Antimicrobial studies of 2,4-dichloro-5-fluorophenyl containing oxadiazoles

Article abstract of DOI:10.1016/j.ejmech.2007.03.013

A series of 2,4-dichloro-5-fluorophenyl containing 1,3,4-oxadiazoles (10 and 11) were synthesized by POCl₃ cyclization of 2,4-dichloro-5-fluorobenzoyl hydrazide (4) and 2-(2,4-dichloro-5-fluorophenyl)cinchoninyl hydrazide (8) with aryloxyacetic

Full text of DOI:10.1016/j.ejmech.2007.03.013

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 25e31
http://www.elsevier.com/locate/ejmech
Original article
Antimicrobial studies of 2,4-dichloro-5-fluorophenyl
containing oxadiazoles
a
Mari Sithambaram Karthikeyan a, , Dasappa Jagadeesh Prasad ,
*
Manjathuru Mahalinga a, Bantwal Shivarama Holla a,
Nalilu Suchetha Kumari b
a Department of Chemistry, Mangalore University, Mangalagangothri, Mangalore, Karnataka 574199, India
b Department of Biochemistry, K.S. Hegde Medical Academy, Deralakatte 574160, India
Received 8 January 2007; received in revised form 4 March 2007; accepted 8 March 2007
Available online 3 April 2007
Abstract
A series of 2,4-dichloro-5-fluorophenyl containing 1,3,4-oxadiazoles (10 and 11) were synthesized by POCl3 cyclization of 2,4-dichloro-5-
fluorobenzoyl hydrazide (4) and 2-(2,4-dichloro-5-fluorophenyl)cinchoninyl hydrazide (8) with aryloxyacetic acids (9). The structures of newly
synthesized compounds were characterized by spectral and elemental analyses. All the compounds were screened for their antibacterial and
antifungal activities. Compounds 10a, 10d and 11g showed very good antimicrobial activity. Compound 10d showed good bactericidal and fun-
gicidal activities.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 2,4,-Dichloro-5-fluorobenzoyl hydrazide; Cinchoninyl hydrazide; POCl3 cyclization; 1,3,4-Oxadiazoles; Antimicrobial activity
1. Introduction
than hydrogen, severalstudies have demonstrated that fluorine is
a reasonable hydrogen mimic and exerts only a minor steric de-
mand at receptor sites [5].
In recent days active research has been initiated on halogen
containing heterocycles, particularly fluorine containing het-
erocycles. 2,4-Dichloro-5-fluoroacetophenone is used in the
synthesis of drugs like ciprofloxacin and their analogues [1].
Moreover, incorporation of fluorine could alter the course of
reaction as well as biological activities [2e4]. Furthermore,
the introduction of fluorine atom or CF3 group into an organic
molecule largely enhances the pharmacological properties as
compared with the non-fluorinated analogues.
Quinoline ring structure is found in plant alkaloids such as
Cinchonin and Quinine, which are used in the treatment of
malaria [6]. Cinchophen (2-phenylquinoline-4-carboxylic
acid) is used as an analgesic and its hydrochloride salt finds
application as antipyretic and uricosuric drug [7]. Some cin-
chophen derivatives display anti-inflammatory, analgesic [8],
immunosuppressive [9], antifebrile anodyne, antirheumatic
and glucosuria metabolic activities [10] etc.
Incorporation of fluorine may also lead to increased lipid sol-
ubility thereby enhancing the rates of absorption and transport of
drugs in vivo. The replacement of hydrogen or a hydroxyl group
by fluorine is a strategy widely used in drug development to alter
biological function. Despite the fact that fluorine has greater size
1,3,4-Oxadiazoles are thermally stable and neutral heteroaro-
matic molecules. 1,3,4-Oxadiazole derivatives display quite
a broad spectrum of biological activities such as antimicrobial
[11], antimycobacterial [12], antiviral [13], anticonvulsant [14],
antiproliferative [15], anti-inflammatory [16] and insecticidal
properties [17]. Certain 1,3,4-oxadiazoles also find application
as photosensitisers, liquid crystals and organic light emitting di-
odes [18]. Polyhalogen substituted oxadiazoles showed various
activities [17].
* Corresponding author. Tel.: þ91 824 2287262; fax: þ91 824 2287367/
2287424.
