Synthesis and study of antibacterial and antifungal activities of novel 1-[2-(benzoxazol-2-yl)ethoxy]- 2,6-diarylpiperidin-4-ones

Article abstract of DOI:10.1016/j.ejmech.2004.02.005

Some novel benzoxazolylethoxypiperidones have been synthesized and their antibacterial activity against streptococcus faecalis, bacillus subtilis, escherichia coli, staphylococcus aureus aand pseudomonas aeruginosa and antifungal activity against Candida-6, Candida albicans, Aspergillus niger, Candida-51 and Aspergillus flavus were evaluated. Compounds 37, 38 and 39 exerted potent in vitro antibacterial activity against Streptococcus faecalis while compounds 40 and 41 exhibited potent in vitro antifungal activity against Candida-51.

Full text of DOI:10.1016/j.ejmech.2004.02.005

European Journal of Medicinal Chemistry 39 (2004) 527–533
www.elsevier.com/locate/ejmech
Short communication
Synthesis and study of antibacterial and antifungal activities of novel
1-[2-(benzoxazol-2-yl)ethoxy]- 2,6-diarylpiperidin-4-ones
C. Ramalingan a, S. Balasubramanian a, S. Kabilan *,a, M. Vasudevan b
a Department of Chemistry, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
b JSS College of Pharmacy, Ooty- 643 001, India
Received 29 September 2003; received in revised form 11 February 2004; accepted 11 February 2004
Available online 02 April 2004
Abstract
Some novel benzoxazolylethoxypiperidones have been synthesized and their antibacterial activity against streptococcus faecalis, bacillus
subtilis, escherichia coli, staphylococcus aureus aand pseudomonas aeruginosa and antifungal activity against Candida-6, Candida albicans,
Aspergillus niger, Candida-51 and Aspergillus flavus were evaluated. Compounds 37, 38 and 39 exerted potent in vitro antibacterial activity
against Streptococcus faecalis while compounds 40 and 41 exhibited potent in vitro antifungal activity against Candida-51.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Piperidin-4-one; Cyanoethylation; Benzoxazole; Antibacterial activity; Antifungal activity
1. Introduction
Recently, we exploited the synthesis of 2,6-
diarylpiperidin-4-one derivatives with a view to incorporate
various other bioactive heterocyclic nucleus intact for evalu-
ation of their biological importance and also as a reagent for
effecting functional group interconversion [9-14].
Substituted piperidin-4-ones are important synthetic inter-
mediates for the preparation of various alkaloids and phar-
maceuticals [1]. The piperidine nucleus can also be fre-
quently recognized in the structure of numerous naturally
occurring alkaloid and synthetic compounds with interesting
biological and pharmacological properties. As a conse-
quence, the development of general methods for the synthe-
sis of piperidine derivatives has been the subject of consider-
able synthetic effort [2]. Benzoxazole nucleus is marked for
its biological activity. 2-Substituted benzoxazoles were
shown to exhibit analgesic [3], fungicidal, insecticidal,
nematocidal [4], potent protease inhibitory [5], anticancer [6]
activities and serve as topoisomerase I poisons [7].
An essential component of the search for new leads in a
drug designing program is the synthesis of molecules, which
are novel yet resemble known biologically active molecules
by virtue of the presence of some critical structural features.
Certain small heterocyclic molecules act as highly funtional-
ized scaffolds and are known pharmacophores of a number of
biologically active and medicinally useful molecules [8]. In
the interest of above, we planned to synthesize a system
which combines these two biolabile components together to
give a compact structure like title compounds.
2. Chemistry
Cyclic ketones normally undergo Baeyer-Villeger oxida-
tion (oxygen insertion reaction) to yield lactones upon treat-
ment with peracids [15]. When 2,6-diarylpiperidin-4-ones
were subjected to Baeyer-Villeger type of reaction by using
m-CPBA, 1-hydroxy-2,6-diarylpiperidin-4-ones [16] re-
sulted instead of lactones. On treatment with acrylonitrile,
substituted tetrahydrothiopyran-4-ones containing active hy-
drogen underwent cyanoethylation yielding 3-[2-cyano-
ethoxy] derivatives [17]. In 1-hydroxy-2,6-diarylpiperidin-4-
ones, there are active methylenic hydrogens at C3 and C5.
Hence expectation of cyanoethylation to occur at these posi-
tions besides at 1-hydroxyl group is quite normal. However
in all the cases, specifically the 1-hydroxy group alone under-
went cyanoethylation [18] to afford 1-(2-cyanoethoxy)-2,6-
diarylpiperidin-4-one in good yields (60-74%) upon treat-
ment with acrylonitrile in the presence of catalyst triton B.
Usually cyanoethylation [19] is a base catalyzed reaction and
invariably requires an alkaline catalyst. But certain amines
* Corresponding author.
E-mail address: kabilan@satyam.net.in (S. Kabilan).
