Synthesis, stereochemistry and antimicrobial studies of novel oxime ethers of aza/diazabicycles

Article abstract of DOI:10.1016/j.bmcl.2009.10.042

Two series of bicyclic oxime ethers viz, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one O-benzyloximes 13-24 and 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonan-9-one O-benzyloximes 31-36 were synthesized and stereochemistry was established by their spectral (1D and 2D NMR) and crystal studies. Synthesized oxime ethers were screened for their in vitro antimicrobial activity against a set of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Escherichia coli and Klebsiella pneumoniae) and fungi (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger and Aspergillus flavus) by twofold serial dilution method, respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the molecules expressed promising antimicrobial profile against the tested pathogens and even a few compounds 16, 21, 22, 33 and 34 were better than standard drugs.

Full text of DOI:10.1016/j.bmcl.2009.10.042

Bioorganic & Medicinal Chemistry Letters 19 (2009) 6981–6985
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, stereochemistry and antimicrobial studies of novel oxime ethers
of aza/diazabicycles
Paramasivam Parthiban a,b, Gopalakrishnan Aridoss a,b, Paramasivam Rathika c, Venkatachalam Ramkumar d,
Senthamaraikannan Kabilan a,
*
a Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
b Division of Image Science and Information Engineering, Pukyong National University, Busan 608 739, Republic of Korea
c Department of Microbiology, Annamalai University, Annamalainagar 608 002, India
d Department of Chemistry, Indian Institute of Technology, Madras, Chennai 600 036, 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 2009
Revised 11 September 2009
Accepted 9 October 2009
Available online 30 October 2009
Two series of bicyclic oxime ethers viz, 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one O-benzyloximes 13–
24 and 2,4,6,8-tetraaryl-3,7-diazabicyclo[3.3.1]nonan-9-one O-benzyloximes 31–36 were synthesized
and stereochemistry was established by their spectral (1D and 2D NMR) and crystal studies. Synthesized
oxime ethers were screened for their in vitro antimicrobial activity against a set of pathogenic bacteria
(Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella typhi, Escherichia coli and Klebsiella pneumo-
niae) and fungi (Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger and Aspergillus flavus) by two-
fold serial dilution method, respectively, using Ciprofloxacin and Amphotericin B as standards. Most of
the molecules expressed promising antimicrobial profile against the tested pathogens and even a few
compounds 16, 21, 22, 33 and 34 were better than standard drugs.
Keywords:
3-ABN
3,7-DABN
Oxime ether
Single crystal XRD
Stereochemistry
Antibacterial activity
Antifungal activity
Ó 2009 Elsevier Ltd. All rights reserved.
Microbes are customary in nature, air, water, on the surface that
we touch in everyday life and even in our regular food. Infections
caused by these small unicellular organisms can range from mild
illness to a fatal one, leading to death.1 Particularly, 2–19% patients
are infected from hospital visits.2 Apart from bacterial infections,
the risk of opportunistic fungal infections has been greatly in-
creased due to the increase of immunocompromised patients such
as AIDS, cancer and organ transplant recipients. But the available
antifungal drugs, polyene macrolides, azoles, flucytosine and can-
dins are non-ideal in terms of efficacy, antifungal spectrum or
safety; and, the invasive candidiasis and aspergillosis has increased
dramatically.3 Hence, the need for new and efficient antimicrobial
agents is emerging nowadays.
3-ABN (3-azabicyclo[3.3.1]nonane) and 3,7-DABN (3,7-diazabi-
cyclo[3.31]nonane) nucleus are of biological interest due to their
presence in the molecular structure of various alkaloids (diter-
pene/norditerpene and lupin) and drugs.4 Also, oxime ethers are
more interested in current affairs due to their antimicrobial effi-
ciency.5 The O-benzyloxime/O-benzyl functionality (Fig. 1) of anti-
fungal drugs (oxiconazole/econazole/miconazole) and antimicrobial
agents (piperidone/chromanone/nafimidone oxime ethers and
inverted oxime ethers of oxiconazole) prompted to synthesize
O-benzyloximes of 3-ABN/3,7-DABN-9-ones with the expectation
of effective antimicrobial profile.
