Tetrahydronaphthyl azole oxime ethers: The conformationally rigid analogues of oxiconazole as antibacterials

Article abstract of DOI:10.1016/j.ejmech.2008.01.006

A series of novel (Z)- and (E)-2-imidazolo-/triazolo-methyl tetrahydronaphthyl oxime ethers (7-28) were synthesized as conformationally constrained analogues of oxiconazole and evaluated for antifungal and antibacterial activities. Many of these derivativ

Full text of DOI:10.1016/j.ejmech.2008.01.006

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 44 (2009) 437e447
http://www.elsevier.com/locate/ejmech
Short communication
Tetrahydronaphthyl azole oxime ethers: The conformationally rigid
analogues of oxiconazole as antibacterials*
a
b
b
Kalpana Bhandari a, , Nagarapu Srinivas , G.B. Shiva Keshava , Praveen K. Shukla
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
b Division of Fermentation Technology, Central Drug Research Institute, Lucknow 226001, India
Received 5 October 2007; received in revised form 5 December 2007; accepted 7 January 2008
Available online 25 January 2008
Abstract
A series of novel (Z )- and (E )-2-imidazolo-/triazolo-methyl tetrahydronaphthyl oxime ethers (7e28) were synthesized as conformationally
constrained analogues of oxiconazole and evaluated for antifungal and antibacterial activities. Many of these derivatives exhibited potent anti-
bacterial activity and surprisingly none of them was active against fungal strains. The SAR studies showed that imidazole oxime ethers were
more active than the corresponding triazole oxime ethers. Imidazole derivatives 8, 11, 12, 15, 18, 19, 21 and 23 exhibited high inhibitory activity
with 1.56e0.39 mg/mL MIC values against Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus. These compounds represent
new structure scaffolds that can be further optimized to give new antibacterial agents with structures significantly different from those of existing
classes of antibiotics.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Oxiconazole; Antimicrobials; Rigid analogues; Tetrahydronaphthyl oxime ethers; Antibacterial activity
1. Introduction
and synthesis of newer antimicrobials will always remain an
area of immense significance.
The development of antimicrobial agents (antibacterials,
antifungals, antivirals and antiparasitics) to treat infections
has been one of the most notable medical achievements of
the past century. These advances in medical care are threat-
ened, however, by a natural phenomenon known as ‘‘antimi-
crobial resistance.’’ The increased use of antibacterial and
antifungal agents in recent years has resulted in the develop-
ment of resistance to these drugs [1e4] with important impli-
cations for morbidity, mortality and health care costs. In spite
of a large number of antibiotics and chemotherapeutics avail-
able for medical use, the antimicrobial resistance created a sub-
stantial medical need for new classes of antimicrobial agents
in the last decades [5,6]. In view of the above, the design
Among the various pharmacophores responsible for antimi-
crobial activity, the azole derivatives [7e9] seem to be a viable
lead structure for a more efficacious, broad spectrum, systemic
antifungal drug. The azoles, which include the imidazole and
triazole compounds, inhibit the synthesis of sterols in fungi by
inhibiting cytochrome P450-dependent 14a-lanosterol deme-
thylase (P-45014DM) [8,9]. Moreover, the disubstituted imid-
azoles are effective inhibitors of enoyl acyl carrier protein
reductase (FabI), a novel antibacterial target [10,11]. Despite
the growing list of azoles, their clinical value has been limited
by their relatively high risk of toxicity, the emergence of drug
resistance, pharmacokinetic deficiencies and/or insufficiencies
in their activity [7,12e14]. This necessitates the development
of more effective broad spectrum antimicrobials with fewer
side effects.
Fig. 1 summarizes the commonly used azole drugs viz. mi-
conazole, oxiconazole and fluconazole. These structures reveal
the presence in all of these molecules one common pharmaco-
phoric portion that is a phenyl ring linked by an ethyl group to
*
C.D.R.I. Communication No. 7309.
* Corresponding author. Tel.: þ91 522 2612413; fax: þ91 522 2623405.
E-mail address: bhandarikalpana@rediffmail.com (K. Bhandari).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.01.006

438
K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
F
Cl
Cl
Cl
Cl
N
N
N
O
N
F
N
N
N
HO
N
Cl
N
O
N
N
Fluconazole
Cl
Miconazole
Cl
Oxiconazole
Cl
R
4
5
8
X
N
3
N
7
1
( )n
X=CH,N
n=1
N
O
I
R1
Fig. 1. Representative azole drugs.
a nitrogen of azole ring (imidazole or triazole) [15]. The ethyl
chain is often substituted on its C-2 by ether group as in mico-
nazole [7], by a methyltriazolyl and hydroxyl group as in flu-
conazole [7], or oxime ether group as in oxiconazole [15]. The
above report prompted us to investigate how the antifungal ac-
tivity of these azoles would be influenced by restricting the
free movement of azolylethyl chain as it is well established
that the incorporation of conformational constraints in ana-
logues of biologically active compounds enhances receptor se-
lectivity and modulates efficacy [16]. It has been carried out
by linking the C-1 carbon atom of azolylethyl chain and C-2
of the phenyl ring through two carbon spacer. Thus herein
we report the synthesis, antifungal and antibacterial activities
of novel tetrahydronaphthyl azole oxime ethers (I) (Fig. 1) as
conformationally constrained or cyclic analogues of
oxiconazole.
d 4.34e4.39 compared to the E-isomer (d 4.30e4.32). This is
due to the paramagnetic effect of the proximal hydroxyl oxy-
gen [22]. Similarly in 5a the proton at C-8 in (E )-isomer was
deshielded and appeared at d 8.52 compared to (Z )-isomer
where it appeared at d 7.95 (Section 5). Moreover, the results
obtained for the chemical shift values of the groups linked di-
rectly to their iminic carbon are consistent with those reported
in the literature for relevant oxime derivatives [22]. The (Z )-
oximes (5aee/6aee) and (E )-oximes (5a, 5d and 5e) were
isolated pure and reacted with proper benzyl halides in the
presence of sodium hydride to furnish the desired (Z )-7e25
and (E )-oximino ethers 26e28. Chemical and physical data
of compounds are reported in Section 5.
3. Results and discussion
Compounds 7e28 were evaluated for their in vitro antimi-
crobial activity against the pathogenic bacteria and fungi. The
evaluation of antibacterial activity of compounds 7e28 against
various strains of pathogenic bacteria, for example, Klebsiella
pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and
Staphylococcus aureus was carried out according to the broth
microdilution technique described by NCCLS [23,24] and the
results are reported in Table 1. The minimum inhibitory con-
centration (MIC) of each compound was determined against
test isolates using this technique. The antibacterial activity
was compared with that of standard antibacterial drug genta-
mycin and also with oxiconazole and the MIC values are ex-
pressed in micrograms per milliliter. Oxiconazole was found
inactive against all the strains except S. aureus (MIC
6.25 mg/mL). Nine compounds (7, 8, 11, 12, 15, 18, 19, 22
and 23) have shown good to moderate activity (MIC 1.563e
6.25 mg/mL) as compared to gentamycin (MIC 0.78 mg/mL)
against K. pneumoniae and all the compounds except 25 and
(E )-isomers 26e28 exhibited very good to moderate activity
(MIC 0.391e25 mg/mL) against E. coli in comparison to gen-
tamycin (MIC 0.18 mg/mL). However, best activity was
2. Chemistry
The synthetic route for the preparation of (Z )- and (E )-2-
imidazolo-/2-triazolo-methyl tetrahydronaphthyl oxime ethers
(7e28) is outlined in Scheme 1. Mannich reaction of 5-
substituted a-tetralones (1aee) [17e19] with pyrrolidine fur-
nished the 2-pyrrolidin-1-yl-methyltetrahydronaphthalen-1-ones
(2aee) which on reaction with imidazole/triazole in the pres-
ence of ethanol/water resulted in the replacement of pyrroli-
dine moiety with imidazole/triazole (3aee/4aee). The keto
intermediate (3aee/4aee) was then transformed to corre-
sponding oxime (5aee/6aee) with hydroxylamine hydrochlo-
ride. The reaction was stereoselective giving (Z )-oxime as the
1
major product with small amount of (E )-isomer (5e8%). H
NMR spectroscopy was used to assign (Z ) or (E ) configura-
tion [20,21] to the geometrical isomers of imidazole (5aee)
and triazole oximes (6aee) and it was possible to allocate sig-
nals to two different isomers. In 5a (R ¼ H) the C-2 proton is
deshielded by the presence of the proximal hydroxyl function
and must therefore be the Z-isomer and appeared lower field at

K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
439
R
R
R
X
a
b
N
N
N
.HCl
O
3a-e/ 4a-e
O
O
c
3a-e, X = H
1 a-e
2a-e
4a-e, X = N
R
R
R
X
4
N
+
X
N
5
X
N
d
2
H
N
N
H
N
1
N
OH
8
N
(Z)-5a-e/ 6a-e
H
R1
H
O
R1 =H,Cl
N
(E)-5a-e/ 6a-e
HO
R = H, Me, Cl, F, Br
(Z)-7-25
5a-e, X = H;6a-e, X = N
R
X
N
d
N
N
O
R1=H,Cl
(E)-26-28
R1
Comp.
X
R
R1
Comp.
X
R
R1
Comp.
X
R1
R
7
8
CH
CH
N
H
15
16
17
18
CH
N
Cl
Cl
Cl
Br
H
H
Cl
H
CH
N
F
F
F
H
Cl
H
Cl
Cl
H
H
H
H
23
24
25
26
Cl
H
9
N
N
10
N
Cl
CH
CH
11
12
CH
H
19
20
CH
Br
Cl
27
28
CH
CH
Cl
Br
H
Cl
CH3
CH
Cl
N
Br
H
CH3
13
14
N
N
H
Cl
21
22
N
CH
Br
F
Cl
H
CH3
CH3
Scheme 1. Synthesis of 7e25. Reagents: (a) (HCHO)3, pyrrolidine hydrochloride, isopropanol; (b) imidazole/1H-1,2,4-triazole, ethanol/water; (c) NH2OH$HCl,
ethanol; (d) NaH, DMF, benzyl halide.
observed against S. aureus where 16 compounds have shown
either better or comparable MIC range (0.781e12.25 mg/mL)
with that of gentamycin (MIC 6.25 mg/mL). Moreover, all
the compounds were inactive against the resistant strain
P. aeruginosa at 50 mg/mL in which gentamycin also showed
very weak activity (MIC 25 mg/mL).
species with the exception of T. mentagrophytes against which
the (E )-isomers 26e28 were more active (MIC 12.25e25 mg/
mL) than corresponding (Z )-isomers (MIC > 50 mg/mL). Rest
of the compounds were inactive at 50 mg/mL concentration
(Table 1).
