A facile synthesis, antibacterial, and antitubercular studies of some piperidin-4-one and tetrahydropyridine derivatives

Article abstract of DOI:10.1016/j.bmcl.2008.10.045

The raise in clinical significance of multidrug-resistant bacterial pathogens has directed us to synthesize 2,6-diarylpiperidin-4-one and Δ³-tetrahydropyridin-4-ol based benzimidazole and O-arylsulfonyl derivatives. X-ray crystal structure of t

Full text of DOI:10.1016/j.bmcl.2008.10.045

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6542–6548
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A facile synthesis, antibacterial, and antitubercular studies
of some piperidin-4-one and tetrahydropyridine derivatives
Gopalakrishnan Aridoss a, Shanmugasundaram Amirthaganesan a, Nanjundan Ashok Kumar a,
Jong Tae Kim a, Kwon Taek Lim a, Senthamaraikannan Kabilan b, Yeon Tae Jeong a,
*
a Division of Image Science and Information Engineering, Pukyong National University, Busan 608-739, Republic of Korea
b Department of Chemistry, Annamalai University, Annamalainagar 608-002, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2008
Revised 10 September 2008
Accepted 10 October 2008
Available online 14 October 2008
The raise in clinical significance of multidrug-resistant bacterial pathogens has directed us to synthesize
2,6-diarylpiperidin-4-one and
atives. X-ray crystal structure of tetrahydropyridinol (23) confirmed a change in conformation and orien-
tation of substituents upon amide formation. Antibacterial activities evaluated against a wide number of
bacterial pathogens (both sensitive and multidrug-resistant) revealed that 19, 27 against Staphylococcus
aureus, 27 against Enterococcus faecalis, and 19, 21, 23, and 27 against Enterococcus faecium are signifi-
D
3-tetrahydropyridin-4-ol based benzimidazole and O-arylsulfonyl deriv-
Keywords:
Tetrahydropyridine
Benzimidazole
cantly good at lowest MIC90 (16 lg/mL). Inhibitory power noticed by 23 against Vancomycin–Linezo-
lid-resistant E. faecalis and 27 against Vancomycin-resistant E. faecium are onefold better than the
standard Linezolid and Trovafloxacin drugs, respectively. Moreover, antitubercular activity for the
selected compounds against Mycobacterium tuberculosis H37Rv revealed that compounds 23, 24, and
27 expressed onefold improved potency compared to the standard Rifampicin drug.
Ó 2008 Elsevier Ltd. All rights reserved.
Sulfonate
Antibacterial activity
Antitubercular activity
Crystal structure
During the past few decades, the alarming rate in the incidence of
life threatening infections caused by multiple drug-resistant Gram-
positive organisms particularly Methicillin-resistant Staphylococcus
aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis
(MRSE) and recently found Vancomycin-resistant enterococci
(VRE) are becoming significant health concern through out the
world. As they do not respond to the current clinical drug therapy,
the morbidity and mortality rate was raised among human popula-
tion, which in turn pose a serious menace and gravely challenging
the scientific community.1 Among the several phenotypes for VRE,
VanA (resistance to Vancomycin and Teicoplanin) is the most
common2 and particularly in USA, VanA accounts for about 60% of
VRE isolates.3 Recently, Linezolid-resistant enterococci (LRE) have
also been identified as an outcome of intensive Linezolid therapy.4
The therapeutic challenge of multidrug-resistant (MDR) enterococci
(not only limited to Vancomycin) has brought their role as an impor-
tant nosocomial pathogens into sharper focus.
second.5 Further, resurgence of TB is being provoked by the emer-
gence of MDR-isolates of M. tuberculosis against the frontline drugs
and thesynergy of this diseasewith AIDS/HIV pandemicand mycotic
infections in immunocompromised patients.6 The hastily develop-
ing multidrug-resistant Gram-positive bacterial strains including
M. tuberculosis to the currently prescribed pharmaceutical agents
has fueled for the vigorous search for novel antibacterial agents in
structural class distinct from the known antibiotic drugs.