As depicted in Scheme 1, 3-ABN-9-one oxime ethers 13–19 and
their N-methyl analogs 20–24 were synthesized. The 1D (1H and
13C) and 2D (1H–1H COSY, 1H–13C COSY, HMBC and NOESY) NMR
spectral studies of 13–24 suggested that all compounds (except
16) exist in chair–chair conformation with equatorial orientation
of aryl groups at C-2 and C-4 as in Figure 2. Single crystal XRD anal-
ysis of the representative compound 15 also proved the same
(Fig. 3). Refer Supplementary data for detailed spectral and crystal
analysis.
In the 1H NMR spectrum of 16, unlike other oxime ethers, dou-
blets observed at 5.25 (1H, J = 12.21 Hz) and 5.17 (1H, J = 12.21 Hz)
ppm. The 1H–1H COSY suggested that the doublets are due to O-
benzyl methylene protons, which are diastereotopic in nature. Be-
sides, the benzylic protons H-2a/H-4a are appeared in the higher
frequency region than 13 and 17 by 0.5 ppm, and the observed vic-
inal coupling constant was appreciably less. These variations sug-
gested that, there may be a change in its stereochemistry. To
overcome this ambiguity, XRD analysis has been carried out.
According to single crystal XRD analysis, compound 16 also exhib-
its similar stereochemistry as 15 (Fig. 4).
* Corresponding author.
E-mail address: prskabilan@rediffmail.com (S. Kabilan).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.10.042

6982
P. Parthiban et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6981–6985
Cl
Cl
O
O
O
N
N
O
Cl
N
Az
N
N
R
CH3
Cl
Nafimidone
oxime ether
Chromanone oxime ether
Oxiconazole
N
N
R
Cl
Az
O
Cl
O
Cl
N
N
O
Cl
R3
R2
N
N
R
R1
R
Cl
R1
Piperidone oxime ether
R
R
N
R = H, Econazole
R = Cl, Miconazole
Inverted oxime ether of
Oxiconazole
Figure 1. Structures of some analogous antimicrobial agents.
O
O
a
O
O
N
H
R
R
H
H
1-7
R
R
c
b
O
N
O
N
R
R
CH3
8-12
N
H
R
R
c
13-19
Entry
R
O
1, 13
2, 14
3, 15
4, 16
5, 17
6, 18
7, 19
8, 20
9, 21
10, 22
11, 23
12, 24
H
m
-F
N
p
o
-F
-Cl
p
p
-Cl
-CH3
p
-OCH3
H
N
p
p
p
p
-F
R
R
-Cl
CH3
-CH3
-OCH3
20-24
Scheme 1. Reagents and conditions: (a) CH3COONH4, EtOH, warm; (b) CH3I, anhydrous K2CO3, dry acetone, reflux; (c) C6H5CH2–O–NH2ÁHCl, CH3COONaÁ3H2O, MeOH, reflux.
In 20–24, owing to the effect of N-methylation, the benzylic car-
shielded by 9.5 and 0.8 ppm, respectively.6 Moreover, the vicinal
bons C-2/C-4 and their protons H-2a/H-4a were deshielded and
coupling constants J2a,1 and J4a,5 were higher than corresponding

P. Parthiban et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6981–6985
6983
Figure 2. Chair–chair conformation with equatorial orientation of the phenyl/
substituted phenyl groups at C-2 and C-4 of compounds 13–24 in CDCl3 solution,
according to one and two dimensional NMR data.
Figure 4. ORTEP of compound 16 with atoms represented as 30% probability
ellipsoids. Compound 16 also exists in chair–chair conformation with equatorial
orientation of ortho-chlorophenyl groups; both Cl atoms are pointed upward, that
is, towards the C@N group.
the plane C1–C4–C5–C6 by À0.673 and 0.707 Å, respectively.
Hence, 31 exists in chair–boat conformation as in Figure 6. Akin
to 31, compound 35 also revealed the chair–boat conformation
(Fig. 7).
In vitro antibacterial activity of the synthesized oxime ethers
was carried out against Pseudomonas aeruginosa, Staphylococcus
aureus, Salmonella typhi, Escherichia coli and Klebsiella pneumoniae
by twofold serial dilution method9 using Ciproflaxacin as standard.
The MIC values are presented in Table 1.