In general, the antibacterial evaluation of the test com-
pounds 7e28 as compared to reference drug gentamycin
showed that the compounds comprising of imidazole moiety
(7, 8, 11, 12, 15, 18, 19, 22 and 23) were more active than cor-
responding triazole derivatives (9, 10, 13, 14, 16, 17, 20, 21,
24 and 25). Comparison between MIC values of the (Z )-
and (E )-isomers against various strains of pathogenic bacteria
revealed that the (Z )-isomers 8, 15 and 19 were more potent
than the corresponding (E )-isomers 26, 27 and 28. In terms
of structureeactivity relationship the comparison of MIC
values of compounds indicated that the substitution in the
naphthalene ring by different groups viz. methyl or halogens
(F, Cl and Br) resulted in no appreciable change in the antibac-
terial activity (Table 1), whereas the substitution of chlorine in
the benzyl group resulted in substantial enhancement (2- to 4-
fold) of the antibacterial activity against all the tested strains.
All the imidazolyl compounds showed significant activity
The antifungal screening of compounds 7e28 against vari-
ous strains of pathogenic fungi, for example, Candida albicans,
Cryptococcus neoformans, Sporothrix schenckii, Trichophyton
mentagrophytes, Aspergillus fumigatus and Candida parapsi-
losis was carried out according to broth microdilution tech-
nique described by NCCLS [23,24]. The antifungal activity
was compared with that of standard antifungal drug flucona-
zole and oxiconazole. MIC of compounds and standard drugs
were determined in 96-well tissue culture plates using RPMI
1640 media buffered with MOPS (3-[N-morpholino]propane
sulfonic acid obtained from Sigma Chemical Co.). Out of
the 22 compounds, three compounds (7, 12 and 18) showed
MIC at 50 mg/mL and compounds 8 and 15 were active at
25 mg/mL against A. fumigatus. There was no appreciable dif-
ference between the activities of (Z )-isomers (8, 15 and 19)
and (E )-isomers (26, 27 and 28) as regards to the tested fungal

440
K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
Table 1
Structures and in vitro antimicrobial activity for compounds 7e25 (MIC, mg/mL)
Compound
X
R
R1
MIC (mg/mL) against bacteria
MIC (mg/mL) against fungi
Kp
Ec
Pa
Sa
Ca
Cn
Ss
Tm
Af
Cp
7
CH
CH
N
H
H
6.25
3.125
>50
>50
6.25
1.563
>50
>50
6.25
>50
>50
3.125
1.563
>50
>50
6.25
1.563
>50
>50
>50
>50
>50
0.78
ND
0.781
0.391
25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
6.25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
ND
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
50
25
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
50
8
H
Cl
H
1.563
>50
12.25
1.563
0.781
>50
6.25
9
H
>50
>50
>50
50
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Gent
Flu
Oxico
N
H
Cl
H
12.25
0.781
0.391
25
CH
CH
N
CH3
CH3
CH3
CH3
Cl
Cl
Cl
Br
Br
Br
Br
F
Cl
H
>50
>50
25
N
Cl
H
6.25
0.391
25
CH
N
1.563
>50
>50
1.563
0.781
12.5
H
>50
>50
50
N
Cl
H
6.25
0.391
0.391
6.25
3.125
0.781
0.391
25
CH
CH
N
Cl
H
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
ND
>50
>50
>50
>50
>50
>50
>50
>50
>50
ND
N
Cl
H
6.25
CH
CH
N
3.125
0.781
>50
>50
6.25
F
Cl
H
F
N
F
Cl
Cl
H
50
CH
CH
CH
H
>50
>50
>50
0.18
ND
Cl
Br
3.125
1.56
6.25
12.5
12.5
ND
Cl
50
ND
50
ND
ND
>50
ND
6.25
0.5
12.5
1.0
0.01
2.0
3.12
1.0
6.25
2.0
6.25
1.0
3.12
>50
>50
Kp, Klebsiella pneumoniae; Ec, Escherichia coli; Pa, Pseudomonas aeruginosa; Sa, Staphylococcus aureus; Ca, Candida albicans; Cn, Cryptococcus neoformans; Ss,
Sporothrix schenckii; Tm, Trichophyton mentagrophytes; Af, Aspergillus fumigatus; and Cp, Candida parapsilosis, ND ¼ not done; Gent ¼ gentamycin; Flu ¼ fluco-
nazole; Oxico ¼ oxiconazole.
against S. aureus, and compounds 12, 19 and 23 were eight
times more active than gentamycin.
antibacterial activity and complete loss in antifungal activity.
However, there was not much difference between the (E )-
and (Z )-isomers as regards to the antifungal activity but the
(Z )-isomers were found more potent than corresponding
(E )-isomers against bacterial strains. Amongst the synthesized
compounds, all the imidazolyl derivatives displayed better in
vitro antibacterial activity against K. pneumoniae, E. coli,
and S. aureus compared to triazolyl derivatives. Compounds
12, 19 and 23 emerged as most active in this series and
were 8-fold more active than gentamycin against S. aureus.
Thus, these compounds represent new lead for further pharma-
comodulation in this series.
The above results demonstrated that restricted analogues
lacked antifungal activity despite of the fact that the azolyl
and oxime ether moieties were unmodified. However, similar
compounds with a benzopyran and an imidazolyl moiety
[20] instead of tetrahydronaphthalene and azolomethyl moiety
have been reported to display potent antifungal activity. As
these compounds are skeletal analogues of oxiconazole with
conformationally constrained structure due to which only
a limited subset of conformations relative to the parent com-
pound oxiconazole is possible. Therefore, the loss of overall
antifungal activity of these azolomethyl tetrahydronaphthyl
oxime ethers might be due to the adoption of an energetically
accessible bioactive conformation suitable/appropriate for an-
tibacterial target [25,26] rather than antifungal target.
5. Experimental
5.1. Chemistry
4. Conclusion
Melting points were determined in open capillaries in an
electrically heated block and are uncorrected. IR spectra of
all the compounds were recorded on PerkineElmer AC-1
spectrophotometer. 1H NMR spectra were recorded on
Brucker WM 200 MHz spectrometer in deuterated solvents
with TMS as internal reference. FAB mass spectra were re-
corded on a Jeol SX 102/DA-6000 mass spectrometer/data
system using argon/xenon (6 kV, 10 mA) as the FAB gas.
The accelerating voltage was 10 kV and the spectra were
In conclusion, we have synthesized a series of novel (Z )-
and (E )-2-imidazolo-/2-triazolo-methyl tetrahydronaphthyl
oxime ethers 7e25 and 26e28 as conformationally rigid ana-
logues of oxiconazole. Antimicrobial activity was evaluated
and compared with standard drugs. The results obtained
from this study suggest that restricting the free movement of
ethyl chain in oxiconazole led to the compounds with high

K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
441
recorded at room temperature. The electrospray mass spectra
were recorded on a Micromass Quattro II triple quadrupole
mass spectrometer. Microanalyses were determined on Carlo
Erba EA-1108 element analyzer within ꢀ0.4% of the theoret-
ical value. Thin layer chromatography was performed on
7.5 ꢁ 3.0 cm precoated silica gel plastic plates (Aldrich). For
column chromatography, basic alumina from Acme Synthetic
Chemicals and silica gel of 60e120 mesh from Qualigen Fine
Chemicals were used. 5-Substituted 1-tetralones (1aee) [13e
15] were prepared from g-butyrolactone and substituted
benzene.
2.43e2.98 (m, 10H, H-2, H-3, H-4, N(CH2e)3), 7.29 (s, 1H,
ArH), 7.53e7.57 (m, 1H, ArH), 7.93e7.97 (d, 1H,
J ¼ 7.85 Hz, ArH);IR(KBr): 2960, 2810, 1684, 1352, 776 cmꢃ1
.
5.1.1.5. 5-Bromo-2-pyrrolidin-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one (2e). With 5-bromo-1-tetralone (1e): yield 79%;
1
oil; MS (ESI): m/z 308 (Mþ þ 1, 100%); H NMR (200 MHz,
CDCl3): d 1.54 (m, 4H, NeCH2eCH2eCH2), 1.96e2.19 (m,
3H, H-2, H-3), 2.94e3.32 (m, 6H, H-4, N(CH2e)3), 7.13e
7.18 (m, 1H, ArH), 7.39e7.45 (m, 1H, ArH), 7.81e7.85 (m,
1H, H-8); IR (Neat): 2932, 1687, 1597, 1358, 769 cmꢃ1
.
5.1.1. General procedure of the preparation of 2-pyrrolidin-
1-ylmethyltetrahydronaphthalen-1-ones (2aee)
5.1.2. General procedure of the preparation of 2-azol-1-
ylmethyl-5-substituted-3,4-dihydro-2H-naphthalen-1-ones
(3aee)/(4aee)
To a suspension of 2aee (4.11 mmol) in ethanol/water
(6 mL, 2:3) was added appropriate azole (imidazole/1H-1,2,4-
triazole, 4.93 mmol) and the reaction mixture was heated for
3e6 h at 90 ꢂC. The organic solvent was distilled off and the
compound was extracted with dichloromethane (5 mL ꢁ 3).
The organic layer was washed with water and dried over sodium
sulphate and distilled to give 3aee/4aee in excellent yield.