2,6-Disubstitutedpiperidin-4-ones are regarded as an important
framework and served as precursors for chiral biologically active
natural alkaloids.7 The biological activities of piperidones were
found to be excellent if 2- and/or 6-positions are occupied by aryl
groups.8 Accordingly, antibacterial and antifungal activities of 2,6-
diarylpiperidin-4-ones and their derivatives have been explored
well.8b,9 Similarly, the functionalized tetrahydropyridines7,10 and
hydroxyl substituted six-membered nitrogen heterocyclic scaf-
folds8b,10 are the ubiquitous structural component of naturally
occurring alkaloids and biologically active synthetic molecules.
Sulfonates (sulfonyl esters) were also reported to exhibit moderate
antibacterial activitiy11a and inhibitory activity for Escherichia coli
aminopeptidase N11b in addition to varied marked pharmacological
activities.11 Generally, incorporation of benzimidazole nuclei is an
important synthetic strategy in drug discovery program as it exerts
broad-spectrum antibacterial12 and antitubercular activities.13
Particularly, against both sensitive and drug-resistant Gram-posi-
tive bacteria, they displayed excellent activities.12a–e Potential
Besides these pathogens, the most infectious Mycobacterium
tuberculosis H37Rv, a slow-growing Gram-positive bacterium is also
a life threatening pathogen and is the etiologic agent of contagious
tuberculosis (TB). As per the estimated data from World Health
Organization (WHO), Southeast Asia and Africawitnessthe alarming
rise in TB cases where it develops at a rate of more than one per
* Corresponding author. Tel.: +82 51 629 6411; fax: +82 51 629 6408.
E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.045

G. Aridoss et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6542–6548
6543
O
N
X
R2
R1
R2
R1
N
O
R
O
R
R
R
R3
Y
1
N
H
2
R1 = H, CH3, CH2CH3
R2 = H, CH3
Z
R = H, Cl, CH3, OCH3
R3 = Cl, morpholine, N-methylpiperazine
X = O, NOH
R1 = R2 = H, CH3
R = H, Cl, CH3, OCH3
Y = N, O; Z = H, N
Figure 1. Some piperidone derivatives reported to exhibit antimicrobial activities.14
biological activities associated with benzimidazole derivatives are
mainly pertaining to the fact that they are the structural isosteres
of the naturally occurring nucleotides, which in turn permit them
for the easy interaction with biopolymers of the living systems.
Our recent investigations and SAR studies on compounds derived
by using 2,6-diarylpiperidin-4-one as template have demonstrated
that introduction of either chloroacetyl,14a morpholinoacetyl,14b N-
methylpiperazino acetyl14c 1 or benzazolylethoxy14d–f moiety 2
(Fig. 1) at nitrogen exerted enhanced antibacterial and antifungal
activities against a panel of pathogenic organisms. Traditionally,
O
R2
R1
O
R2
R1
i. EtOH / heat / con.HCl
ii. NH3
O
O
+
H
H
N
H
NH4OAc
1-8
R
R
R
R
ClCOCH2Cl
30-35 oC
NEt3 / stirring
O
O
R2
R1
R2
R1
4
3
2
5
6
Dry DMF / calcinated K2CO3
benzimidazole
6I
2I
1
N
N
O
stirring / rt
R
O
R
R
N
R
Cl
9-15
N
16-22
R1
Entry
R2
R
1
2
3
4
5
6
7
9
16
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
3,5-OCH3
4-OCH3
4-CH3
10
11
12
13
14
15
17
18
19
CH3
CH3
CH3
CH3
4-OCH3
4-CH3
2014g
21
2-OCH3
2-Cl
22
Scheme 1. Synthesis of target compounds 16–22.

6544
G. Aridoss et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6542–6548
small molecules have been a reliable source for discovering novel
biologically active agents.
