Synthesis and antimicrobial activity of 1,2,3-triazoles containing quinoline moiety

Article abstract of DOI:10.1007/s12272-010-1204-3

A new series of substituted 1,2,3-triazoles (4a-n) were synthesized from 4-azido-2,8-bistrifluoromethylquinoline 2. The 1,3-dipolar cycloaddition reaction of 2 with ethyl acetoacetate afforded 1-(2,8- Bistrifluoromethylquinolin-4-yl)-5-methyl-1,2,3-triazole-4-carboxylic acid 3, which was then converted into its corresponding acid hydrazide 3a. Condensation of this hydrazide with different aromatic aldehydes resulted in the formation of Schiff's bases, N-[1-Arylmethylene]-1-[2,8-bistrifluoromethylquinoline-4-yl]-5- methyl-1H-1,2,3-triazole-4-carbohydrazides (4a-n). These newly synthesized 1,2,3-triazole derivatives were characterized by analytical and spectral data. All the synthesized compounds were evaluated in vitro for their antibacterial and antifungal activity. A brief investigation of the structure activity relationships revealed that the nature of the substituent on position 4 of the triazole ring influences the antimicrobial activity. Among the newly synthesized compounds, the most active compound was 4n, which contained the 3-methylthien-2-yl moiety and showed a broad spectrum of antimicrobial activity against all the strains used for testing. Compounds 4b, 4c, 4e, 4f, 4h and 4l showed significant antimicrobial activity at the concentration of 6.25 μg/mL.

Full text of DOI:10.1007/s12272-010-1204-3

Arch Pharm Res Vol 33, No 12, 1911-1918, 2010
DOI 10.1007/s12272-010-1204-3
Synthesis and Antimicrobial Activity of 1,2,3-Triazoles Containing
Quinoline Moiety
V. Sumangala1,2, Boja Poojary1, N. Chidananda1,2, Jennifer Fernandes3, and N. Suchetha Kumari4
2
1Department of Chemistry, Mangalore University, Mangalagangothri-574199, Karnataka, India, SeQuent Scientific Lim-
3
ited, Mangalore-575011, Karnataka, India, Department of Pharmachemistry, N G S M College of Pharmacy, Panner,
4
Deralakatte-574 160, Karnataka, India, and Department of Biochemistry, K.S.Hegde Medical Academy, Deralakatte-574
162, Karnataka, India
(Received March 15, 2010/Revised June 12, 2010/Accepted June 13, 2010)
A new series of substituted 1,2,3-triazoles (4a-n) were synthesized from 4-azido-2,8-bistrifluo-
romethylquinoline
2. The 1,3-dipolar cycloaddition reaction of 2 with ethyl acetoacetate
afforded 1-(2,8-Bistrifluoromethylquinolin-4-yl)-5-methyl-1,2,3-triazole-4-carboxylic acid
3,
which was then converted into its corresponding acid hydrazide 3a. Condensation of this
hydrazide with different aromatic aldehydes resulted in the formation of Schiff’s bases, N-[1-
Arylmethylene]-1-[2,8-bistrifluoromethylquinoline-4-yl]-5-methyl-1H-1,2,3-triazole-4-carbohy-
drazides (4a-n). These newly synthesized 1,2,3-triazole derivatives were characterized by ana-
lytical and spectral data. All the synthesized compounds were evaluated in vitro for their
antibacterial and antifungal activity. A brief investigation of the structure activity relation-
ships revealed that the nature of the substituent on position 4 of the triazole ring influences
the antimicrobial activity. Among the newly synthesized compounds, the most active com-
pound was 4n, which contained the 3-methylthien-2-yl moiety and showed a broad spectrum
of antimicrobial activity against all the strains used for testing. Compounds 4b
, 4c, 4e, 4f, 4h
and 4l showed significant antimicrobial activity at the concentration of 6.25 g/mL.
µ
Key words: 1,3-Dipolar cycloaddition, 4-Bromo-2,8-bistrifluoromethylquinoline, 4-Azido-2,8-
bistrifluoromethylquinoline, Ethyl acetoacetate, Antimicrobial activity
routine disease caused by bacterial and fungal patho-
gens has become challenging due to the rapid spread
INTRODUCTION
The increased prevalence of diseases caused by of these pathogens as well as the lack of economic
microorganisms has become a worldwide problem. feasibility. In this context, development of new chemi-
The gradual development of pathogen resistance to cals with dual activity against bacterial and fungal
routinely used pesticides demands a renewed effort to pathogens is required to overcome this problem.
seek antimicrobial agents effective against pathogenic
Functionalized 1,2,3-triazoles constitute one of the
microbes (Vinaya et al., 2009). Furthermore, the use common fragments in biologically active compounds
of combinations of pesticides with different modes of (Bohm and Karow, 1981). This has resulted in a wealth
activity can delay the process of resistance develop- of synthetic methodologies for their preparation and
ment among these pathogens. Fungicide mixtures incorporation in more complex structures. Interest in
may also interact synergistically so that the amount of these compounds continues to be expressed in the
active ingredient used can be reduced. The control of pharmaceutical community, and the biological proper-
ties of these agents have been the subject of ongoing
investigations (Campos et al., 2009).