The unsubstituted phenyl groups at C-2 and C-4 of 3-ABN-9-one
oxime ether 13 showed poor activity or inactivity even at 200 lg/
mL. However, N-methylation (20) exerted a marginal improve-
ment against all the tested bacterial strains. Likewise, the introduc-
tion of CH3/OCH3 substituents at phenyl groups exhibited a
marginal improvement. Surprisingly, the F substituent on 13 and
20, that is, compounds 14/15 (non N-methyl) and 21 (N-methyl)
exerted significant improvement in their activity. In specific, 21
Figure 3. ORTEP of compound 15 with atoms represented as 30% probability
ellipsoids; shows the existence in chair–chair conformation with equatorial
orientation of para-fluorophenyl group on both sides of the secondary amino
group. Of the chairs, the piperidine ring is in near ideal chair whereas cyclohexane
deviates from the ideal chair.
registered its best MIC at 12.5 lg/mL against P. aeruginosa and
E. coli. Also, the Cl substituent on 13 and 20, that is, compounds
16, 17 and 22 expressed an appreciable improvement against all
strains. Amongst, 16 (ortho-Cl) recorded remarkable MICs at 6.25
non N-methylated oxime ethers, due to the lower electronegativity
of N-CH3 group than NH.
and 12.5 lg/mL against P. aeruginosa and S. aureus/E. coli,
After a careful comparison of the observed coupling constants of
13 with corresponding monocyclic oxime ether 37 (2,6-diph-
enylpiperidin-4-one O-benzyloxime)7 provided the insight; in 37,
the vicinal coupling constant on the syn side (J5e,6a = 3.0 Hz) was
more than anti side (J2a,3e = 2.9 Hz), but in 13, the vicinal coupling
constant on the syn side was (J4a,5 = 1.97 Hz) less than anti side
respectively.
The 3,7-DABN-9-one oxime ether 31 exerted poor activity
against all the tested bacterial strains while the incorporation of
fluorine on meta/para position (compounds 32/33) enhanced their
activity. The activity of para-F compound 33 was better than 32
and lies in the range of 6.25–12.5
by Cl/CH3/OCH3 in 33 afforded 34/35/36. Astonishingly, all of them
exerted remarkable inhibition against P. aeruginosa (6.25–
12.5 g/mL) whereas decreased against rest of the strains.
lg/mL. The replacement of F
(J2a,1 = 2.09 Hz). This divergence was due to syn
the syn -proton presumably moved toward the syn b-proton
whereas in 13, the syn -proton moved away from the syn b-proton
a-proton; in 37,
a
a
a
l
to minimize the interaction with the oximino group.
All the synthesized oxime ethers were tested for their in vitro
antifungal activity against Candida albicans, Candida-51, Rhizopus
sp., Aspergillus niger and Aspergillus flavus using Amphotericin B
as standard. The MIC values are summarized in Table 2.
According to Scheme 2, the 3,7-DABN-9-one oxime ethers 31–
36 were synthesized. Based on the 1D and 2D NMR studies,8 dy-
namic chair–boat conformation (Fig. 5) was proposed to them.
Single crystal XRD analysis of 31 proved that, one of the piper-
idine rings C1–C2–N1–C3–C4–C7 adopted the near ideal chair
conformation with the deviation of ring atoms N1 and C7 from
the C1–C2–C3–C4 plane by À0.665 and 0.687 Å, respectively. How-
ever, another piperidine ring C1–C7–C4–C5–N2–C6 adopted boat
conformation with the deviation of ring atoms N2 and C7 from
When compared to 13, its N-methyl analog 20 exhibited
improvement against C. albicans and Rhizopus sp. at 50
20, the para-F compound 21 was better than non N-methyl analog
15 against all strains, whose best MIC was 12.5 g/mL against C.
lg/mL. Like
l
albicans. The replacement of F by Cl in 15 and 21 provided 17
and 22; both exerted improvements against all strains except 22

6984
P. Parthiban et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6981–6985
Scheme 2. Reagents and conditions: (a) CH3COONH4, EtOH, warm; (b) C6H5CH2–O–NH2ÁHCl, CH3COONaÁ3H2O, CHCl3/EtOH (1:1), reflux.