C(3)–C(4) bond owing to the more acidic nature of the axial hydro-
gen at C-3 which is alpha to the –COOCH2CH3 group. Further, the
signal due to benzylic protons (refer spectrum in Supplementary
files) at C-2 and C-6 are broadened and deshielded as a result of re-
stricted rotation about N–C@O bond. Thus, the more deshielded
broad singlet at 5.28 ppm is assigned to H-6 proton while the other
at 4.00 ppm is due to H-2 proton as they correspond to each one
proton integral. Similarly, on the basis of integral value, the multi-
plet in the region 4.12–4.18 ppm is characteristic for acetyl meth-
ylene (N–COCH2) and –COOCH2CH3 protons whereas a doublet and
a triplet centered at 2.84 and 1.09 ppm are pertinent to H-5a/H-5e
and –COOCH2CH3 protons. The above made assignments were fur-
ther confirmed by the observed correlations in its HOMOCOSY and
NOESY spectra (refer Supplementary files). These unambiguous
characterizations of protons in 23 paved a way for the precise
assignment of its carbon signals in 13C NMR through the observed
1H–13C correlations. SEFT and DEPT spectra proved the quaternary
nature of the signal at 99.2 ppm and thus could be assigned to C-3
carbon by keeping in view the b-effect15 of N-acyl group while C-4
carbon is merged with aromatic carbons. All these noticed facts
demonstrate clearly the existence of double bond about C(3)–
C(4) bond and presence of enolic OH at C-4. Structure and change
in conformation is also confirmed beyond doubt by its X-ray crys-
tallographic study. The ORTEP diagram (The asymmetric unit of the
compound 23 contains two crystallographically independent mol-
ecules.) of 23 is displayed in Figure 2 with important bond lengths
and bond angles. These observed bond parameters confirm the
coplanarity of N–COCH2 group. Further, distinct from its parent
piperidone 8 (where phenyl groups are in equatorial disposition),16
phenyl groups [at C(1) and C(5) in Fig. 2] in 23 are oriented axially
in order to avoid steric repulsion (A1,3 strain)17 with coplanar –
COCH2 group. As well, shortening of C(3)–C(4) bond length
(1.34 Å) compared to other bonds (ꢀ1.48 Å) in the heterocyclic ring
clearly confirms its double bond character. Similarly, existence of
Encouraged by the earlier reports and in continuation of our re-
cent research program to find out novel antimicrobials,14 we have
designed and synthesized acetyl derivative of few 2,6-diarlypiperi-
din-4-ones framework coupled with benzimidazole system. Fur-
ther, to study the impact of biological activity upon double bond
incorporation into the piperidine nucleus, we have also synthe-
sized
D
3-tetrahydropyridin-4-ol and their sulfonates. The synthe-
sized compounds (16–29) were evaluated for their antibacterial
and antitubercular activities besides establishing the effect of aro-
matic phenyl substituents with regard to the substituent position
on antibacterial and antitubercular efficacies.
The facile synthetic routes which furnished the target com-
pounds are shown in Schemes 1 and 2. Chloroacetylation15 of
variously substituted 2,6-diarylpiperidin-4-ones followed by con-
densation with benzimidazole in dry DMF using calcinated K2CO3
to about 2–4 h (in room temperature) afforded the desired prod-
ucts in good yields. Facile synthesis of N-chloroacetyl-3-carboxy-
ethyl-2,6-diphenyl-4-hydroxy-D
3-tetrahydropyridine (23) was
achieved exclusively from 3-carboxyethyl-2,6-diphenylpiperidin-
4-one (8) by simple amide formation. To furnish compound 24,
benzene was used as a solvent in place of DMF under refluxed con-
dition. Likewise, nucleophilic substitution of OH at C-4 in 23 was
accomplished with diversely substituted arylsulfonyl chlorides
using DMAP as base in dry DCM at room temperature. The synthe-
sized compounds were analyzed by IR, mass, and one and two-
dimensional NMR techniques.
