Synthesis, antioxidant and antimicrobial activity of novel vanillin derived piperidin-4-one oxime esters: Preponderant role of the phenyl ester substituents on the piperidin-4-one oxime core

Article abstract of DOI:10.1016/j.bmcl.2012.10.019

The study has been achieved the efficient synthesis of vanillin derived piperidin-4-one oxime esters (5a-m) via four step reaction involved Mannich reaction of vanillin, acetone and ammonium acetate to obtain 2,6-bis(4-hydroxy-3-methoxyphenyl)-piperidin-4-one 2 followed by N-methylation and oximation. Further, to enhance the biological activity of vanillin derived piperidin-4-one oxime core, esterification of 4 with substituted benzoyl chlorides in the presence of strong organic base t-BuOK accomplished a series of vanillin derived piperidin-4-one oxime esters (5a-m). The synthesized analogues are screened for their antioxidant and antimicrobial studies and the preponderant effect of the phenyl ester substituents on the biological activity of piperidin-4-one oxime core was demonstrated. Among the tested compounds, 5i and 5j are emerged as outperformed antioxidants than standard Butylated hydroxy anisole (BHA) whereas, compounds 5b and 5d manifested potent antibacterial and antifungal activity than standard streptomycin and fluconazole respectively.

Full text of DOI:10.1016/j.bmcl.2012.10.019

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7588–7592
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antioxidant and antimicrobial activity of novel vanillin derived
piperidin-4-one oxime esters: Preponderant role of the phenyl ester
substituents on the piperidin-4-one oxime core
Salakatte Thammaiah Harini a, Honnaiah Vijay Kumar b, Javarappa Rangaswamy a, Nagaraja Naik a,
⇑
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, Karnataka, India
b Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2012
Revised 9 September 2012
Accepted 2 October 2012
Available online 11 October 2012
The study has been achieved the efficient synthesis of vanillin derived piperidin-4-one oxime esters (5a–
m) via four step reaction involved Mannich reaction of vanillin, acetone and ammonium acetate to obtain
2,6-bis(4-hydroxy-3-methoxyphenyl)-piperidin-4-one 2 followed by N-methylation and oximation. Fur-
ther, to enhance the biological activity of vanillin derived piperidin-4-one oxime core, esterification of 4
with substituted benzoyl chlorides in the presence of strong organic base t-BuOK accomplished a series of
vanillin derived piperidin-4-one oxime esters (5a–m). The synthesized analogues are screened for their
antioxidant and antimicrobial studies and the preponderant effect of the phenyl ester substituents on the
biological activity of piperidin-4-one oxime core was demonstrated. Among the tested compounds, 5i
and 5j are emerged as outperformed antioxidants than standard Butylated hydroxy anisole (BHA)
whereas, compounds 5b and 5d manifested potent antibacterial and antifungal activity than standard
streptomycin and fluconazole respectively.
Keywords:
Vanillin
Piperidin-4-one oxime
Phenyl esters
Piperidin-4-one oxime ester
Antioxidants
Antimicrobials
Ó 2012 Elsevier Ltd. All rights reserved.
Heterocyclic compounds carrying piperidine skeleton are
attractive targets of organic synthesis owing to their pharmacolog-
ical activity and their wide occurrence in nature. Specifically,
piperidine based chemical entities with aryl substituents at car-
bons 2 and 6 of the piperidine ring have been documented as po-
tent antimicrobial agent.1 Piperidinone derivatives and oxime
analogues (Fig. 1) are found to possess diversified pharmacological
activity and form an essential part of the molecular structures of
some drugs.2–4
Vanillin (4-hydroxy-3-methoxybenzaldehyde) is a widely used
flavor compound in food and cosmetics, with an estimated annual
worldwide consumption of more than 2000 tons.5 Vanillin has
been reported to inhibit mutagenesis induced by chemical and
physical mutagens and to suppress the invasion and migration of
cancer cells.6 It also displays chemopreventive effects in multior-
gan carcinogenesis and hepatocarcinogenesis models in rats.7
Moreover, vanillin displays antimicrobial and antioxidant proper-
ties and is used as a food preservative and for medicinal pur-
poses.8,9 In particular, piperidinone oximes and their derivatives
represent an important class of organic molecules that attract the
interest of both synthetic and medicinal chemists. But it is envis-
aged from the literature that there is scarcity of reports on synthe-
sis and biological importance of piperidin-4-one oxime esters.