E-mail address: karthims02@rediffmail.com (M.S. Karthikeyan).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.03.013

26
M.S. Karthikeyan et al. / European Journal of Medicinal Chemistry 43 (2008) 25e31
Prompted by the biological activities of fluorine containing
Further evidence for the formation of oxadiazole (10a) was
obtained by recording its mass spectrum. The mass spectrum
of the compound (10a) showed molecular ion peak at m/z 352,
in conformity with the molecular formula C16H11Cl2FN2O2.
The other fragmentation peaks observed are at m/z 191 (10%)
and 107 (22%). The characterization data of oxadiazoles (10
and 11) are given in Table 1.
heterocycles, cinchophen and 1,3,4-oxadiazoles, it was con-
templated to synthesize 2,4-dichloro-5-fluorophenyl contain-
ing 1,3,4-oxadiazoles and to pursue in vitro antibacterial and
antifungal screening. The results of the antibacterial and anti-
fungal activities are discussed in this paper.
2. Chemistry
4. Pharmacology
2,4-Dichloro-5-fluorobenzoic acid was obtained by halo-
form reaction of 2,4-dichloro-5-fluoroacetophenone [11].
2,4-Dichloro-5-fluorobenzoyl hydrazide (4) was prepared
from the corresponding acid according to the literature method
[17]. 2-(2,4-Dichloro-5-fluorophenyl)cinchoninic acid (6) was
prepared by reaction of isatin (5) with 2,4-dichloro-5-fluoroace-
tophenone under Pfitzinger conditions [19]. 2-(2,4-Dichloro-5-
fluorophenyl)cinchoninyl hydrazide (8) was obtained from
corresponding acid by esterification and further treatment with
hydrazine hydrate. Aryloxyacetic acids (9) were prepared
from the corresponding phenols [20]. Aryloxyacetic acids
when treated with 4 and 8 in presence of POCl3 produced 2,5-
disubstituted-1,3,4-oxadiazoles (10 and 11) in good yields.
The reaction sequences are outlined in Schemes 1e3.
4.1. Antibacterial studies
The newly prepared compounds were screened for their an-
tibacterial activity against Escherichia coli (ATCC-25922),
Staphylococcus aureus (ATCC-25923), Pseudomonas aerugi-
nosa (ATCC-27853) and Klebsiella pneumoniae (recultured)
bacterial strains by disc diffusion method [21,22]. A standard
inoculum (1e2 ꢁ 107 c.f.u./ml 0.5 McFarland standards) was
introduced on to the surface of sterile agar plates, and a sterile
glass spreader was used for even distribution of the inoculum.
The discs measuring 6.25 mm in diameter were prepared from
Whatman no. 1 filter paper and sterilized by dry heat at 140 ꢂC
for 1 h. The sterile discs previously soaked in a known concen-
tration of the test compounds were placed in nutrient agar me-
dium. Solvent and growth controls were kept. The plates were
inverted and incubated for 24 h at 37 ꢂC. Ciprofloxacin was
used as a standard drug. Inhibition zones were measured and
compared with the controls. The bacterial zones of inhibition
values are given in Table 2.
Minimum inhibitory concentrations (MICs) were deter-
mined by broth dilution technique. The nutrient broth, which
contained logarithmic serially two fold diluted amount of test
compound and controls were inoculated with approximately
5 ꢁ 105 c.f.u. of actively dividing bacteria cells. The cultures
were incubated for 24 h at 37 ꢂC and the growth was monitored
visually and spectrophotometrically. The lowest concentration
(highest dilution) required to arrest the growth of bacteria was
regarded as minimum inhibitory concentration (MIC).
3. Results and discussion
The IR spectrum of compound 10a, showed an absorption
band at 3075 cmꢀ1 due to aromatic stretch. Another absorption
band at 2924 cmꢀ1 was due to aliphatic stretch. The absorption
band for C]N group was observed at 1616 cmꢀ1. The other
prominent absorption bands observed in the IR spectrum are
at 1267 (CeOeC), 1083 (CeF), 821 and 758 (CeCl) cmꢀ1
.
1
The H NMR spectrum of 10a, showed a singlet at d 2.25
attributable to CH3 protons. The OCH2 protons resonated as
a singlet at d 4.62. The aromatic protons of p-cresyloxy moiety
appeared as two doublets at d 6.90 and d 7.14 (J ¼ 8.5 Hz)
each integrating for two protons, respectively. A doublet at
d 7.97 (JHeF meta ¼ 6.4 Hz) integrating for one proton was at-
tributable to the C3 proton of dichlorofluorophenyl moiety.
