Synthesis, conformational preferences and antimicrobial evaluation of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones

Article abstract of DOI:10.1016/j.molstruc.2016.05.028

Five new N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 have been synthesized and characterized using IR, ¹H, ¹³C, DEPT & 2D NMR and mass spectral studies. The NMR spectral data indicate that the N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 prefer to exist in an equilibrium between B1 and B2 conformations. Furthermore, the antibacterial and antifungal studies were carried out. The results show that the piperazinoacetyl piperidin-4-ones 11-15 exhibit good activity against the selected bacterial and fungal strains.

Full text of DOI:10.1016/j.molstruc.2016.05.028

Accepted Manuscript
Synthesis, conformational preferences and antimicrobial evaluation of N-
piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones
A. Akila, P. Jeganathan, S. Ponnuswamy
PII:
S0022-2860(16)30474-4
10.1016/j.molstruc.2016.05.028
MOLSTR 22542
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 3 March 2016
Revised Date: 23 April 2016
Accepted Date: 10 May 2016
Please cite this article as: A. Akila, P. Jeganathan, S. Ponnuswamy, Synthesis, conformational
preferences and antimicrobial evaluation of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones, Journal
of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.05.028.
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ACCEPTED MANUSCRIPT
Synthesis, conformational preferences and antimicrobial evaluation
of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones
A. Akila, P. Jeganathan, S. Ponnuswamy*
P G. & Research Department of Chemistry, Government Arts College (Autonomous), Coimbatore 641 018, Tamil Nadu, India.
* corresponding author. E-mail address : kspons2001@gmail.com
Mobile number : +919244645744
Graphical abstract
A series of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones have been synthesized
and their stereochemistry established. All the synthesized compounds have been
evaluated for their antibacterial and antifungal activities and the results reveal a better
structure – activity relationship.
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Synthesis, conformational preferences and antimicrobial evaluation
of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones
A. Akila, P. Jeganathan, S. Ponnuswamy*
P G. & Research Department of Chemistry, Government Arts College (Autonomous), Coimbatore 641 018, Tamil Nadu, India.
* corresponding author. E-mail address : kspons2001@gmail.com
Mobile number : +919244645744
Abstract
Five new N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 have
1
been synthesized and characterized using IR, H, 13C, DEPT & 2D NMR and mass
spectral studies. The NMR spectral data indicate that the N-piperazinoacetyl-r-2,c-6-
diphenylpiperidin-4-ones 11-15 prefer to exist in an equilibrium between B1 and B2
conformations. Furthermore, the antibacterial and antifungal studies were carried out.
The results show that the piperazinoacetyl piperidin-4-ones 11-15 exhibit good activity
against the selected bacterial and fungal strains.
Keywords: N-Piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones, NMR spectra, A1,3-
strain, stereochemistry, distorted boat conformation.
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1. Introduction
Over the past decades, the incidence of systematic microbial infections has been
increasing dramatically due to an increase in the number of immune-compromised
hosts [1]. In recent years, there has been a growing interest pertaining to the synthesis
of bioactive heterocyclic compounds in the field of medicinal chemistry. Piperazine
nucleus is one of the most important heterocyclic moieties exhibiting remarkable
pharmacological activities [1b].
The nitrogen atoms of the piperazine ring confer bioactivity to molecules and
enhance favourable interaction with macromolecules [2,3].
Piperazinyl linked
ciprofloxacin dimers are potent antibacterial agents against resistant strains,
antimalarial agents and potential antiphychotic agents [4-6]. Piperazine derivatives
containing tetrazole nucleus have been reported as antifungal agents [7]. Substituted
benzamide piperazine derivatives have shown strong antagonistic activity while the
substituted acetamide piperazine derivatives have better dopamine D4 receptor agonist
activity [8,9].
Diphenylpiperazine derivatives possess broad pharmacological action on central
Nervous System (CNS) especially on dopaminergic neurotransmission [10]. N-