© 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.02.005

528
C. Ramalingan et al. / European Journal of Medicinal Chemistry 39 (2004) 527–533
R
R
Table 1
Analytical data of compounds 25-42
O
R1
R1
Entry
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
R1
H
R2
R
Yield (%)
70
m.p (°C)
87
R1
H
ii
H
H
i
NH
N
OH
O
O
O
H
CH3
CH3
H
H
74
76
2
R
CH3
H
H
69
92
R2
R2
R2
1 - 3
Cl
65
71
4 - 6
7 - 15
16 - 24
H
CH3
CH3
H
Cl
64
60
R
R
CH3
H
Cl
67
68
iii
R
OCH3
OCH3
OCH3
H
69
80
H
CH3
CH3
H
70
73
R
CH3
H
63
62
54
139
95
R1
R1
H
CH3
CH3
H
H
58
N
O
CH3
H
H
55
116
88-89
75-76
106
100
119-120
81
iv
OCH2CH2
N
O
OCH2CH2CN
N
O
NH2
Cl
32
R2
H
CH3
CH3
H
Cl
27
R2
OH
CH3
H
Cl
40
25 - 33
34 - 42
OCH3
OCH3
OCH3
58
R
R
H
CH3
CH3
50
(i) NH4OAc, C2H5OH
(ii) m-CPBA
(iii) CH2=CH.CN, Triton B
(iv) H+
CH3
50
Scheme 1.
NB from 24 h old bacterial cultures on nutrient agar at 37°C
while fungal spores from 24 h - 7 days old Sabourauds agar
slant cultures were suspended in SDB. The colony forming
units (cfu) of the seeded broth were determined by plating
technique and adjusted in the range of 104-105 cfu per ml.
0.2 ml of the solution of test compound was added to 1.8 ml
of seeded broth to form the first dilution. One ml of this was
diluted with a further 1 ml of the seeded broth to give the
second dilution and so on till 6 such dilutions were obtained.
A set of assay tubes containing only seeded broth was kept as
control and likewise solvent controls were also run simulta-
neously. The tubes were incubated in BOD incubators at
37°C for bacteria and 28°C for fungi. The minimum inhibi-
tory concentrations (MICs) were recorded by visual observa-
tions after 24 h (for Bacteria) and 72-96 h (for fungi) of
incubation. Penicillin, Streptomycin and Amphotericin B
were used as standards.
are quite exceptional. Oxides, hydroxides, alkoxides, alkali
metal hydrides etc. are useful for this purpose. Solubility of
the bases in organic solvents should be taken in to account.
Mono or multiple cyanoethylation depends upon the proper
choice of a catalyst with sufficient basicity to remove the
labile proton from the compound undergoing cyanoethyla-
tion. Triton B is particularly employed here on account of its
basicity and its solubility in organic media. Cyanoethylation
requires cooling to avoid polymerization of acrylonitrile.
Inert solvents like benzene, dioxane, acetonitrile or pyridine
can be used to dissolve solid reactants or to moderate the
reaction.
1-(2-Cyanoethoxy)-2,6-diarylpiperidin-4-ones upon con-
densation with o-aminophenol in acid medium resulted 1-[2-
(benzoxazol-2-yl)ethoxy]-2,6-diarylpiperidin-4-ones
in
moderate yields. Formation of an iminoyl chloride from the
cyanoethylated compound in the presence of HCl is pre-
sumed to be essential for the condensation. The importance
of the title compounds is due to their diverse potential,
broad-spectrum biological activity. The schematic represen-
tation and the analytical data of compounds 25-42 are given
in Scheme 1 and Table 1 respectively. The spectral character-
ization data for the novel intermediates 25-33 are furnished
in Table 2.
4. Results and Discussion
Structure activity relationship results
4.1. Antibacterial activity
All the synthesized novel benzoxazolylethoxypiperidones
34-42 were tested for their antibacterial activity in vitro
against Bacillus subtilis, Streptococcus faecalis, Escherichia
coli, Staphylococcus aureus and Pseudomonas aeruginosa.
Penicillin and Streptomycin were used as standard drugs
whose minimum inhibitory concentration (MIC) values were
furnished in Table 3.
In general all the synthesized novel benzoxazolylethox-
ypiperidones exerted a wide range of modest in vitro antibac-
terial activity against all the tested organisms except 34-36
against S.aureus and B.subtilis and 34 against S.faecalis. The
3. Pharmacology
In vitro antibacterial and antifungal sensitivity
The in vitro activities of the compounds were tested in
Sabourauds dextrose broth (SDB) for fungi and Nutrient
broth (NB) for bacteria by the twofold serial dilution method
[20]. The test compounds were dissolved in DMSO (dimeth-
ylsulphoxide) to obtain 1 mg/ml stock solutions. Seeded
broth (broth containing microbial spores) was prepared in

C. Ramalingan et al. / European Journal of Medicinal Chemistry 39 (2004) 527–533
529
Table 2
Spectral characterization data for compounds 25 – 33
Entry
25
Spectral characterization data
Mass: m/z 320(M+) (M.F. C20H20O2N2), 294, 280, 267, 250, 222, 208, 194, 163, 91, 77(100%), 65, 53, 51. 1H-NMR: d 2.58-2.81 (m, 6H, H3, H5,
OCH2CH2), 3.75(t, 2H, OCH2CH2), 4.01 (dd, 2H, H2, H6), 7.25-7.46(m, 10H, aryl protons). 13C-NMR: d 19.623 (OCH2CH2), 51.078(C3, C5),
65.314 (C2, C6), 70.123 (OCH2CH2), 124.310(C≡N), 124.862, 126.537, 127.131, 146.810(aryl carbons), 206.310 (C=O).
Mass: m/z 334(M+) (M.F. C21H22O2N2), 294, 281, 264, 222, 177, 131, 118, 105, 91, 77(100%), 65, 53, 51. 1H-NMR: d 0.81 (d, 3H, CH3),
2.57-2.84 (m, 5H, H3, H5, OCH2CH2), 3.57(d, 1H, H2), 3.74(t, 2H, OCH2CH2), 3.95 (dd, 1H, H6), 7.28-7.48(m, 10H, aryl protons). 13C-NMR:
d 10.604(CH3 at 3), 19.629 (OCH2CH2), 50.908(C3) 51.592(C5), 65.625(C6), 70.131(OCH2CH2), 71.136(C2), 124.324(C≡N), 124.642 126.312,
126.463, 127.192, 127.560, 139.958, 149.548 (aryl carbons), 207.712 (C=O).