The C6 proton of dichlorofluorophenyl moiety resonated as
doublet at d 8.07 (JHeF ortho ¼ 9.4 Hz).
To obtain the minimum bacterial concentration (MBC),
0.1 ml volume was taken from each tube and spread on agar
plates. The number of c.f.u. was counted after 18e24 h of
F
COCH3
F
COOH
F
COOEt
Cl
Haloform
reaction
EtOH
Cl
Cl
Cl
Cl
Cl
1
2
3
N2H4,
F
CONHNH2
Cl
Cl
4
Scheme 1.

M.S. Karthikeyan et al. / European Journal of Medicinal Chemistry 43 (2008) 25e31
27
COOH
F
COCH3
Cl
O
Cl
NaOH
+
O
Cl
N
H
N
6
5
1
Cl
F
EtOH
CONHNH2
COOEt
Cl
Cl
N2H4,
N
N
Cl
Cl
8
7
F
F
Scheme 2.
incubation at 35 ꢂC. MBC was defined as the lowest drug con-
centration at which 99.9% of the inoculum was killed. The
minimum inhibitory concentration and minimum bactericidal
concentration are given in Table 3.
The investigation of antibacterial screening data revealed
that all the tested compounds showed moderate to good bacte-
rial inhibition. Compounds 10a, 10b, 10d, 11d, 11c and 11g
showed good inhibition against S. aureus and E. coli species
CONHNH2
Cl
N
N
Cl
O
R
POCl3
O
Cl
F
Cl
F
10
4
+
R
OH
O
O
9
+
CONHNH2
Cl
N
N
POCl3
N
N
O
Cl
Cl
O
8
11
Cl
R
F
F
Scheme 3. Synthesis of 2,5-disubstituted-1,3,4-oxadiazole (10 and 11).

28
M.S. Karthikeyan et al. / European Journal of Medicinal Chemistry 43 (2008) 25e31
Table 1
Characterization data of oxadiazoles (10 and 11)
Compd.
R
Mol. formula
M.p. [ꢂC]
Yield [%]
Analysis (%) found (calculated)
C
H
N
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
11f
Dichlorofluorophenyl
Dichlorofluorphenyl
Dichlorofluorophenyl
Dichlorofluorophenyl
Dichlorofluorophenyl
Cinchoninyl
4-CH3
2-CH3
2-Cl
C16H11Cl2FN2O2
C16H11Cl2FN2O2
C15H8Cl3FN2O2
C16H10Cl3FN2O2
C16H10Cl3FN2O2
C25H16Cl2FN3O2
C25H16Cl2FN3O2
110e112
169e172
104e106
126e128
136e138
162e164
174e177
159e161
215e217
186e189
194e197
200e02
78
65
72
81
70
75
68
72
77
80
85
71
53.95 (54.39)
54.09 (54.39)
47.85 (48.19)
49.31 (49.55)
49.40 (49.55)
62.21 (62.50)
62.25 (62.50)
57.22 (57.54)
57.31 (57.54)
57.95 (58.31)
58.03 (58.31)
53.48 (53.83)
3.00 (3.12)
3.05 (3.12)
2.08 (2.14)
2.22 (2.58)
2.29 (2.58)
3.20 (3.33)
3.25 (3.33)
2.47 (2.60)
2.40 (2.60)
2.80 (2.85)
2.75 (2.85)
2.12 (2.24)
7.05 (7.19)
7.10 (7.19)
7.42 (7.50)
7.15 (7.23)
7.10 (7.23)
8.63 (8.75)
8.60 (8.75)
8.21 (8.39)
8.15 (8.39)
8.09 (8.04)
8.04 (8.04)
7.49 (7.85)