Correspondence to: Boja Poojary, Department of Chemistry,
The triazole scaffold has a wide range of therapeutic
Mangalore University, Mangalagangothri, Karnataka 574 199,
uses as it is found ubiquitously in drugs. The deriva-
India
tives of 1,2,3-triazoles constitute an important family of
heterocyclic compounds due to their chemotherapeu-
Tel: 91-824-2287262, Fax: 91-824-2284367
E-mail: bojapoojary@gmail.com
1911

1912
V. Sumangala et al.
tic values (Sanghvi et al., 1990). Some 1,2,3-triazoles antimicrobial activity.
are used as DNA cleaving agents and potassium chan-
nel activators (Biagi et al., 2004). Since many of them
have remarkable antimicrobial (Karimkulov et al.,
1991; Sherement et al., 2004), analgesic (Savini et al.,
1994), anti-inflammatory (Savini et al., 1994), local
MATERIALS AND METHODS
Chemistry
Melting points were determined in open capillaries
anesthetic (Banu et al., 1999), antimalarial (Julino using Sewell Instruments, Inc. melting point appara-
and Malcolm, 1998), antiviral (Diana and Nitz, 1993), tus and were uncorrected. The purity of the compounds
antiproliferating (Manfredini et al., 2000), anticon- was checked by thin layer chromatography on a silica-
vulsant (Meier, 1986), antineoplastic (Passannanti et coated aluminum sheet (silica gel F254). The Infrared
al., 1998) and anticancer activity (Deng et al., 2008), (IR) spectra (KBr pellets) were recorded on a Shimadzu
their synthesis and transformations have received FT-IR 157 spectrophotometer. Nuclear magnetic res-
particular interest for some time.
onance (1H-NMR) spectra were recorded on Bruker
Fluorinated compounds exhibit dramatically improv- Avance II 400 (400 MHz) spectrometer using CDCl3/
ed potency compared to their non-fluorinated analo- CD3OD as a solvent and TMS as an internal standard
gues (Secor and DeBardeleben, 1971) since the incor- (chemical shift in
δ ppm). The spin multiplets are
poration of fluorine alters the electronic, lipophilic and given as s (singlet), d (doublet), t (triplet), q (quartet)
steric parameters and can critically increase the in- and m (multiplet). Mass spectra were recorded on a
trinsic activity and the chemical and metabolic stabil- Jeol JMS-D 300 mass spectrometer operating at 70eV.
ity. In particular, the introduction of the CF3 group Elemental analysis was carried out using FlashEA
into organic molecules immensely increases both the 1112 Series, CHNSO Analyzer (Thermo). Mass spectra
pharmacological activity and the lipophilicity (Barnard were determined on a Jeol SX 102/Da-600 mass spec-
et al., 1993).
trometer/Data System using Argon/Xenon (6 kV, 10
Recently, we reported the synthesis and antimicro- mA) as the FAB gas. Elemental analyses were obtained
bial studies of bioactive 1,2,3-triazoles attached to a on a CHNS elemental analyzer. Solvents and reagents
quinoline moiety with a CF3 group (Holla et al., 2005). of the appropriate grade were purchased from commer-
In a continuation of our research on bioactive hetero- cial vendors and were used without purification.
cycles and their biological evaluation, we synthesized
The new derivatives of 1,2,3-triazoles (4a-n) were
some 1,2,3-triazoles containing bistrifluoromethyl- prepared by the method outlined in Scheme 1. Ini-
substituted quinoline moiety and evaluated the in vitro tially, 4-bromo-2,8-bistrifluoromethylquinoline
1 was
Scheme 1

Synthesis of Some 1,2,3-Triazoles
1913
prepared in good yield as described (Guenter and the mobile phase. After the completion of the reaction,
Vogt, 1977), and subsequently treated with sodium the reaction mixture was cooled to 20oC and quenched
azide in DMF to afford 4-azido-2,8-bistrifluoromethyl- with ice water, the precipitated yellow 4-azido-2,8-
quinoline
tion reaction of compound
the presence of sodium methoxide in methanol at 0oC gave pure product (7.6 g, 85%).
yielded 1-(2,8-Bistrifluoromethylquinolin-4-yl)-5-methyl- IR (KBr,
/cm-1): 3060 (Ar-H), 2130 (N3), 980 (C-F);
1,2,3-triazole-4-carboxylic acid 7.51 (s, Ar-H, 1H), 7.65
. The triazole carboxy- 1H-NMR (CDCl3, 400 MHz):
lic acid was treated with thionyl chloride in dichlo- (t, 1H, Ar-H, = 9.0 Hz), 8.18 (d, 1H, Ar-H, = 6.0
= 6.00 Hz). Anal. Calcd. for
2
(Holla et al., 2005). 1,3-Dipolar cycloaddi- bistrifluoromethyl-quinoline was isolated by filtration.
