol) (PS01) was
suspended in water (9 ml), and 0.1 mol of KOH (85% solution) was added under
stirring at room temperature. After a few minutes (5–10 min), the solution was
brought to 0°C in an ice bath, and halo-substituted aromatic compound (0.1 mol)
was dropped in with vigorous stirring. The reaction mixture was checked by TLC
(Et2O as eluant). When reaction was complete, concentrated sulfuric acid (10 ml)
was added, and from the crude mixture a white precipitate was formed slowly
(PS02, PS03, PS04, PS05, and PS08). This was filtered, washed with water, and
crystallized from ethanol.
Step 5
Acetic anhydride (0.19 ml, 0.002 mole) was added (Clerici and Donato, 2001; Afaf
et al., 2000) to a boiling solution of 4-amino-5-phenyl-4H-[1,2,4]-triazole-3-thiol
(0.001 mole) (PS01) in glacial acetic acid (3 ml). After refluxing for 2 h, the
reaction mixture was cooled and poured into ice-cold water. The formed precipitate
was filtered off and recrystallized from ethanol to give the title compound (PS07).
TLC was used to reach the completion of reaction and purity of the compounds
synthesized. Melting points were determined in open glass capillary tubes using
Thiels tube containing liquid paraffin and were uncorrected. IR spectra were
obtained in KBr discs on a Shimadzu-8400S FTIR spectrophotometer. Elemental
1
analysis was performed using EL 11/carlo Ebra 1108 analyzer. H NMR spectra
were recorded on a FT NMR (500 MHz); MeOD was used as a solvent. Chemical
shifts are reported as d (ppm). The fast atom bombardment (FAB) mass spectra were
recorded on a JEOL SX 102/DA-6000 mass spectrometer/data system using argon/
xenon (6 kV, 10 mA) as the FAB gas. Elemental analysis was within 0.4% of
theoretical values. Substitution pattern and characterization data of the synthesized
compounds are reported in Tables 1, 2, respectively. The spectral data are presented
in Table 3.

Med Chem Res (2010) 19:127–135
131
Table 1 Substitutions on the 1,2,4-triazole ring of compounds PS01–08
N
N
R3
R1
N
R2
Compd.
R1
R2
R3
PS01
PS02
PS03
PS04
PS05
PS06
PS07
PS08
–C6H5
–C6H5
–C6H5
–C6H5
–C6H5
–NH2
–NH2
–NH2
–NH2
–NH2
–NH2
–SH
–S(C6H4)4–SO2Cl
–S(C6H4)4–Br
–S(C6H4)4–CCl3
–S(C6H4)4–Cl
–SH
–(C6H4)2–OH
–C6H5
–NHCOCH3
–NH2
–SH
–C6H5
–(C6H3)–2,4–(NO2)2
Table 2 Characterization of the title compounds (PS01–08)
Compd No.
Formula (m. wt.)
M. P. (°C)
Yield (%)
% Analysis (calculated)/found
C
PS01
PS02
PS03
PS04
PS05
PS06
PS07
PS08
C8H5N4S (189.19)
198–200
230–232
208–210
122–124
223–225
202–205
192–196
234–236
72
67
64
68
64
74
72
69
(49.98) 49.94
(45.84) 45.74
(48.43) 48.40
(46.71) 46.68
(55.53) 55.50
(46.14) 46.05
(51.27) 51.25
(46.93) 46.86
C
C
C
C
14H11ClN4O2S2 (366.85)
14H11BrN4S (347.24)
15H11Cl3N4S (385.70)
14H11ClN4S (302.78)
C8H8N4OS (208.22)
C10H10N4OS (234.28)
C
14H10N6O4S (358.34)
Biological activities
Antibacterial activities
The newly synthesized compounds were screened for their antibacterial activity
against Escherichia coli DH5a, Bacillus subtilis ATCC 6633, Pseudomonas
aeruginosa MTCC 3363, and Pseudomonas fluoroscens ATCC 3458 (recultured)
bacterial strains by paper disc diffusion method (Chandrasekharan et al., 2005).
Muller–Hinton agar medium (38 g/l) was sterilized by autoclave at 121°C for
15 min and then poured into a Petri disc to a depth of 3–4 mm and allowed to
solidify. Plates were dried and 0.1 ml standardized inoculum suspension of the
microorganism [105 colony-forming units (CFU) /ml] was poured and uniformly

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Med Chem Res (2010) 19:127–135
Table 3 Spectral data for the newly synthesized compounds
Compound Spectral data
PS01
PS02
PS03
PS04
PS05
PS06
PS07
PS08
IR: (KBr, cm-1): 3412, 3070, 2667, 1640; 1H NMR (MeOD): d5.6 (s, 2H, NH2) and
7.25–7.6 (m, 5H, Ar–H and SH); MS: m/z 193 (M??1).