Conc. HCl was added dropwise to a stirred solution of 1-
tetralones (1aee) (11 mmol) and pyrrolidine hydrochloride
(10 mmol) in isopropanol (15 mL) and the pH of the solution
was adjusted to 4. One-fifth portion of paraformaldehyde
(20 mmol) was added to the above mixture. The reaction mix-
ture was then heated in an oil bath at 90e95 ꢂC for 30 min
with stirring. Other four portions of paraformaldehyde were
added at 15 min interval. The reaction mixture was further re-
fluxed for 4 h. The solvent was distilled off. The residue ob-
tained was washed with hexane (5 mL ꢁ 2) and treated with
sodium bicarbonate solution to make the pH alkaline and ex-
tracted with dichloromethane (15 mL ꢁ 3). Combined organic
extracts were dried over Na2SO4 and distilled to afford the
Mannich bases (2aee) in good yield.
5.1.2.1. 2-Imidazol-1-ylmethyl-3,4-dihydro-2H-naphthalen-1-
one (3a). With 2a and imidazole: yield 74%; MS (ESI): m/z
1
227 (Mþ þ 1, 100%); H NMR (200 MHz, CDCl3): d 1.71e
1.79 (m, 1H, H-3), 2.06e2.11 (m, 1H, H-3), 2.78e3.05 (m,
3H, H-4, H-2), 4.37e4.46 (m, 2H, NCH2), 6.92 (s, 1H,
ArH), 7.02 (s, 1H, ArH), 7.16e7.36 (m, 2H, ArH), 7.44e
7.49 (m, 2H, ArH), 8.02e8.06 (d, 1H, J ¼ 7.79 Hz, H-8); IR
5.1.1.1. 2-Pyrrolidin-1-ylmethyl-3,4-dihydro-2H-naphthalen-1-
one (2a). With 1-tetralone (1a): yield 91%; oil; MS (ESI): m/z
1
230 (Mþ þ 1, 100%); H NMR (200 MHz, CDCl3): d 1.72e
(Neat): 3117, 2932, 1676, 1600, 1076, 716 cmꢃ1
.
1.80 (m, 5H, NeCH2eCH2eCH2, H-3), 2.20e2.87 (m, 10H,
H-2, H-3, H-4, N(CH2e)3), 6.97e7.21 (m, 3H, ArH), 7.96e
7.92 (d, 1H, J ¼ 8.04 Hz, H-8); IR (Neat): 2931, 2790, 1681,
5.1.2.2. 2-Imidazol-1-ylmethyl-5-methyl-3,4-dihydro-2H-naph-
thalen-1-one (3b). With 2b and imidazole: yield 81%; MS
(ESI): m/z 241 (Mþ þ 1, 100%); 1H NMR (200 MHz,
CDCl3): d 1.73e1.76 (m, 1H, H-3), 2.02e2.11 (m, 1H, H-
3), 2.37 (s, 3H, ArCH3), 2.77e2.99 (m, 3H, H-2, H-4),
4.37e4.45 (m, 2H, NCH2), 6.94 (s, 1H, ArH), 7.03 (s, 2H,
ArH), 7.10e7.14 (d, 1H, J ¼ 3.5 Hz, ArH), 7.51 (s, 1H,
ArH), 7.92e7.96 (d, 1H, J ¼ 8.01 Hz, H-8); IR (Neat): 3112,
1352, 1151, 744 cmꢃ1
.
5.1.1.2. 5-Methyl-2-pyrrolidin-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one (2b). With 5-methyl-1-tetralone (1b): yield 86%;
1
oil; MS (ESI): m/z 244 (Mþ þ 1, 100%); H NMR (200 MHz,
CDCl3): d 1.78e1.82 (m, 5H, NeCH2eCH2eCH2, H-3),
2.30e2.98 (m, 13H, ArCH3, H-2, H-3, H-4, N(CH2e)3),
7.04e7.15 (m, 2H, ArH), 7.89e7.93 (d, 1H, J ¼ 7.94 Hz, H-
2935, 1676, 1609, 1079, 713 cmꢃ1
.
8); IR (Neat): 2898, 1692, 1607, 1315, 708 cmꢃ1
.
5.1.2.3. 5-Fluoro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one (3c). With 2c and imidazole: yield 87%; oil;
MS (ESI): m/z 245 (Mþ þ 1, 100%); 1H NMR (200 MHz,
CDCl3): d 1.67e1.82 (m, 1H, H-3), 1.98e2.31 (m, 1H, H-
3), 2.74e3.06 (m, 3H, H-2, H-4), 4.27e4.38 (m, 2H,
NCH2), 6.86e6.97 (m, 2H, ArH), 7.13e7.19 (m, 2H, ArH),
7.45 (s, 1H, ArH), 7.97 (s, 1H, ArH); IR (Neat): 2925, 2367,
5.1.1.3. 5-Fluoro-2-pyrrolidin-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one(2d). With 5-fluoro-1-tetralone (1d): yield 83%; oil;
MS (ESI): m/z 248 (Mþ þ 1, 100%); 1H NMR (200 MHz,
CDCl3): d 1.78 (m, 5H, NeCH2eCH2eCH2, H-3), 2.47e2.93
(m, 10H, H-2, H-3, H-4, N(CH2e)3), 7.17 (s, 1H, ArH), 7.52e
7.60 (m, 1H, ArH), 7.93e7.97 (d, 1H, J ¼ 7.84 Hz, H-8); IR
1594, 1351, 762 cmꢃ1
.
(Neat): 2931, 2364, 1687, 1602, 760 cmꢃ1
.
5.1.2.4. 5-Chloro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one (3d). With 2d and imidazole: yield 85%; oil; MS
(ESI): m/z 261 (Mþ þ 1, 100%); 1H NMR (200 MHz, CDCl3):
d 1.72e1.80 (m, 1H, H-3), 2.27e2.29 (m, 1H, H-3), 2.89e3.13
(m, 3H, H-2, H-4), 4.73e4.99 (m, 2H, NCH2), 7.21e7.33
5.1.1.4.
5-Chloro-2-pyrrolidin-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one (2c). With 5-chloro-1-tetralone (1c): yield
78%; oil; MS (ESI): m/z 264 (Mþ þ 1, 100%); 1H NMR
(200 MHz, CDCl3): d 1.79 (m, 5H, NeCH2eCH2eCH2, H-3),

442
K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
(m, 1H, ArH), 7.56e7.73 (m, 3H, ArH), 7.94e7.98 (m, 1H,
ArH); IR (Neat): 2935, 1682, 1588, 1081, 761, 669 cmꢃ1
(Mþ þ 3, 30%); 1H NMR (200 MHz, CDCl3): d 1.81 (m,
1H, H-3), 1.90e1.96 (m, 1H, H-3), 2.92e3.09 (m, 3H, H-2,
H-4), 4.44e4.79 (dd, 2H, J ¼ 4.76, 14.16 Hz, NCH2), 7.15
(s, 1H, ArH), 7.56e7.60 (d, 2H, J ¼ 8.03 Hz, ArH), 7.92 (s,
1H, triazole H), 8.21 (s, 1H, triazole H ); IR (Neat): 2926,
.
5.1.2.5. 5-Bromo-2-imidazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one (3e). With 2e and imidazole: yield 89%; oil;
MS (ESI): m/z 305 (Mþ þ 1, 100%), 307 (Mþ þ 2, 95%);
1H NMR (200 MHz, CDCl3): d 1.73e1.81 (m, 1H, H-3),
2.05e2.14 (m, 1H, H-3), 2.78e2.97 (m, 3H, H-2, H-4),
4.37e4.45 (m, 2H, NCH2), 6.93e7.04 (m, 2H, ArH), 7.42e
7.61 (m, 3H, ArH), 7.88e7.92 (m, 1H, ArH); IR (Neat):
1679, 1275, 1013, 679 cmꢃ1
.
5.1.3. General procedure of the preparation of 2-azol-1-
ylmethyl-7-substituted-3,4-dihydro-2H-naphthalen-1-one
oximes (5aee/6aee)
2928, 1683, 1603, 1355, 1117, 768 cmꢃ1
.
Hydroxylamine hydrochloride (13.33 mmol) was added to
a solution of 3aee/4aee (4.44 mmol) in absolute ethanol
(10 mL) and the mixture was refluxed for 3e4 h at 90 ꢂC.
The organic solvent was distilled off and the compound was
basified by aqueous saturated potassium bicarbonate. The ox-
ime was isolated as solid in 92% yield and the diastereomers
separated on silica gel (230e400 mesh) column with chloro-
form as an eluent giving mainly the (Z )-oximes (5aee/6aee)
with small amount (5e8%) of (E )-isomers (5aee/6aee). Fur-
ther, proceeded for next step with (Z )- and (E )-isomers 5aee/
5.1.2.6. 2-(1,2,4)-Triazol-1-ylmethyl-3,4-dihydro-2H-naphtha-
len-1-one (4a). With 2a and 1-H-1,2,4-triazole: yield 84%;
oil; MS (ESI): m/z 228 (Mþ þ 1, 100%), 229 (Mþ þ 2,
1
57%); H NMR (200 MHz, CDCl3): d 1.81e1.96 (m, 1H, H-
3), 2.15e2.25 (m, 1H, H-3), 2.95e3.03 (m, 2H, H-4), 3.07e
3.09 (m, 1H, H-2), 4.43e4.79 (dd, 2H, J ¼ 6.13, 14.08 Hz,
NCH2), 7.19e7.34 (m, 2H, ArH), 7.43e7.47 (d, 1H,
J ¼ 7.44 Hz, ArH), 7.87 (s, 1H, triazole H ), 7.98e8.02 (d,
1H, J ¼ 7.78 Hz, H-8), 8.18 (s, 1H, triazole H ); IR (Neat):
1
6aee. H NMR data of representative (Z )- and (E )-oximes
(5aee/6aee) are given below.
2925, 1681, 1350, 1141, 1357, 762, 680 cmꢃ1
.