Thus, in continuation of our interest in functionalization of tricyclic
and heterocyclic compounds10–12 and in searching of new biologi-
cally active piperidin-4-one analogues, the title compounds vanil-
lin derived piperidin-4-one oxime esters (Fig. 2) was synthesized.
The numerous pharmacological activities of piperidin-4-ones
and piperidin-4-one oxime prompted us to study the antioxidant
and antimicrobial activity of newly synthesized compounds using
various assays.
In the present work, four step synthetic strategies are adapted
for the preparation of vanillin derived piperidin-4-one oxime es-
ters (5a–m). The representation describing the routes of synthesis
is depicted in the Scheme 1. The basic compound 2,6-bis(4-hydro-
xy-3-methoxyphenyl)piperidin-4-one 2 was synthesized by con-
densation reaction (Mannich reaction) of vanillin, acetone and
ammonium acetate in 2:1:1 ratio respectively.13,14 In the next step,
compound 2 on N-methylation upon reflux with iodomethane in
the presence of anhydrous potassium carbonate (K2CO3) as base
in acetone afforded 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-meth-
ylpiperidin-4-one 3 with excellent yield. Further, compound 3 was
converted to corresponding oxime that is, 2,6-bis(4-hydroxy-3-
methoxyphenyl)-1-methylpiperidin-4-one oxime
4 by treating
⇑
Corresponding author. Tel.: +91 9482959088.
with hydroxylamine hydrochloride (NH2OHꢀHCl) in the presence
of sodium acetate trihydrate in absolute alcohol. In the present
investigation, esterification of oxime 4 was done by using t-BuOK
E-mail addresses: st.harini988@gmail.com (S.T. Harini), vijaycftri@gmail.com
(H.V. Kumar), rangaswamyteertha@gmail.com (J. Rangaswamy), drnaikchem@
gmail.com (N. Naik).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.019

S. T. Harini et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7588–7592
7589
Cl
O
O
F
COOH
F
COOH
Cl
O
Cl
N
Z
N
R
N
N
N
HN
N
O
N
Cl
H3C
CH3
N
Norfloxacin : R = ethyl; Z = H
Ofloxacin
Oxiconazole
loxacin
: R = cyclopropyl; Z =H
Enoxacine : R = ethyl; Z = N
Figure 1. Structures of piperidinone and oxime derived pharmacologically active drugs.
as base proceeded with fair yields irrespective of substituted ben-
zoyl chlorides used (Table 1). Very recently, the conversion of
oxime into oxime esters by using triethylamine (Et3N) as base
has been reported.15 The present communication represented an
efficient and a mild variant potassium tertiarybutoxide (t-BuOK)
assisted convenient procedure for the preparation of vanillin de-
rived piperidin-4-one oxime esters (5a–m). The structure of com-
pounds was elucidated by elemental analysis, IR, NMR (1H, 13C)
and mass spectral studies.
In order to study the vital role of the phenyl ester substituents
possessing diversified functional groups at different position on the
piperidin-4-one oxime core towards antioxidant and antimicrobial
potential, all the synthesized analogues (5a–m) were subjected to
in vitro antioxidant and antimicrobial assays. Evaluation of antiox-
idant activity for the newly synthesized analogues was undertaken
by using three in vitro assays such as 2,20-diphenyl-1-picryl-hydra-
zyl (DPPH) radical scavenging activity, 2,20-azino-bis(3-ethylbenz-
thiazoline-6-sulfonic acid) (ABTSÅ+) radical scavenging activity and
inhibition of microsomal lipid peroxidation (LPO).
piperidin-4-one oxime esters endowed notable improvement in
radical scavenging activity. Nearly, all the tested compounds (5a–
m) exhibited positive efficacy for scavenging DPPH free radical.