Sulfonamide derivatives of 1-(4-flurophenyl)-methylpiperazine exhibit potent
antibacterial activity [11]. Most of the quinoline drugs, such as norfloxacin and
ciprofloxacin having piperazine nucleus have shown broad spectrum activity against
respiratory, urinary, gastrointestinal tract, skin and soft tissue infection caused by
bacteria [12]. Various cyanopiperazine derivatives have been known for their use in the
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synthesis of pharmaceutical intermediates, peptide analogues and antibacterial drugs
[13-15].
The ring conformations of piperidin-4-ones have been changed drastically due to
the attachment of nitroso and acyl functions at nitrogen. The relative influences of allylic
strain, torsional strain, resonance energy due to delocalization of the lone-pair electrons
of nitrogen with the hetero π electron systems have been studied on N- nitroso [16] and
N-acyl [17-24] piperidin-4-ones and other related systems [23g-j].
The synthesis and stereochemistry of N-methylpiperazinoacetyl-2,6-diaryl-
piperidin-4-ones were reported by Kabilan et al [24b]. They possess good antibacterial,
analgesic and antipyretic activities against selected strains. In order to test the activity
of piperazine moiety without a methyl group, some N-piperazinoacetyl-2,6-diphenyl-
piperidin-4-ones have been synthesized and their antibacterial and antifungal activities
evaluated.
2. Experimental
2.1 Materials, methods and instruments
The melting points reported in this work are uncorrected and measured using
melting point apparatus. All IR spectra were recorded in SHIMADZU FTIR 8400S
1
spectrometer and BRUKER - alpha model FTIR using KBr pellets. The H and 13C
NMR spectra were recorded in a CDCl3 solution using TMS as the internal standard in
Bruker DRX 500 and 125 MHz Bruker AMX 400 and 100 MHz NMR spectrometers and
the chemical shifts were referenced to TMS. A 0.05 M solution of the sample prepared
in CDCl3 was used for obtaining the 2D NMR spectra. The tubes used for recording the
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NMR spectra were of 5-mm diameter. Electron impact mass spectra were recorded
using a JEOL GS mate spectrometer. Unless otherwise stated, all the reagents and
solvents were of high grade and purchased from Aldrich and Merck. All the solvents
were distilled prior to use. The parent 2,6-diarylpiperidin-4-one 1-5 and N-chloroacetyl-
r-2,c-6-diphenylpiperidin-4-ones 6-10 were prepared by following the literature
procedures [23-25].
2.2 General procedure for N-piperazinoacetyl-2,6-diphenyl-piperidin-4-ones 11-15
A mixture of N-chloroacetylpiperidin-4-ones 6-10 (1 mmol), piperazine (0.086 g, 1
mmol) and triethylamine (1 ml, 7.2 mmol) in anhydrous benzene (30 ml) was stirred at
RT for 7 hours. The precipitated ammonium salt was filtered and the benzene solution
was washed with water (4x10 ml). The resulting solution was passed through a short
column of silica and concentrated. The pasty mass was purified by crystallization from
benzene and pet-ether (60-80ºC) in the ratio of 95: 5. The analytical data of these
compounds 11-15 are furnished in Table-1.
2.3 Antibacterial activity
All the synthesized N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones (11-15)
were tested for their in vitro antibacterial activity against Proteus mirabilis,
Staphylococcus, E.Coli, Enterococcus faecalis and Klebsiella using Muller-Hint agar
medium by disc diffusion technique [26]. Sterile Muller-Hinton agar plates were
prepared and the agar surface was inoculated with the bacteria. Compounds 11-15
were dissolved in 1mL of DMSO in various concentrations in separate tubes.
Commercially available sterile discs were soaked in the preparation for half an hour. It
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was then placed in empty petri plates for air-drying. Using sterile forceps, the discs
were placed on the surface of the agar plates and gently pressed on to the agar
surface. The culture plates were inverted and incubated for 24-48 hrs at 37°C. After
incubation, zone of clearance was observed and its diameter measured using
microscope.
Zone of inhibition of extracts was compared with standard
Chloramphenicol for antibacterial activity.
2.4 Antifungal activity
The invitro antifungal activity of compounds 11-15 was studied against the fungal
strains viz., Aspergillus niger, Aspergillus flavus, Aspergillus oryzae, Aspergillus
fungigates and Tricoderma viride. For antifungal, assays measuring inhibition of