5.1.2.7. 5-Methyl-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one (4b). With 2b and 1-H-1,2,4-triazole: yield
87%; oil; MS (ESI): m/z 242 (Mþ þ 1, 100%); 1H NMR
(200 MHz, CDCl3): d 1.78e1.90 (m, 1H, H-3), 2.13e2.22
(m, 1H, H-3), 2.37 (s, 3H, ArCH3), 2.96e3.09 (m, 3H, H-2,
H-4), 4.44e4.79 (dd, 2H, J ¼ 6.18, 14.09 Hz, NCH2), 7.04
(s, 1H, ArH), 7.10e7.14 (d, 1H, J ¼ 14.08 Hz, ArH), 7.82
(m, 2H, ArH, triazole H ), 8.21 (s, 1H, triazole H ); IR
5.1.3.1. (Z )-2-Imidazol-1-ylmethyl-3,4-dihydro-2H-naphtha-
len-1-one oxime (5a). With 3a: yield 71%; m.p. 161e62 ꢂC;
MS (ESI): m/z 242 (Mþ þ 1, 100%); 1H NMR (200 MHz,
CDCl3): d 1.62e1.69 (m, 1H, H-3), 1.81e1.89 (m, 1H, H-
3), 2.68e2.93 (m, 2H, H-4), 3.94e4.06 (m, 2H, NCH2),
4.34e4.38 (m, 1H, H-2), 7.03 (s, 2H, imidazole H ), 7.13e
7.31 (m, 3H, ArH), 7.55 (s, 1H, imidazole H ), 7.91e7.95 (d,
1H, J ¼ 7.42 Hz, H-8); IR (KBr): 2924, 1600, 1445, 1351,
(Neat): 2939, 1683, 1352, 1140, 680 cmꢃ1
.
1137, 677 cmꢃ1
.
5.1.2.8. 5-Fluoro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one (4c). With 2c and 1-H-1,2,4-triazole: yield
76%; oil; MS (ESI): m/z 246 (Mþ þ 1, 100%), 247 (Mþ þ 2,
5.1.3.2. (E )-2-Imidazol-1-ylmethyl-3,4-dihydro-2H-naphtha-
len-1-one oxime (5a). With 3a: yield 7%; m.p. 161e162 ꢂC;
MS (ESI): m/z 242 (Mþ þ 1, 100%); 1H NMR (200 MHz,
CDCl3): d 1.75e1.79 (m, 1H, H-3), 1.97e2.02 (m, 1H, H-
3), 2.87e2.96 (m, 2H, H-4), 3.96e4.05 (m, 2H, NCH2),
4.30e4.32 (m, 1H, H-2), 6.97 (s, 2H, imidazole H ), 7.23e
7.35 (m, 3H, ArH), 7.51 (s, 1H, imidazole H ), 8.51e8.47 (d,
1H, J ¼ 8.82 Hz, H-8); IR (KBr): 3409, 2927, 2238, 1659,
1
20%); H NMR (200 MHz, CDCl3): d 1.82e1.92 (m, 1H, H-
3), 2.16e2.25 (m, 1H, H-3), 2.97e3.08 (m, 2H, H-4), 3.08e
3.15 (m, 1H, H-2), 4.44e4.80 (dd, 2H, J ¼ 6.14, 14.15 Hz,
NCH2), 7.19e7.34 (m, 2H, ArH), 7.64e7.80 (m, 1H, ArH),
7.92 (s, 1H, triazole H ), 8.23 (s, 1H, triazole H ); IR (Neat):
2927, 1685, 1580, 1320, 1246, 1012, 679 cmꢃ1
.
1596, 1441, 970 cmꢃ1
.
5.1.2.9. 5-Chloro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one (4d). With 2d and 1-H-1,2,4-triazole: yield
79%; oil; MS (ESI): m/z 262 (Mþ þ 1, 100%), 263 (Mþ þ 2,
5.1.3.3. (Z )-5-Methyl-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one oxime (5b). Withþ3b: yield 72%; m.p. 156e
158 ꢂC; MS (ESI): m/z 256 (M þ 1, 100%); 1H NMR
(300 MHz, CDCl3): d 1.73e1.91 (m, 2H, H-3), 2.36 (s, 3H,
ArCH3), 2.64e2.74 (m, 1H, H-4), 2.87e2.90 (m, 1H, H-4),
3.97e4.04 (m, 2H, NCH2), 4.33e4.37 (m, 1H, H-2), 6.98e7.12
(m, 4H, ArH), 7.60 (s, 1H, imidazole H ), 7.76e7.78 (d, 1H,
1
39%); H NMR (200 MHz, CDCl3): d 1.79e1.81 (m, 1H, H-
3), 2.18e2.24 (m, 1H, H-3), 2.86e2.99 (m, 2H, H-4), 3.02e
3.12 (m, 1H, H-2), 4.66e4.79 (dd, 2H, J ¼ 4.88, 14.18 Hz,
NCH2), 7.32 (s, 1H, ArH), 7.56e7.60 (d, 1H, J ¼ 7.74 Hz,
ArH), 7.92 (s, 1H, triazole H ), 7.93e7.97 (d, 1H,
J ¼ 8.72 Hz, H-8), 7.99 (s, 1H, triazole H ); IR (Neat): 2933,
J ¼ 4.0 Hz, ArH); IR (KBr): 2927, 1594, 1381, 1024, 700 cmꢃ1
.
1681, 1275, 1013, 680 cmꢃ1
.
5.1.3.4. (Z)-5-Fluoro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one oxime (5c). With 3c: yield 62%; m.p.þ182e
84 ꢂC; MS (ESI): m/z 260 (Mþ þ 1, 100%), 262 (M þ 3,
5.1.2.10.
5-Bromo-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
1
2H-naphthalen-1-one (4e). With 2e and 1-H-1,2,4-triazole:
yield 81%; oil; MS (ESI): m/z 307 (Mþ þ 1, 100%), 309
30%); H NMR (200 MHz, CDCl3): d 1.79e1.83 (m, 2H, H-
3), 2.75e2.89 (m, 2H, H-4), 3.94e4.04 (m, 2H, NCH2),

K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
443
4.25e4.35 (m, 1H, H-2), 6.87e7.09 (m, 4H, ArH), 7.24 (s, 1H,
ArH), 7.55 (s, 1H, imidazole H ); IR (KBr): 2930, 1595, 1350,
(200 MHz, CDCl3): d 1.76e1.91 (m, 2H, H-3), 2.33 (s, 3H,
ArCH3), 2.73 (m, 1H, H-4), 2.90e2.96 (m, 1H, H-4), 3.97e
4.01 (m, 1H, H-2), 4.23e4.60 (dd, 2H, J ¼ 5.1, 13.64 Hz,
NCH2), 6.98e7.09 (m, 2H, ArH), 7.79e7.83 (d, 1H,
J ¼ 8.0 Hz, ArH), 7.98 (s, 1H, triazole H ), 8.25 (s, 1H, triazole
1078, 987, 774 cmꢃ1
.
5.1.3.5. (Z )-5-Chloro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one oxime (5d). Wþith 3d: yield 70%; m.p.þ189e
191 ꢂC; MS (ESI): m/z 276 (M þ 1, 100%), 278 (M þ 3,
H ); IR (KBr): 2924, 1600, 1445, 1351, 765, 677 cmꢃ1
.
1
33%); H NMR (200 MHz, CDCl3): d 1.74e1.82 (m, 2H, H-
5.1.3.11. (Z)-5-Fluoro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
3), 2.71e2.96 (m, 2H, H-4), 3.90e4.03 (m, 2H, NCH2),
4.24e4.37 (m, 1H, H-2), 7.01 (s, 2H, imidazole H ), 7.16e
7.20 (m, 1H, H-7), 7.22e7.24 (d, 1H, J ¼ 7.91 Hz, ArH), 7.56
(s, 1H, imidazole H ), 7.88e7.92 (d, 1H, J ¼ 7.45 Hz, H-8); IR
2H-naphthalen-1-one oxime (6c). Witþh 4c: yield 58%; m.p.
1
201e203 ꢂC; MS (ESI): m/z 261 (M þ 1, 100%); H NMR
(200 MHz, CDCl3): d 1.75e1.88 (m, 2H, H-3), 2.67e2.96
(m, 2H, H-4), 3.96e4.03 (m, 1H, H-2), 4.16e4.22 (m, 2H,
NCH2), 6.87e7.18 (m, 3H, ArH), 7.94 (s, 1H, triazole H ),
8.11 (s, 1H, triazole H ); IR (KBr): 2820, 2364, 1593, 1351,
(KBr): 2954, 1593, 1496, 1392, 1153, 1085, 677 cmꢃ1
.
5.1.3.6. (E )-5-Chloro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one oxime (5d). Wþith 3d: yield 6%; m.p.þ196e
197 ꢂC; MS (ESI): m/z 276 (M þ 1, 100%), 278 (M þ 3,
756, 660 cmꢃ1
.
5.1.3.12. (Z)-5-Chloro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one oxime (6d). With 4þd: yield 64%; m.p.
193e195 ꢂC; MS (ESI): m/z 277 (M þ 1, 100%), 278
1
33%); H NMR (200 MHz, CDCl3): d 1.79e2.04 (m, 2H, H-
3), 2.75e2.96 (m, 2H, H-4), 3.96e4.01 (m, 2H, NCH2),
4.20e4.29 (m, 1H, H-2), 6.89 (s, 2H, imidazole H ), 7.17e
7.21 (m, 1H, H-7), 7.58 (s, 1H, imidazole H ), 7.64e7.68 (d,
1H, J ¼ 7.84 Hz, H-6), 8.54e8.60 (d, 1H, J ¼ 8.20 Hz, H-8);
1
(Mþ þ 3, 20%); H NMR (200 MHz, CDCl3): d 1.77e1.89
(m, 1H, H-3), 2.67e2.75 (m, 1H, H-3), 2.82e2.97 (m, 2H,
H-4), 3.96e4.02 (m, 1H, H-2), 4.23e4.47 (dd, 2H, J ¼ 5.63,
14.63 Hz, NCH2), 7.08e7.41 (m, 3H, ArH), 7.98 (s, 1H, tria-
zole H ), 8.30 (s, 1H, triazole H ); IR (KBr): 2822, 2384,
IR (KBr): 2957, 2234, 1648, 1593, 1363, 1017, 706 cmꢃ1
.