Among the synthesized molecules and the positive control BHA,
the top two for scavenging radicals are compounds 5i and 5j hav-
ing additional pair of hydroxyl groups on the aryl ester moiety.
Generally, the more number of hydroxyl substituents on the phe-
nyl moiety, more the antioxidant properties.17 The next promising
antioxidant activity was showed by compounds (5f–h) having one
hydroxyl group at different position on aryl ester moiety. The
incorporation of –OCH3 groups on the phenyl ring at different po-
sition in the compounds (5k–m) demonstrated slight increase in
the radical scavenging capabilities. This may be due to the pres-
ence of electron donating –OCH3 groups.18 The introduction of
groups like F, Br, Cl and NO2 on the phenyl ring at C-4 position
demonstrated no affects for the enhancement of radical scavenging
capacity. The reason might be the electron withdrawing capabili-
ties of these groups.19
The synthesized piperidin-4-one oxime esters having different
The synthesized molecules (5a–m) can quench DPPH free radi-
cals (i.e., by providing hydrogen atoms or by electron donation,
conceivably via a free-radical attack on the DPPH molecule) and
convert them to a colorless/bleached product (i.e., 2,20-diphenyl-
1-picryl-hydrazine, or a substituted analogous hydrazine), result-
ing in a decrease in absorbance at 517 nm. Hence, the more rapidly
the absorbance decreases, the more potent the radical scavenging
concentrations (10, 25, 50, 100, 200, 500 lM) were subjected to
ABTSÅ+ radical scavenging activity.20 ABTS radical scavenging assay
is a facile and elegant method to exploit antioxidant activity of the
array of newly synthesized compounds. The technique is based on
direct production of the blue/green ABTSÅ+ chromophore through
the reaction between ABTS and potassium persulfate. The findings
of present study (Table 2) indicated that the majority of oxime es-
ters exhibited moderate to high radical scavenging ability. The
incorporation of these two substituted benzoyl chlorides (3,5 dihy-
droxy and 3,4,5 trihydroxy) to oxime core 4 led to compound 5i
and 5j respectively, has showed twelve to fifteen fold more activity
compared to piperidin-4-one oxime core 4 and these are outper-
formed antioxidants among the tested molecules. Introduction of
electron withdrawing groups such as F, Br, Cl, NO2 in compounds
(5b–e) was inadequate to show enhanced activity. Whereas, the
compounds (5f–h) having single electron releasing hydroxyl group
at ortho, meta and para position of phenyl ester exhibited nine to
10-fold more radical scavenging capacity than 4. Electron donating
methoxy group holding compounds (5k–m) exhibited antioxidant
activity slightly lesser than compounds (5f–h). Analogue 5a which
does not have any substituent on the phenyl ring showed least
activity compared to other analogues.
activity of the compound.16 50% inhibitory concentrations (IC50
)
were calculated and are depicted in Table 2. Initially, vanillin de-
rived piperidin-4-one oxime core 4 exhibited considerable activity.
The reason would be the presence of electron releasing hydroxyl
and electron donating methoxy groups on phenyl moiety on either
side of the piperidin-4-one oxime skeleton. Further, inclusion of
substituted benzoyl chlorides to 4 results the vanillin derived
HO
OCH3
O
R
O
N
Me
N
In LPO assay, the abilities of the array of compounds to scavenge
free radicals was further confirmed by inhibition of microsomal li-
pid peroxidation indices in a liposome model system. LPO has been
broadly defined as the oxidative deterioration of polyunsaturated
lipids.21 IC50 values of LPO inhibition for the newly synthesized
analogues are depicted in Table 2 and reflects whole of the tested
compounds exhibited certain degree of antioxidant activity. The
compounds (5f–h) possessing single hydroxyl group at different
position on the phenyl ester moiety exhibits good activity whereas,
HO
OCH3
R = phenyl substituents
Figure 2. General structure of vanillin derived piperidin-4-one oxime esters.