2
with ethyl acetoacetate in Recrystallization of the crude product from methanol
γ
3
δ
3
J
J
romethane to afford acid chloride; subsequent treat- Hz), 8.33 (d, 1H, Ar-H,
J
ment with hydrazine hydride at 0oC gave the corres- C11H4F6N4 (in %) : C, 43.15; H, 1.32; N, 18.30. Found:
ponding 1-[2,8-bistrifluoromethylquinolin-4-yl]-5-methyl- C, 43.15; H, 1.30; N, 18.10.
1H-1,2,3-triazole-4-carbohydrazide 3a in good yield.
Finally, the acid hydrazide was treated with different
aromatic aldehydes to yield the corresponding Schiff’s
bases, N-[1-arylmethylene]-1-[2,8-bistrifluoromethyl-
Synthesis of 1-(2, 8-Bistrifluoromethylquinolin-
4-yl)-5-methyl-1,2,3-triazole-4-carboxylic acid (3)
To a solution of 4-azido-2,8-bistrifluoromethylquinoline
quinolin-4-yl]-5-methyl-1H-1,2,3-triazole-4-carbohydra-
(2, 5 g, 0.016 mol) in 25 mL of methanol, ethyl acetoa-
zides (4a-n).
cetate (2.125 g, 0.016 mol) was added and the mixture
The structures of the synthesized compounds were was cooled to 0oC. Sodium methoxide (0.88 g, 0.016
established on the basis of spectral and analytical mol) was then added to the above mixture under a ni-
data. The C, H, N analysis of these compounds is in trogen atmosphere over a period of 30 min with stir-
agreement with the calculated values within the limits ring. Stirring was continued for 8 h. The progress of
of experimental error. The characterization data of the reaction was monitored by TLC using ethyl acetate:
the synthesized compounds are presented in Table I.
hexane (1.5:4.5, v/v) as the mobile phase. After com-
pletion of the reaction, the reaction mass was quench-
ed with ice water and neutralized with acetic acid.
Synthesis of 4-Azido-2, 8-bistrifluoromethyl-
quinoline (2)
The compound
3 was isolated by filtration as a yellow
4-Bromo-2,8-bistrifluoromethylquinoline (10 g, 0.03 solid. The crude product was purified by converting it
mol) was treated with sodium azide (2.08 g, 0.03 mol) into its corresponding sodium salt and then neutraliz-
in 25 mL of DMF. The reaction mixture was heated to ing it with acetic acid. The precipitated compound was
90oC for 1 h. The progress of the reaction was moni- filtered, washed and dried. The isolated product was
tored by TLC using hexane:methanol (9.9:0.1, v/v) as recrystallized by ethyl acetate (3.18 g, 50%).
Table I. Characterization data of compounds 4a-n
Compounds
Ar
Mol. formula
Mol. weight
m.p. (oC)
Yield (%)
2
3
-
-
-
C11H4F6N4
C15H8F6N4O2
C15H10F6N6O
C22H14F6N6O
C23H16F6N6O2
C23H16F6N6O2
C24H18F6N6O3
C22H14F6N6O2
C22H14F6N6O2
C22H14F6N6O4
C23H16F6N6O3
C22H13F6N7O3
C24H17F6N7O5
C28H18F6N6O
C27H18F6N6O2
C21H13F6N7O
C21H14F6N6OS
306.16
390.24
404.27
492.37
522.40
522.40
552.42
508.37
508.37
540.37
538.40
537.40
597.42
568.47
572.46
493.34
512.43
63-65
86
50
88
60
65
64
64
70
62
70
68
74
66
60
75
68
72
118-120
189-193
180-182
138-142
186-188
214-216
176-178
105-107
210-212
198-200
200-202
>280
3a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
C6H5
4-OCH3-C6H4
3-OCH3-C6H4
3,4-(OCH3)2-C6H3
2-OH-C6H4
4-OH-C6H4
2,3,4-(OH)3-C6H2
2-OH-3-OCH3-C6H3
4-NO2-C6H4
2-NO2-3,4-(OCH3)2-C6H2
4-C6H5-C6H4
6-OCH3-2-Naphthyl
3-Pyridyl
140-148
202-204
234-236
105-106
3-Methylthien-2-yl

1914
V. Sumangala et al.
IR (KBr,
γ
/cm-1): 3400 (O-H), 3060 (Ar-H), 2940 (C-H), 7.77 (m, 2H, phenyl), 8.13 (d, 1H, trifluoromethylqu-
1
1690 (C=O), 980 (C-F); H-NMR (CDCl3, 400 MHz):
δ
inolinyl,
= 8.48 Hz), 7.96 H), 8.51 (d, 1H, trifluoromethylquinolinyl,
= 8.16 Hz), 8.37 (s, Ar-H, 1H), 8.43 (d, MS (m/z, %): 492 (M+, 25). Anal. calcd for C22H14F6N6O
J
= 6.0 Hz), 8.32 (s, 1H, =CH), 8.50 (s, 1H, N-
2.53 (s, CH3, 3H), 7.83 (d, 1H, Ar-H,
(t, 1H, Ar-H,
1H, Ar-H,
J
J
= 6.0 Hz);
J
J
= 7.2 Hz), 9.8 (s,1H, -OH); MS (m/z, %): 390 (in%): C, 53.67; H, 2.87; N, 17.07. Found: C, 53.65; H,
(M+, 5). Anal. calcd for C15H8F6N4O2 (in %): C, 46.17; H, 2.83; N, 17.09.