IR: (KBr, cm-1): 3450, 3070, 1640, 648; 1H NMR (MeOD): d5.6(s, 2H, NH2), 7.1–7.8
(m, 9H, Ar–H); MS: m/z 366 (M?), 368 (M??2).
IR: (KBr, cm-1): 3490, 3050, 760, 560; 1H NMR (MeOD): d6.9(s, 2H, NH2); MS: m/z 346
(M?), 348 (M??2).
IR: (KBr, cm-1): 3445, 3070, 1630, 1014, 627; 1H NMR (MeOD): d7.2–7.75 (m, 11H, Ar–H
and NH2); MS: m/z 384 (M?), 386 (M??2), 388 (M??4), 390 (M??6).
IR: (KBr, cm-1): 3490, 1014, 760; 1H NMR (MeOD): d6.85 (s, 2H, NH2), 7.38 (m, 9H,
Ar–H); MS: m/z 304 (M??2).
IR: (KBr, cm-1): 3400, 3312, 2667; 1H NMR (MeOD): d7.25–7.6 (m, 5H, Ar–H and SH),
6.85 (s, 2H, NH2), 9.5 (s, 1H, OH); MS: m/z 208 (M?).
IR: (KBr, cm-1): 3210, 2667; 1H NMR (MeOD): d2.2 (s, 3H, COCH3), 3.3 (bs, 1H, NH),
7.2–8.5 (m, 6H, Ar–H and SH); MS: m/z 234 (M?).
IR: (KBr, cm-1): 3312, 3047, 1511, 1325, 630; 1H NMR (MeOD): d7.15 (s, 2H, NH2),
7.6–8.4 (m, 8H, Ar–H); MS: m/z 358 (M?).
spread. Then the paper impregnated with the test and standard compound was
placed on the solidified medium. The plates were preincubated for 1 h at room
temperature and incubated at 30°C for 24 h. Then, after this incubation, the
minimum inhibitory concentration (MIC) was noted by observing the lowest
concentration of the drug at which there was no visible growth. A number of
antibacterial discs were placed on the agar for the sole purpose of producing zones
of inhibition in the bacterial lawn. Antibacterial activity was determined by
measuring the diameter of inhibition zone. Activity of each compound was
compared with ceftriaxone as standard. Zone of inhibition were determined for
PS01–08 and the results are summarized in Table 4.
Antifungal activities
Newly prepared compounds were screened for antifungal activity against Asper-
gillus niger ATCC 4578, Sacharomyces cerevisiae 180, Trichoderma sp. ATCC
5248, and Fusarium monaliforme NCIM 1276 by the same method as in the
antibacterial screening but the medium was replaced by potato dextrose agar
medium (39 g/l). Antifungal activity was determined by measuring the diameter of
the inhibition zone. Activity of each compound was compared with ketoconazole as
standard. Zones of inhibition were determined for PS01–08 and the results are
summarized in Table 5.
Results and discussion
The investigation of antibacterial and antifungal screening data revealed that all the
tested compounds (PS01–08) showed moderate to good inhibition at 5–20 lg/ml in

Med Chem Res (2010) 19:127–135
133
Table 4 Antibacterial activity of compounds PS01–08
Compd.
MIC in lg/ml and zone of inhibition (mm)
E. coli
B. subtilis
P. aeruginosa
P. fluoroscens
PS01
12.5 (16–20)
15.0 (\10)
12.5 (16–20)
15.0 (\10)
12.5 (16–20)
15.0 (\10)
12.5 (16–20)
15.0 (\10)
PS02
PS03
10.0 (16–20)
5.0 (14–20)
10.0 (16–20)
12.5 (16–20)
15.0 (\10)
10.0 (16–20)
5.0 (14–20)
10.0 (16–20)
12.5 (16–20)
15.0 (\10)
10.0 (16–20)
5.0 (16–22)
10.0 (16–20)
12.5 (16–24)
15.0 (\10)
10.0 (16–20)
5.0 (14–18)
10.0 (16–20)
12.5 (16–20)
15.0 (\10)
PS04
PS05
PS06
PS07
PS08
15.0 (\10)
15.0 (\10)
15.0 (\10)
15.0 (\10)
Ceftriaxone
5.0 (16–20)
5.0 (16–20)
5.0 (18–25)
5.0 (16–20)
MIC values were evaluated using concentration range 5–20 lg/ml
Escherichia coli (E. coli) DH5a, Bacillus subtilis (B. subtilis) ATCC 6633, Pseudomonas aeruginosa
(P. aeruginosa) MTCC 3363, Pseudomonas fluoroscens (P. fluoroscens) ATCC 3458
Table 5 Antifungal activity of compounds PS01–08
Compound
MIC in lg/ml and zone of inhibition (mm)