7590
S. T. Harini et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7588–7592
O
+
H3C
CH3
O
H
H
H3CO
HO
OCH3
OH
absolute EtOH, HCl
30 °C
H3CO
HO
OCH3
OH
N
H
O
O
NH4OAc
(2)
(1)
(1)
MeI, K2CO3, Me2CO
reflux, 4 h
HO
H3CO
OH
O
N
Me
N
OCH3
H3CO
HO
OCH3
NH2OH.HCl, EtOH
NaOAc.3H2O, reflux, 2 h
Me
OH
N
OH
(3)
(4)
RCOCl, t-BuOK
DMF, rt, 1 h
HO
OCH3
O
R
O
Me
N
N
HO
OCH3
(5a-m)
Scheme 1. Reaction protocol for the synthesis of vanillin derived piperidin-4-one oxime esters (5a–m).
compounds 5i and 5j holding two and three hydroxyl groups on
the phenyl ester skeleton dominantly inhibits the lipid peroxida-
tion compared to all analogues and standard BHA as well. Electron
releasing methoxy group substituted compounds (5k–m) were the
next most effective LPO inhibitors followed by rest of compounds
(5b–e) and 5a.
The antimicrobial activity of newly synthesized compounds
(5a–m) was determined by well plate method.22,23 The potentiality
of the synthesized compounds as antimicrobials was appraised for
their antibacterial studies against different strains of human
pathogens namely Escherichia coli ATCC 25922, Staphylococcus
aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853. Anti-
fungal studies against human pathogen fungal strains such as
Aspergillus flavus MTCC 3306, Candida albicans MTCC 3017 and
Chrysosporium keratinophilum MTCC 2827.
at concentration of 1000 and 500 lg/mL. The reason would be
more lipophilic nature of piperidin-4-one moiety2 along with the
presence of electronegative groups like halogens.
The results of antibacterial activities (Table 3) revealed that the
majority of the synthesized compounds showed varying degree of
inhibition against tested micro organisms. Compounds 5b and 5d
possessing fluoro and chloro group at para position in phenyl moi-
ety exhibited almost equipotent efficacy compared to standard
drug streptomycin against P. aeruginosa and E. coli. Compound 5c
possessing bromo group exhibited slightly less antibacterial activ-
ity than standard followed by 5e having electron withdrawing ni-
tro group. Compounds bearing hydroxyl groups such as (5f–j) were
demonstrated moderate activity against three tested bacterial
strains. Introduction of methoxy groups in compounds (5k–m)
were inadequate to show moderate antibacterial activity. The com-
pound 5a having no substitution on aryl ester moiety exhibited
least antibacterial activity.
The results obtained as zone of inhibition (mm) are presented in
Table 3 and Table 4, respectively. It is more attractive to speculate
the observation that the result of the antimicrobial activity of the
different derivatives of oxime esters appeared to be related to
the nature of substituents on the phenyl unit. Among the deriva-
tives, compounds (5b–d) showed enhanced antimicrobial activity
The investigation of antifungal activity (Table 4) reveals that
compound 5b possessing most electronegative fluoro group in para
position of phenyl ester moiety emerged as active antifungal agent
against A. flavus compared with standard fluconazole. Replacement

S. T. Harini et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7588–7592
7591
Table 1
Chemical structures and yields of vanillin derived piperidin-4-one oxime esters (5a–m)
Compounds
Entry R
Yield (%)
Compounds
Entry R
Yield (%)
5a
88.00
5h
75.02
71.65
84.20
80.45
OH
HO
5b
5c
5d
77.00
78.30
77.00
5i
OH
OH
F
5j
HO
OH
Br
5k
OCH3
OCH3
Cl
OCH3
5e
85.00
5l
76.78
79.20
NO2
OH
OH
5f
79.32
76.21
5m
H3CO
OCH3
OCH3
5g
Table 2
Concentration required for 50% inhibition (IC50) of DPPHÅ, LPOÅ and ABTSÅ+ radicals by
Thus, the most remarkable result of these antioxidant and anti-
microbial assays is the critical influence of the phenyl ester substit-
uents on the vanillin derived piperidin-4-one oxime core.