26
27
Mass: m/z 348(M+) (M.F. C22H24O2N2), 308, 298, 278, 144, 121, 84, 77(100%), 59, 56, 53. 1H-NMR: d 0.82 (d, 6H, CH3), 2.59 (t, 2H,
OCH2CH2), 2.71-2.78(m, 2H, H3, H5), 3.60(d, 2H, H2, H6), 3.77(t, 2H, OCH2CH2), 7.27-7.53(m, 10H, aryl protons). 13C-NMR: d 10.981(CH3
at 3), 19.627(OCH2CH2), 51.210(C3, C5), 70.123 (OCH2CH2), 71.326 (C2, C6), 124.298(C≡N), 124.936, 126.692, 127.252, 147.821(aryl
carbons), 209.448 (C=O).
28
29
Mass: m/z 388(M+) (M.F. C20H18O2N2Cl2), 362, 348, 338, 290, 276, 197, 137, 111, 75, 65, 53(100%), 50. 1H-NMR: d 2.58-2.84 (m, 6H, H3, H5,
OCH2CH2), 3.76(t, 2H, OCH2CH2), 4.04 (dd, 2H, H2, H6), 7.30, 7.36(2d, 8H, aryl protons). 13C-NMR: d 19.663 (OCH2CH2), 51.325(C3, C5),
64.524(C2, C6), 70.129 (OCH2CH2), 124.410(C≡N), 128.054, 128.203, 133.106, 146.538(aryl carbons), 204.982 (C=O).
Mass: m/z 402(M+) (M.F. C21H20O2N2Cl2), 362, 349, 304, 290, 239, 196, 152, 139, 111, 75, 65, 53(100%), 50. 1H-NMR: d 0.78 (d, 3H, CH3),
2.59-2.87 (m, 5H, H3, H5, OCH2CH2), 3.64(d, 1H, H2), 3.76(t, 2H, OCH2CH2), 4.03(dd, 1H, H6), 7.32-7.45(m, 8H, aryl protons). 13C-NMR: d
10.712(CH3 at 3), 19.674 (OCH2CH2), 51.165(C3) 51.842(C5), 64.825(C6), 70.141(OCH2CH2), 70.524(C2), 124.372(C≡N), 127.186, 128.652,
128.783, 131.243, 131.980, 133.924, 138.911, 146.392 (aryl carbons), 206.204 (C=O).
30
31
32
33
Mass: m/z 416(M+) (M.F. C22H22O2N2Cl2), 376, 363, 318, 207, 183, 155, 111, 91, 84, 75, 65, 53(100%), 50. 1H-NMR: d 0.79 (d, 6H, CH3), 2.61
(t, 2H, OCH2CH2), 2.73-2.88(m, 2H, H3, H5), 3.62(d, 2H, H2, H6), 3.75(t, 2H, OCH2CH2), 7.33, 7.39(2d, 8H, aryl protons). 13C-NMR: d
10.870(CH3 at 3), 19.668(OCH2CH2), 51.462(C3, C5), 70.133(OCH2CH2), 70.526(C2, C6), 124.640(C≡N), 128.216, 128.386, 133.192,
146.738(aryl carbons), 208.196 (C=O).
Mass: m/z 380(M+) (M.F. C22H24O4N2), 340, 327, 282, 254, 193, 133, 107, 75, 65, 53(100%). 1H-NMR: d 2.50-2.79 (m, 6H, H3, H5, OCH2CH2),
3.76(t, 2H, OCH2CH2), 3.81(s, 6H, aryl OCH3), 4.03(dd, 2H, H2, H6), 6.89, 7.34(2d, 8H, aryl protons). 13C-NMR: d 19.638(OCH2CH2),
50.981(C3, C5), 54.314(aryl OCH3), 64.669(C2, C6), 70.160(OCH2CH2), 124.432(C≡N), 115.532, 127.841, 141.897, 157.874(aryl carbons),
206.194 (C=O).
Mass: m/z 394(M+) (M.F. C23H26O4N2), 354, 341, 296, 207, 192, 148, 107, 75, 65, 53(100%), 50. 1H-NMR: d 0.79 (d, 3H, CH3), 2.51-2.81 (m,
5H, H3, H5, OCH2CH2), 3.62(d, 1H, H2), 3.76(t, 2H, OCH2CH2), 3.81(s, 6H, aryl OCH3), 4.03(dd, 1H, H6), 6.84-6.86, 7.35-7.37(m, 8H, aryl
protons). 13C-NMR: d 10.608(CH3 at 3), 19.667(OCH2CH2), 50.810(C3) 51.497(C5), 54.423(aryl OCH3), 64.980(C6), 70.172(OCH2CH2),
70.548(C2), 124.278(C≡N), 114.380, 115.786, 128.016, 130.943, 134.723, 141.598, 157.271, 159.216(aryl carbons), 207.792(C=O).
Mass: m/z 408(M+) (M.F. C24H28O4N2), 368, 355, 310, 204, 151, 133, 107, 84, 75, 59, 53(100%), 50. 1H-NMR: d 0.81 (d, 6H, CH3), 2.61 (t, 2H,
OCH2CH2), 2.70-2.87(m, 2H, H3, H5), 3.62(d, 2H, H2, H6), 3.77(t, 2H, OCH2CH2), 3.82(s, 6H, aryl OCH3), 6.89, 7.36(2d, 8H, aryl protons).