2.07; N, 14.36. Found: C, 46.15; H, 2.05; N, 14.33.
1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(4-meth-
Synthesis of 1-(2,8-Bistrifluoromethylquinolin- oxybenzylidene)-5-methyl-1 -1,2,3-triazole-4-car-
H
4-yl)-5-methyl-1
(3a)
H
-1,2,3-triazole-4-carbohydrazide
bohydrazide (4b)
IR (KBr,
γ
/cm-1): 3343 (N-H), 3075 (Ar-H), 1692 (C=O),
1
Compound
of dry chloroform containing one 0.1 mL of DMF and CH3), 3.88 (s, 3H, OCH3), 6.99 (d, 1H, trifluoromethyl-
cooled to 0-5oC. The resulting mixture was treated quinolinyl,
= 8.0 Hz), 7.130 (s, 1H, trifluoromethyl-
with thionyl chloride (0.011 mol) in drops. The tem- quinolinyl), 7.59 (t, 1H, trifluoromethylquinolinyl,
perature was slowly increased and the reaction mass 8.0 Hz), 7.72 (d, 1H, trifluoromethylquinolinyl, = 8.0
was refluxed for 5 h to yield the acid chloride. Excess Hz), 8.00 (d, 1H, 4-methoxy phenyl, = 8.0 Hz), 8.09
= 8.0 Hz), 8.12 (s, 1H,
3 (3.0 g, 0.0077 mol) was taken in 10 mL 985 (C-F); H-NMR (CDCl3, 400 MHz): δ 2.59 (s, 3H,
J
J
=
J
J
thionyl chloride and solvent were removed by distilla- (d, 1H, 4-methoxy phenyl,
J
tion under vacuum. In another flask, the acid chloride =CH), 8.50 (s, 1H, N-H); MS (m/z, %): 522 (M+, 25).
was added dropwise to 5 mL of methanol. The result- Anal. calcd for C23H16F6N6O2 (in %): C, 52.88; H, 3.09;
ing methyl ester was isolated after removing the solv- N, 16.09. Found: C, 52.84; H, 3.13; N, 16.06.
ent by vacuum. The ester was then refluxed with hy-
drazine hydrate (0.011 mol) in ethanol for 8 h at 80oC. 1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(3-meth-
The solvent was removed under vacuum and the resi- oxybenzylidene)-5-methyl-1H-1,2,3-triazole-4-car-
due was quenched with ice water to obtain the white bohydrazide (4c)
solid. The solid was filtered, washed, dried and recry-
stallized from aqueous methanol to get the pure com- 980 (C-F); 1H-NMR (CD3OD, 400 MHz):
pound 3a (2.75 g, 88%). CH3), 4.87 (s, 3H, OCH3), 6.90 (d, 2H, 3-methoxy
IR (KBr, = 8.0 Hz), 7.28 (t, 2H, 3-methoxy phenyl,
/cm-1): 3360 (N-H), 3060 (Ar-H), 2955 (C- phenyl,
6.0 Hz), 7.31 (s, 1H, trifluoromethyl quinolinyl), 7.59
(t, 1H, trifluoromethylquinolinyl, = 8.0 Hz), 7.72 (s,
1H, 3-methoxy phenyl), 8.07 (d, 1H, trifluoromethyl
quinolinyl, = 8.0 Hz), 8.18 (s, 1H, =CH), 8.39 (d, 1H,
trifluoromethyl-quinolinyl, = 8.0 Hz), 8.50 (s, 1H, N-H);
MS (m/z, %): 522 (M+, 25). Anal. calcd for C23H16F6N6O2
IR (KBr,
γ
/cm-1): 3340 (N-H), 3075 (Ar-H), 1695 (C=O),
2.50 (s, 3H,
δ
γ
J
J =
H), 1695 (C=O), 980 (C-F).