In conclusion, we have achieved a convenient protocol for the
synthesis of vanillin derived piperidin-4-one oxime esters (5a–
m) through the pathway involved Mannich reaction of vanillin,
acetone and ammonium acetate to obtain 2,6-bis(4-hydroxy-3-
methoxyphenyl)-piperidin-4-one 2 followed by N-methylation
and oximation. In order to improve the pharmacological activity
of piperidin-4-one oxime core, esterification of 2,6-bis(4-hydro-
the compounds (5a–m) and the standard antioxidant compound BHA
Tested compounds
Scavenging activitya (IC50
LPO
)
DPPHÅ
ABTSÅ+
4
144 0.18
141 0.12
133 0.81
103 0.31
110 0.23
76 0.42
167 0.56
165 0.21
140 0.54
112 0.12
121 0.45
82 0.55
158 0.12
156 0.33
141 0.32
108 0.51
112 0.63
79 0.91
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
BHA
14.8 0.65
15.6 0.22
14.2 0.41
10.8 0.71
10 0.23
24.1 0.61
25.3 0.81
22.5 0.26
17.2 0.41
16.1 0.22
40 0.57
15.9 0.30
16.5 0.47
15.1 0.25
12.3 0.50
11.8 0.64
33 0.14
xy-3-methoxyphenyl)-1-methylpiperidin-4-one oxime
4
with
substituted benzoyl chlorides was successfully done by employing
a t-BuOK assisted reaction. The synthesized molecules were as-
sessed for their antioxidant and antimicrobial capacities. It is note-
worthy that compounds 5i and 5j possessed dominant antioxidant
capacity than standard because of having highest phenolic content.
The antimicrobial study was undertaken to evaluate their inhibi-
tory activities on the growth of pathogenic bacteria and fungi.
Presence of electron withdrawing substituent particularly fluoro
and chloro group at para position of aryl ester in compounds 5b
and 5d found to be essential for potent antimicrobial. Overall,
the biological tests revealed the determinant influence of the phe-
nyl ester substituents on the antioxidant and antimicrobial activity
of vanillin derived piperidin-4-one oxime core. Our results prompt
that, further studies on these compounds may be operating as a
positive reinforce for the construction of novel chemical entities
with better pharmacological profiles.
28 0.33
32 0.12
52 0.71
41 0.17
40 0.91
61 0.22
53 0.51
12 0.21
18.5 0.11
13 0.42
Each value represents mean SD (n = 3).
a
The values are expressed as
lM concentration. Lower IC50 values indicate
higher radical scavenging activity.
of fluoro group by chloro led to compound 5d was the next effec-
tive antifungal agent. Compounds 5c and 5e bearing Br, NO2 groups
exhibited moderate growth inhibitory activities. The rest of the
compounds showed weak to moderate antifungal activity against
all the tested fungal strains.

7592
S. T. Harini et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7588–7592
Table 3
Inhibitory zone (diameter) mm of the synthesized compounds (5a–m) against tested bacterial strains by well plate method
Compound no.
Escherichia coli
Staphylococcus aureus
Pseudomonas aeroginosa
Concentration (lg/mL)
1000
500
1000
500
1000
500
00 0.02
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
01 0.01
03 0.02
18 0.03
11 0.01
17 0.02
08 0.02
06 0.01
07 0.01
05 0.02
04 0.01
07 0.02
03 0.01
06 0.02
05 0.02
18 0.01
00 0.02
02 0.01
13 0.02
07 0.01
12 0.01
04 0.01
04 0.01
06 0.02
04 0.02
05 0.01
05 0.01
02 0.02
04 0.02
04 0.01
12 0.01
01 0.02
04 0.02
15 0.01
09 0.02
13 0.01
08 0.01
05 0.02
07 0.01
06 0.02
05 0.01
06 0.02
04 0.01
05 0.01
06 0.02
15 0.02
00 0.03
03 0.01
13 0.02
07 0.01
09 0.01
05 0.01
05 0.02
05 0.01
04 0.02
05 0.01
04 0.02
02 0.01
03 0.01
04 0.02
12 0.01
01 0.01
02 0.01
16 0.02
09 0.01
15 0.01
08 0.01
04 0.02
05 0.01
03 0.02
05 0.01
04 0.02
04 0.01
06 0.01
05 0.02
16 0.01
01 0.01
13 0.02
07 0.01
012 0.02
05 0.02
03 0.02
03 0.01
02 0.02
04 0.01
03 0.01
03 0.02
06 0.02
03 0.01
13 0.02
Streptomycin (standard)
Table 4
Inhibitory zone (diameter) mm of the synthesized compounds (5a–m) against tested fungal strains by well plate method
Compound no.