13C-NMR: d 10.897(CH3 at 3), 19.693(OCH2CH2), 51.117(C3, C5), 54.562(aryl OCH3), 70.166(OCH2CH2), 71.196(C2, C6), 124.512(C≡N),
115.386, 127.792, 141.898, 158.486(aryl carbons), 207.430 (C=O).
compounds 34-36 without any substituents at the para posi-
tion of the aryl groups at C2 and C6 positions of the six
membered heterocyclic moiety did not exhibit in vitro anti-
bacterial activity even at the maximum concentration of
200µg/ml against S. aureus and B. subtilis. Of these 34-36,
introduction of methyl group at C3 position of the six mem-
bered heterocyclic moiety (35) improved the activity com-
pared to 34 against P.aeruginosa and S.faecalis while the
activity did not change appreciably against E.coli. There was
no further improvement in the activity when another methyl
group was substituted at the C5 position of the six membered
heterocyclic ring as well (36) compared to 35 against these
organisms.
Replacement of hydrogen present at the para position of
the aryl moieties at C2 and C6 positions of the six membered
heterocyclic ring by a chloro function in 34 (i.e., in 37)
showed activity in the range of 12.50 µg/ml to 100 µg/ml
against all the tested organisms. Introduction of methyl group
at C3 in 37 (i.e., in 38) did not exhibit appreciable change in
the activity against S.aureus, E.coli and P.aeruginosa
whereas activity reduced against B.subtilis. Against S. faeca-
lis, the activity was enhanced by this introduction compared
to 37. But the introduction of another methyl group at C5
position of the six membered heterocyclic ring in 37 (i.e., in
39) exhibited similar activity against B.subtilis, E.coli and
P.aeruginosa while against S.faecalis and S.aureus activity
reduced compared to 38.
Table 3
In vitro antibacterial activity of compounds 34-42
Entry
Minimum inhibitory concentration (MIC) in µg/ml
B.subtilis S.faecalis E.coli S.aureus P.aeruginosa
34
-
-
200
200
200
100
100
100
25
-
100
50
50
25
25
25
50
25
50
50
25
35
-
200
200
12.5
6.25
12.5
50
-
36
-
-
37
25
50
50
200
200
200
25
100
100
50
38
39
40
200
100
200
12.5
50
41
25
12.5
25
Due to the introduction of methoxy groups at the para
position of the aryl groups at C2 and C6 positions of the six
membered heterocyclic moiety in the place of chloro func-
tions in 37 (i.e., in 40), the activity was suppressed against all
42
25
penicillin
25
50
streptomycin 12.5
12.5
12.5
‘-’ no inhibition at 200 µg/ml

530
C. Ramalingan et al. / European Journal of Medicinal Chemistry 39 (2004) 527–533
Table 4
200µg/ml by the introduction of methyl group at C3 (i.e., in
35) and methyl groups at C3 and C5 (i.e., in 36).
In vitro antifungal activity of compounds 34-42
Entry
Minimum inhibitory concentration (MIC)
in µg/ml against fungi
Due to the replacement of hydrogens at the para position
of the aryl groups at C2 and C6 positions of the six membered
heterocyclic moiety (34) by chloro functions (i.e., in 37),
activity enhanced compared to 34 against all the tested or-
ganisms. Introduction of methyl group at C3 position of the
six membered heterocyclic moiety in 37 (i.e., in 38) in-
creased the activity against C.albicans, Candida-6 while
against Candida-51, A. niger and A. flavus, the activity sup-
pressed by this introduction compared to 37. Similarly, due to
the introduction of another methyl group at C5 position of the
six membered heterocyclic moiety (i.e., in 39), activity re-
duced against C. albicans, Candida-6 and activity enhanced
against A. flavus. Against Candida-51 and A. niger, this
introduction did not improve the activity compared to 38.
Introduction of methoxy functions at the para position of
the aryl groups at C2 and C6 positions of the six membered
heterocyclic ring in the place of chloromoieties in 37 (i.e., in
40) did not change the activity against C. albicans and A.
flavus. But against Candida-6 and Candida-51, the activity
was improved due to this introduction compared to 37.
Against A. niger, the activity suppressed due to the introduc-
tion of methoxy groups. Of 40-42, the activity of 41 was
remained unchanged against C. albicans and Candida-51
even when one of the hydrogens at C3 position of the six
membered heterocyclic moiety was replaced by a methyl
group. Against Candida-6, A. niger andA. flavus, the activity
of compound 41 was enhanced due to the introduction of
methyl group compared to 40. Similarly, due to the introduc-
tion of another methyl group at the C5 position of the six
membered heterocyclic ring, the activity of 42 did not change
against C. albicans and Candida-6 while activity reduced
against rest of the organisms viz., Candida-51, As. niger and
As. flavus compared to 41.
Candida-6 C. albicans A. niger Candida-51 A. flavus
34
35
36
37
38
39
40
41
42
200
200
200
100
50
100
50
50
50
50
12.5
25
25
50
25
50
50
100
100
100
25
200
-
100
50
-
50
100
50
50
25
50
50
25
50
100
50
50
50
50
12.5
12.5
25
25
50
25
50
Amphotericin 25
B
25
25
‘-’ no inhibition at 200 µg/ml
the tested organisms except E.coli against which activity
enhanced by this introduction compared to 37. Replacement
of hydrogen at C3 position of the six membered heterocyclic
moiety by a methyl group in 40 (i.e., in 41) did not improve
the activity against B.subtilis while against S.aureus, E.coli,
P.aeruginosa and S.faecalis, the activity was enhanced com-
pared to 40. Similarly, the replacement of a another hydrogen
at C5 as well by a methyl group (42) exhibited no appreciable
change in the activity compared to 41 against B.subtilis and
S.faecalis. The activity was reduced compared to the same
against rest of the organisms tested viz., P.aeruginosa, E.coli
and S.aureus.