J
General procedure for the synthesis of 1-(2,8-
bistrifluoromethylquinolin-4-yl)-N'-(arylmeth-
J
J
ylidene)-5-methyl-1H-1,2,3-triazole-4-carbohy-
drazides (4a-n)
Compound 3a was treated with an equimolar qu- (in %): C, 52.88; H, 3.09; N, 16.09. Found: C, 52.85; H,
antity of aromatic aldehyde in 10 volumes of methanol 3.05; N, 16.05.
and 1 volume of acetic acid and refluxed for 1 h. Com-
pletion of the reaction was checked by TLC using ethyl 1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(3,4-di-
acetate:hexane (1:4, v/v) as the mobile phase. The methoxybenzylidene)-5-methyl-1
H-1,2,3-triazole-
reaction was cooled to 0oC, and the resulting solid was 4-carbohydrazide (4d)
filtered and washed with cold methanol to yield
IR (KBr,
γ
/cm-1): 3340 (N-H), 3072 (Ar-H), 1690 (C=O),
2.30 (s, 3H,
CH3), 3.89 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 7.04 (d,
1H, 3,4-di-methoxyphenyl, = 6.0 Hz), 7.28 (t, 1H, tri-
fluoromethylquinoline, = 9.0 Hz), 7.46 (s, 1H, trifluo-
compound 4a-n. Recrystallization in methanol yielded 980 (C-F); 1H-NMR (CD3OD, 300 MHz):
δ
60-70% of pure product.
J
1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(4-ben-
J
zylidene)-5-methyl-1
drazide (4a)
H
-1,2,3-triazole-4-carbohy- romethylquinolinyl), 7.65 (d, 1H, 3,4-dimethoxyphenyl,
= 6.0 Hz), 8.12 (d, 1H, trifluoromethylquinolinyl,
J
J =
IR (KBr, γ
/cm-1): 3345 (N-H), 3070 (Ar-H), 1699 (C=O), 9.0 Hz), 8.26 (s, 1H, =CH), 8.26 (s, 1H, 3,4-dimethoxy-
985 (C-F); 1H-NMR (CD3OD, 300 MHz):
δ 2.53 (s, 3H, phenyl), 8.52 (d, 1H, trifluoromethylquinolinyl, J = 9.0
CH3), 7.40-7.38 (m, 2H, phenyl), 7.45-7.42 (m, 1H, Hz), 8.52 (s, 1H, N-H); MS (m/z, %): 552 (M+, 25).
phenyl), 7.47 (s, 1H, trifluoromethylquinolinyl), 7.67 Anal. calcd for C24H18F6N6O3 (in %): C, 52.18; H, 3.28;
(t, 1H, trifluoromethyl quinolinyl,
J = 7.65 Hz), 7.79- N, 15.21. Found: C, 52.15; H, 3.25; N, 15.20.

Synthesis of Some 1,2,3-Triazoles
1915
1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(2-nitro- CH3), 7.77 (t, 1H, pyridyl,
J
= 9.0 Hz), 7.82 (s, 1H, pyri-
3,4-dimethoxybenzylidene)-5-methyl-1
H
-1,2,3-tri-
dyl), 8.10 (s, 1H, trifluoromethylquinolinyl), 8.16 (d,
1H, pyridyl, = 6.0 Hz), 8.31 (d, 1H, pyridyl, = 6.0 Hz),
azole-4-carbohydrazide (4j)
J
J
IR (KBr,
(NO2, sym and asym str.), 1700 (C=O), 980 (C-F); 1H-
NMR (CDCl3, 400 MHz): 2.44 (s, 3H, CH3), 3.90 (s, 3H, 7.5 Hz), 8.90 (d, 1H, trifluoromethylquinolinyl,
γ
/cm-1): 3345 (N-H), 3070 (Ar-H), 1340, 1535 8.37 (s, 1H, =CH), 8.53 (d, 1H, trifluoromethylquinolinyl,
J
= 9.0 Hz), 8.85 (t, 1H, trifluoromethylquinolinyl,
J
=
=
δ
J
OCH3), 4.0 (s, 3H, OCH3), 7.45 (t, 1H, trifluoromethyl- 9.0Hz), 9.04 (s, 1H, NH); MS (m/z, %): 493 (M+, 25).
quinolinyl,
inolinyl,
olinyl), 7.66 (d, 1H, trifluoromethylquinolinyl,
Hz), 7.97 (d, 1H, nitrodimethoxyphenyl, = 8.0 Hz), 8.50 1-(2,8-Bistrifluoromethylquinolin-4-yl)-5-methyl-
(d, 1H, nitrodimethoxyphenyl, = 8.0 Hz), 9.05 (s, 1H, N'-(3-[3-methylthien-2-yl]methylidene)-1 -1,2,3-
=CH), 11.37 (s, 1H, N-H). Anal. calcd for C24H17F6N7O5 triazole-4-carbohydrazide (4n)
/cm-1): 3333 (N-H), 3055 (Ar-H), 2940 (C-H),
1697 (C=O), 1077 (C-F); 1H-NMR (CD3OD, 300 MHz):
2.18 (s, 3H, CH3), 2.30 (s, 3H, CH3), 6.89 (d, 1H,
1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(4-phenyl- thienyl, = 4.8 Hz), 7.02 (d, 1H, thienyl, = 4.8 Hz),
-1,2,3-triazole-4-carbohy- 8.12 (s, 1H, trifluoromethylquinolinyl), 8.27 (s, 1H,
J
= 8.0 Hz), 7.48 (d, 1H, trifluoromethylqu- Anal. calcd for C21H13F6N7O (in%): C, 51.12; H, 2.66;
= 8.0 Hz), 7.52 (s, 1H, trifluoromethylquin- N, 19.87. Found: C, 51.10; H, 2.66; N, 19.85.