Structure of the compound 23 was elucidated without ambigu-
ity by 1H/13C NMR, HOMOCOSY, NOESY, HSQC, SEFT, and DEPT
analysis. Proton NMR spectrum of this compound indicates the
presence of a new sharp singlet for C(4)–OH at 12.43 ppm and
the absence of a signal at 3.68 ppm due to C-3 methine proton of
its precedent piperidone. This confirms the enolization along
O
COOCH2CH3
H
O
N
H
4
COOCH2CH3
5
3
8
6
Dry DMF / calcinated K2CO3
2'
6'
2
ClCOCH2Cl / NEt3
30-35 oC / stirring
1N
stirring / rt
O
H
AN
O
H
O
N
G
H
B
COOCH2CH3
F
COOCH2CH3
Enolization
N
I
C
E
D
N
O
24
O
O
S
Ar
Cl
Cl
23
O
N
O
4
COOCH2CH3
5
3
6
Entry
Ar
25
26
27
28
29
6'
2'
2
1
H
S
H
Z'
O
NO2
H
Z
Cl
25-29
NO
NO
2
2
Scheme 2. Synthesis of target compounds 23–29.

G. Aridoss et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6542–6548
6545
Figure 2. Stick model and ORTEP diagram of 23. The important bond lengths (Å): C(1)–N(1) = 1.48; C(5)–N(1) = 1.48; C(21)–N(1) = 1.36; C(21)–O(4) = 1.21; C(21)–
C(22) = 1.53; C(2)–C(3) = 1.49; C(3)–C(4) = 1.34; C(4)–C(5) = 1.50. The important bond angles (°): C(21)–C(22)–Cl(1) = 107.70; O(4)–C(21)–N(1) = 122.50; N(1)–C(21)–
C(22) = 119.80; N(1)–C(5)–C(6) = 111.05; C(5)–N(1)–C(1) = 117.46; C(21)–N(1)–C(5) = 117.03; C(21)–N(1)–C(1) = 125.30.
partial double bond character about N–C@O bond is revealed from
their decreased bond lengths [C(21)–N(1) = 1.36 Å and C(21)–
O(4) = 1.21 Å]. Therefore, the change in chair conformation of the
parent compound upon chloroacetylation into energetically favor-
able non-chair conformation is revealed from its ORTEP. Further-
more, introduction of arylsulfonyl groups at C(4)–OH deshielded
H(2), C(2) and C(3) resonances due to the electronic interaction
with O@S@O group in the assumed conformation. Assignments
of the deshielded signals were also confirmed by NOESY and HSQC
correlations (refer Supplementary files).
Methicillin-resistant Staphylococcus epidermidis, Enterococcus fae-
calis, Enterococcus faecium, Vancomycin-resistant Enterococcus fae-
calis/Enterococcus faecium and Vancomycin, and Linezolid-resistant
Enterococcus faecalis. Minimum inhibitory concentrations (MIC90
)
were determined by broth micro dilution in accordance with the
methods of the National Committee for Clinical Laboratory Stan-
dards (NCCLS)18 and are furnished in Table 1. Linezolid and Trova-
floxacin drugs were used as positive controls while DMSO served
as negative control. Test compounds were prepared up to a con-
centration of 128 lg/mL.
