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Article history: Three series of oxime ethers viz, 2,6-diarylpiperidin-4-one O-benzyloximes 5a–o, 2,6-diaryltetrahydro-
Received 5 March 2009 pyran-4-one O-benzyloximes 7a–e and 2,6-diaryltetrahydrothiopyran-4-one O-benzyloximes 11a–b
Revised 9 April 2009 and 12a–c were synthesized and stereochemistry is established by their spectral and single crystal anal-
Accepted 10 April 2009
ysis. A SAR study has been carried out for the above oxime ethers against a panel of antibacterial (Pseu-
Available online 18 April 2009
domonas aeruginosa, Staphylococcus aureus, Salmonella typhi and Escherichia coli) and antifungal agents
(Candida albicans, Candida-51, Rhizopus sp., Aspergillus niger, Aspergillus flavus and Cryptococcus neofor-
Keywords:
mans), respectively, using Ciprofloxacin and Amphotericin B as standards. Most of the chloro/methyl/
Heterocycles
Oxime ethers
methoxy substituted compounds exerted moderate to good activity against all the tested organisms;
Stereochemistry moreover, some compounds (5i, 5l, 5n, 5o, 7c2, 7d1, 7d2, 7e, 11b and 12c) exhibited promising activity
Antibacterial activity than standard drugs.
Antifungal activity Ó 2009 Elsevier Ltd. All rights reserved.
Though infections caused by microorganisms are common, it is and position of substituents were considerably important factors
very serious and often leads to death.1 Up to 19% patients are in- to effect the biological actions.7
fected from hospital visits throughout the world.2 Most of the nos- On the other hand, oxime ether function of various heterocycles
ocomial infections are associated with urinary tract and cause a is reported to possess microbiological properties. Particularly, O-
wide range of severe infections including pneumonia, bloodstream benzyl oxime ether functionality (Fig. 1) shows very significant
and surgical wounds and infections of immunocompromised pa- antimicrobial activities.8 With a view of above, we have incorpo-
tients such as AIDS, cancer and organ transplant recipients. Major- rated bio-active N, O and S heterocycles with O-benzyl moiety to
ity of the nosocomial pathogens are resistant to most of the make biologically potent oxime ether pharmacophore C@N–O–Bn.
antibiotics.3 Beside the antibacterial, there are many studies fo- As illustrated in Scheme 1, the oxime ethers 5a–o were synthe-
cused on antifungal research due to the need of new, safe and po- sized. Conversion of ketone into oxime ether primarily depends
tent antifungal molecules. The use of available antifungal drugs, upon the substitution on active methylene carbons and phenyl.
polyene macrolides, azoles, flucytosine and candins are not ideal The C-3, C-5 unsubstituted and C-3 substituted ketones yield the
in terms of efficacy, antifungal spectrum and safety; and the inva- corresponding oxime ethers respectively within 6 and 7–25 h,
sive candidiasis and aspergillosis has increased dramatically.4 depending on nature and size of the substituent. But ketones with
Though Amphotericin B is efficacious against both candidiasis methyl substitution at C-3 and C-5 take more than 30 h for the
and aspergillosis, it shows severe renal toxicity.5 Hence, the urgent conversion. All 3,5-unsubstituted/3-substituted compounds adopt
need of new molecules to combat bacterial and fungal infections is chair conformation as in Figure 2 (refer Supplementary data for
immense. further details).
Widespread interest in the chemistry of piperidones, pyrans Single crystal XRD study has been carried out for 5b to confirm
and thiopyrans in a large number of natural products has attracted the stereochemistry established by NMR studies.9 Analysis of tor-
due to their biological activities.6 Structure–activity relationship sion angles, asymmetry parameters and least-squares plane calcu-
(SAR) studies from piperidone heterocycles indicated that nature lation10 shows that the piperidine ring adopts a chair conformation
with deviation of ring atoms N1 and C9 from C7/C8/C10/C11 plane
by 0.672(4) and 0.597(2) Å, respectively (Fig. 3). The smallest dis-
* Corresponding author.
E-mail address: prskabilan@rediffmail.com (S. Kabilan). placement parameters q2 = 0.068(2) and q3 = 0.566(2) Å, total
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.038
2982 P. Parthiban et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2981–2985
Figure 2. Chair conformation of compounds 5a–e, 5g–h, 5j–k, 5m–n, 7a–b and
11a–b with equatorial orientation of substituents at C-2, C-3 and C-6.
Scheme 2. Reagents and conditions: (a) KOH, aqueous EtOH, vigorous stirring; (b) Figure 6. Predominant chair conformation of compounds 12a–c with equatorial
C6H5CH2–O–NH2HCl, CH3COONa3H2O, MeOH, reflux. and axial orientations of aryl groups, respectively, at C-2 and C-6, in solution.