mycelia growth on agar media were used. Compounds 11-15 were dissolved in 1 ml of
sterile Dimethyl sulfoxide (DMSO) serving as a stock solution. Then it was transferred it
to 4 ml Sabouraud dextrose agar (SDA) growth media in separate tubes and autoclaved
at 121°C for 15 minutes. These tubes were allowed to cool to 50 C and non solidified
SDA of each tube was loaded with various concentration of drug solution. Tubes were
then allowed to solidify at room temperature. Then each glass tube was inoculated with
4 m diameter piece of inoculums removed from 7 days old culture of fungus [27,28]. All
these tubes were incubated at 28±1°C for 10 days. A relative humidity was maintained
at 40-50% in the incubation room. Growth in the media was determined [29] by
measuring linear growth (mm) of the compounds 11-15 and compared with
chloramphenicol which was used as a standard reference.
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3. Results and discussion
The N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 were synthesized
by the reaction of piperazine on the corresponding N-chloroacetyl-r-2,c-6-
diphenylpiperidin-4-ones 6-10. N-Chloroacetyl-r-2,c-6-diphenylpiperidin-4-ones 6-10
were prepared by the action of chloroacetylchloride on the corresponding r-2,c-6-
diphenylpiperidin-4-ones 1-5 in dry benzene using triethylamine as a catalyst [23a,
Scheme-1]. The analytical data of the compounds are presented in Table-1.
In the IR spectra of the compounds 11-15, the appearance of new N-H peak
(Figure-1) around 3320 cm-1 (Table-2) confirms the formation of piperazine derivatives.
1
Furthermore, in the H NMR spectra of 11-15, the shielding of signals of N–COCH2
protons (6-10: 3.92-4.05 ppm [23a] due to the removal of chlorine and appearance of
piperazine signals also confirm the formation of these compounds.
The preferred conformations of the N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-
ones 11-15 have been arrived at from the 1H and 13C NMR spectral data in comparison
with those of the parent r-2,c-6-diphenylpiperidin-4-ones 1-5 [23a]. The N-chloroacetyl-
r-2,c-6-diphenylpiperidin-4-ones 6-10 prefer to exist in a conformational equilibrium
between syn rotamer of boat conformation B1 and anti rotamer of boat conformation B2
[23a].
3.1 1H NMR spectra
1
The signals of H NMR spectra of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-
ones 11-15 are assigned based on their positions, multiplicities and in comparison with
those of the parent amines 6-10. In all these compounds the aromatic protons of 11-15
show signals around 7.53-6.96 ppm. The signals in the range of 6.56-4.93 ppm are due
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to H2 and H6 protons of 11-15. The piperazine protons of 11-15 appear in the range of
3.09-2.90 and 2.58-2.44 ppm (Figure-2). The complete assignments of all the 1H NMR
signals of 11-15 are presented in Table-3. The cis and trans vicinal coupling constants
for the H6 benzylic protons of 12-14 are extracted from their coupling partners H5a and
H5e. The extracted coupling constant values of 12-14 are presented in Table-4. The
vicinal coupling constant data are employed to calculate the dihedral angles between
the vicinal protons by DAERM (Dihedral Angle Estimation by Ratio Method) [30].
3.2 13C NMR spectra
13
In the C NMR spectra, the signals in the range of 128.8-122.6 ppm are due to
aromatic carbons of 11-15. The CO of N-COCH2 carbon appears around 170.1-171.6
ppm for 11-15. Similarly, the C=O group at C4 of 11-15 appears around 203.5-211.1
ppm. The signals in the range of 60.0-63.0 and 53.9-63.0 pm are due to C2 and C6
carbons of 11-15, respectively. The C3 and C5 carbons of 11-15 show signals around
31.5-58.1 and 44.2-52.4 ppm, respectively. The piperazine carbons of 11-15 appear in
the range of 43.7-54.7 ppm (Figure-3). The unambiguous assignment of 13C NMR
signals of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 has been made
using their DEPT 135 and HSQC NMR (Figure-4) spectra and is presented in Table-5.
3.3 Orientation of >C=O group
The N-X=Y group can adopt either coplanar or perpendicular orientation to the
dynamically averaged plane of the ring. The broadening of one of the benzylic protons
signal of 11-15 at room temperature is due to existence of restricted rotation about N-
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CO bond in the molecule, which could be possible only in the coplanar orientation with
respect to C2-N1-C6 plane of the piperidine ring system.