4.2. Antifungal activity
The in vitro antifungal activity of the novel compounds
34-42 was studied against the fungal strains viz., Candida–6,
Candida albicans, Aspergillus niger, Candida-51 and As-
pergillus flavus.Amphotericin-B was used as a standard drug
whose minimum inhibitory concentration (MIC) values were
furnished in Table 4.
5. Conclusion
The compounds 34-36 without any substituents at the para
position of the aryl groups present at the C2 and C6 positions
of the six membered heterocyclic moiety exerted modest
antifungal activity in the range of 50 µg/ml to 200 µg/ml
against all the tested organisms except 35 and 36 against A.
flavus, which did not exhibit antifungal activity even at the
maximum concentration of 200 µg/ml. Of 34-36, replace-
ment of one of the hydrogens at C3 position of the six
membered heterocyclic moiety by a methyl group (i.e., in 35)
increased the activity against C. albicans, while against
Candida-6, Candida-51 and A. niger no appreciable change
in the activity was resulted compared to 34 by this introduc-
tion. Introduction of another methyl group at C5 position of
the six membered heterocyclic moiety (i.e., in 36) did not
improve the activity appreciably against Candida-6,
Candida-51 and A. niger while activity reduced by this intro-
duction against C.albicans compared to 35.AgainstA. flavus,
the compound 34 showed activity at 200 µg/ml whereas the
activity disappeared at the maximum concentration of
An examination of the in vitro antibacterial and antifungal
activity profile of variety of substituted novel benzox-
azolylethoxypiperidones against the bacterial strains viz.,
Bacillus subtilis, Streptococcus faecalis, Escherichia coli,
Staphylococcus aureus, Pseudomonas aeruginosa and the
fungal strains viz., Candida–6, Candida albicans,Aspergillus
niger, Candida-51, Aspergillus flavus respectively provide a
structure activity correlate, which may be summarised as
follows. The compounds with chloro or methoxy functions at
the para position of the aryl moieties at C2 and C6 positions of
the six membered heterocyclic moiety along with / without
methyl substituents at C3/C5 and C5 positions play an impor-
tant role in eliciting biological response. Specifically of the
novel benzoxazolylethoxypiperidones tested, the com-
pounds with chloro function at the para position of the aryl
moieties at C2 and C6 positions along with the methyl group
at C3 position of the six membered heterocyclic moiety

C. Ramalingan et al. / European Journal of Medicinal Chemistry 39 (2004) 527–533
531
exhibited good activity against S.faecalis. The novel benzox-
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-diphenylpiperidin-
4-one 34. mixture of 1-[2-cyanoethoxy]-2,6-
azolylethoxypiperidone with chloro moieties at the para po-
sition of the aryl groups at C2 and C6 positions of the six
membered heterocyclic ring and the benzoxazolylethoxypi-
peridone with methoxy functions at the para position of the
aryl groups present at the C2 and C6 positions along with /
without methyl substituent at C3 position of the six mem-
bered heterocyclic moiety exerted good antifungal activity
againstAs.niger and Candida-51. Thus, in future this class of
novel benzoxazolylethoxypiperidones may be used as tem-
plates to generate better drugs to combat bacterial and fungal
infections.
A
diphenylpiperidin-4-one 13 (0.005 mole), o-aminophenol
(0.005 mole) and dilute hydrochloric acid (10cc of Con. HCl
in 100cc of water) was taken in a 250ml round bottom flask
and was allowed to reflux in an oil bath for 18 h. After
cooling, the contents in the flask were leached with 100cc of
diethylether and the separated ether extract was washed with
five 25cc portions of 4N sodium hydroxide solution. The
ether layer was separated, dried with calcium chloride and
freed of ether by distillation. The solid thus obtained was
recrystallised twice from ethanol.
IR:cm-1(KBr) 2924.1, 2850.6, 2767.2,(C-H Stretching),
1706.4(C=O Stretching). Other characteristic bands are
1600.3, 1456.7, 1429.3, 1392.3, 1374.7, 1347.6, 1287.1,
1255.3, 1237.8, 1155.4, 1104.9, 1076.2, 1035.4, 945.3,
904.7, 856.4, 788.2, 748.9, 689.1, 658.2, 604.8, 518.6, 500.7,
472.1. Mass:m/z 412(M+) (M.F : C26H24N2O3), 280, 267,
250, 222, 208, 194, 167, 145, 132, 118, 103 (100%), 91.77,
65, 55, 51. 1H NMR:d 4.04(dd, 3J=12.64Hz; 3.86Hz; 2H) H2
and H6, 2.60-2.85(m, 6H) H3, H5 and –OCH2-CH2-, 7.29-
7.49(m, 14H) aryl protons, 3.93(t, J=6.50 Hz; 2H)–OCH2-
CH2-. 13C NMR:d 69.262(C2, C4), 49.312(C3, C5),
206.050(C=O), 67.573(–OCH2- CH2-), 27.647 (–OCH2-
CH2-), 109.738, 114.284, 118.943, 119.058, 127.798,
129.773, 130.731, 133.105, 143.134(aryl carbons),
141.739(C2′ and C6′), 162.605(C2 of benzoxazole moiety).