4-Cl-2-CH3
4-Cl-3-CH3
4-CH3
Cinchoninyl
Cinchoninyl
2-CH3
4-Cl
2-Cl
C24H13Cl3FN3O2
Cinchoninyl
Cinchoninyl
C24H13Cl3FN3O2
C25H15Cl3FN3O2
C25H15Cl3FN3O2
C24H12Cl4FN3O2
4-Cl-2-CH3
4-Cl-3-CH3
2.4-Cl2
Cinchoninyl
Cinchoninyl
11g
at 6.25 mg/ml concentrations. Compounds 10a, 10b, 10d, 11c
and 11g exhibited good antibacterial activity almost equivalent
to that of standard. The MBC of few compounds was found to
be the same as MIC but in most of the compounds it was two
or three or four folds higher than their corresponding MIC re-
sult. Compound 10d showed good bactericidal activity against
S. aureus, P. aeruginosa and K. pneumoniae bacterial strains.
made and each well was labeled. A control was also prepared
in triplicate and maintained at 37 ꢂC for 3e4 days. The fungal
activity of each compound was compared with Greseofulvin as
standard drug. Inhibition zones were measured and compared
with the controls. The fungal zones of inhibition values are
given in Table 4.
The nutrient broth, which contained logarithmic serially two
fold diluted amount of test compound and controls was inocu-
lated with approximately 1.6 ꢁ 104e6 ꢁ 104 c.f.u./ml. The
cultures were incubated for 48 h at 35 ꢂC and the growth was
monitored. The lowest concentration (highest dilution) required
to arrest the growth of fungus was regarded as minimum inhib-
itory concentration (MIC). To obtain the minimum fungicidal
concentration (MFC), 0.1 ml volume was taken from each
tube and spread on agar plates. The number of c.f.u. was
counted after 48 h of incubation at 35 ꢂC. MFC was defined
as the lowest drug concentration at which 99.9% of the inocu-
lum was killed. The minimum inhibitory concentration and
minimum fungicidal concentration are given in Table 5.
4.2. Antifungal studies
The newly prepared compounds were screened for their an-
tifungal activity against Candida albicans, Aspergillus fumiga-
tus, Penicillium marneffei and Trichophyton mentagrophytes
(recultured) in DMSO by agar diffusion method [23,24]. Sab-
ourands agar media was prepared by dissolving peptone (1 g),
D-glucose (4 g) and agar (2 g) in distilled water (100 ml) and
adjusting pH to 5.7. Normal saline was used to make a suspen-
sion of spore of fungal strain for lawning. A loopful of partic-
ular fungal strain was transferred to 3 ml saline to get
a suspension of corresponding species. Twenty millilitres of
agar media was poured into each petri dish. Excess of suspen-
sion was decanted and the plates were dried by placing in an
incubator at 37 ꢂC for 1 h. Using an agar punch, wells were
Table 3
MIC and MBC results of oxadiazoles (10 and 11)
Compd. Staphylococcus Escherichia
Pseudomonas Klebsiella
pneumoniae
Table 2
Zone of inhibition (mm) of oxadiazoles (10 and 11)
aureus
coli
aeruginosa
MIC
MBC
MIC MBC MIC
MBC MIC MBC
Compd.
Staphylococcus
aureus
Escherichia
coli
Pseudomonas
aeruginosa
Klebsiella
pneumoniae
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
11f
6.25
6.25
12.5
6.25
25
12.5
25
6.25
6.25 25
6.25 6.25 12.5
6.25
12.5
6.25 12.5
25
50
50
10a
10b
10c
22
19
15
20
10
15
12
19
e
25
27
18
24
15
10
12
25
20
e
32
28
15
29
e
18
16
12
19
12
15
e
50
6.25 12.5 12.5
6.25 12.5
12.5 100
25
6.25
25
6.25
6.25
6.25
6.25
50
100
25
e
e
50
e
e
10d
10e
12.5
12.5
6.25
e
25
12.5
50
25
25
e
12.5
e
12.5
25
25
e
e
11a
11b
11c
8
12.5
6.25 6.25 6.25 25
6.25 50
25
100
e
e
e
25
12.5
50
50
32
22
12
26
30
32
18
e
e
6.25
e
6.25
25
e
12.5
e
e
11d
11e
e
6.25
12.5
25
6.25 25
6.25 12.5
6.25 12.5
e
12.5
12.5
e
12.5
12.5
17
e
11g
6.25 12.5
6.25 12.5
11f
11g
Standard
17
26
27
e
Standard 6.25
20
22
17
19
e Indicates bacteria are resistant to the compounds >100 mg/ml; MIC
(mg/ml) ¼ minimum inhibitory concentration, i.e., the lowest concentration
to completely inhibit bacterial growth; MBC (mg/ml) ¼ minimum bactericidal
concentration, i.e., the lowest concentration to completely kill bacteria.
e Indicates bacteria are resistant to the compounds >100 mg/ml. Ciprofloxacin
is used as the standard.