5.1.3.7. (Z )-5-Bromo-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one oxime (5e). Wþith 3e: yield 74%; m.p.þ162e
164 ꢂC; MS (ESI): m/z 321 (M þ 1, 100%), 223 (M þ 3,
1593, 1349, 669 cmꢃ1
.
5.1.3.13. (Z)-5-Bromo-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one oxime (6e). With 4þe: yield 61%; m.p.
174e175 ꢂC; MS (ESI): m/z 322 (M þ 1, 100%), 323
1
82%); H NMR (200 MHz, CDCl3): d 1.79e1.87 (m, 2H, H-
3), 2.66e2.97 (m, 2H, H-4), 3.98e4.09 (m, 2H, NCH2),
4.21e4.47 (m, 1H, H-2), 7.04 (s, 1H, imidazole H ), 7.12e
7.35 (m, 3H, ArH), 7.60 (s, 1H, imidazole H ), 7.92e7.96 (d,
1H, J ¼ 7.28 Hz, H-8); IR (KBr): 2954, 1593, 1392, 1085,
1
(Mþ þ 2, 70%); H NMR (200 MHz, CDCl3): d 1.76e1.88
(m, 2H, H-3), 2.82e2.99 (m, 2H, H-4), 3.97e4.04 (m, 1H,
H-2), 4.24e4.57 (dd, 2H, J ¼ 7.24, 13.46 Hz, NCH2), 7.29e
7.43 (m, 2H, ArH), 7.77e7.81 (d, 1H, J ¼ 9.14 Hz, H-8),
7.92 (s, 1H, triazole H ), 8.18 (s, 1H, triazole H ); IR (KBr):
677 cmꢃ1
.
5.1.3.8. (E)-Bromo-2-imidazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one oxime (5e). With þ3e: yield 6%; m.p. 162e
63 ꢂC; MS (ESI): m/z 321 (M þ 1, 100%), 323 (Mþ þ 3,
3446, 2366, 1592, 762, 673 cmꢃ1
.
5.1.3.14. (E)-5-Bromo-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one oxime (6e). Witþh 4e: yield 5%;þ m.p.
169e170 ꢂC; MS (ESI): m/z 321 (M , 70%), 323 (M þ 2,
1
82%); H NMR (200 MHz, CDCl3): d 1.81e2.05 (m, 2H, H-
3), 2.85e3.01 (m, 2H, H-4), 3.97e4.08 (m, 2H, NCH2),
4.18e4.38 (m, 1H, H-2), 6.88e7.28 (m, 2H, H-7, imidazole
H ), 7.61 (s, 1H, imidazole H ), 7.65e7.68 (d, 1H,
J ¼ 6.92 Hz, H-6), 8.46e8.51 (d, 1H, J ¼ 8.85 Hz, H-8); IR
1
100%); H NMR (200 MHz, CDCl3): d 1.78e2.11 (m, 2H,
H-3), 2.90e2.98 (m, 2H, H-4), 3.98e4.02 (m, 1H, H-2),
4.29e4.54 (dd, 2H, J ¼ 6.19, 13.37 Hz, NCH2), 7.10e7.40
(m, 2H, ArH), 7.96 (s, 1H, triazole H ), 8.24 (s, 1H, triazole
H ), 8.50e8.45 (d, 1H, J ¼ 9.18 Hz, H-8); IR (KBr): 3470,
(KBr): 2928, 2340, 1655, 1630, 1382, 1084, 723 cmꢃ1
.
5.1.3.9. (Z )-2-(1,2,4)-Triazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one oxime (6a). With 4a:þ yield 77%; m.p. 174e
175 ꢂC; MS (ESI): m/z 243 (M þ 1, 100%); 1H NMR
(200 MHz, CDCl3): d 1.72e1.88 (m, 2H, H-3), 2.70e2.79
(m, 1H, H-4), 2.92e3.01 (m, 1H, H-4), 4.08e4.12 (m, 1H,
H-2), 4.24e4.60 (dd, 2H, J ¼ 5.16, 13.18 Hz, NCH2), 7.16e
7.34 (m, 3H, ArH), 7.90e7.97 (d, 1H, J ¼ 7.03 Hz, H-8),
7.97 (s, 1H, triazole H ), 8.11 (s, 1H, triazole H ); IR (KBr):
2681, 1633, 1508, 1451, 970, 737 cmꢃ1
.
5.1.4. General procedure of the preparation of 2-azol-1-
ylmethyl-3,4-dihydro-2H-napthalen-1-one oxime ethers (7e28)
A solution of (E )-, (Z )-oxime (5a/5d/5e), (5aee/6aee)
(0.416 mmol) in dimethyl sulphoxide (DMSO) (0.5 mL) was
added dropwise to stirred suspension of sodium hydride
(0.833 mmol) in DMSO (0.5 mL). The reaction mixture was
stirred at room temperature for 5 min and benzyl bromide or
3-chlorobenzyl bromide (0.416 mmol) was added dropwise
to it. Stirred for 15 min to 1 h for the completion of the reac-
tion. The reaction was discontinued, and treated with water
(5 mL) and extracted with ethyl acetate (3 mL ꢁ 3). The
2816, 2364, 1597, 1352, 671 cmꢃ1
.
5.1.3.10. (Z )-5-Methyl-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one oxime (6b). With 4b: yield 68%; m.p.
1
167e169 ꢂC; MS (ESI): m/z 257 (Mþ þ 1, 100%); H NMR

444
K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
combined organic layer was washed with water (10 mL ꢁ 6),
dried over sodium sulphate and concentrated to give the crude
product which was chromatographed on a 230e400 mesh sil-
ica gel column using chloroform as an eluent to get the desired
oximino ethers 7e28 in good yield.
(Neat): 2927, 2858, 1359, 1210, 1019, 762, 669 cmꢃ1. Anal.
Calcd for C20H19N4OCl: C, 65.48; H, 5.18; N, 15.27. Found:
C, 65.42; H, 5.09; N, 15.25.
5.1.4.5. (Z )-2-Imidazol-1-ylmethyl-5-methyl-3,4-dihydro-2H-
naphthalen-1-one O-benzyl-oxime (11). With (Z)-5b and ben-
zyl bromide: yield 69%; oil; MS (ESI): m/z 346 (Mþ þ 1,
100%), 347 (Mþ þ 2, 30%); 1H NMR (200 MHz, CDCl3):
d 1.75e2.21 (m, 2H, H-3), 2.29 (s, 3H, ArCH3), 2.69 (m,
2H, H-4), 3.84e3.90 (m, 2H, NCH2), 4.19e4.24 (m, 1H, H-
2), 5.23e5.25 (d, 2H, J ¼ 4.21 Hz, PhCH2eOe), 6.85 (s,
1H, imidazole H ), 6.96e7.10 (m, 4H, ArH), 7.36e7.40 (m,
5H, ArH), 7.88e7.92 (d, 1H, J ¼ 8.01 Hz, H-8); IR (Neat):
3124, 2933, 2851, 1509, 1283, 1081, 659 cmꢃ1. Anal. Calcd
for C22H23N3O: C, 76.52; H, 6.66; N, 12.17. Found: C,
76.43; H, 6.30; N, 12.03.
5.1.4.1. (Z )-2-Imidazol-1-ylmethyl-3,4-dihydro-2H-napthalen-
1-one O-benzyl-oxime (7). With (Z)-5a and benzyl bromide:
yield 82%; oil; MS (ESI): m/z 332 (Mþ þ 1, 100%), 333
1
(Mþ þ 2, 22%); H NMR (200 MHz, CDCl3): d 1.83e1.90
(m, 1H, H-3), 2.48 (m, 1H, H-3), 2.71e2.90 (m, 2H, H-4),
3.84e3.97 (m, 2H, NCH2), 4.18e4.25 (m, 1H, H-2), 5.24 (s,
2H, PhCH2eOe), 6.85 (s, 1H, imidazole H ), 7.02 (s, 1H, im-
idazole H ), 7.16e7.26 (m, 5H, ArH), 7.28e7.44 (m, 4H,
ArH), 7.98e8.02 (d 1H, J ¼ 7.82 Hz, H-8); IR (Neat): 2926,
1596, 1352, 1088, 700 cmꢃ1. Anal. Calcd for C21H21N3O:
C, 76.13; H, 6.34; N, 12.68. Found: C, 76.57; H, 6.39; N,
12.59.
5.1.4.6. (Z )-2-Imidazol-1-ylmethyl-5-methyl-3,4-dihydro-2H-
naphthalen-1-one O-(3-chloro-benzyl)-oxime (12). With (Z)-
5b and 3-chloro-benzyl chloride: yield 83%; oil; MS
(ESI): m/z 380 (Mþ þ 1, 100%), 382 (Mþ þ 3, 30%); 1H
NMR (200 MHz, CDCl3): d 1.68e1.80 (m, 2H, H-3), 2.33
(s, 3H, ArCH3), 2.70e2.84 (m, 2H, H-4), 3.87e3.98 (m,
2H, NCH2), 4.16e4.23 (m, 1H, H-2), 5.17e5.19 (d, 2H,
J ¼ 3.91 Hz, PhCH2eOe), 6.88 (s, 1H, imidazole H ),
6.96e7.11 (m, 3H, ArH), 7.22e7.30 (m, 3H, ArH), 7.39e
7.42 (d, 2H, J ¼ 5.34 Hz, ArH), 7.85e7.89 (d, 1H,
J ¼ 8.05 Hz, H-8); IR (Neat): 3016, 2940, 2368, 1669,
1507, 1031, 669 cmꢃ1. Anal. Calcd for C22H22N3OCl: C,
69.56; H, 5.79; N, 11.06. Found: C, 69.43; H, 5.82; N,
11.01.
