Stereochemical effect on biological activities of new series of piperidin-4-one derivatives

Article abstract of DOI:10.1080/14786419.2015.1009456

New series of (2S,3R,4S,6R)-3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol were synthesised by the reduction of cis-3-alkyl-2,6-diarylpiperidin-4-one using Grignard reagent. The structural assignments and conformational studies of the synthesised compounds wer

Full text of DOI:10.1080/14786419.2015.1009456

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Stereochemical effect on biological
activities of new series of piperidin-4-
one derivatives
Periyasamy Venkatesana & Thiyagarajan Maruthavananb
a Department of Chemistry, Mahendra Institute of Technology,
Namakkal637 503, India
b Department of Chemistry, Sona College of Technology, Salem636
005, India
Published online: 12 Feb 2015.
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To cite this article: Periyasamy Venkatesan & Thiyagarajan Maruthavanan (2015): Stereochemical
effect on biological activities of new series of piperidin-4-one derivatives, Natural Product
Research: Formerly Natural Product Letters, DOI: 10.1080/14786419.2015.1009456
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Natural Product Research, 2015
http://dx.doi.org/10.1080/14786419.2015.1009456
Stereochemical effect on biological activities of new series of piperidin-4-
one derivatives
Periyasamy Venkatesana* and Thiyagarajan Maruthavananb
b
aDepartment of Chemistry, Mahendra Institute of Technology, Namakkal 637 503, India; Department of
Chemistry, Sona College of Technology, Salem 636 005, India
(Received 13 November 2014; final version received 15 January 2015)
New series of (2S,3R,4S,6R)-3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol were syn-
thesised by the reduction of cis-3-alkyl-2,6-diarylpiperidin-4-one using Grignard
reagent. The structural assignments and conformational studies of the synthesised
compounds were established based on the IR, 1H NMR, 13C NMR, NOESY and mass
spectral studies. Their stereochemical effect on antibacterial, antifungal and
anthelmintic activities was studied.
Keywords: piperidin-4-one; Grignard reagent; mannich reaction; stereochemical
effect; biological activity
1. Introduction
Piperidine derivatives are the versatile building blocks in many naturally occurring alkaloids and
intermediate for the synthesis of bioactive molecules including thiazolidones, oxirane, thiazine
(Flick & Padwa 2013; Senguttuvan et al. 2013). The compound containing piperidine scaffold
acts as pharmaceutical agents like antihypertensive, antibacterial, antimalarial, anticonvulsant,
antifungal, antituberculosis, antipyretic and antiinflammatory agents (Pulgar & Harp 2014).
In the present investigation, a new series of piperidin-4-one derivatives were synthesised in
continuation of our earlier work (Maruthavanan & Venkatesan 2013) in order to find out their
stereochemical effect on in vitro antibacterial, in vitro antifungal and in vitro anthelmintic
activities.
2. Results and discussion
2.1. Chemistry
The parent compounds, cis-2,6-diarylpiperidin-4-one (1–5) were synthesised by Mannich
reaction (Noller & Baliah 1948; Maruthavanan & Venkatesan 2013). The reduction of parent
*Corresponding author. Email: venkatesanps@yahoo.co.in
q 2015 Taylor & Francis