All the synthesized compounds were screened for their antibac-
terial efficacy in vitro against a spectrum of Gram-positive patho-
genic bacteria including resistant strains viz. Methicillin-resistant
and -sensitive Staphylococcus aureus, Staphylococcus epidermidis,
A glance at the MIC90 values in Table 1 indicates that among the
benzimidazole derivatives 16–22, ortho-methoxyphenyl bearing
compound (21) with C-3/C-5 methyl groups showed moderate
activity (32 lg/mL) against S. aureus and better activity (16 lg/

6546
G. Aridoss et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6542–6548
Table 1
In vitro antibacterial activities (MIC90 in
l
g/mL) of compounds 16–29 against selected sensitive and resistant Gram-positive bacterial strains
*
S. No.
Strain
Minimum inhibitory concentration (MIC90
)
in
lg/mL
Linezolid
Trovafloxacin
16
17
18
19
20
21
22
23
24
25
26
27
28
29
LCB0001
LCB0002
LCB0003
LCB0004
LCB0005
LCB0006
LCB0007
LCB0008
LCB0009
S. aureus
1
2
1
2
2
2
64
2
2
<0.0625
1
<0.0625
<0.0625
0.128
8
16
64
8
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
128
NA
NA
NA
NA
NA
NA
NA
NA
64
16
64
64
32
64
32
64
64
128
32
64
32
64
16
32
64
NA
128
NA
NA
128
NA
NA
NA
NA
16
64
64
64
16
32
64
32
16
NA
NA
NA
NA
NA
NA
NA
NA
NA
32
64
64
128
NA
NA
NA
NA
32
S. aureusMR
128
NA
NA
64
NA
NA
NA
16
NA
NA
NA
64
NA
NA
NA
16
NA
NA
128
NA
NA
NA
NA
NA
NA
128
NA
64
NA
128
NA
64
NA
NA
NA
128
NA
NA
NA
128
S. epidermidis
S. epidermidisMR
E. faecalis
NA
NA
128
128
NA
NA
32
E. faecalisVanA (VR)
E. faecalisVanA (VLR)
E. faeciumVanA (VR)
E. faecium
LCB, M/s LegoChem Biosciences, Inc., Deajeon, South Korea (where the activity test was carried out).
MR, Methicillin-resistant; VanA, phenotype; VR, Vancomycin-resistant; VLR, Vancomycin, and Linezolid-resistant.
NA – no activity even at highest concentration (i.e., 128 g/mL) tested in this study.
MIC90 is the minimum concentration of an antibacterial agent that will significantly inhibits the growth of 90% of organisms after a period of incubation.
l
*
mL) against E. faecium whereas its para-methoxy analogue (19)
exerted onefold improved activity (16 g/mL) against S. aureus
onefold elevated efficacies against S. aureus, MR S. epidermidis, E.
faecalis, VR E. faecalis, and VR E. faecium, while against rest of the
strains the same activity was restored except against VLR E. faecalis
– for which onefold decreased activity was noted. A surprising
observation here is that, potency of compound 27 was doubled
against VR E. faecium compared to standard Trovafloxacin drug
but an equi-potency was noticed with standard Linezolid drug
against VLR E. faecalis tested at the same laboratory condition.
Though thiophen-2-sulfonyl analogue of 27 (compound 29) pro-
duced moderate activty against four Staphylococcus species,
4-vinylbenzenesulfonyl counter part (28) did not display activity
even at highest concentration tested in this study, that is,
l
but retains the same activity against E. faecium. However, the
para-methyl analogue of 19 (compound 20) registered two and
onefold decreased activities against the above said strains, respec-
tively. But, meta-dimethoxy (16), para-methoxy (17), and para-
methyl (18) analogues with C-3 methyl group and ortho-chloro
(22) counterpart of 21 are almost inactive up to 128
all the tested organisms except 18 and 22 against E. faecium and S.
aureus, respectively (MIC90 = 64 g/mL). Among tetrahydropyridi-
lg/mL against
l
nol 23 and its derivatives 24–29, compound 23 with carbethoxy
group at C-3 and unsubstituted phenyl moieties at C-2 and C-6
exhibited moderate to good activities (MIC90 between 16 and
128
lg/mL. Therefore, the inhibitory potencies of compound 23
64
l
g/mL) against all the tested Gram-positive organisms. In par-
and few of its arylsulfonyl derivatives are relatively better than
the benzimidazole series and falls in the order 27 > 23 > 29 >
19 > 21.