M.S. Karthikeyan et al. / European Journal of Medicinal Chemistry 43 (2008) 25e31
29
Table 4
Zone of inhibition (mm) of oxadiazoles (10 and 11)
6. Experimental protocols
Compd.
Candida
albicans
Aspergillus
fumigatus
Trichophyton
mentagrophytes
Penicillium
marneffei
6.1. Chemistry
10a
10b
10c
27
15
10
28
e
26
10
19
25
8
24
e
12
22
e
18
8
Melting points were determined by open capillary method
and are uncorrected. The IR spectra (in KBr pellets) were re-
corded on a Shimadzu FT-IR 157 spectrophotometer. 1H NMR
spectra were recorded either on a Bruker or AMX 400 MHz
NMR spectrometer using TMS as an internal standard. The
mass spectra were recorded on a FAB mass spectrometer op-
erating at 70 eV. The purity of compounds was checked by
thin layer chromatography (TLC) on silica gel plate using
a mixture of petroleum ether and ethyl acetate.
e
10d
10e
19
10
15
e
11a
11b
11c
e
e
e
17
18
15
e
19
e
25
12
20
e
16
e
12
15
27
27
20
12
e
11d
11e
11f
11g
Standard
e
12
19
20
29
30
21
24
6.2. Procedure for the preparation of 2,4-dichloro-5-
fluorobenzoyl hydrazide (4)
e Indicates fungus are resistant to the compounds >100 mg/ml; greseofulvin is
used as the standard drug.
2,4-Dichloro-5-fluorobenzoic acid was obtained by halo-
form reaction of 2,4-dichloro-5-fluoroacetophenone [11].
2,4-Dichloro-5-fluorobenzoyl hydrazide (4) was prepared
according to the literature method [17].
The antifungal screening data showed only moderate activ-
ity. Among the screened compounds, 10a, 10d and 11g
showed good inhibition against all the fungal strains. The
MBC of few compounds was found to be the same as MIC
but in most of the compounds it was two or three or four folds
higher than the corresponding MIC result. Compound 10d
showed good fungicidal activity against C. albicans, A. fumi-
gatus and P. marneffei fungal strains.
6.3. General procedure for the preparation 2-(2,4-
dichloro-5-fluorophenyl)-cinchoninyl hydrazide (8)
2-(2,4-Dichloro-5-fluorophenyl)cinchoninic acid (6) was
prepared by reaction of isatin and 2,4-dichloro-5-fluoroaceto-
phenone under Pfitzinger conditions [19] and converted to
hydrazide by usual methods.
5. Conclusion
We have synthesized series of 2,4-dichloro-5-fluorophenyl
bearing 1,3,4-oxadiazoles. Among the synthesized oxadia-
zoles, compounds with methyl, chloromethyl and dichloro
substituents in the phenyl ring at 5th position of oxadiazoles
were found to increase the antimicrobial activity. Compound
with chloromethylphenyl moiety showed good bactericidal
and fungicidal activities.
6.4. General procedure for the preparation of
aryloxyacetic acids (9)
Aryloxyacetic acids (9) were prepared from the corre-
sponding phenols according to the literature procedure [20].
6.5. Synthesis of 2,5-disubstituted-1,3,4-oxadiazoles
(10 and 11)
Table 5
MIC and MFC results of oxadiazoles (10 and 11)
Compd. Candida
albicans
Aspergillus
fumigatus
Trichophyton
mentagrophytes
Penicillium
marneffei
A mixture of hydrazide (4 and 8) (0.01 mol), aryloxyacetic
acid (9) (0.01 mol) and phosphorus oxychloride (10 ml) was
refluxed on a water bath for w9 h. Excess of phosphorus oxy-
chloride was removed under reduced pressure. The reaction
mixture was cooled and poured onto crushed ice and neutral-
ized with aqueous ammonia. The resulting solid product was
filtered, dried and recrystallized from a mixture of ethanol
and dimethylformamide.