17 and 35 were moderately active. This preliminary structure–
activity study reveals that compounds with electron withdrawing
substituents at ortho/para position played a vital role in antimicro-
bial efficacy and was further enhanced by the introduction of a
methyl group at ring nitrogen. Albeit the exact molecular mecha-
nism of this SAR profile is unknown, presently, we consider that
the aforementioned substituents may influence their mechanism
of inhibition action. The present study provides new classes of
Figure 5. Dynamic chair–boat conformation of compounds 31–36 in CDCl3
solution, according to one and two dimensional NMR data. The phenyl/substituted
phenyl groups at C-2/C-4 and C-6/C-8 adopted the equatorial and axial orientations
in chair and boat forms, respectively.
against A. flavus and C. albicans. In specific, 17 and 22 recoded
their best MIC at 12.5 lg/mL against Rhizopus sp. and Candida-51/
Rhizopus sp./A. niger, respectively. Of the compounds tested, 16
(ortho-Cl) was distinctively registered a remarkable inhibition
against Candida-51 at 6.25 lg/mL. The CH3/OCH3 substituents of
13 (i.e., 18/19) and their N-methyl analogs (23/24) did not show
inhibition profile as F/Cl compounds.
Other than C. albicans and A. niger (100
lg/mL), 31 required
200 g/mL or more concentration to inhibit the visible growth of
l
the tested fungal strains. Introduction of fluoro substituent on
meta/para position of the above provided 32/33. Of the two, 33
expressed better inhibition against all except A. flavus, which re-
corded the best MIC at 12.5
sp. The replacement of F by Cl (34) also registered best MIC at
12.5 g/mL against C. albicans and A. flavus whereas required
25 g/mL against Rhizopus sp. However, the activity was reduced
by the replacement of F by CH3 (35) and OCH3 (36) substituents.
In summary, among the synthesized oxime ethers, 16, 21, 22, 33
and 34 were potent against most of the tested pathogens. Also, 15,
lg/mL against C. albicans and Rhizopus
l
l
Figure 6. ORTEP of compound 31 with atoms represented as 30% probability
ellipsoids; shows the existence of the molecule in chair–boat conformation with
equatorial and axial orientations of the phenyl groups in chair and boat forms,
respectively.

P. Parthiban et al. / Bioorg. Med. Chem. Lett. 19 (2009) 6981–6985
6985
Table 2
Antifungal activity of compounds 13–24 and 31–36
Compds
Minimum inhibitory concentration (lg/mL)
C. albicans
Candida-51
Rhizopus sp.
A. niger
A. flavus
13
14
15
16
17
18
19
20
21
22
23
24
31
32
33
34
35
36
Stda
100
50
25
12.5
25
50
50
50
12.5
25
50
25
100
25
12.5
12.5
25
200
200
100
6.25
50
100
50
200
25
12.5
50
50
>200
50
25
>200
50
50
50
12.5
25
50
50
25
12.5
50
50
200
50
12.5
25
50
>200
100
50
50
25
100
100
200
25
12.5
100
25
100
50
25
200
100
100
12.5
50
100
100
>200
50
100
25
100
200
25
50
12.5
25
50
50
50
50
100
25
25
50
25
50
50
25
50
25
Figure 7. ORTEP of compound 35 with atoms represented as 30% probability
ellipsoids. The bicycle exists in chair–boat conformation with equatorial and axial
orientations of the para-methylphenyl groups in chair and boat forms, respectively.
a
Amphotericin B.
Supplementary data
Table 1
Antibacterial activity of compounds 13–24 and 31–36
Supplementary crystallographic data for 15 (CCDC No. 711365),
16 (CCDC No. 711364), 31 (CCDC No. 715424) and 35 (CCDC No.
715425) can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.bmcl.2009.10.042.
Compds
Minimum inhibitory concentrationa
(
l
g/mL)
P. aeruginosa
S. aureus
S. typhi
E. coli
K. pneumoniae
13
14
15
16
17
18
19
20
21
22
23
24
31
32
33
34
35
36
Stdc
200
25
25
6.25
12.5
25
>200b
100
100
12.5
25
200
100
50
50
25
100
50
100
25
25
50
50
100
25
25
25
50
100
50
100
25
25
12.5
50
100
50
100
12.5
50
100
25
100
25
12.5
50
>200
100
50
50
100
200
100
200
25
References and notes
25
50
100
200
50
12.5
25
1. (a) Gastmeier, P.; Sohr, D.; Geffers, C.; Behnke, M.; Daschner, F.; Rüden, H.
Infection 2005, 33, 50; (b) Potera, C. Science 1999, 46, 4830.
100
12.5
12.5
25
2. (a) Talbot, G. H.; Bradley, J.; Edwards, J. E.; Gilbert, D.; Scheld, M.; Bartlett, J. G.