2
P. Venkatesan and T. Maruthavanan
compounds with suitable Grignard reagents yielded a new series of 3-methyl-4-alkyl-2,6-
diarylpiperidin-4-ol (6–15) as shown in Scheme 1. The products were subjected to column
chromatography with benzene–chloroform (3:1) eluent.
The cis-3-alkyl-2,6-diarylpiperidin-4-ones (1–5) showed ZCvO (str) absorption band at
1700–1710 cm21 for the confirmation of keto group at C(4) position. However, it was not found
when the reduction of parent compound to corresponding tertiary alcohol. In addition, a new
broad absorption band around 3391–3593 cm21 is observed due to the formation of ZOH group,
which was broadened while diluting the sample solution. This clearly indicates that the keto
group of parent compounds (1–5) were reduced to tertiary alcohol at C(4) of targeted
compounds (6–15).
The 1H NMR spectra reveal that the aromatic protons of 3-methyl-4-alkyl-2,6-
diarylpiperidin-4-ol (6–15) resonated around 7 ppm. The H(2) proton of the synthesised
compounds was appeared as doublet at 3.58–4.03 ppm. The doublet of doublet around 4.04–
4.36 ppm was assigned to H(6) proton. The H(5) protons resonated around 1.58–2.74 ppm and
the multiplets in the region around 1.55–2.68 ppm were observed for H(3) in 3-methyl-4-alkyl-
2,6-diarylpiperidin-4-ol (6–15).
The alkyl substituent and methoxy substituent resonated around 0.65–1.64 ppm and 3.82–
3.87 ppm respectively. The proton corresponding to ZNH group and ZOH group appeared as
broad singlet around 1.47–2.19 ppm. However, the coupling constant value plays vital role in
conformational analysis. Based on the coupling constant value, the large coupling constant about
10.30–13.5 Hz and the small coupling constant about 2–4 Hz were observed for C(5)ZC(6)
bond. The coupling constant about 10.0 Hz was measured for C(2)ZC(3) bond. Thus, it reveals
that the 3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol (6–15) exist in normal chair conformation
with equatorial orientations of aryl rings at C(2) and C(6), and the equatorial orientations of
methyl group at C(3).
From the 13C NMR spectra, the aromatic carbons were easily distinguished by their
characteristic absorption that appeared around 120 ppm. The ipso carbons were absorbed at
higher frequency in the order of 140 ppm compared with other aromatic carbons. For all the 3-
methyl-4-alkyl-2,6-diarylpiperidin-4-ol (6–15), the upfield signals in the region 10–20 ppm
were assigned to methyl carbons at C(3). In all the compounds, the C(4) was readily
distinguished from other heterocyclic ring carbons by their characteristic downfield absorption
around 70 ppm and also by their low intensities due to quaternary carbon. Among the benzylic
carbons (C(2) and C(6)) resonated around 60 ppm and the one that occurred at higher frequency
was assigned to C(2). Among the remaining signals around 45–50 ppm which were due to C(3)
and C(5) the high frequency signal was assigned to C(3). In addition, the mass spectra reveal that
the observed molecular ion peak was in good agreement with the calculated mass. It was further
confirmed by elemental analysis. Thus, the purity of compounds was confirmed by the data
obtained from elemental analysis and mass spectra.
The NOESY correlation data reveal that a strong NOE exists between hydroxyl protons
(1.81 ppm) and benzylic protons at C(2) (resonated at 3.86 ppm) and C(6) (resonated at
O
O
HO R'
O
CH3
R
1. EtOH
2. HCl/NH3
2
R
CH3
R
+
R'MgBr
Dry ether
H
N
H
(1-5)
R
N
H
NH4OAc
R
(6-15)
6–10: R'=CH3CH2–; 11–15: R'=(CH3)2CH–; 1,6,11: R=C6H5–; 2,7,12: R=furfuryl;
3,8,13: R=p–Cl(C6H4)–; 4,9,14: R=p–OCH3(C6H4)–; 5,10,15: R=p–CH3(C6H4)–
Scheme 1. Synthesis of 3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol (6–15).

Natural Product Research
3
4.24 ppm). In addition, there was no correlation observed between benzylic proton and ethyl
substituent at C(4). Hence, it clearly confirms that the hydroxyl group exists in axial position and
ethyl group at equatorial position at C(4).
The strong correlation between methyl group at C(3) and axial proton of C(2) is possible
only when the methyl group at C(3) occupies the equatorial position. In case the methyl
substituent occupies the axial position, no correlation exists between them. So, it confirms that
the substituent at C(3) can exist in equatorial orientation. It is further supported by the
observation of weak correlation between methyl group at C(3) and the hydroxyl group. In
addition, the equatorial hydrogen of C(5) has only one weak correlation with axial proton of C
(6). Thus, the NOE correlation confirms that the structure of compound 6 is (2S,3R,4S,6R)-3-
methyl-4-ethyl-2,6-diphenylpiperidin-4-ol. The similar NOE correlation was observed for
compound 11. Akin to the representative compound 6, we can assign similar orientation for rest
of the synthesized compounds 7–15.
2.2. Pharmacology
The results of in vitro antibacterial and in vitro antifungal activities were given in Tables 1 and 2
respectively. Most of the compounds showed significant antibacterial and antifungal activity
against panel of the tested species.
Among the three possible conformations of the isopropyl group at C(4) as shown in Figure 1
(a)–(c), the methyl group of the isopropyl substituent lies gauche with respect to both the C(3)
and C(5) in conformations (a) and (c), and it is less in conformation (b). However, the
conformation (b) and (c) showed gauche-gauche (syn) interaction, which causes more steric
interaction and makes the molecule less stable as given in Figure 1(d). Thus, conformation (b)
and (c) is ruled out. Even though conformation (a) has severe gauche interaction it becomes the
most favourable for compounds 11–15. It is further confirmed by the observation of the NOESY
correlation between an OH group and a methyl group of isopropyl substituent at C(4) and that of
a C(3) alkyl substituent. Hence, both the antibacterial and antifungal activities was decreased in
(2S,3R,4R,6R)-3-methyl-4-(propan-2-yl)-2,6-diarylpiperidin-4-ol (11–15) due to the steric
crowd of hydroxyl group.
The p-chloro substituent on the phenyl ring in (2S,3R,4S,6R)-3-methyl-4-ethyl-2,6-di-(4-
chlorophenyl)piperidin-4-ol (8) and (2S,3R,4R,6R)-3-methyl-4-(propan-2-yl)-2,6-di-(4-chloro-
phenyl) piperidin-4-ol (13) showed less antibacterial activity than their representative
Table 1. In vitro antibacterial activity of compounds 6–15.
Diameter of zone inhibition in mMa
Compounds
B. subtilis
S. aureus
E. coli
S. typhi
6
7
8
9
10
11
12
13
14
14 ^ 0.9 (6.25)
16 ^ 0.8 (12.5)
12 ^ 0.6 (25)
15 ^ 0.8 (50)
–
13 ^ 0.8 (25)
15 ^ 1.1 (6.25)
–
16 ^ 1.1 (12.5)
18 ^ 0.6 (25)
–
15 ^ 1.4 (6.25)
–
–
16 ^ 0.6 (12.5)
–
14 ^ 0.9 (12.5)
15 ^ 0.7 (12.5)
,10 (100)
16 ^ 0.7 (6.25)
14 ^ 0.9 (12.5)
–
14 ^ 0.7 (6.25)
,10 (100)
16 ^ 0.8 (25)
13 ^ 0.5 (6.25)
22–28 (6.25)
–
13 ^ 0.7 (12.5)
14 ^ 0.6 (6.25)
13 ^ 0.6 (25)
18 ^ 0.6 (50)
–
–
–
13 ^ 0.9 (12.5)
–
20–23 (6.25)
–
15 ^ 0.6 (12.5)
–
19–21 (6.25)
15
Ciprofloxacin
–
21–26 (6.25)
a In bracket, MIC value is given in mg/mL.