= 8.0
J
J
J
J
H
(in %): C, 48.25; H, 2.87; N, 16.41. Found: C, 48.22; H,
2.86; N, 16.40.
IR (KBr, γ
δ
J
J
benzylidene)-5-methyl-1
H
drazide (4k)
=CH), 8.52-8.50 (d, 1H, trifluoromethylquinolinyl,
J
=
J
IR (KBr,
γ
/cm-1): 3345 (N-H), 3070 (Ar-H), 1699 (C=O), 9.0 Hz), 8.84-8.81 (t, 1H, trifluoromethylquinolinyl,
1
985 (C-F); H-NMR (CDCl3, 300 MHz):
CH3), 7.41 (d, 2H, phenyl,
phenyl, = 6.0 Hz), 7.50 (s, 1H, trifluoromethylquino- 5). Anal. calcd for C21H14F6N6OS (in%): C, 49.22; H,
linyl), 7.66-7.64 (m, 2H, phenyl), 7.72-7.67 (m, 3H, 2.75; N, 16.40. Found: C, 49.19; H, 2.78; N, 16.38.
phenyl), 7.87 (d, 1H, trifluoromethylquinolinyl, = 6.0
Hz), 7.90 (s, 1H, =CH), 8.08-8.06 (d, 1H, trifluoromethyl-
quinolinyl, = 6.0 Hz), 8.14-8.12 (t, 1H, trifluoromethyl-
quinolinyl), 8.63 (s, 1H, NH). Anal. calcd for C28H18F6N6O
δ
2.54 (s, 3H, = 7.5 Hz), 8.88-8.86 (d, 1H, trifluoromethylquinolinyl,
J
= 6.0 Hz), 7.47 (d, 2H,
J
= 9.0 Hz), 9.01 (s, 1H, NH); MS (m/z, %): 512 (M+,
J
J
Biology
Antibacterial activity
The newly synthesized compounds were screened
J
(in %): C, 59.16; H, 3.19; N, 14.78. Found: C, 59.13; H, for their antibacterial activity against Escherichia coli
3.17; N, 14.75.
(ATTC-25922), Staphylococcus aureus (ATTC-25923),
Pseudomonas aeruginosa (ATCC-27853) and Klebsiella
1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(6-meth- pneumoniae (recultured) bacterial strains by serial
oxy-2-naphthylmethylidene)-5-methyl-1
H
-1,2,3-
plate dilution method (MacLowry et al., 1970; Barry,
1991). Serial dilutions of the drug in Muller-Hinton
triazole-4-carbohydrazide (4l)
IR (KBr,
980 (C-F); 1H-NMR (CD3OD, 300 MHz):
CH3), 3.92 (s, 3H, OCH3), 7.14 (d, 1H, naphthyl,
Hz), 7.17 (d, 1H, naphthyl,
= 9.0 Hz), 7.24 (s, 1H, tube and incubated for 16-18 h at 37oC. The minimum
naphthyl), 7.66 (t, 1H, trifluoromethylquinolinyl, inhibitory concentration (MIC) was the lowest concen-
7.5 Hz), 7.88 (s, 1H, naphthyl), 7.80 (d, 1H, naphthyl, tration of the drug at which there was no visible growth.
γ
/cm-1): 3350 (N-H), 3073 (Ar-H), 1700 (C=O), broth were taken in tubes, and their pH was adjusted
δ
2.23 (s, 3H, to 5.0 using phosphate buffer. A standardized suspen-
= 9.0 sion of the test bacterium was inoculated into each
J
J
J
=
J
= 9.0 Hz), 7.90 (s, 1H, trifluoromethylquinolinyl),
A number of antibacterial discs were placed on the
8.02 (d, 1H, naphthyl,
trifluoromethylquinolinyl,
=CH), 8.51 (s, 1H, N-H), 8.52 (d, 1H, trifluoromethyl- media were poured into each Petri dish. The excess
quinolinyl, = 9.0 Hz). Anal. calcd for C27H18F6N6O2 suspension was decanted and plates were dried in an
(in %): C, 56.65; H, 3.17; N, 14.68. Found: C, 56.65; H, incubator at 37oC for an hour. Using a punch, wells
J
= 9.0 Hz), 8.14-8.11 (d, 1H, agar for the sole purpose of producing zones of inhibi-
J
= 9.0 Hz), 8.42 (s, 1H, tion in the bacterial lawn. Twenty milliliters of agar
J
3.16; N, 14.63.