The coplanar orientation of the compounds 11-15 has been further confirmed from
the following observations:
(i) Greater deshielding of benzylic protons compared to the parent piperidin-4-ones
1-5 in the 1H NMR spectra (Table-6).
(ii) Greater shielding of benzylic carbons (C2 & C6) in the 13C NMR spectra (Table-6),
when compared to piperidin-4-ones 1-5.
3.4 Preferred conformation of the ring
All the N-piperazinoacetyl compounds 11-15 have similar trend in the NMR spectral
data compared to those of the parent N-chloroacetylpiperidin-4-ones 6-10. Hence,
compound 14 is taken as a representative example for the conformational analysis.
The possible conformations for the N-piperazinoacetyl-c-3,t-3-dimethyl-r-2,c-6-
diphenylpiperidin-4-one (14) with coplanar orientation of N-C=O group are depicted in
Figure-5.
(i) Chair conformation with equatorial phenyl groups (CE)
(ii) Alternate chair conformation with axial phenyl groups (CA)
(iii)Boat conformation with equatorial phenyl groups (BE)
(iv)Boat conformation with axial phenyl groups (BA)
(v) Boat conformation B1 & B2
In the chair conformation CE of N-piperazinoacetyl-c-3,t-3-dimethyl-r-2,c-6-
diphenylpiperidin-4-one (14), the dihedral angles expected between H6 benzylic proton
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and H5e & H5a protons are around 60o and 180o, respectively, (φcis = φ6a, 5e ≈ 60o and
φ
trans = φ6a, 5a ≈ 180o). However, the observed cis coupling constant (3J6a,5e) value of 7.0
Hz for the compound 14 (Table-4) and the corresponding dihedral angle of 36o (Table-
4) could not be explained using the CE conformation. In addition, the chair
conformation CE with equatorial phenyl groups is destabilized by A1,3-strain and the
benzylic protons at C2 and C6 occupy axial orientations and are in out of plane region.
The observed deshielding of H2 and H6 (∆δ = 0.03 and 0.15 ppm) from the parent 9
cannot be explained using the model proposed by Paulsen and Todt for the anisotropic
effect of amides [31]. Hence, the possibility of chair conformation CE is ruled out. In
order to alleviate A1, 3-strain, an alternate chair CA may be considered.
In the alternate chair conformation CA and boat conformation BA with axial phenyl
groups, A1,3-strain is relieved. But the two phenyl groups would exhibit 1,3-diaxial
interaction which destabilizes the ring. The expected cis and trans coupling constants
would be around 2-4 Hz. But the observed J value could not be used to explain the
conformation CA & BA. Hence, the possibility of conformation CA & BA is ruled out.
The boat conformation BE is destabilized by the A1,3-strain and bond eclipsing
interaction. Expected vicinal coupling constant would be around 8 Hz and 4Hz, but the
observed values eliminated the possibility of BE conformation.
The deshielding of benzylic protons and the observed higher value of the vicinal
coupling constants similar to N-chloroacetyl-2,6-dipheylpiperidin-4-ones 6-10, could only
be explained by assuming the equilibrium between the boat conformation B1 and B2
with one axial and one equatorial phenyl groups. The shielding of C2 and C6 carbons
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also supports the above conformation. The N-C=O group is coplanar to the C2-N-C6
plane of the piperidine ring causing γ-eclipsing interaction between C-O and N1-C2/N1-
C6 bonds. This may be explained by considering a slight twist along N-C2-C3 bond.
The slight twisting along N-C2-C3 bond would reduce the dihedral angle between N-C-O
and C-N-C2 Plane.
Hence, it is concluded that the N-piperazinoacetyl-c-3,t-3-dimethyl-r-2,c-6-
diphenylpiperidin-4-one (14) prefers to adopt an equilibrium between the boat
conformations B1 and B2 (Figure-5). Similarly all the N-piperazinoacetyl-r-2,c-6-
diphenylpiperidin-4-ones 11-15 prefer to exist in an equilibrium between the boat
conformations B1 and B2 (Figure-5).
3.5 Antibacterial activity
In general all the synthesized compounds exert a wide range of modest
antibacterial activity against the tested organism except 11 (Table-7). Among the N-
piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15 the compounds 13 & 15 with
isopropyl group at C3 position and two methyl groups at C3 & C5 positions, respectively,
have superior activity against all the organisms. The compound 12 containing ethyl
group at C3 position exhibits superior activity against Proteus mirabilis, Staphylococcus,
and Enterococcus faecalis. The compound 12 shows better activity against E.Coli and
Klebsiella. Furthermore, compound 13 with an isopropyl group shows better activity