MIC MBC MIC MBC MIC
6.25 6.25 6.25 12.5 6.25
12.5 25 25 100
25 50 6.25 12.5 12.5
6.25 6.25 6.25 6.25 6.25
50
MBC
MIC MBC
10a
10b
10c
10d
10e
11a
11b
11c
11d
11e
11f
6.25
e
50
6.25 12.5
100
e
25
e
e
25
e
6.25
6.25
e
e
e
e
25
e
e
25
50
25
e
e
6.25
6.25
12.5
12.5
e
12.5
e
6.25 25
12.5 50
6.25 12.5
e
6.25
6.25
e
6.25 25
e
6.25 12.5
12.5 25
e
e
6.5.1. Compound 10c
IR (KBr, y cmꢀ1): 3097 (Ar-H), 2965 (CeH), 1585
(C]N), 1105 (CeF), 827 and 731 (CeCl); 1H NMR (d,
CDCl3): 5.63 (s, 2H, OCH2), 7.02e7.07 (m, 1H, o-chlorophe-
noxy protons), 7.32e7.40 (m, 2H, o-chlorophenoxy protons),
7.46 (d, 1H, o-chlorophenoxy protons J ¼ 7.8 Hz), 8.05 (d,
e
e
e
e
12.5
12.5
50
25
6.25
12.5
e
e
e
e
12.5
50
6.25
6.25 12.5
11g 6.25 6.25 6.25 12.5
Standard 6.25 12.5 6.25 12.5
6.25
6.25
25
12.5
6.25
e Indicates bacteria are resistant to the compounds >100 mg/ml; MIC
(mg/ml) ¼ minimum inhibitory concentration, i.e., the lowest concentration
to completely inhibit fungal growth; MFC (mg/ml) ¼ minimum fungicidal
concentration, i.e., the lowest concentration to completely kill fungus.
1H, dichlorofluorophenyl proton, JHeF
(d, 1H, dichlorofluorophenyl proton, JHeF meta ¼ 6.6 Hz).
¼ 9.3 Hz), 8.13
ortho

30
M.S. Karthikeyan et al. / European Journal of Medicinal Chemistry 43 (2008) 25e31
6.5.2. Compound 10d
6.5.8. Compound 11g
IR (KBr, y cmꢀ1): 3091 (Ar-H), 1578 (C]N), 1110 (CeF),
838 and 727 (CeCl); H NMR (d, DMSO-d6): 5.73 (s, 2H,
OCH2), 7.42e7.49 (m, 2H, dichlorophenyl protons), 7.63 (d,
1H, dichlorophenyl protons, J ¼ 2.2 Hz), 7.86e8.01 (m, 3H,
cinchoninyl protons), 8.05 (d, 1H, dichlorofluorophenyl pro-
IR (KBr, y cmꢀ1): 3080 (Ar-H), 2915 (CeH), 1600
(C]N), 1089 (CeF), 833 and 736 (CeCl); 1H NMR (d,
CDCl3): 2.22 (s, 3H, CH3), 5.34 (s, 2H, OCH2), 6.91 (dd,
1H, p-chloro-o-cresyloxy proton, J ¼ 8.2 Hz), 7.12 (d, 1H, p-
chloro-o-cresyloxy proton, J ¼ 2.2 Hz), 7.15 (s, 1H, p-
chloro-o-cresyloxy proton), 7.63 (d, 1H, dichlorofluorophenyl
proton, JHeF meta ¼ 6.4 Hz), 7.85 (d, 1H, dichlorofluorophenyl
proton, JHeF ortho ¼ 8.9 Hz); mass (%): Mþ 387 (25), 191 (10),
155 (22).
1
ton, JHeF
¼ 6.7 Hz), 8.24 (d, 1H, cinchoninyl protons,
meta
J ¼ 8.2 Hz), 8.34 (s, 1H, cinchoninyl proton), 9.04 (d, 1H, di-
chlorofluorophenyl proton, JHeF
¼ 8.2 Hz); mass (%):
ortho
Mþ 534 (65), 373 (8), 289 (12).