In order to extend the evaluation of antibacterial activities, they
were also tested against Gram-negative bacterial strains such as
three different E. coli strains, Pseudomonas aeruginosa, Klebsiella
pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
The noticed MIC90’s are reproduced in Table 2.
ticular, its inhibitory activity was doubled against VLR E. faecalis
compared to that of the standard Linezolid drug whereas against
VR E. faecium, potency is at par with Trovafloxacin drug tested at
the same laboratory condition. Similarly, against S. aureus/E. faecal-
is and E. faecium, growth inhibition was noticed at 32 and 16 lg/
mL, respectively. Nucleophilic substitution of benzimidazole to
23 (i.e., compound 24) suppressed the activities against all the
organisms except against S. aureus for which the same activity
was retained. Therefore, to explore the impact of arylsulfonylation
on antibacterial activities through nucleophilic substitution of OH
in 23, compounds 25–26 were synthesized and assessed. Some of
these sulfonates showed marginal enhancement in activity. Like
24, compounds 25 and 26 with ortho- and meta-nitro substituents,
respectively, in the benzenesulfonyl moiety are also profoundly
decreased in their antibacterial activities against all the tested
Gram-positive organisms. However, their para-nitro derivative 27
produced significant inhibitory profiles against both sensitive and
resistant organisms. Compared to 23, compound 27 registered
According to the observed results from Table 2, unexpectedly,
an appreciable drop in the antibacterial potencies against Gram-
negative organisms has been noted. Even though a few of the com-
pounds showed the sign of inhibitory potencies at 64 and 128 lg/
mL against P. aeruginosa, K. pneumoniae, H. influenzae, and three dif-
ferent E. coli (LCB0010, 0011, and 0012) strains, most of them failed
to exert activities up to the maximum concentration tested (i.e.,
128
aeruginosa and 27 against K. pneumoniae are superior to the stan-
dard Linezolid drug (which is not active up to 128 g/mL) as they
recorded better activity at 64 g/mL. Interestingly, compounds 19,
lg/mL). Additionally, the noticed potencies of 23 against P.
l
l
Table 2
In vitro antibacterial activities (MIC90 in
l
g/mL) of compounds 16–29 against selected Gram-negative bacterial strains
*
S. No.
Strain
Minimum inhibitory concentration (MIC90
)
in
lg/mL
Linezolid
Trovafloxacin
16
17
18
19
20
21
22
23
24
25
26
27
28
29
LCB0010
LCB0011
LCB0012
LCB0013
LCB0014
LCB0015
LCB0016
E. coli
E. coli
E. coli
P. aeruginosa
K. pneumoniae
H. influenzae
M. catarrhalis
NA
16
64
NA
NA
16
8
<0.0625
<0.0625
<0.0625
0.125
0.125
<0.0625
<0.0625
NA
NA
NA
NA
NA
NA
NA
NA
NA
128
NA
NA
NA
NA
NA
NA
128
NA
NA
NA
NA
NA
NA
128
NA
NA
NA
16
NA
128
128
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
64
NA
NA
32
NA
NA
NA
NA
NA
NA
64
NA
128
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
128
NA
NA
64
NA
NA
128
NA
NA
NA
NA
32
128
128
NA
NA
128
NA
NA
32
LCB, M/s LegoChem Biosciences, Inc., Deajeon, South Korea (where the activity test was carried out).
NA – no activity even at highest concentration (i.e., 128 g/mL) tested in this study.
MIC90 is the lowest concentration of an antibacterial agent that will significantly inhibits the visible growth of a bacterial organism after a period of incubation.
l
*

G. Aridoss et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6542–6548
6547
Table 3
azid and Rifampicin drugs were used as positive controls whereas
DMSO was used as solvent. Test compounds were prepared up to a
concentration of 256 lg/mL.