were made on these seeds agar plates, and minimum
inhibitory concentrations of the test compounds in
dimethyl sulfoxide (DMSO) were added into each la-
1-(2,8-Bistrifluoromethylquinolin-4-yl)-N'-(3-pyr-
idylmethylidene)-5-methyl-1
carbohydrazide (4m)
H
-1,2,3-triazole-4- beled well. A control was also prepared for the plates
in the same way using DMSO as a solvent. The Petri
IR (KBr,
γ
/cm-1): 3333 (N-H), 3075 (Ar-H), 1700 (C=O), dishes were prepared in triplicate and maintained at
977 (C-F); 1H-NMR (CD3OD, 300 MHz):
δ
2.30 (s, 3H, 37oC for 3-4 days. Antibacterial activity was determin-

1916
V. Sumangala et al.
ed by measuring the diameter of the inhibition zone. zone. The activity of each compound was compared
The activity of each compound was compared with with cyclopiroxolamine as a standard. Zones of inhi-
that of ciprofloxacin as a standard (Fenlon et al., 1986; bition were determined for 4a-n
Davis et al., 1996). The zone of inhibition was deter-
mined for 4a-n
.
.
RESULTS
Antifungal activity
Several new derivatives of 1,2,3-triazoles containing
Newly synthesized compounds were also screened quinoline moiety 4a-n were synthesized by 1,3-dipolar
for their antifungal activity against Aspergillus flavus addition in normal to good yield. All the test com-
(NCIM No. 524), Aspergillus fumigatus (NCIM No. pounds 4a-n were evaluated by the serial plate dilu-
902), Penicillium marneffei (recultured) and Tricho- tion method for antimicrobial activity against four
phyton mentagrophytes (recultured) in DMSO by serial bacterial strains, E. coli,
plate dilution method (Verma et al., 1998; Arthington- K. pneumoniae, and against four fungal strains, A.
Skaggs et al., 2000). Sabourands agar media was flavus A. fumigatus P. marneffei and T. mentagro-
S. aureus, P. aeruginosa and
,
,
prepared by dissolving peptone (1 g), D-glucose (4 g) phytes. All the test compounds showed moderate to
and agar (2 g) in distilled water (100 mL) and adjust- good antibacterial and antifungal activities against
ing the pH to 5.7. Normal saline was used to make pathogenic strains. Compound 4n showed the highest
suspensions of spores of fungal strains for lawning. A activity against the microbial strains used for screen-
loopful of a particular fungal strain was transferred to ing. Significant activity against bacterial and fungal
3 mL of saline to prepare a suspension of the corres- pathogens was also provided by compounds 4b
ponding species. Twenty milliliters of agar media was 4e
4f 4h and 4l at the concentration of 6.25 g/mL.
poured into each Petri dish. The excess suspension Compounds 4a exhibited significant activity against
, 4c,
,
,
µ
was decanted and plates were dried in an incubator at P. aeruginosa
, K. pneumoniae, A. flavus and T. menta-
37oC for 1 h. Using a punch, wells were made on these grophytes. However, it showed moderate activity
seeded agar plates. Minimum inhibitory concentra- against the remaining four bacterial and fungal strains.
tions of the test compounds in DMSO were added into On the other hand, compounds 4d, 4g, 4i, 4j, 4k and
each labeled well. A control was also prepared for the 4m exhibited marginal antimicrobial activity. The
plates in the same way using DMSO as solvent. The minimum inhibitory concentrations and zones of inhi-
Petri dishes were prepared in triplicate and maintain- bition of the test compounds are presented in Tables
ed at 37oC for 3-4 days. Antifungal activity was deter- II and III.
mined by measuring the diameter of the inhibition
Table II. Antibacterial activity of compounds 4a-n
Compounds
S. aureus
E. coli
P. aeruginosa
K. pneumoniae
4a
12.5 (11-15)
6.25 (20-26)
6.25 (16-20)
25 (13-17)
12.5 (11-16)
6.25 (19-25)
6.25 (17-22)
12.5 (11-15)
12.5 (11-18)
12.5 (12-17)
12.5 (12-18)
6.25 (16-20)
12.5 (11-15)
25 (13-17)
6.25 (16-20)
6.25 (20-25)
6.25 (15-20)
12.5 (12-18)
6.25 (16-20)
6.25 (18-24)
12.5 (14-22)
12.5 (15-20)
25 (13-17)
6.25 (16-22)
6.25 (20-27)
6.25 (17-20)
25 (13-18)
4b
4c
4d
4e
6.25 (15-20)
6.25 (16-20)
12.5 (12-18)
6.25 (16-19)
12.5 (11-15)
25 (13-17)
6.25 (18-24)
6.25 (19-23)
12.5 (13-18)
6.25 (16-20)
25 (16-20)
4f
4g
4h
4i
4j
25 (13-17)
25 (13-17)
4k
25 (13-17)
25 (15-19)
25 (13-18)
25 (15-19)
4l
6.25 (16-21)
25 (13-17)
12.5 (11-15)
25 (13-17)
6.25 (16-20)
25 (13-17)
6.25 (16-20)
25 (13-17)
4m
4n
3.125 (18-24)
1.56 (22-30)
6.25 (20-25)
6.25 (30-40)
6.25 (16-20)
6.25 (25-33)
6.25 (16-20)
6.25 (23-27)
Standard (ciprofloxacin)
The MIC values were evaluated over the concentration range, 1.56-25
values in g/mL and the corresponding zone of inhibition in mm.