4
P. Venkatesan and T. Maruthavanan
Table 2. In vitro antifungal activity of compounds 6–15.
Diameter of zone inhibition in mMa
Compounds
A. flavus
A. niger
P. chrysogenum
F. moneliforme
14 ^ 1.1 (12.5)
6
7
8
9
10
11
12
13
14
17 ^ 1.1 (6.25)
18 ^ 0.6 (12.5)
14 ^ 0.9 (25)
15 ^ 1.1 (12.5)
17 ^ 0.8 (6.25)
–
16 ^ 0.8 (12.5)
–
14 ^ 0.6 (25)
16 ^ 0.8 (12.5)
20–24 (6.25)
16 ^ 0.6 (25)
17 ^ 1.2 (12.5)
15 ^ 0.7 (50)
14 ^ 0.9 (12.5)
19 ^ 0.8 (6.25)
14 ^ 1.1 (12.5)
16 ^ 0.8 (25)
–
16 ^ 0.8 (12.5)
16 ^ 0.7 (12.5)
,10 (100)
16 ^ 0.8 (50)
19 ^ 1.1 (12.5)
–
14 ^ 0.9 (25)
,10 (100)
13 ^ 0.6 (12.5)
14 ^ 0.9 (12.5)
19–21 (6.25)
16 ^ 0.9 (6.25)
15 ^ 1.0 (25)
14 ^ 0.6 (12.5)
18 ^ 0.8 (6.25)
13 ^ 0.6 (25)
16 ^ 0.8 (12.5)
–
16 ^ 0.8 (25)
16 ^ 0.7 (50)
19–22 (6.25)
–
15
Fluconazole
15 ^ 0.7 (6.25)
19–21 (6.25)
a In bracket, MIC value is given in mg/mL.
compounds 6 and 11 respectively. In addition, the replacement of phenyl ring with furfuryl ring
enhances both the antibacterial and antifungal activity. This is due to the fact that the alkyl group
at C(3) experience severe gauche interaction with aryl group at C(2). In order to avoid it, the ring
3
was flattened about the C(2)ZC(3) bond. Thus, the lowering of the magnitude of J2a,3a is
observed and hence, the variation in antimicrobial activity was observed.
Among the synthesized compounds, (2S,3R,4S,6R)-3-methyl-4-ethyl-2,6-di(furan-2-yl)-
piperidin-4-ol (7) showed excellent antibacterial activity for S. aureus with zone of inhibition up
to 19 mM at the concentration of 25 mg/mL and also sensitive to all the tested bacterial species.
In addition, (2S,3R,4S,6R)-3-methyl-4-ethyl-2,6-di(furan-2-yl)piperidin-4-ol (7) showed
good antifungal activity against all the tested fungi species. It showed good inhibition growth at
18 mm with concentration of 12.5 mg/mL against A. flavus. Even though its concentration was
reduced to 6.25 mg/mL, it showed good antifungal activity against F. moniliforme. Interestingly,
the synthesized compounds 6–15 showed good antibacterial activity against gram positive
pathogenic bacteria (B. subtilis and S. aureus).
The in vitro anthelmintic activity of compounds 6–10 was given in Table 3. While
introducing p-chloro substituent on phenyl ring, the anthelmintic activity is enhanced for the
compound, (2S,3R,4S,6R)-3-methyl-4-ethyl-2,6-diphenylpiperidin-4-ol (6) with mean death
time 21, 25 and 21 min against Megascoplex konkanensis, Pontoscotex corethruses and Eudrilus
eugeniea respectively. Similar effect was observed while replacing 4-ethyl substituent with 4-
isopropyl substituent. However, if C(3) position was substituted with ethyl group instead of
methyl group, the anthelmintic activity was drastically decreased. From the above observation, it
is clear that the existence of methyl substituent at C(3) position is the pharmacophore for
showing anthelmintic activity.
(a)
(b)
H3C
(c)
H3C
(d)
C6
OH
OH
H
OH
C2
H
CH3
N
CH3
H
H
alkyl
alkyl
alkyl
He
C4
CH3
He
He
C5
H3C
H3C
C5
C3
C5
C3
Ha
C5
Ha
C3
C3
Ha CH3Ha
Ha CH3 Ha
H
Figure 1. (a–c) Possible conformation of isopropyl group at C(4) of compounds 11–15. (d) Gauche–
Gauche (syn) steric interaction at C(3)–C(4) of compounds 11–15.