Clin. Infect. Dis. 2006, 42, 657; (b) Gastmeier, P.; Sohr, D.; Geffers, C.; Behnke, M.;
Ruden, H. Infect. Control Hosp. Epidemiol. 2007, 28, 466; (c) Facts sheet—Swiss
Hand Hygiene Campaign, 2007, http://www.swiss-noso.ch.; (d) http://www.
wrongdiagnosis.com/n/nosocomial_infections/stats-country.
3. (a) Fridkin, S. K.; Jarvis, W. R. Clin. Microbiol. Rev. 1996, 9, 499; (b) Marr, K. A.
Oncology 2004, 18, 9; (c) Prasad, R.; Kapoor, K. Int. Rev. Cytol. 2004, 242, 215; (d)
Akins, R. A. Med. Mycol. 2005, 42, 285.
4. (a) Wang, F. P.; Liang, X. T.. In The Alkaloids: Chemistry and Pharmacology; Cordell,
G. A., Ed.; Academic: New York, 1992; Vol. 42, p 151; (b) Dzhakhagirov, F. N.;
Sultankhodzhaev, M. N.; Tashkhodzhaev, B.; Silmov, B. T. Khim. Prir. Soedin.
1997, 33, 254; (c) Henry, A. Plant Alkaloids; Churchill: London, 1966. p 75; (d)
Pelletier, S. W. Chemistry of Alkaloids; Van Nostrand: New York, 1970. p 503.
5. (a) Parthiban, P.; Aridoss, G.; Rathika, P.; Ramkumar, V.; Kabilan, S. Bioorg. Med.
Chem. Lett. 2009, 19, 2981; (b) Parthiban, P.; Balasubramanian, S.; Aridoss, G.;
Kabilan, S. Med. Chem. Res. 2005, 14, 523; (c) Ramalingan, C.; Park, Y. T.; Kabilan,
S. Eur. J. Med. Chem. 2006, 41, 683; (d) Bhandari, K.; Srinivas, N.; Kesava, G. B. S.;
Shukla, P. K. Eur. J. Med. Chem. 2009, 44, 437; (e) Mixich, G.; Thiele, K. Arzneim.-
Forsch./Drug Res. 1979, 29, 1510; (f) Polak, A. Arzneim.-Forsch./Drug Res. 1982, 32,
17; (g) Rossello, A.; Bertini, S.; Lapucci, A.; Macchia, M.; Martinelli, A.;
Rapposelli, S.; Herreros, E.; Macchia, B. J. Med. Chem. 2002, 45, 4903; (h)
Emami, S.; Falahati, M.; Banifatemi, A.; Amanlouc, M.; Shafiee, A. Bioorg. Med.
Chem. 2004, 12, 3971; (i) Karakurt, A.; Dalkara, S.; Ozalp, M.; Ozbey, S.; Kendy,
E.; Stables, J. P. Eur. J. Med. Chem. 2001, 36, 421; (j) Milanese, L.; Giacche, N.;
Schiaffella, F.; Vecchiarelli, A.; Macchiarulo, A.; Fringuelli, R. Chem. Med. Chem.
2007, 2, 1208.
50
100
100
>200
50
25
50
100
100
50
25
50
100
12.5
6.25
6.25
6.25
12.5
12.5
200
12.5
12.5
25
25
25
25
50
25
25
a
MIC is the lowest concentration of an antimicrobial agent to significantly pre-
vent the visible growth of a pathogen after a period of incubation; MIC values are
represented in micrograms per milliliter ( g/mL).
l
b
No activity up to 200
Ciprofloxacin.
lg/mL.
c
oxime ethers with antibacterial and antifungal efficiency. They
may be used as templates to construct better antimicrobial agents.
Acknowledgments
6. Parthiban, P.; Rani, M.; Kabilan, S. Monatsh. Chem. 2009, 140, 287.
7. Parthiban, P.; Balasubramanian, S.; Aridoss, G.; Kabilan, S. Spectrochim. Acta Part
A 2008, 70, 11.
8. Parthiban, P.; Ramachandran, R.; Aridoss, G.; Kabilan, S. Magn. Reson. Chem.
2008, 46, 780.
Authors would like to acknowledge the NMR research centre,
IISc-Bangalore and Department of Chemistry, IIT-Madras, respec-
tively for recording NMR and single crystal XRD. We extend our
thanks to RMMCH, Annamalai University for the antimicrobial
studies.
9. Dhar, M. L.; Dhar, M. M.; Dhawan, B. N.; Mehrotra, B. N.; Ray, C. Indian J. Exp. Biol.
1968, 6, 232.