The compounds 35-42 were synthesised similarly.
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-diphenyl-3-methyl-
piperidin-4-one 35. IR:cm-1(KBr) 2965.7, 2938.2, 2856.5,
2805.3(C-H Stretching), 1696.5(C=O Stretching). Other
characteristic bands are 2352.8, 1952.1, 1813.2, 1589.3,
1488.2, 1449.7, 1368.2, 1335.1, 1269.3, 1251.7, 1229.4,
1198.2, 1131.9, 1089.8, 1024.2, 951.2, 930.7, 913.4, 871.8,
841.5, 834.6, 748.3, 686.9, 670.2, 635.0, 593.3, 551.8, 526.4.
Mass:m/z 426(M+), (M.F : C27H26N2O3), 294, 281, 264, 239,
172, 162, 145, 132, 118, 103(100%), 91, 77, 69, 65, 51. 1H
NMR:d 4.02(dd, 3J=13.03Hz; 3.36Hz, 2H) H6, 3.60(d,
3J=11.65Hz, 1H)H2, 2.60-2.88(m, 5H) H3, H5 and –OCH2-
CH2-, 7.28-7.48(m, 14H) aryl protons, 3.92(t, J=6.49 Hz,
2H) –OCH2-CH2-, 0.81(d, J=6.58Hz, 3H) CH3. 13C NMR:d
6. Experimental
TLC was performed to access the reactions and purity of
products. Melting points were recorded in open capillaries
and were uncorrected. IR spectra were recorded in Perkin -
Elmer 297 spectrophotometer in KBr pellets and only note-
worthy absorption levels (reciprocal centimeter) are listed.
1H - NMR spectra were recorded at 400 MHz on Bruker amx
400 MHz spectrophotometer in CDCl3 using TMS as internal
standard and 13C-NMR spectra were recorded at 100 MHz on
Bruker amx 400 MHz spectrophotometer in CDCl3. Mass
spectra were recorded on a VG analytical 7070E instrument
equipped with VG 11-250 data acquision system. Satisfac-
tory microanalysis were obtained on Carlo Erba 1106 and
Perkin Elmer models 240 CHN analyzer.
From the literature precedent [21], 2,6-diarylpiperidin-4-
ones 7-15 were prepared by the condensation of appropriate
ketones, aldehydes and ammonium acetate in 1:2:1 ratio.
1-Hydroxy-2,6-diphenylpiperidin-4-one 16: A solution
of 2,6-diphenylpiperidin-4-one 7 (0.005 mol) and m-CPBA
(0.005 mol) in 40 ml of chloroform was stirred for 15 min.
and kept aside for overnight at 20°C. Then the mixture was
extracted with chloroform and washed with 10% sodium
bicarbonate solution. The chloroform layer was dried over
anhydrous sodium sulphate and distilled off under reduced
pressure. Purifications with silicagel column chromatogra-
phy with 8:2 benzene:pet-ether (bp40-60) mixture yielded
the product 16. The compounds 17-24 were prepared simi-
larly.
1-(2-Cyanoethoxy)-2,6-diphenylpiperidin-4-one 25: A
mixture of 1-hydroxy-2,6-diphenylpiperidin-4-one 16
(0.005 mol) and acrylonitrile (0.005 mol) in 50 ml of 1,4-
dioxane was taken in 100 ml round bottom flask and cooled
in an ice bath. A few crystals of resorcinol were added
followed by dropwise addition of triton B (5 ml) with shak-
ing. Then the content was stirred under warm for 9 h. at
65-75°C and was concentrated. After cooling, the resulting
solution was poured over benzene:pet-ether 1:3 mixture for
extraction. The solid thus obtained from the extract after
removal of solvents at reduced pressure was recrystallised
from methanol to afford 25. The compounds 26-33 were
prepared similarly.
75.767(C2),
69.570(C6),
49.140(C3),
48.787(C5),
207.498(C=O), 67.608(–OCH2-CH2-), 27.718(–OCH2-
CH2-), 109.757, 114.194, 118.938, 119.101, 127.754,
129.712, 129.820, 130.601, 130.714, 133.110, 143.137(aryl
carbons), 140.979(C2′), 141.820(C6′), 162.618(C2 of ben-
zoxazole moiety), 10.589(CH3).
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-diphenyl-3,5-dime-
thylpiperidin-4-one 36 IR:cm-1(KBr) 2965.2, 2923.3,
2876.4, 2847.4, 2813.3(C-H Stretching), 1697.7(C=O
Stretching). Other characteristic bands are 2354.9, 1596.7,
1485.4, 1433.9, 1375.2, 1349.4, 1260.5, 1195.0, 1088.3,
1041.9, 1022.4, 980.0, 927.3, 882.1, 787.2, 760.7, 691.3,
673.2, 623.0, 554.3, 513.2. Mass: m/z 440(M+), (M.F:
C28H28N2O3), 322, 295, 266, 190, 177, 159, 146, 132, 118,
103(100%), 100, 77, 69, 56, 51. 1H NMR:d 3.62(d,

532
C. Ramalingan et al. / European Journal of Medicinal Chemistry 39 (2004) 527–533
3J=11.66Hz, 2H) H2 and H6, 2.83-2.88(m, 2H) H3 and H5,
2.71(t, J=6.52Hz, 2H) –OCH2-CH2-, 7.29-7.50(m, 14H) aryl
protons, 3.92(t, J=6.50Hz, 2H) –OCH2-CH2-, 0.81(d,
J=6.62Hz, 6H) CH3. 13C NMR:d 76.025(C2,C6), 49.440(C3
and C5), 209.169(C=O), 67.609(–OCH2-CH2-), 27.684(–
OCH2-CH2-), 109.746, 114.257, 118.940, 119.097, 127.854,
129.791, 130.676, 133.107, 143.140(aryl carbons),
141.120(C2′,C6′), 162.620(C2 of benzoxazole moiety),
10.968(CH3).