5.1.4.2. (Z )-2-Imidazol-1-ylmethyl-3,4-dihydro-2H-naphtha-
len-1-one O-(3-chloro-benzyl)-oxime (8). With (Z)-5a and 3-
chloro-benzyl chloride: yield 82%; oil; MS (ESI): m/z 366
1
(Mþ þ 1, 100%), 367 (Mþ þ 2, 15%); H NMR (200 MHz,
CDCl3): d 1.80e1.86 (m, 1H, H-3), 2.56 (m, 1H, H-3),
2.67e2.95 (m, 1H, H-4), 3.89e4.00 (m, 2H, NCH2), 4.20e
4.25 (m, 1H, H-2), 5.19 (s, 2H, PhCH2eOe), 6.89 (s, 1H, im-
idazole H ), 7.00 (s, 1H, imidazole H ), 7.13e7.17 (d, 2H,
J ¼ 7.65 Hz, ArH), 7.22e7.30 (m, 4H, ArH), 7.40e7.43 (d,
2H, J ¼ 6.1 Hz, ArH), 7.96e8.00 (d, 1H, J ¼ 7.49 Hz, H-8);
IR (Neat): 3014, 2840, 1527, 1041, 759, 671 cmꢃ1. Anal.
Calcd for C21H20N3OCl: C, 69.13; H, 5.48; N, 11.52. Found:
C, 68.97; H, 4.86; N, 11.68.
5.1.4.7. (Z )-5-Methyl-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one O-benzyl-oxime (13). With (Z)-6b and
benzyl bromide: yield 81%; oil; MS (ESI): m/z 347 (Mþ þ 1,
100%), 348 (Mþ þ 2, 20%); 1H NMR (200 MHz, CDCl3):
d 1.77e1.91 (m, 1H, H-3), 2.32 (s, 3H, ArCH3), 2.61e2.69
(m, 1H, H-3), 2.84e2.98 (m, 2H, H-4), 3.96e3.97 (m, 1H,
H-2), 4.15e4.46 (dd, 2H, J ¼ 13.57, 4.99 Hz, NCH2), 5.20
(s, 2H, PhCH2eOe), 6.96e7.09 (m, 3H, ArH), 7.09e7.26
(m, 4H, ArH), 7.40 (s, 1H, ArH), 7.88e7.89 (m, 2H, ArH);
IR (Neat): 2939, 2363, 1595, 1351, 683 cmꢃ1. Anal. Calcd
for C21H22N4O: C, 72.83; H, 6.35; N, 16.18. Found: C,
72.82; H, 6.38; N, 16.17.
5.1.4.3. (Z )-2-(1,2,4)-Triazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one O-benzyl-oxime (9). With (Z)-6a and benzyl bro-
mide: yield 73%; oil; MS (ESI): m/z 333 (Mþ þ 1, 100%),
1
334 (Mþ þ 2, 20%); H NMR (200 MHz, CDCl3): d 1.79e
1.90 (m, 1H, H-3), 2.66e2.75 (m, 1H, H-3), 2.88e3.00 (m,
2H, H-4), 3.95e4.00 (m, 1H, H-2), 4.17e4.53 (m, 2H,
NCH2), 5.22 (s, 2H, PhCH2eOe), 7.13e7.16 (d, 2H,
J ¼ 6.78 Hz, ArH), 7.16e7.26 (m, 3H, ArH), 7.26e7.40 (m,
3H, ArH), 7.89 (s, 1H, triazole H ), 7.89e7.96 (d, 1H,
J ¼ 13.02 Hz, H-8), 8.01 (s, 1H, triazole H ); IR (Neat): 3433,
2925, 1597, 1352, 762, 669 cmꢃ1
.
Anal. Calcd for
C20H20N4O: C, 72.28; H, 6.02; N, 16.86. Found: C, 72.23; H,
6.30; N, 16.97.
5.1.4.8. (Z )-5-Methyl-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one O-(3-chloro-benzyl)-oxime (14). With
(Z)-6b and 3-chloro-benzyl chloride: yield 83%; oil; MS
(ESI): m/z 381 (Mþ þ 1, 100%), 383 (Mþ þ 3, 20%); 1H
NMR (200 MHz, CDCl3): d 1.75e1.87 (m, 1H, H-3), 2.33
(s, 3H, ArCH3), 2.72 (m, 1H, H-3), 2.74 (m, 2H, H-4), 4.02
(m, 1H, H-2), 4.17e4.44 (dd, 2H, J ¼ 13.64, 5.49 Hz,
NCH2), 5.15e5.17 (d, 2H, J ¼ 3.66 Hz, PhCH2eOe), 6.97e
7.05 (m, 3H, ArH), 7.26e7.29 (d, 2H, J ¼ 6.25 Hz, ArH),
7.39 (s, 1H, ArH), 7.84e7.88 (d, 1H, J ¼ 8.03 Hz, H-8),
7.91 (s, 1H, triazole H ), 7.95 (s, 1H, triazole H ); IR (Neat):
3127, 2936, 1672, 1209, 759, 672 cmꢃ1. Anal. Calcd for
5.1.4.4. (Z )-2-(1,2,4)-Triazol-1-ylmethyl-3,4-dihydro-2H-naph-
thalen-1-one O-(3-chloro-benzyl)-oxime (10). With (Z)-6a and
3-chloro-benzyl chloride: yield 71%; oil; MS (ESI): m/z 367
1
(Mþ þ 1, 100%), 369 (Mþ þ 3, 20%); H NMR (200 MHz,
CDCl3): d 1.79e1.83 (m, 1H, H-3), 2.77e2.88 (m, 1H, H-3),
2.92e2.97 (m, 2H, H-4), 4.01e4.06 (m, 1H, H-2), 4.18e4.46
(m, 2H, NCH2), 5.17 (s, 2H, PhCH2eOe), 7.14 (s, 1H, ArH),
7.18e7.21 (d, 2H, J ¼ 6.18 Hz, ArH), 7.24e7.29 (m, 3H,
ArH), 7.40 (s, 1H, ArH), 7.92e7.95 (d, 1H, J ¼ 7.04 Hz, H-
8), 7.97 (s, 1H, triazole H ), 7.98 (s, 1H, triazole H ); IR

K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
445
C21H21N4OCl: C, 66.22; H, 5.51; N, 14.71. Found: C, 66.19;
H, 5.60; N, 14.68.
5e and 3-chlorobenzyl chloride: yield 66%; oil; MS (ESI):
m/z 445 (Mþ þ 1, 100%), 447 (Mþ þ 3, 30%); 1H NMR
(200 MHz, CDCl3): d 1.80e1.90 (m, 1H, H-3), 2.73e2.77
(m, 1H, H-3), 2.77e2.91 (m, 2H, H-4), 3.87e4.0 (m, 2H,
NCH2), 4.18e4.28 (m, 1H, H-2), 5.19 (s, 2H, PhCH2eOe),
6.89 (s, 1H, imidazole H ), 7.05 (s, 1H, imidazole H ), 7.17e
7.21 (d, 2H, J ¼ 7.64 Hz, ArH), 7.21e7.30 (m, 3H, ArH),
7.40e7.43 (d, 2H, J ¼ 6.25 Hz, ArH), 7.95e7.99 (d, 1H,
J ¼ 7.99 Hz, H-8); IR (Neat): 2926, 2366, 1598, 1352, 1099,
669 cmꢃ1. Anal. Calcd for C21H19N3OBrCl: C, 58.69; H,
4.27; N, 9.44. Found: C, 58.66; H, 4.74; N, 9.18.
5.1.4.9. (Z )-5-Chloro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-benzyl-oxime (15). With (Z)-5d and benzyl
bromide: yield 78%; oil; MS (ESI): m/z 366 (Mþ þ 1, 100%),
1
368 (Mþ þ 3, 30%); H NMR (200 MHz, CDCl3): d 1.74e
1.76 (m, 1H, H-3), 2.70e2.74 (m, 1H, H-3), 2.88e2.98 (m,
2H, H-4), 3.86e3.90 (m, 2H, NCH2), 4.12e4.16 (m, 1H, H-
2), 5.22e5.25 (d, 2H, J ¼ 4.19 Hz, PhCH2eOe), 6.85 (s, 1H,
imidazole H ), 7.06 (s, 1H, imidazole H ), 7.10e7.15 (d, 2H,
J ¼ 10.31 Hz, ArH), 7.16e7.23 (m, 3H, ArH), 7.36e7.40 (m,
3H, ArH), 7.91e7.99 (m, 1H, ArH); IR (Neat): 2932, 1674,
1588, 1507, 1081, 761 cmꢃ1. Anal. Calcd for C21H20N3OCl:
C, 68.94; H, 5.47; N, 11.49. Found: C, 68.76; H, 5.50; N, 11.37.
5.1.4.14. (Z)-5-Bromo-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one O-benzyl-oxime (20). With (Z)-6e and
benzyl bromide: yield 68%; oil; MS (ESI): m/z 412 (Mþ þ 1,
1
100%); H NMR (200 MHz, CDCl3): d 1.67e1.85 (m, 2H,
5.1.4.10. (Z )-5-Chloro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihy-
dro-2H-naphthalen-1-one O-benzyl-oxime (16). With (Z)-6d
and benzyl bromide: yield 72%; oil; MS (ESI): m/z 367
H-3), 2.62e3.01 (m, 2H, H-4), 3.95e3.97 (m, 1H, H-2),
4.16e4.46 (dd, 2H, J ¼ 13.79, 5.71 Hz, NCH2), 5.22 (s, 1H,
PhCH2eOe), 7.0e7.21 (m, 1H, ArH), 7.31 (m, 2H, ArH),
7.31e7.39 (m, 5H, ArH), 7.82 (s, 1H, triazole H ), 7.97 (s,
1H, triazole H ); IR (Neat): 2929, 2860, 1599, 1453, 1016,
758 cmꢃ1. Anal. Calcd for C20H19N4OBr: C, 58.39; H, 4.62;
N, 13.62. Found: C, 58.29; H, 4.70; N, 13.62.