when compared to compound 12. Compound 13 exhibits superior activity against
Proteus mirabilis, Staphylococcus, E.Coli, Enterococcus faecalis and Klebsiella.
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Introduction of another methyl group at C3 position (Compound 14) shows
superior activity against Proteus mirabilis, better activity against Staphylococcus and
Klebsiella, good activity against E.Coli, and better activity against Enterococcus
faecalis. Similarly the two methyl groups at 3 and 5 positions in compound 15 increase
the activity against all the organisms. It shows double the amount of activity against
Enterococcus faecalis, Klebsiella, Staphylococcus, Proteus mirabilis and E.Coli. All the
compounds exhibit significant antibacterial activity at 250ꢀg/mL. The graphical
representation of the antibacterial activity is presented in Figure-6.
The antibacterial activity of the N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-
ones 11-15 is comparable to that of N-methylpiperazinoacetyl-r-2,c-6-diphenylpiperidin-
4-ones [24b] but it is found to be less when compared with that of compounds
containing p-chlorophenyl piperidin-4-ones [24b].
3.6 Antifungal activity
Generally all the synthesized compounds exert a modest in vitro antifungal
activity against all the tested organisms except 11 (Table-8). The compound 12,
containing ethyl group at C-3 position exhibits superior activity against Aspergillus
flavus, Aspergillus oryzae and Aspergillus fumigates when compared to the standard
chloramphenicol. Compound 12 shows better activity against Tricoderma viride and
significant activity against Aspergillus niger.
Compound 13 obtained by the replacement of isopropyl group in place of ethyl
group at C3 in compound 12 shows superior activity against Aspergillus flavus and
Aspergillus fumigates and good activity against Aspergillus oryzae and Tricoderma
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Viride and significant activity against Aspergillus niger. Compound 14 obtained by the
introduction of one more methyl group at C3 position in compound 11 increases the
activity against Aspergillus oryzae and a better activity against Aspergillus fumigates
and good activity against Aspergillus flavus and Tricoderma viride and significant
activity against Aspergillus niger.
Compound 15 containing two methyl groups at C3 and C5 position shows better
activity against Aspergillus oryzae, Aspergillus fumigates & Tricoderma viride and good
activity against Aspergillus niger & Aspergillus flavus. In general, all the compounds
exhibit significant antifungal activity at 250ꢀg/mL. The graphical representation of the
antifungal activity is presented in Figure-7.
Thus the antifungal activity of the N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-
ones 11-15 is more compared to that of N-methylpiperazinoacetyl-r-2,c-6-
diphenylpiperidin-4-ones [24b] but it is less when compared with that of compounds
containing p-chlorophenylpiperidin-4-ones [24b].
Conclusion
Thus, in this work, five N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15
have been synthesized and their stereochemistry studied with the help of 1H, 13C, DEPT
and 2D NMR (1H-1H COSY and HSQC) spectral data. In addition mass spectra were
also recorded. On the basis of NMR spectral data, it is concluded that the compounds
11-15 prefer to adopt an equilibrium between boat conformations B1 and B2.
Furthermore, the antibacterial and antifungal studies have been carried out. The results
show the greater activity of all the compounds 11-15 against all the tested micro
organisms when compared to the standard reference drug.
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Acknowledgements
SP thanks UGC for financial assistance in the form of Major Research Project.
[No. F. 39-724/2010 (SR)]. We thank (SAIF) IIT Chennai, (SIF) IISC Bangaluru for
recording NMR spectra. We thank Dr. R. Venkataramanan for his useful suggestions.
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b) G. Aridoss, P. Parthiban, R. RamaChandran, M. Prakash, S. Kabilan, Y. T. Jeong,
Eur. J. Med. Chem. 44 (2009) 577-592.
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b) V. Baliah, R. Jeyaraman, L. A. Chandrasekaran, Chem. Rev. 83 (1983) 379-423.
c) V. Baliah, A. Ekambaram, T. S. Govindarajan, Curr. Sci. 23 (1954) 264.
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28. J. N. Eloff, J. Ethanopharmacol. 60 (1998)1-8.
29. W. W. Anokbonggo, J. Plant Media. 28 (1975) 69-75.
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17