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-bis(p-chlorophenyl)
piperidin-4-one 37 IR:cm-1(KBr) 2927.1, 2841.7,
2796.2(C-H Stretching), 1704.8 (C=O Stretching). Other
characteristic bands are 1628.7, 1492.2, 1409.3, 1371.3,
1323.4, 1280.8, 1265.3, 1237.7, 1129.1, 1116.9, 1044.5,
1005.3, 954.7, 895.2, 820.8, 740.3, 690.8, 518.1, 490.9,
475.9. Mass:m/z 480(M+), (M.F : C26H22N2O3Cl2), 348,
335, 318, 290, 276, 262, 194, 166, 146, 137, 132, 118, 111,
75, 53(100%), 50. 1H NMR:d 4.07(dd, 3J=12.64Hz; 3.87Hz,
2H) H2 and H6, 2.60-2.86(m, 6H) H3, H5 and –OCH2-CH2-,
7.31-7.58(m, 12H) aryl protons, 3.92(t, J=6.50 Hz; 2H)
–OCH2-CH2-.13C NMR:d 68.470(C2, C6), 48.986(C3, C5),
205.062(C=O), 67.576(–OCH2- CH2-), 27.642 (–OCH2-
CH2-), 109.750, 114.290, 118.984, 119.080, 129.130,
129.963, 133.124, 143.347(aryl carbons), 134.932(C2′′′′ and
C6′′′′), 139.892 (C2′and C6′), 162.614(C2 of benzoxazole
moiety).
J=6.49Hz, 2H) –OCH2-CH2-, 0.80(d, J=6.57Hz, 6H) CH3.
13C NMR:d 75.283(C2,C6), 49.201(C3,C5), 208.176(C=O),
67.628(–OCH2-CH2-), 27.699(–OCH2-CH2-), 109.784,
114.222, 118.943, 119.162, 129.290, 129.820, 133.018,
143.359(aryl
carbons),
134.841(C2′′′′,C6′′′′),
139.130(C2′,C6′), 162.648(C2 of benzoxazole moiety),
10.865(CH3).
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-bis(p-methoxyphe-
nyl)-3,5-dimethylpiperidin-4-one 40. IR:cm-1(KBr) 2926.7,
2853.2, 2786.9(C-H Stretching), 1706.8(C=O Stretching).
Other characteristic bands are 1639.2, 1465.7, 1378.9,
1366.5, 1259.1, 1236.4, 1189.3, 1137.9, 1040.4, 1025.3,
925.0, 856.4, 800.9, 744.7, 652.1, 602.9, 524.3, 510.7. Mass:
m/z 472(M+), (M.F : C28H28N2O5), 354, 327, 310, 282, 268,
254, 194, 162, 147, 145, 132, 118, 107, 75, 65, 55, 53(100%),
50. 1H NMR:d 4.06(dd, 3J=12.65Hz; 3.85Hz, 2H) H2 and H6,
2.59-2.84(m, 6H) H3, H5 and –OCH2-CH2-, 6.90(d, 4H) and
7.34-7.55(m, 8H) aryl protons, 3.92(t, J=6.52Hz, 2H)
–OCH2-CH2-, 3.81(s, 6H) OCH3. 13C NMR:d 68.612(C2,
C6), 49.401(C3, C5), 206.164(C=O), 67.614(–OCH2- CH2-),
27.674(–OCH2-CH2-), 109.785, 114.342, 114.490, 118.974,
119.005, 133.019, 133.148, 143.358(aryl carbons),
158.800(C2′′′′ and C6′′′′), 135.571 (C2′ and C6′), 162.598(C2
of benzoxazole moiety), 55.107(OCH3).
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-bis(p-methoxyphe-
nyl)-3-methylpiperidin-4-one 41 IR:cm-1(KBr) 2937.9,
2837.7(C-H Stretching), 1698.7(C=O Stretching). Other
characteristic bands are 2360.4, 2340.3, 1580.4, 1451.7,
1376.8, 1349.9, 1256.3, 1242.7, 1177.6, 1035.7, 1020.0,
932.6, 890.2, 842.2, 791.7, 656.5, 640.7, 535.1, 450.9.