µg/mL. The figures in the table show the MIC
µ

Synthesis of Some 1,2,3-Triazoles
1917
Table III. Antifungal activity of compounds 4a-n
Compounds
A. flavus
A. fumigatus
P. marneffei
T. mentagrophytes
4a
4b
4c
4d
4e
4f
4g
4h
6.25 (16-20)
6.25 (21-27)
6.25 (17-22)
12.5 (15-19)
6.25 (16-20)
6.25 (13-18)
12.5 (12-16)
6.25 (18-24)
12.5 (13-18)
25 (13-17)
12.5 (13-18)
6.25 (19-26)
6.25 (16-20)
25 (13-17)
6.25 (18-24)
6.25 (15-18)
12.5 (14-19)
6.25 (18-24)
12.5 (12-17)
12.5 (11-15)
25 (13-17)
12.5 (12-16)
6.25 (20-29)
6.25 (15-22)
12.5 (11-15)
6.25 (15-20)
6.25 (13-19)
12.5 (13-18)
12.5 (19-25)
25 (15-19)
6.25 (18-22)
6.25 (18-25)
6.25 (16-20)
25 (15-20)
6.25 (16-21)
6.25 (14-20)
12.5 (15-21)
6.25 (15-20)
25 (15-20)
4i
4j
4k
25 (13-17)
25 (15-20)
25 (13-17)
25 (14-19)
25 (15-19)
4l
4m
6.25 (17-22)
25 (13-17)
6.25 (18-24)
25 (15-18)
6.25 (19-24)
25 (13-18)
6.25 (18-23)
25 (14-17)
4n
3.125 (15-20)
3.125 (25-30)
6.25 (16-20)
6.25 (25-30)
6.25 (16-20)
6.25 (20-27)
6.25 (16-20)
3.125 (27-33)
Standard (cyclo-piroxolamine)
The MIC values were evaluated over the concentration range, 1.56-25
values in g/mL and the corresponding zone of inhibition in mm.
µg/mL. The figures in the table show the MIC
µ
ring with a naphthyl ring with an electron-releasing
substituent (4l) did not appreciably change the acti-
DISCUSSION
From the antimicrobial activity results, the struc- vity. On the other hand, replacement of the phenyl
ture activity relationship can be deduced for the test ring with biphenyl (4k) and pyridyl (4m) rings drama-
compounds (4a-n). The antimicrobial activity of the tically decreased the activity.
test compounds was explored by varying only one sub-
Based on the investigation of SAR of the new 1,2,3-
stituent, viz. N-arylidene carbohydrazide at position 4 triazoles containing different substituents at position
of the 1,2,3-triazole moiety. Different electron-donat- 4 of the triazole ring, one or two electron-releasing
ing or electron-withdrawing groups attached to the substituents in the phenyl ring produced relatively
phenyl ring as the substituent linked to the carbohy- significant antimicrobial activity. On the other hand,
drazide group were replaced to explore the antimicro- an electron-withdrawing substituent or addition of
bial potency. Among the tested compounds, 4n ex- more than three substituents marginally reduced the
hibited maximum antimicrobial activity against all of activity. Pyridyl and biphenyl rings dramatically re-
the microbial pathogens, which may be due to the pre- duced the activity, while the thiophene ring enhanced
sence of the electron-rich 3-methylthien-2-yl moiety. the activity. These results suggest that the effect of 4-
The compounds 4b, 4c, 4e and 4f containing one substitution in the triazole moiety on antimicrobial
electron-releasing group, such as 4-OMe, 3-OMe, 2- activity is mostly due to the electronic and steric factors
OH, or 4-OH, in the phenyl ring also exhibited en- of the groups.
hanced activity. The compound with the 4-OMe group
(
4b) produced maximum inhibition zone compared to
ACKNOWLEDGEMENTS
3-OMe, 2-OH and 4-OH substituents. On the other
hand, compounds with an unsubstituted phenyl group
The authors are grateful to the management of Se-
(4a) and with one electron-withdrawing 4-NO2 sub- quent Scientific Limited for providing the necessary
stituent (4i) showed moderate and marginal anti- facilities and to CDRI Luknow and IISc, Bangalore,
microbial activity, respectively. However, the intro- for providing spectral data. Thanks are also due to
duction of two electron-releasing substituents, namely UGC-SAP for the infrastructure facility.
3,4-(OMe)2 (4d) and 2-OH-3-OMe (4h), did not en-
hance the activity. But the introduction of three elec-
tron-releasing groups in the phenyl ring reduced the
activity, as is evident from the activity results of 4g
and 4j with 2,3,4-(OH)3 and 2-NO2-3,4-(OMe)2 substi-
tuents, respectively. The replacement of the phenyl
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