The Table 3 clearly illustrates that the benzimidazole deriva-
tives of piperidin-4-one 19 bearing methoxy functionality at the
para-position of the phenyl groups besides methyl groups at C-3/
Antitubercular activity of selected compounds against M. tuberculosis H37Rv (ATCC
27294)
Entrya
Substituent
MICb(APc)
R/Ar
R1
R2
19
21
23
24
4-OCH3
2-OCH3
—
CH3
CH3
—
CH3
CH3
—
64 (0.39S1/50S2
)
128 (0.19S1/25S2
16 (1.56S1/200S2
16 (1.56S1/200S2
)
)
)
C-5 produced inhibition potency at 64 lg/mL but its ortho-meth-
oxy analogue (compound 21) showed onefold decline in activity.
Virtually, tetrahydropyridinol 23 and its benzimidazole 24 and
arylsulfonyl derivatives 25, 26, 27, and 29 exhibited promising
antitubercular activity. Due to the substitution of benzimidazole
moiety in place of chlorine in 23 (compound 24) retain the activity
without any alteration. But, introduction of ortho- (25) and meta-
nitro (26) benzenesulfonyl moieties at C(4)–OH in 23 makes the
—
—
—
25
—
—
NA
NO2
compound impotent up to 256
tion power of para-nitro analogue (27) noticed at 16
l
g/mL. However, excellent inhibi-
g/mL reveals
l
26
27
29
—
—
—
—
—
—
NA
that impotency of 25 and 26 can be significantly alleviated by sim-
ple structural amendment. A comparison of antitubercular potency
(%) of tested compounds with Rifampicin drug was made by
employing the formula: antitubercular potency (AP in %) = MIC of
Rifampicin/MIC of test compound  100 and is displayed as bar
graph in Figure 3. From this figure, it is apparent that the com-
pounds 23/24/27 and 29, respectively, displayed 200% and 100%
antitubercular potency compared to the standard Rifampicin drug.
In conclusion, a three steps synthetic practice furnished 1-[2-
(1H-benzimidazol-1-yl)acetyl]-2,6-diarylpiperidin-4-ones (16–22)
in good yields. Similarly, tetrahydropyridinol (23) and their sulfo-
nates (24–29) were achieved by simple synthetic strategy and
structurally identified by X-ray crystallography, one and two-
dimensional NMR techniques. The surprising level of activity seen
with tetrahydropyridinol 23 and one of its sulfonate derivatives 27
against susceptible and resistant organisms of several Gram-posi-
tive strains including M. tuberculosis suggests that enolization
across C(3)–C(4) bond upon chloroacetylation seems to be more
important than the keto analogues (16–22) even though the later
analogues bear biologically accepted benzimidazole pharmaco-
phore. As well, C(2) and C(6) aryl groups in chloroacetyl intermedi-
ates of 16–22 are oriented in axial and equatorial directions,20
respectively, whereas in 23, both the phenyl groups are disposi-
tioned axially. From this it is well conceived that enolization about
C(3)–C(4) bond, orientation of aryl groups at C(2)/C(6) and the con-
formational preferences play a crucial role in exhibiting better bio-
logical response as they presumed to execute different mode of
action. The marked activity associated with sulfonate 27, as well
as the apparent ability of the nitro group in the para-position to
permit the restoration of activity from the otherwise inactive
NO2
16 (1.56S1/200S2
)
)
NO
2
S
32 (0.78S1/100S2
Isoniazid
Rifampicin
—
—
—
—
—
—
0.25
32
S1 and S2 – AP compared to Isoniazid and Rifampicin standards, respectively.
NA – no activity even at highest concentration (i.e., 256 g/mL) tested in this study.
Only selected compounds were screened for antitubercular activity.
l
a
b
c
MIC, minimum inhibitory concentration represented in
Antitubercular potency (AP in%) = MIC of Rifampicin/MIC of test
lg/mL.
compound  100.