2984 P. Parthiban et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2981–2985
Table 2 groups at C-3 and/or C-5 positions play a significant role in eliciting
Antifungal activity of compounds 5a–o, 7a–e and 11a–12c good antimicrobial properties. Hence, these classes of oxime ethers
Compds Minimum inhibitory concentration (lg/mL) can be used as sketch to conquer both bacterial and fungal
C. Candida- Rhizopus A. A. C. infections.
albicans 51 sp. niger flavus neoformans
5a 200 200 >200 >200 200 >200
Acknowledgments
5b 100 200 200 200 100 >200
5c 100 100 50 50 >200 200 The authors would like to acknowledge NMR research center,
5d 50 200 50 200 200 100 IISc-Bangalore and Department of Chemistry, IIT-Madras, respec-
5e 50 100 200 200 100 100
tively, for recording NMR and single crystal XRD. We extend our
5f1 50 50 100 100 200 100
5f2 100 100 50 100 >200 200 thanks to RMMCH, Annamalai University for the antimicrobial
5g 50 200 >200 50 200 100 studies.
5h 25 50 100 50 50 50
5i 25 25 50 25 25 25
5j 200 100 100 200 100 200
Supplementary data
5k 50 50 25 100 100 100
5l 50 6.25 12.5 50 25 50 Complete experimental details, analytical, IR, mass and NMR
5m 100 50 50 100 100 100 data of all compounds. Conformation of alkyl group at C-3 of 5b–
5n 25 12.5 25 50 50 25
d, 5h, 5k, 5n and 7a–b. Crystal data for 5b and 12a. Supplementary
5o 12.5 6.25 25 25 100 12.5
7a 100 100 200 200 200 100 crystallographic data for 5b (CCDC No. 717888) and 12a (CCDC No.
7b 100 100 100 200 100 50 717889) can be obtained free of charge at www.ccdc.cam.ac.uk/
7c1 50 50 50 100 50 25 conts/retrieving.html. Supplementary data associated with this
7c2 12.5 25 25 50 25 12.5 article can be found, in the online version, at doi:10.1016/
7d1 25 50 50 50 50 50
7d2 6.25 6.25 25 50 25 25
j.bmcl.2009.04.038.
7e 50 12.5 25 50 100 6.25
11a >200 200 200 100 >200 >200 References and notes
11b 100 100 50 50 100 200
12a 200 >200 >200 200 100 200 1. Potera, C. Science 1999, 46, 4830.
12b 50 200 50 100 100 50 2. (a) Facts sheet-Swiss Hand Hygiene Campaign, 2007. http://www.swiss-
12c 25 25 50 25 25 12.5 noso.ch.; (b) Gastmeier, P.; Sohr, D.; Geffers, C.; Behnke, M.; Rüden, H. Infect.
Stda 25 25 25 50 50 25 Control Hosp. Epidemiol. 2007, 28, 466; (c) http://www.wrongdiagnosis.com/n/
nosocomial_infections/stats-country.
a
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against Candida-51 and Rhizopus sp. inhibit the visible growth of Oncology 2004, 18, 9; (c) Akins, R. A. Med. Mycol. 2005, 42, 285.
fungi at 50 lg/mL. Compounds 5g, 5j and 5m show better MICs 5. Masubuchi, M.; Ebiike, H.; Kawasaki, K.; Sogabe, S.; Morikami, K.; Shiratori, Y.;
while incorporating methyl at C-3 (compounds 5h, 5k and 5n) Tsujii, S.; Fujii, T.; Sakata, K.; Hayase, M.; Shindoh, H.; Aoki, Y.; Ohtsuka, T.;
Shimma, N. Bioorg. Med. Chem. 2003, 11, 4463.
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doubly potent than Amphotericin B against Rhizopus sp., A. flavus Aridoss, G.; Parthiban, P.; Ramachandran, R.; Prakash, M.; Kabilan, S.; Jeong, Y.
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with methyl at C-3 and C-5 show better activity than correspond-
W.; Taylor, H. W. Int. J. Cancer 1975, 16, 318.
ing piperidone analog in the range of 25–50 lg/mL for most of the 8. (a) Parthiban, P.; Balasubramanian, S.; Aridoss, G.; Kabilan, S. Med. Chem. Res.
tested pathogens. In specific, the Me substitution at C-20000 and C- 2005, 14, 523; (b) Ramalingan, C.; Park, Y. T.; Kabilan, S. Eur. J. Med. Chem. 2006,
41, 683; (c) Bhandari, K.; Srinivas, N.; Kesava, G. B. S.; Shukla, P. K. Eur. J. Med.
60000 show better MICs than others; of the two isomers 7d1 and
Chem. 2009, 44, 437; (d) Mixich, G.; Thiele, K. Arzneim.-Forsch./Drug Res. 1979,
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against C. albicans, Candida-51 and C. neoformans, respectively. Macchia, B. J. Med. Chem. 2002, 45, 4903; (g) Emami, S.; Falahati, M.;
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the trans-isomer 12c shows more potency against all the tested mixture, 9:1, flow rate: 5.0 mL/min, column (stationary phase): symmetry ODS
columnÒ, condition: isocratic, instrument: Waters 486 Tunable absorbance
fungal strains, whose MICs fall in the range of 12.5–50 lg/mL. detector, solution: 50 mg/mL; (b) solvent system: acetonitrile–water mixture,
When compare to the cis-isomer of the piperidone analog 5m, 1:1, flow rate: 3.5 mL/min..
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In overall, the hetero atom of synthesized compounds paved by
chloro/methyl/methoxy-phenyl on either side along with alkyl