6.5.3. Compound 10e
IR (KBr, y cmꢀ1): 3089 (Ar-H), 2915 (CeH), 1604
(C]N), 1101 (CeF), 831 and 736 (CeCl); 1H NMR (d,
DMSO-d6): 2.35 (s, 3H, CH3), 5.34 (s, 2H, OCH2), 6.81 (dd,
1H, p-chloro-m-cresyloxy proton, J ¼ 2.9 Hz), 6.91 (d, 1H,
p-chloro-m-cresyloxy proton, J ¼ 2.8 Hz), 6.96 (d, 1H, p-
chloro-m-cresyloxy proton, J ¼ 8.2 Hz), 7.63 (d, 1H, dichloro-
Acknowledgement
The authors are grateful to Head, NMR Research Center,
1
CDRI, Lucknow for providing H NMR and mass spectral
data. M.S.K. is grateful to CSIR New Delhi for providing Se-
nior Research Fellowship.
fluorophenyl proton, JHeF
¼ 6.5 Hz), 7.84 (d, 1H,
meta
dichlorofluorophenyl proton, JHeF ortho ¼ 8.9 Hz); mass (%):
Mþ 387 (11), 191 (55), 141 (14), 128 (10), 64 (30).
References
[1] D.T.W. Chu, P.B. Fernandes, A.K. Claiborne, E. Pihuleac,
C.W. Nordeen, R.E. Maleczka Jr., A.G. Pernet, J. Med. Chem. 28
(1985) 1558e1564.
6.5.4. Compound 11a
IR (KBr, y cmꢀ1): 3095 (Ar-H), 2986 (CeH), 1602
(C]N), 1105 (CeF), 854 and 740 (CeCl); 1H NMR (d,
DMSO-d6): 2.31 (s, 3H, CH3), 4.66 (s, 2H, OCH2), 6.93 (d,
2H, p-cresyloxy proton, J ¼ 8.5 Hz), 7.12 (d, 2H, p-cresyloxy
proton, J ¼ 8.5 Hz), 7.75e7.93 (m, 3H, cinchoninyl protons),
8.04 (d, 1H, dichlorofluorophenyl proton, JHeF meta ¼ 6.7 Hz),
8.14e819 (m, 2H, cinchoninyl protons), 9.04 (d, 1H, dichlor-
ofluorophenyl proton, JHeF ortho ¼ 7.9 Hz).
[2] R. Filler, Chem. Tech. 4 (1974) 752.
[3] R.G. Plevey, J.C. Tatlow, Sci. Org. Oxy. 58 (1970) 481.
[4] K.C. Joshi, A. Dandia, S. Khanna, Indian J. Chem. 29B (1990) 1125e
1128.
[5] B. Kevin Park, N.R. Kitteringham, P.M. O’Neill, Annu. Rev. Pharmacol.
Toxicol. 41 (2001) 443e470.
[6] F.S. Yates, in: A.R. Katritzky, C.W. Rees (Eds.), Comprehensive
Heterocyclic Chemistry, vol. 2, Pergamon Press, New York, 1984,
p. 512.
[7] M. Windholz (Ed.), The Merck Index, ninth ed. Merck and Co. Inc., New
Jersey, 1976, p. 2278.
6.5.5. Compound 11d
IR (KBr, y cmꢀ1): 3081 (Ar-H), 1557 (C]N), 1102 (CeF),
835 and 727 (CeCl); H NMR (d, DMSO-d6): 4.85 (s, 2H,
OCH2), 6.95e7.46 (m, 4H, o-chlorophenoxy and cinchoninyl
protons), 7.75e7.93 (m, 4H, o-chlorophenoxy and cinchoninyl
[8] F. Sparatore, F. Savelli, G. Cordella, Il Farmaco 35 (1980) 735e751.
[9] D.G. Batt, R.A. Copeland, R.L. Dowling, T.L. Gardner, E.A. Jones,
M.J. Orwat, D.J. Pinto, W.J. Pitts, R.L. Magolda, B.D. Jaffe, Bioorg.
Med. Chem. 5 (1995) 1549e1554.
1
[10] L.M. Chen, Z.Y. Zhang, Z.X. Wang, X. Zhang, J. Lanzhou Univ. 24
(1988) 49.
protons), 8.04 (d, 1H, dichlorofluorophenyl proton, JHeF meta
6.7 Hz), 8.15 (d, 1H, cinchoninyl proton, J ¼ 8.1 Hz), 8.38 (d,
1H, dichlorofluorophenyl proton, JHeF ortho ¼ 8.2 Hz).