1
(Mþ þ 1, 100%), 369 (Mþ þ 3, 30%); H NMR (200 MHz,
CDCl3): d 1.72e1.78 (m, 1H, H-3), 2.55e2.63 (m, 1H, H-3),
2.75e2.86 (m, 2H, H-4), 3.84e3.98 (m, 1H, H-2), 4.06e4.31
(dd, 2H, J ¼ 13.4, 4.76 Hz, NCH2), 5.12 (s, 2H, PhCH2eOe),
6.98e7.02 (d, 2H, J ¼ 8.42 Hz, ArH), 7.07e7.12 (d, 2H,
J ¼ 8.84 Hz, ArH), 7.18e7.30 (m, 4H, ArH), 7.80 (s, 1H, tria-
zole H ), 7.89 (s, 1H, triazole H ); IR (Neat): 2927, 2857, 1737,
1505, 1018, 767, 700 cmꢃ1. Anal. Calcd for C20H19N4OCl: C,
65.48; H, 5.18; N, 15.27. Found: C, 65.44; H, 5.27; N, 15.31.
5.1.4.15. (Z)-5-Bromo-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one O-(3-chloro-benzyl)-oxime (21). With
(Z)-6e and 3-chlorobenzyl chloride: yield 80%; oil; MS (ESI):
m/z 446 (Mþ þ 1, 100%); 1H NMR (200 MHz, CDCl3):
d 1.67e1.85 (m, 2H, H-3), 2.62e2.71 (m, 1H, H-4), 2.89e
2.97 (m, 1H, H-4), 3.95 (m, 1H, H-2), 4.16e4.46 (dd, 2H,
J ¼ 5.77, 13.74 Hz, NCH2), 5.22 (s, 2H, PhCH2eOe), 7.00e
7.26 (m, 3H, ArH), 7.26e7.40 (m, 3H, ArH), 7.40 (s, 1H,
ArH), 7.82 (s, 1H, triazole H ), 7.88 (s, 1H, triazole H ); IR
(Neat): 2926, 2366, 1598, 1353, 1015, 679 cmꢃ1. Anal. Calcd
for C20H18N4OBrCl: C, 53.87; H, 4.04; N, 12.57. Found: C,
53.82; H, 4.09; N, 12.49.
5.1.4.11. (Z )-5-Chloro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one O-(3-chloro-benzyl)-oxime (17). With
(Z)-6d and 3-chlorobenzyl chloride: yield 79%; oil; MS (ESI):
m/z 401 (Mþ þ 1, 100%), 403 (Mþ þ 3, 30%); 1H NMR
(200 MHz, CDCl3): d 1.72e1.86 (m, 1H, H-3), 2.17e2.27 (m,
1H, H-3), 2.54e2.96 (m, 2H, H-4), 3.99e4.09 (m, 1H, H-2),
4.16e4.40 (dd, 2H, J ¼ 12.6, 5.36 Hz, NCH2), 5.14 (s, 2H,
PhCH2eOe), 7.13e7.17 (d, 2H, J ¼ 7.8 Hz, ArH), 7.21e7.38
(m, 5H, ArH), 7.51 (s, 1H, triazole H ), 7.92e7.96 (d, 2H,
J ¼ 8.36, ArH); IR (Neat): 2924, 2366, 1596, 1352, 1018,
678 cmꢃ1. Anal. Calcd for C20H18N4OCl: C, 59.57; H, 4.44;
N, 13.94. Found: C, 59.48; H, 4.60; N, 13.92.
5.1.4.16. (Z )-5-Fluoro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-benzyl-oxime (22). With (Z)-5c and ben-
zyl bromide: yield 78%; oil; MS (ESI): m/z 350 (Mþ þ 1,
100%), 351 (Mþ þ 2, 22%); 1H NMR (200 MHz, CDCl3):
d 1.74e1.89 (m, 1H, H-3), 2.69e2.71 (m, 1H, H-3), 2.78e
2.88 (m, 2H, H-4), 3.83e3.91 (m, 2H, NCH2), 4.18 (m, 1H,
H-2), 5.23e5.25 (d, 2H, J ¼ 3.16 Hz, PhCH2eOe), 6.85 (s,
1H, imidazole H ), 7.03 (s, 1H, imidazole H ), 7.13e7.26 (m,
2H, ArH), 7.26e7.30 (m, 3H, ArH), 7.30e7.40 (m, 3H,
ArH), 7.65e7.72 (dd, 1H, J ¼ 10.3, 2.5 Hz, ArH); IR (Neat):
2927, 2373, 1595, 1351, 1025, 761, 602 cmꢃ1. Anal. Calcd
for C21H20N3OF: C, 72.20; H, 5.73; N, 12.03. Found: C,
72.16; H, 5.84; N, 12.08.
5.1.4.12. (Z )-5-Bromo-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-benzyl-oxime (18). With (Z)-5e and ben-
zyl bromide: yield 79%; oil; MS (ESI): m/z 411 (Mþ þ 1,
1
100%); H NMR (200 MHz, CDCl3): d 1.77e1.84 (m, 1H,
H-3), 2.65e2.73 (m, 1H, H-3), 2.82e2.98 (m, 2H, H-4),
3.86e3.97 (m, 2H, NCH2), 4.20e4.25 (m, 1H, H-2), 5.25 (s,
2H, PhCH2eOe), 6.85 (s, 1H, ArH), 7.02 (s, 1H, imidazole
H ), 7.12e7.16 (d, 2H, J ¼ 7.37 Hz, ArH), 7.26e7.31 (m,
4H, ArH), 7.36e7.40 (d, 2H, J ¼ 8.29 Hz, ArH), 7.98e8.02
(d, 1H, J ¼ 7.41 Hz, H-8); IR (Neat): 2937, 2366, 1507,
1453, 1219, 760 cmꢃ1. Anal. Calcd for C21H20N3OBr: C,
61.46; H, 4.87; N, 10.24. Found: C, 61.42; H, 4.91; N, 10.18.
5.1.4.17. (Z )-5-Fluoro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-(3-chloro-benzyl)-oxime (23). With (Z)-
5c and 3-chlorobenzyl chloride: yield 73%; oil; MS (ESI):
m/z 384 (Mþ þ 1, 100%), 386 (Mþ þ 3, 22%); 1H NMR
(200 MHz, CDCl3): d 1.83e1.84 (m, 1H, H-3), 2.71e2.75
(m, 1H, H-3), 2.86e2.96 (m, 2H, H-4), 3.86e3.97
5.1.4.13. (Z )-5-Bromo-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-(3-chloro-benzyl)-oxime (19). With (Z)-

446
K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
(m, 2H, NCH2), 4.13e4.17 (m, 1H, H-2), 5.16e5.18 (d, 2H,
J ¼ 4.91 Hz, PhCH2eOe), 6.85 (s, 1H, imidazole H ), 6.98
(s, 1H, ArH), 6.99e7.32 (m, 5H, ArH), 7.38e7.40 (d, 2H,
J ¼ 4.17 Hz, ArH), 7.40e7.59 (m, 1H, ArH); IR (Neat):
2928, 2858, 2374, 1575, 1458, 1023, 768 cmꢃ1. Anal. Calcd
for C21H19N3OFCl: C, 65.71; H, 4.95; N, 10.95. Found: C,
65.70; H, 4.94; N, 10.84.
762 cmꢃ1. Anal. Calcd for C21H20N3OCl: C, 68.94; H, 5.47;
N, 11.49. Found: C, 68.87; H, 5.51; N, 11.41.
5.1.4.22. (E )-5-Bromo-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-(3-chloro-benzyl)-oxime (28). With (E)-
5e and 3-chlorobenzyl chloride: yield 66%; oil; MS (ESI):
m/z 445 (Mþ þ 1, 100%), 447 (Mþ þ 3, 33%); 1H NMR
(200 MHz, CDCl3): d 1.81e1.92 (m, 1H, H-3), 2.71e2.75
(m, 1H, H-3), 2.79e2.90 (m, 2H, H-4), 3.86e4.01 (m, 2H,
NCH2), 5.10e5.14 (m, 1H, H-2); 5.18 (s, 2H, PhCH2eOe),
6.87 (s, 1H, imidazole H ), 7.05 (s, 1H, imidazole H ), 7.18e
7.22 (d, 2H, J ¼ 7.63 Hz, ArH), 7.20e7.31 (m, 3H, ArH),
7.43e7.45 (d, 2H, J ¼ 6.25 Hz, ArH), 8.32e8.29 (d, 1H,
J ¼ 7.61 Hz, H-8); IR (Neat): 2925, 2367, 1599, 1352, 1091,
672 cmꢃ1. Anal. Calcd for C21H19N3OClBr: C, 58.69; H,
4.27; N, 9.44. Found: C, 58.61; H, 4.22; N, 9.39.
5.1.4.18. (Z )-5-Fluoro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihy-
dro-2H-naphthalen-1-one O-benzyl-oxime (24). With (Z)-6c
and benzyl bromide: yield 74%; oil; MS (ESI): m/z 351
1
(Mþ þ 1, 100%), 352 (Mþ þ 2, 22%); H NMR (200 MHz,
CDCl3): d 1.80e2.18 (m, 2H, H-3), 2.63e2.94 (m, 2H, H-
4), 3.95e3.97 (m, 1H, H-2), 4.15e4.38 (m, 2H, NCH2),
5.21 (s, 2H, PhCH2eOe), 6.86e7.20 (m, 5H, ArH), 7.26e
7.38 (m, 3H, ArH), 7.78e7.82 (d, 1H, J ¼ 7.68 Hz, H-8),
7.88 (s, 1H, triazole H ); IR (Neat): 3436, 2366, 1597,
1352, 1014, 767, 672 cmꢃ1. Anal. Calcd for C20H19N4OF:
C, 68.57; H, 5.42; N, 16.18. Found: C, 68.62; H, 5.34; N,
16.17.