23, 24, 27, and 29 prominently inhibited the growth of M. catarrh-
alis with the MIC90 ranging from 16 to 64
at the top on the basis of effectiveness (i.e., MIC90 at 16
Antibacterial activity tests for the compounds under study evi-
dently demonstrate that compounds 19, 21, 23–27, and 29
expressed moderate to elevated potency thereby render them to
assess further for their antitubercular activity against Mycobacte-
rium tuberculosis H37Rv (ATCC 27294). Antitubercular activity test
was done by radiometric respiratory technique using the BACTEC
system as described earlier19 and MIC’s are given in Table 3. Isoni-
l
g/mL, in which 19 ranks
lg/mL).
Comparison of antitubercular potency (%) of compounds with
Rifampicin (standard drug) againstM. tuberculosis H37Rv
by radiometric respiratory technique using the BACETEC system
250
200
150
100
50
0
19
21
23
24
Compounds
(DMSO is negative control)
25
26
27
29 DMSO
Figure 3. Comparison of antitubercular potency (%) of compounds with standard Rifampicin drug (antitubercular potency (AP in%) = MIC of Rifampicin/MIC of test
compound  100).

6548
G. Aridoss et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6542–6548
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ortho- (compound 25) and meta-nitro (compound 26) analogues
points quite specific substituent effect possibly related to the en-
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compounds 23 and 27 (Fig. 4) render them as an attractive leads
for further structural optimization.
Acknowledgments
This research work was supported by the grant from second stage
of BK21 program. We are also grateful to M/s Lego Chem Biosciences,
Inc., Deajeon, South Korea and Vimta Labs Ltd. Hyderabad, India for
their help in conducting antibacterial and antitubercular screening
tests, respectively.
ˇ
Chem. 2005, 40, 203; (b) Klimešová, V.; Koci, J.; Waisser, K.; Kaustová, J. Il
ˇ
Farmaco 2002, 57, 259; (c) Klimešová, V.; Koci, J.; Pour, M.; Stachel, J.; Waisser,
K.; Kaustová, J. Eur. J. Med. Chem. 2002, 37, 409.
14. (a) Aridoss, G.; Balasubramanian, S.; Parthiban, P.; Ramachandran, R.; Kabilan,
S. Med. Chem. Res. 2007, 16, 188; (b) Aridoss, G.; Balasubramanian, S.;
Parthiban, P.; Kabilan, S. Eur. J. Med. Chem. 2007, 42, 851; (c) Aridoss, G.;
Parthiban, P.; Ramachandran, R.; Prakash, M.; Kabilan, S.; Jeong, Y. T. Eur. J.
Med. Chem. 2008. doi:10.1016/j.ejmech.2008.03.031; (d) Aridoss, G.;
Balasubramanian, S.; Parthiban, P.; Kabilan, S. Eur. J. Med. Chem. 2006, 41,
268; (e) Balasubramanian, S.; Aridoss, G.; Parthiban, P.; Kabilan, S. Biol. Pharm.
Bull. 2006, 29, 125; (f) Balasubramanian, S.; Ramalingan, C.; Aridoss, G.;
Kabilan, S. Eur. J. Med. Chem. 2005, 40, 694; (g) Aridoss, G.; Amirthaganesan, S.;
Kim, M. S.; Cho, B. G.; Lim, K. T.; Jeong, Y. T. ARKIVOC 2008, XV, 133.
15. Aridoss, G.; Balasubramanian, S.; Parthiban, P.; Kabilan, S. Spectrochim. Acta
Part A 2007, 68, 1153.
Supplementary data
Complete experimental details and characterization data for all
the compounds along with NMR, NOE and HSQC spectra for the
representative compounds are furnished. The crystallographic data
of 23 have been deposited at Cambridge Crystallography Data Cen-
ter (CCDC No. 686632). Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2008.10.045.
16. Manimekalai, A.; Sabapathy Mohan, R. T.; Mubeen, Taj.; Subramani, K.;
Senthilvadivu, B. Pol. J. Chem. 2000, 74, 1685.
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