Natural Product Research
E. eugeniea
5
Table 3. In vitro anthelmintic activity of compounds 6–15.
M. konkanensis P. corethruses
Compounds
MPTa
MDTa
MPTa
MDTa
MPTa
MDTa
6
7
8
9
10
11
12
13
14
11 ^ 0.21
14 ^ 0.52
11 ^ 0.44
14 ^ 0.31
12 ^ 0.28
10 ^ 0.26
16 ^ 0.52
12 ^ 0.44
13 ^ 0.41
14 ^ 0.47
13 ^ 0.22
16 ^ 0.45
22 ^ 0.39
21 ^ 0.48
26 ^ 0.52
21 ^ 0.47
18 ^ 0.51
25 ^ 0.41
24 ^ 0.55
26 ^ 0.33
21 ^ 0.34
23 ^ 0.16
18 ^ 0.34
16 ^ 0.41
16 ^ 0.38
18 ^ 0.21
16 ^ 0.62
16 ^ 0.24
17 ^ 0.28
17 ^ 0.34
17 ^ 0.45
15 ^ 0.28
17 ^ 0.38
22 ^ 0.52
26 ^ 0.55
25 ^ 0.46
29 ^ 0.52
24 ^ 0.39
22 ^ 0.45
28 ^ 0.41
26 ^ 0.37
25 ^ 0.28
24 ^ 0.52
28 ^ 0.42
15 ^ 0.44
11 ^ 0.48
13 ^ 0.52
15 ^ 0.47
11 ^ 0.21
14 ^ 0.34
14 ^ 0.33
11 ^ 0.32
15 ^ 0.52
13 ^ 0.44
13 ^ 0.28
21 ^ 0.41
20 ^ 0.38
21 ^ 0.41
26 ^ 0.40
21 ^ 0.52
19 ^ 0.54
28 ^ 0.29
21 ^ 0.28
25 ^ 0.34
22 ^ 0.43
23 ^ 0.44
15
Mendazole
a Time in minutes.
In addition, the activity is decreased while introducing p-methoxy substituent on phenyl ring
or replacing with furfuryl ring. However, the anthelmintic activity is enhanced while introducing
p-methyl substituent. The (2S,3R,4S,6R)-3-methyl-4-ethyl-2,6-diphenylpiperidin-4-ol (6) and
(2S,3R,4S,6R)-3-methyl-4-(propan-2-yl)-2,6-diphenylpiperidin-4-ol (11) showed excellent
anthelmintic activity against M. konkanensis.
3. Conclusion
The NOESY experiments and other spectral studies confirm that the new series of synthesized
compounds, (2S,3R,4S,6R)- 3-methyl-4-alkyl-2,6-diarylpiperidin-4-ol (6–15) exist in the chair
conformation and all the substituents oriented in equatorial position. The substituent on the
phenyl ring at C(2) and C(6), and C(4) substituents significantly influenced the biological
activities.
Supplementary material
Experimental details relating to this paper are available online.
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