ACCEPTED MANUSCRIPT
Scheme caption:
Scheme 1:
Synthesis of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-ones 11-15
18

ACCEPTED MANUSCRIPT
Figure captions:
Figure – 1
IR spectrum of compound 13
Figure - 2
1H NMR spectrum of compound 13
Figure - 3
13 C NMR spectrum of compound 13
Figure – 4
HSQC NMR spectrum of compound 13
Figure – 5
Possible conformation of the compounds 11-15
Figure – 6
Graphical representation of antibacterial activity for the compounds 11-15
Figure – 7
Graphical representation of antifungal activity for the compounds 11-15
19

ACCEPTED MANUSCRIPT
Table captions
Table - 1
Analytical data for the compounds 11-15
Table - 2
IR spectral data for compounds 11-15
Table - 3
1H NMR Chemical shift values (δ ppm) of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-
4-ones 11-15
Table - 4
Coupling constant and dihedral angles for selected N-piperazinoacetyl-r-2,c-6-
diphenylpiperidin-4-ones 11-15
Table - 5
13C NMR Chemical shift values (δ ppm) of N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-
4-ones 11-15
Table - 6
Chemical shift differences between the N-piperazinoacetyl-r-2,c-6-diphenylpiperidin-4-
ones 11-15 and their parent N-chloroacetyl-r-2,c-6-diphenylpiperidin-4-ones 6-10
Table - 7
Antibacterial activity for the compounds 11-15
Table - 8
Antifungal activity for the compounds 11-15
20

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Table - 1
Melting point
Yield
%
Compounds Molecular formula
°C
11
12
13
14
15
C24H29N3O2
(391)
226-228
51.2
64.1
50.1
49.3
44.4
C25H31N3O2
(405)
220-222
142-144
108-110
113-114
C26H33N3O2
(419)
C25H31N3O2
(405)
C25H31N3O2
(405)
1

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Table 2
Compounds
IR (cm-1)
3392(N-H), 3056-3030 (C-H Aromatic), 2935-2824 (C-H
Aliphatic), 1715(C=O at C4), 1642(C=O of N-COCH2), 1453,
1079
11
3340(N-H), 3056-3030 (C-H Aromatic), 2944-2820 (C-H
Aliphatic), 1711(C=O at C4), 1634(C=O of N-COCH2), 1496,
1024
12
13
14
15
3328(N-H), 3090-3030 (C-H Aromatic), 2968-2816 ( C-H
Aliphatic), 1702(C=O at C4), 1631(C=O of N-COCH2), 1498,
1017
3305(N-H), 3064 (C-H Aromatic), 2999( C-H Aliphatic),
1714(C=O at C4), 1647(C=O of N-COCH2), 1600, 1024
3326(N-H), 3087-3031 (C-H Aromatic), 2975-2819( C-H
Aliphatic), 1716(C=O at C4), 1635(C=O of N-COCH2), 1585,
1016
2