A. niger
S. cerevisiae
T. sp.
F. monaliforme
PS01
12.5 (16–22)
15.0 (\12)
12.5 (16–22)
15.0 (\12)
12.5 (16–22)
15.0 (\12)
12.5 (16–22)
15.0 (\12)
PS02
PS03
10.0 (16–22)
5.0 (14–18)
10.0 (16–22)
12.5 (16–22)
15.0 (\12)
10.0 (16–22)
5.0 (16–20)
10.0 (16–22)
12.5 (16–22)
15.0 (\12)
10.0 (16–22)
5.0 (22–26)
10.0 (16–22)
12.5 (16–22)
15.0 (\12)
10.0 (16–22)
5.0 (18–22)
10.0 (16–22)
12.5 (16–22)
15.0 (\12)
PS04
PS05
PS06
PS07
PS08
15.0 (\12)
15.0 (\12)
15.0 (\12)
15.0 (\12)
Ketoconazole
5.0 (16–20)
5.0 (18–24)
5.0 (25–32)
5.0 (20–26)
MIC values were evaluated using concentration range 5–20 lg/ml
Aspergillus niger (A. niger) ATCC 4578, Sacharomyces cerevisiae (S. cerevisiae) 180, Trichoderma sp.
(T. sp.) ATCC 5248, Fusarium monaliforme (F. monaliforme) NCIM 1276
ethanol. The screening results indicate that all of the compounds tested exhibited
significant antibacterial and antifungal activities when compared with the reference
drugs. It was observed that the compound containing chloro-substituted group in 3-
position with free NH2 group in 4-position of 1,2,4-triazole (PS04) shows maximum
bactericidal as well as fungicidal activity as compared with other compounds,
whereas PS03 and PS05 showed good activity. This good activity is attributed to
presence of pharmacologically active 4-chloro, 4-bromo, and 4-trichloromethyl
groups attached to phenyl ring of the triazole ring. The compounds with free NH2
groups at the 4-position (PS01 and PS06) showed moderate activity as compared

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Med Chem Res (2010) 19:127–135
with PS04. The other compounds (PS02, PS07, and PS08) showed lower fungicidal
effects compared with their bactericidal effects.
Conclusions
We report successful synthesis and antimicrobial activity of a new 1,2,4-triazole
moiety. The antimicrobial activity study revealed that all the tested compounds
showed moderate to good antibacterial and antifungal activities against pathogenic
strains. Structure and biological activity relationship of title compounds showed that
presence of 4-chloro, 4-bromo, and 4-carbon trichloride groups attached to phenyl
ring to the triazole ring of the title compounds is responsible for good antimicrobial
activity.
The field is further open for study of these compounds with respect to toxicity,
chronic toxicity, pharmacokinetics, and clinical studies to establish these molecules
as drugs in the market.
Acknowledgments The authors are grateful to the Head of the School of Pharmacy, Devi Ahilya
Vishwavidyalay, Indore, Madhya Pradesh, India and Sophisticated Analytical Instrument Facility, Central
Drug Research Institute, Lucknow, India for elemental analysis, 1H NMR, and mass spectral data of the
synthesized compounds reported herein. One of the authors, Mr. Priyabrata Pattanayak, is grateful to the
All India Council of Technical Education (AICTE) for providing financial aid.
References
Afaf HE, Fahmy HH, Ali SH (2000) Synthesis and antimicrobial activity of some new benzimidazole
derivatives. Molecules 5:1429–1438. doi:10.3390/51201429
Blank B, Nichols DM, Vaidya PD (1972) Synthesis of 1,2,4-triazoles as potential Hypoglycemic Agents.