5.2. In vitro antifungal and antibacterial activities’
evaluation by MIC assay
The prepared (Z )- and (E )-2-imidazolo-/2-triazolo-methyl
benzocycloalkyl oxime ethers (7e28) were evaluated for their
in vitro antifungal activity against C. albicans, C. neoformans,
S. schenckii, T. mentagrophytes, A. fumigatus (all strains are
patients’ isolates) and C. parapsilosis (ATCC 22019) and an-
tibacterial activity against K. pneumoniae (ATCC 27736), E.
coli (ATCC 9637), P. aeruginosa (ATCC BAA427), and S. au-
reus (ATCC 25923). In this process, minimum inhibitory con-
centration of compounds 7e28 was tested according to
standard microbroth dilution as per NCCLS [19,20] protocol.
Briefly, testing was performed in flat-bottomed 96-well tissue
culture plates (CELLSTARÒ Greiner Bio-one GmbH, Ger-
many) in RPMI 1640 medium buffered with MOPS (3-[N-
morpholino]propane sulfonic acid, Sigma Chemical Co.,
MO, USA) for fungal strains and in Muller Hinton broth (Titan
Biotech Ltd, India) for bacterial strains. The concentration
range of tested compounds was 50e0.36 mg/mL for standard
compounds. Initial inocula of fungal and bacterial strain
were maintained at 1e5 ꢁ 103 cells/mL. These plates were in-
cubated in a moist chamber at 35 ꢂC and absorbance at 492 nm
was recorded on Versa Max microplate reader (Molecular De-
vices, Sunnyvale, USA) after 48 h for C. albicans and C. para-
psilosis, 72 h for A. fumigatus, S. schenckii, and C. neoformans
and 96 h for T. mentagrophytes while bacterial strains were in-
cubated for 24 h. MIC was determined as 90% inhibition of
growth with respect to the growth control, was observed by us-
ing SOFTmax Pro 4.3 Software (Molecular Devices, Sunny-
vale, USA).
5.1.4.19. (Z)-5-Fluroro-2-(1,2,4)-triazol-1-ylmethyl-3,4-dihydro-
2H-naphthalen-1-one O-(3-chloro-benzyl)-oxime (25). With (Z)-
6c and 3-chlorobenzyl chloride: yield 73%; oil; MS (ESI): m/z
1
385 (Mþ þ 1, 100%); H NMR (200 MHz, CDCl3): d 1.80e
1.84 (m, 1H, H-3), 2.71e2.78 (m, 1H, H-3), 2.83e2.94 (m,
2H, H-4), 3.93e4.03 (m, 1H, H-2), 4.14e4.39 (m, 2H, NCH2),
5.20 (s, 2H, PhCH2eOe), 7.06e7.16 (m, 3H, ArH), 7.20e
7.38 (m, 3H, ArH), 7.39 (s, 1H, ArH) 7.89 (s, 1H, triazole H ),
7.96 (s, 1H, triazole H ); IR (Neat): 2363, 1598, 1353, 1015,
763, 678 cmꢃ1. Anal. Calcd for C20H18N4OFCl: C, 62.42; H,
4.68; N, 14.56. Found: C, 62.39; H, 4.54; N, 14.57.
5.1.4.20. (E )-2-Imidazol-1-ylmethyl-3,4-dihydro-2H-naphtha-
len-1-one O-(3-chloro-benzyl)-oxime (26). With (E)-5a and
3-chloro-benzyl chloride: yield 91%; oil; MS (ESI): m/z 366
1
(Mþ þ 1, 100%), 367 (Mþ þ 2, 15%); H NMR (200 MHz,
CDCl3): d 1.79e1.83 (m, 1H, H-3), 2.49 (m, 1H, H-3),
2.62e2.88 (m, 1H, H-4), 3.89e4.00 (m, 2H, NCH2), 5.08e
5.19 (m, 1H, H-2), 5.21 (s, 2H, PhCH2eOe), 6.90e7.12 (m,
2H, ArH), 7.16e7.29 (m, 6H, ArH), 7.38e7.42 (d, 2H,
J ¼ 6.1 Hz, ArH), 8.44e8.49 (d, 1H, J ¼ 7.63 Hz, H-8); IR
(Neat): 3012, 2976, 2838, 1524, 1112, 761, 681 cmꢃ1. Anal.
Calcd for C21H20N3OCl: C, 69.13; H, 5.48; N, 11.52. Found:
C, 69.08; H, 5.33; N, 11.41.
5.1.4.21. (E )-5-Chloro-2-imidazol-1-ylmethyl-3,4-dihydro-2H-
naphthalen-1-one O-benzyl-oxime (27). With (E)-5d and 3-
chloro-benzyl chloride: yield 86%; oil; MS (ESI): m/z 401
1
(Mþ þ 1, 100%); H NMR (200 MHz, CDCl3): d 1.76e1.78
Acknowledgements
(m, 1H, H-3), 2.69e2.73 (m, 1H, H-3), 2.84e2.93 (m, 2H,
H-4), 3.88e3.91 (m, 2H, NCH2), 5.07e5.16 (m, 1H, H-2),
5.19e5.22 (d, 2H, J ¼ 4.14 Hz, PhCH2eOe), 6.86 (s, 1H, im-
idazole H ), 7.04 (s, 1H, imidazole H ), 7.10e7.22 (m, 5H,
ArH), 7.37e7.41 (m, 3H, Ar), 8.37e8.42 (d, 1H,
J ¼ 7.59 Hz, H-8); IR (Neat): 2933, 2837, 1588, 1507, 1089,
N.S. thanks the University Grants Commission (India) and
Shiva K. to Council of Scientific and Industrial Research (In-
dia) for the award of Senior Research Fellowship. The authors
are thankful to Mr. Anoop K. Srivastava for providing techni-
cal assistance.

K. Bhandari et al. / European Journal of Medicinal Chemistry 44 (2009) 437e447
447
[14] W.J. Watkins, T.E. Renau, in:A.M. Dohery(Ed.), Annual Reports in Medic-
inal Chemistry, vol. 35, Academic Press, New York, 1999, pp. 157e166.
[15] A. Rossello, S. Bertini, A. Lapucci, M. Maccia, A. Martinelli,
S. Rapposelli, E. Herreos, B. Macchia, J. Med. Chem. 45 (2002) 4903.
[16] P. Krogsgaard-Larsen, H. Bundgaard, A Textbook of Drug Design and
Development, Harwood Academic Publishers, Chur, 1991.
References
[1] D. Abbanat, M. Macielag, K. Bush, Expert Opin. Investig. Drugs 12
(2003) 379.
[2] J. Pootoolal, J. Neu, G.D. Wright, Annu. Rev. Pharmacol. Toxicol. 42
(2002) 381.
[17] C.E. Olson, A.R. Barder, Org. Synth. Coll. Vol. 4 (1963) p. 898.
[18] C. Paul, R. Alfred, C. Danise, Bull. Soc. Chim. Fr. 3 (1969) 985e991 (Fr).
[19] F.G. Baddar, S. Lanson, El. Assal, N.A. Doss, J. Chem. Soc. (1959) 1027.
[20] S. Emami, M. Falahati, A. Banifatemi, K. Moshiri, A. Shafiee, Arch.
Pharm. Pharm. Med. Chem. 335 (2002) 318.
[3] I.I. Raad, H.A. Hanna, R.Y. Hachem, T. Dvorak, R.B. Arbuckle,
G. Chaiban, R.B. Rice, Antimicrob. Agents Chemother. 48 (2004) 3583.
[4] F.W. Goldstein, Clin. Microbiol. Infect. 13 (s2) (2007) 2e6.
[5] D.F. Fidler, Emerg. Infect. Dis. 4 (1998) 169e177.
[6] A. Macchiarulo, G. Constantino, D. Fringuelli, A. Vecchiarelli,
F. Schiaffella, R. Fringuelli, Bioorg. Med. Chem. 10 (2002) 3415e
3423.
[21] S. Emami, A. Shafiee, Heterocycles 55 (2001) 2059.
[22] H. Baji, M. Flammang, T. Kimny, F. Gasques, P.L. Compagnon,
A. Delcourt, Eur. J. Med. Chem. 30 (1995) 617.
[7] D.J. Sheehan, C.A. Hitchcock, C.M. Sibley, Clin. Microbiol. Rev. 12
(1999) 40e79.
[23] National Committee for Clinical Laboratory Standard, Reference Method
for Broth Dilution Antifungal Susceptibility Testing of Yeast, Approved
Standard Document M27-A, National Committee for Clinical Laboratory
Standards, Wayne, PA, 1997.
[8] R.G. Lovey, A.J. Elliott, J.J. Kaminski, D. Loebenberg, R.M. Parmegiani,
D.F. Rane, V.M. Girijavallabhan, R.E. Pike, H. Guzik, B. Antonacci,
T.Y. Tomaine, J. Med. Chem. 35 (1992) 4221.
[24] National Committee for Clinical Laboratory Standard, Reference Method
for Broth Dilution Antifungal Susceptibility Testing of Conidium Form-
ing Lamentous Fungi: Proposed Standard Document M38-P, National
Committee for Clinical Laboratory Standard, Wayne, PA, 1998.
[25] I.J. Sud, D.S. Feingold, Antimicrob. AgentsChemother. 22(1982) 470e474.
[26] R.A. Helmick, A.E. Fletcher, A.M. Gardner, C.R. Gessner, A.N. Hvitved,
M.C. Gustin, P.R. Gardner, Antimicrob. Agents Chemother. 49 (2005)
1837e1843.
[9] G.P. Bodey, Clin. Infect. Dis. 14 (1992) S161.
[10] D.A. Heerding, G. Chan, E.D. Walter, P.F. Andrew, C.A. Janson,
K.S. Vaidya, C.K. Yuan, F.W. Huffman, Bioorg. Med. Chem. Lett. 11
(2001) 2061e2065.
[11] R.J. Heath, C.O. Rock, Nature 406 (2000) 145.
[12] M.A. Ghannoum, L.B. Rice, Clin. Microbiol. Rev. 12 (1999) 501.
[13] J.M. Balkovec, in: J.A. Bristol (Ed.), Annual Reports in Medicinal
Chemistry, vol. 33, Academic Press, New York, 1998, pp. 173e182.