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Table – 3
Com
pound
CH2 of Aromatic
NCOCH2 protons
CH at
C3
CH2 at
C3
CH3 at
C3
H2
H3
H5a
H5e
H6 Pip (a) Pip(b) NH
11
12
13
14
15
6.57
a
2.80
a
6.11
3.04
2.91
2.91
3.02
3.12
2.52 2.16
a
7.53-6.99
-
-
1.07
1.06
6.28 2.87 3.03 2.70 5.81
6.56 2.80 2.84 2.75 5.70
2.44 1.71 3.17,3.03 7.38-6.85
2.47 2.14 3.27,2.95 7.36-6.96
-
1.28
2.03
-
-
-
1.04,1.13
1.32
6.20
4.93
-
b
c
2.92 5.59
4.93
2.54 4.93
2.58 5.46
b
c
7.34-6.65
7.35-7.11
-
-
c
c
1.03
a, b, c indicates merged with Piperazine (a) protons
3

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Table – 4
Compound
3J5e,6a
3J5a,6a
7.0
Φ5e,6a
Φ5a,6a
167
12
13
14
3.0
6.50
7.0
47
32
36
8.0
152
10.0
156
4

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Table – 5
Com
pound
Pip (a)
carbons carbons
Pip(b)
CO
CO of
Aromatic
Carbons
Ipso
carbons
CH CH2
CH3 at
C3
C2
C3
C5
C6
NCOCH2
62.7
at C4 NCOCH2
at
C
at
C
62.2 32.8 47.3 56.9
62.9 31.5 23.3 52.3
60.4 58.2 44.4 56.9
62.0 47.4 45.1 56.9
63.0 45.4 45.4 63.0
45.7
45.9
45.8
44.1
43.7
53.4
54.7
54.7
52.1
51.4
209.6
209.9
209.8
211.2
211.2
171.2
171.6
171.4
170.5
171.4
128.8-125.8 141.2,128.9
128.8-126.3 141.6,129.0
-
-
19.6
11.9
11
12
13
14
15
54.8
-
14.1
62.8
128.6-127.2 141.1,126.2 28.2
-
-
-
20.5,21.7
21.5,25.9
14.1
61.6
129.5-125.1 142.6,139.0
128.8-127.6 141.0,129.0
-
-
61.3
5

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Table – 6
Compound
H2
H6
C2
C6
11
6
6.56
5.40
3.62
6.27
6.14
3.73
6.56
6.49
3.99
6.20
6.17
3.84
6.11
5.93
4.09
5.81
5.53
4.07
5.70
5.44
4.09
5.59
5.44
4.07
62.0
54.5
68.4
60.0
56.5
66.7
60.4
57.2
66.6
62.0
62.8
69.7
53.9
61.6
61.5
54.8
56.5
61.8
56.9
54.6
61.7
56.9
57.4
61.8
1
12
7
2
13
8
3
14
9
4
15
10
5
4.93
63.0
61.1
68.8
5.49
3.61
6

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Table - 7:
Sample
Zone of inhibition (mm)
Proteus mirabilis Staphylococcus E.Coli E. faecalis Klebsiella
(250 µg/disc)
11
12
13
14
15
3
6
6
6
7
5
6
7
3
4
7
10
11
6
12
11
4
14
7
13
7
12
11
15
16
Chloramphenicol
5
7
9
6
8
250 µg/disc
Table - 8
Zone of inhibition (mm)
Sample
(250 µg/disc)
A. niger
A. flavus
A. oryzae
A. fumigatus T.viride
11
12
13
14
15
4
6
7
6
5
3
7
6
7
4
5
9
6
8
6
4
5
7
6
5
6
6
8
7
8
Chloramphenicol
6
5
7
6
8
250 µg/disc
7

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R
R1
H
1
2
3
4
5
Me
Et
6
11
12
13
14
15
H
7
i-Pr
H
8
(Me)2 H
Me Me
9
10
Scheme - 1

ACCEPTED MANUSCRIPT
Figure - 1