Aspergillus flavus
Chrysosporium keratinophilum
Candida albicans
Concentration (lg/mL)
1000
500
1000
500
1000
500
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
01 0.03
02 0.02
17 0.03
06 0.01
15 0.02
04 0.02
04 0.01
02 0.01
01 0.02
02 0.01
04 0.02
06 0.01
05 0.02
03 0.02
14 0.01
00 0.03
01 0.01
13 0.02
05 0.01
12 0.01
03 0.01
03 0.01
01 0.02
12 0.02
01 0.01
02 0.01
05 0.02
04 0.02
04 0.01
12 0.02
01 0.02
03 0.02
12 0.01
07 0.02
10 0.01
05 0.01
06 0.02
02 0.01
03 0.02
01 0.01
04 0.02
04 0.01
05 0.01
06 0.02
17 0.02
01 0.01
02 0.01
14 0.02
05 0.01
12 0.01
04 0.01
04 0.02
01 0.01
02 0.02
02 0.01
03 0.02
04 0.01
04 0.01
03 0.02
16 0.01
01 0.01
03 0.01
20 0.02
09 0.01
19 0.01
06 0.01
06 0.02
03 0.01
02 0.02
03 0.01
08 0.02
07 0.01
06 0.01
03 0.02
22 0.02
00 0.01
02 0.01
18 0.02
08 0.01
16 0.02
07 0.02
02 0.02
01 0.01
02 0.02
03 0.01
06 0.01
05 0.02
04 0.02
03 0.01
20 0.02
Fluconazole (standard)
5. Walton, N. J.; Mayer, M. J.; Narba, A. Phytochemistry 2003, 63, 505.
6. Lirdprapamongkol, K.; Sakurai, H.; Kawasaki, N.; Choo, M. K.; Saitoh, Y.;
Aozuka, Y.; Singhirunnusorn, P.; Ruchirawat, S.; Svasti, J.; Saiki, I. Eur. J. Pharm.
Sci. 2005, 25, 57.
All the antioxidant assays were carried out in triplicate for 3
separate experiments. The amount of compound needed to inhibit
DPPH, ABTS+Å and LPO radical by 50% inhibitory concentration
7. Akagi, K.; Hirose, M.; Hoshiya, T.; Mizoguchi, Y.; Ito, N.; Shirai, T. Cancer Lett.
1995, 94, 113.
8. Fitzgerald, D. J.; Stratford, M.; Gasson, M. J.; Ueckert, J.; Bos, A.; Narbad, A. J.
Appl. Microbiol. 2004, 97, 104.
9. SantoshKumar, S. S.; Priyadarsini, K. I.; Sainis, K. B. J. Agric. Food Chem. 2004, 52,
139.
(IC50
algorithm.
) was graphically estimated using a linear regression
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10. Kumar, H. V.; Naik, N. Eur. J. Med. Chem. 2010, 45, 2.
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12. Naik, N.; Kumar, H. V.; Harini, S. T. Eur. J. Chem. 2011, 2, 337.
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15. Bindu, P. J.; Mahadevan, K. M.; Satyanarayan, N. D.; Ravikumar Naik, T. R.
Bioorg. Med. Chem. Lett. 2012, 22, 898.
The authors are thankful to NMR Research Center, Indian Insti-
tute of Science, Bangalore for providing spectral data.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
10.019.
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