J Med Chem 15:694–696. doi:10.1021/jm00276a040
Chandrasekharan M, Venkatesalu V, Sivasankar S (2005) Antibacterial activity of fatty acid methyl esters
of Ipomoea Pes-Caprae(L.) Sweet. Indian Drugs 42:275–281
Clerici F, Donato P (2001) Synthesis of 2-amino-5-sulphanyl-1,3,4-thiadiazole derivatives and evaluation
of their antidepressant and anxiolytic activity. J Med Chem 44:931–936. doi:10.1021/jm001027w
Demirba N, Uurluolu R, Demirba A (2002) Synthesis of 3-alkyl(aryl)-4-alkylidenamino-4,5-dihydro-1H–
1,2,4-triazol-5-ones and 3-alkyl-4-alkylamino-4,5-dihydro-1H–1,2,4-triazol-5-ones as antitumor
agents. Bioorg Med Chem 10:3717–3723. doi:10.1016/S0968-0896(02)00420-0
El-Essawy A, El-Sayed WA, El-Kafrawy SA, Morshedy AS, Abdel-Rahman AH (2008) Anti-hepatitis B
virus activity of new 1,2,4-triazol-2-yl- and 1,3,4-oxadiazol-2-yl-2-pyridinone derivatives. Z
Naturforsch 63(C):667–674
Fidler DF (1998) Legal issues associated with antimicrobial drug resistance. Emerg Infect Dis 4:169
Kakefuda A, Suzuki T, Tobe T, Tsukada J, Tahara A, Sakamoto S, Tsukamoto S (2002) Synthesis and
pharmacological evaluation of 5-(4-biphenyl)-3-methyl-4-phenyl-1,2,4-triazole derivatives as a
novel class of selective antagonists for the human vasopressin V(1A) receptor. J Med Chem
45:2589–2598. doi:10.1021/jm010544r
Kane JM, Dubley MW, Sorensen SM, Miller FP (1988) 2,4-Dihydro-3H–1,2,4-triazole-3-thiones as
potential antidepressant agents. J Med Chem 31:1253–1258. doi:10.1021/jm00401a031
Karabasanagouda T, Adhikari AV, Shetty NS (2007) Synthesis and antimicrobial activities of some novel
1,2,4-triazolo[3,4-b]-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines carrying thioalkyl and
sulphonyl phenoxy moieties. Eur J Med Chem 42:521–529. doi:10.1016/j.ejmech.2006.10.010
´
¨
Klimesova V, Zahajska L, Waisser K, Kaustova J, Mollmann U (2004) Synthesis and antimycobacterial
activity of 1,2,4-triazole 3-benzylsulfanyl derivatives. Farmaco 59:279–288. doi:10.1016/j.farmac.
2004.01.006

Med Chem Res (2010) 19:127–135
135
˘
Ku¨c¸u¨kgu¨zel I, Gu¨niz Ku¨c¸u¨kgu¨zel S, Rollas S, Otu¨k-Sanis¸ G, Ozdemir O, Bayrak I, Altug T, Stables JP
(2004) Synthesis of some 3-(arylalkylthio)-4-alkyl/aryl-5-(4-aminophenyl)-4H–1,2,4-triazole deriv-
atives and their anticonvulsant activity. Farmaco 59:893–901. doi:10.1016/j.farmac.2004.07.005
Mhasalkar MY, Shah MH, Nikam ST, Anantanarayanan KG, Deliwala CV (1970) 4-Alkyl-5-aryl-4H–
1,2,4-triazole-3-thiols as hypoglycemic agents. J Med Chem 13:672–674. doi:10.1021/jm00298a021
Mullican MD, Wilson MW, Cornor DT, Kostlan CR, Schrier DJ, Dyer RD (1993) Design of 5-(3,5-
di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles,-1,3,4-oxadiazoles and -1,2,4-triazoles as orally
active, nonulcerogenic antiinflammatory agents. J Med Chem 36:1090–1099. doi:10.1021/jm000
60a017
´
Sztanke K, Tuzimski T, Rzymowska J, Pasternak K, Kandefer-Szerszen
M (2008) Synthesis,
determination of the lipophilicity, anticancer and antimicrobial properties of some fused 1,2,4-
triazole derivatives. Eur J Med Chem 43:404–419. doi:10.1016/j.ejmech.2007.03.033
Tozkoparan B, Ku¨peli E, Yes¸ilada E, Is¸ik S, Ozalp M, Ertan M (2005) Synthesis and evaluation of
analgesic/ anti-inflammatory and antimicrobial activities of 3-substituted-1,2,4-triazole-5-thiones.
Arzneimittelforschung 55:533–540
Youichiro N, Akahoshi F, Takeda S, Okada T, Kajii M, Nishimura H, Sugiura M, Fukaya C, Kagitani Y
(1996) Synthesis and pharmacological activity of triazole derivatives inhibiting eosinophilia. J Med
Chem 39:3019–3029. doi:10.1021/jm9507993
Wang Z, Shi H (2001) Novel synthesis of condensed heterocyclic systems containing 1,2,4- Triazole ring.
Synth Commun 31:2841–2848. doi:10.1081/SCC-100105335