Mass:m/z 486(M+), (M.F : C29H30N2O5), 354, 341, 324, 299,
254, 192, 176, 162, 148, 145, 133, 118, 107, 75, 69, 65,
53(100%), 50. 1H NMR:d 4.05(dd, 3J=12.99Hz; 3.33Hz, 1H)
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-bis(p-chlorophenyl)
–3-methylpiperidin-4-one 38. IR:cm-1(KBr) 2964.7,
2931.7, 2852.4, 2726.9(C-H Stretching), 1694.9(C=O
Stretching). Other characteristic bands are 2363.3, 1945.0,
1820.1, 1633.2, 1586.1, 1492.1, 1380.2, 1304.4, 1258.3,
1221.9, 1139.2, 1110.7, 1039.5, 1009.9, 948.2, 918.7, 898.1,
866.6, 773.1, 689.7, 633.4, 563.8, 499.9. Mass:m/z 494(M+),
(M.F : C27H24N2O3Cl2), 362, 349, 332, 307, 262, 196, 180,
3
H6, 3.66(d, J=11.67Hz, 1H) H2, 2.59-2.87(m, 5H) H3, H5
1
166, 155, 146, 137, 118, 111, 75, 69, 53(100%), 50. H
and –OCH2-CH2-, 6.89(4H) and 7.27-7.50(m, 8H) aryl pro-
tons, 3.92(t, J=6.52Hz, 2H) –OCH2-CH2-, 3.80(s, 6H)
OCH3, 0.80(d, J=6.58Hz, 3H) CH3. 13C NMR:d 75.169(C2),
68.985(C6), 49.229(C3) 48.892(C5), 207.387(C=O),
67.768 (–OCH2-CH2-), 27.654(–OCH2-CH2-), 109.742,
114.102, 114.648, 114.879, 118.768, 118.980, 132.999,
133.121, 143.380(aryl carbons), 135.132(C2′), 135.847(C6′),
158.569(C2′′′′), 158.940(C6′′′′), 162.504(C2 of benzoxazole
moiety) 55.188(OCH3), 10.598(CH3).
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-bis(p-methoxyphe-
nyl)-3,5-dimethylpiperidin-4-one 42. IR:cm-1(KBr) 2930.4,
2839.2(C-H Stretching), 1698.6(C=O Stretching). Other
characteristic bands are 2351.7, 2337.4, 1580.2, 1504.8,
1344.3, 1301.5, 1257.8, 1234.7, 1076.1, 1040.8, 1033.6,
827.9, 791.4, 660.2, 537.6, 473.1. Mass:m/z 500(M+), (M.F :
C30H32N2O5), 382, 355, 326, 220, 207, 189, 176, 161, 146,
132, 118, 107, 100, 75, 69, 53(100%), 50. 1H NMR:d 3.64(d,
3J=11.69Hz, 2H) H2 and H6, 2.81-2.86(m, 2H) H3 and H5
2.70(t, J=6.50Hz, 2H) –OCH2-CH2-, 6.88(4H) and 7.36-
7.49(m, 8H) aryl protons, 3.92(t, J=6.50Hz, 2H) –OCH2-
CH2-, 3.80(s, 6H) OCH3, 0.81d, J=6.53Hz, 6H) CH3. 13C
NMR:d 75.476(C2,C6), 49.548(C3,C5), 209.399(C=O),
NMR:d 4.06(dd, 3J=13.02Hz; 3.36Hz, 1H) H6, 3.69 (d,
3J=11.64Hz, 1H) H2, 2.61-2.90(m, 5H) H3, H5 and –OCH2-
CH2-, 7.13-7.43(m, 12H) aryl protons, 3.93(t, J=6.50Hz, 2H)
–OCH2-CH2, 0.79(d, J=6.54Hz, 3H) CH3. 13C NMR:d
74.970(C2),
68.842(C6),
48.856(C3)
48.476(C5),
206.211(C=O), 67.614(–OCH2-CH2-), 27.702(–OCH2-
CH2-), 109.768, 114.202, 118.976, 119.154, 129.361,
129.373, 129.883, 130.004, 133.120, 143.354(aryl carbons),
139.094(C2′), 139.953(C6′), 134.753(C2′′′′), 134.920(C6′′′′),
162.627(C2 of benzoxazole moiety), 10.681(CH3).
1-[2-(Benzoxazol-2-yl)ethoxy]-2,6-bis(p-chlorophenyl)
–3,5-dimethylpiperidin-4-one 39 IR:cm-1(KBr) 2957.7,
2929.9, 2844.1, 2796.7(C-H Stretching), 1696.5(C=O
Stretching). Other characteristic bands are 2355.2, 1651.1,
1585.3, 1478.0, 1410.5, 1373.7, 1319.6, 1268.7, 1198.9,
1080.0, 1048.6, 1006.3, 975.3, 883.7, 824.9, 697.4, 645.2,
560.0. Mass:m/z 390(M-118), (M.F: C28H26N2O3Cl2), 363,
334, 224, 211, 193, 180, 165, 152, 146, 132, 118, 111, 100,
91, 75, 53(100%), 50. 1H NMR:d 3.65 (d, 3J=11.66Hz, 2H)
H2 and H6, 2.83-2.89(m, 2H) H3 and H5, 2.71(t, J=6.53Hz,
2H) –OCH2-CH2-, 7.31-7.52(m, 12H) aryl protons, 3.92(t,

C. Ramalingan et al. / European Journal of Medicinal Chemistry 39 (2004) 527–533
533
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143.347(aryl carbons), 158.880(C2′′′′,C6′′′′), 135.127(C2′,C6′),
162.602(C2 of benzoxazole moiety), 55.201(OCH3),
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Acknowledgements
The authors are grateful to Prof. K. Pandiarajan, Head,
Department of Chemistry, Annamalai University for provid-
ing needed facilities. One of the authors SK is grateful to
University Grants Commission, New Delhi for financial sup-
port. SB wishes to thank Council of Scientific & Industrial
Research, New Delhi for the award of Senior Research Fel-
lowship.
[10] C. Ramalingan, S. Balasubramanian, S. Kabilan, M. Vasudevan, Med.
Chem. Res. 12 (2003) 26.
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Chem. Res. 12 (2003) 41.
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(2002) 2402.
[14] S. Balasubramanian, C. Ramalingan, S. Kabilan, Synth. Commun. 33
(2003) 2979.
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