¼
[11] G. Sahin, E. Palaska, M. Ekizoglu, M. Ozalp, Il Farmaco 57 (2002) 539e
542;
K.S. Bhat, M.S. Karthikeyan, B.S. Holla, Indian J. Chem. 43B (2004)
1765e1769.
6.5.6. Compound 11e
IR (KBr, y cmꢀ1): 3089 (Ar-H), 2895 (CeH), 1602
(C]N), 1098 (CeF), 821 and 740 (CeCl); mass (%): Mþ
514 (90), 387 (25), 290 (43), 191(10), 155 (25), 125 (10).
[12] F. Macaev, G. Rusu, S. Pogrebnoi, A. Gudima, E. Stingaci, L. Vlad,
N. Shvets, F. Kandemirli, A. Dimoglo, R. Reynolds, Bioorg.
Med. Chem. 13 (2005) 4842e4850.
[13] T.M.C. Tan, Y. Chen, K.H. Kong, J. Bai, Y. Li, S.G. Lim, T.H. Ang,
Y. Lam, Antiviral Res. 71 (2006) 7e14.
6.5.7. Compound 11f
[14] A. Almasirad, S.A. Tabatabai, M. Faizi, A. Kebriaeezadeh, N. Mehrabi,
A. Dalvandi, A. Shafiee, Bioorg. Med. Chem. Lett. 14 (2004) 6057e
6059.
IR (KBr, y cmꢀ1): 3099 (Ar-H), 2955 (CeH), 1610
(C]N), 1108 (CeF), 832 and 721 (CeCl); 1H NMR (d,
DMSO-d6): 2.19 (s, 3H, CH3), 5.62 (s, 2H, OCH2), 7.25e
7.29 (m, 3H, p-chloro-m-cresyloxy and cinchoninyl protons),
7.89e8.02 (m, 3H, p-chloro-m-cresyloxy and cinchoninyl pro-
[15] L. Jin, J. Chen, B. Song, Z. Chen, S. Yang, Q. Li, D. Hu, R. Xu, Bioorg.
Med. Chem. Lett. 16 (2006) 5036e5040.
[16] M.M. Burbuliene, V. Jakubkiene, G. Mekuskiene, E. Udrenaite,
R. Smicius, P. Vainilavicius, Il Farmaco 59 (2004) 767e774.
[17] X. Zheng, Z. Li, Y. Wang, W. Chen, Q. Huang, C. Liu, G. Song, J. Fluo-
rine Chem. 123 (2003) 163e169;
tons), 8.06 (d, 1H, dichlorofluorophenyl proton, JHeF meta
¼
6.7 Hz), 8.24 (d, 1H, cinchoninyl proton, J ¼ 8.1 Hz), 8.34 (s,
1H, cinchoninyl proton), 9.04 (d, 1H, dichlorofluorophenyl pro-
ton, JHeF ortho ¼ 8.4 Hz); mass (%): 514 (Mþ, 25), 389 (5),
(65), 289 (12), 155 (22).
W. Shi, X. Quian, R. Zhang, G. Song, J. Agric. Food Chem. 49 (2001)
124e130.
[18] S. Zhan, X. Ying-Ge, L. Xia, Y. Tao, J. Microelectronics 37 (2006) 714e
717.

M.S. Karthikeyan et al. / European Journal of Medicinal Chemistry 43 (2008) 25e31
31
[19] H.A. Burch, J. Med. Chem. 12 (1969) 535e536;
B.S. Holla, K.N. Poojary, B. Poojary, K.S. Bhat, N.S. Kumari, Indian J.
Chem. 44B (2005) 2114e2119.
[22] A.H. Collins, in: Microbiological Methods, second ed. Butterworth,
London, 1976.
[23] Z.K. Khan, In vitro and vivo screening techniques for bioactivity
screening and evaluation, Proc. Int. Workshop UNIDO-CDRI, 1997,
210e211.
[20] Vogel’s Text Book of Practical Organic Chemistry, fifth ed. Longman,
England, 1996, pp. 1160e1161.
[21] R. Cruickshank, J.P. Duguid, B.P. Marmion, R.H.A. Swain, Medicinal
Microbiology, twelfth ed, vol. II, Churchill Livingstone, London, 1975,
pp. 196e202.
[24] R.S. Varma (Ed.), Antifungal Agents: Past, Present and Future pros-
pects, National Academy of Chemistry & Biology, Lucknow, India,
1998.