Synthesis and antibacterial activity of some novel piperazinophanes with an intraannular ester functionality

Article abstract of DOI:10.1039/c6nj01956k

1:1 and 2:2 oligomeric piperazinophanes with an intraannular ester functionality have been synthesized via Mannich reaction of various aromatic esters with piperazine by a one-pot reaction under benign conditions through the multicomponent reaction methodology. The newly synthesized piperazinophanes were characterized using spectral and analytical methods. The ester based 1:1 oligomeric piperazinophanes exhibit good target binding ability in molecular docking studies and also show better antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pyogenes bacteria than the 2:2 oligomeric piperazinophanes.

Full text of DOI:10.1039/c6nj01956k

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Synthesis and antibacterial activity of some novel Piperazinophanes
with intra annular ester functionality
Sivasamy Selvarani and Perumal Rajakumar*
Department of Organic Chemistry, University of Madras, Maraimalai (Guindy) Campus
Chennai – 600 025, INDIA
Abstract:
1:1 and 2:2 oligomeric piperazinophanes with intra annular ester functionality
have been synthesized by Mannich reaction of various aromatic esters with piperazine by
a oneꢀpot reaction under benign condition through multicomponent reaction
methodology. The newly synthesized piperazinophanes were characterized by spectral
and analytical methods. The ester based 1:1 oligomeric piperazinophanes exhibit good
target binding ability in molecular docking studies and also show better antibacterial
activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and
Streptococcus pyogens bacteria than the 2:2 oligomeric piperazinophanes.
Keywords: supramolecular, piperazine, hostꢀguest, ester, Mannich reaction, antibacterial.
Eꢀmail: perumalrajakumar@gmail.com
Tel: 044ꢀ22202814; Fax: +91 44 235 2494.
________________________________________________________________________
Introduction:
Recently, cyclophanes containing piperazine bridge with intra annular ester
functionality have attracted the researchers due to their biological activity and by the
presence of multidentate coordinating sites. Mostly, ester derivatives such as aspirin,
methyl salicylate are dispensed as prodrugs, which on hydrolysis get converted to the
corresponding active form, because the drug molecules containing ester functionality
undergo rapid hydrolysis when compared to other functional groups.1 Ester
1

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functionalized compounds are used in perfume industry because of their aroma nature.2 In
general ester derivatives are able to enhance solubility and crystallinity3 and generate
bioactive molecules or modify the properties of existing bioactive molecule. Ester
derivatives are also used in electron transfer and electron exchange devices and also have
been widely used in various fields such as textiles,3 drug synthesis,4 lubricant additives,5
flavoring agents,6 personal care,7 plastics,8 pharmaceuticals,9 house hold products and for
biological activities such as antibacterial,10 antifungal11 and so on.
Cyclophane with heterocyclic ring system possesses binding site for metal ions12
and provide propitious properties as molecular hosts. Host Guest system observed in
molecular recognition reveal molecular expletive in supramolecular chemistry.13
Molecular recognition plays vital role in biological systems involving host guest
interactions. Molecular recognition in supramolecular chemistry is regulated by nonꢀ
covalent intermolecular interactions such as hydrogen bonding, metal coordination,
hydrophobic πꢀπ stacking, vanderwaal’s and electrostatic interactions. Cyclophanes help
in developing selective probes for various guest molecules by forming nonꢀcovalent
interactions in the form of inclusion complexes inside the defined cavity with binding
sites for metal ions providing propitious properties as molecular host.14 However, the
biological activity of piperazinophanes are rarely reported.15 Piperazinophanes with ester
functionality could furnish supramolecular sensing, recognition and self assembling
properties.
Piperazines are new motif that can participate in multiple nonꢀcovalent
16
17
18
interactions such as metal coordination, anion recognition self assembly and also
can exhibit wide applications in biology if used in the synthesis of rigid cavity
2

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cyclophanes and hence can have ability to form complexes with selectivity that can
sharply change the spectral properties. Piperazine moiety function as multiple target due
to their auspicious properties such as solubility, bioavailability, hydrophilic and
pharmocophoric nature. Further, it can enhance the hydrophilicity and binding with
macromolecules as seen in drug molecules like sildenafil, imatinib.19
Considering the therapeutic importance of various aromatic esters and piperazine
derivatives, our interest is to synthesize ester based piperazinophanes from readily
available aromatic carboxylic acid and propargyl alcohol under Mannich reaction
conditions. The present investigation focus on the synthesis, characterization and
antibacterial activity of a new class of ester based piperazinophanes by a one pot Multi
Component Reaction (MCR) of terminal alkyne with piperazine through Mannich
reaction.
Result and discussions:
Ester based Piperazinophanes
Ester based piperazinophanes 1-10 (Figure 1) can be synthesized from the
corresponding bispropargyloxy biacyl precyclophane. The bisalkyne precyclophane can
be obtained by the reaction of the various carboxylic acid chlorides with propargyl
alcohol. Mannich reaction in the current study is efficiently utilized for the synthesize of
macrocycles by a one pot process of coupling the terminal alkyne, secondary diamine,
and formaldehyde. In order to synthesis ester functionalized piperazinophanes 1-10, the
required precyclophanes 16, 17, 18, 19 and 20 are obtained by the reaction of various
acid chlorides with propargyl alcohol.
3

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NO2
O
O
O
O
N
N
N
N
O
O
O
O
O
N
O
N
O2N
NO2
O
O
O
O
6
1
O
O
N
N
N
N
O
O
O
O
O
O
O
O
7
N
N
2
O
O
O
O
O
O
O
O
O
O
N
N
N
N
O
O
O
O
O
N
O
N
8
3
O
O
O
O
N
N
N
N
O
O
O
N
O
N
9
4
O
O
O
O
O
N
N
O
S
O
N
O
N
S
S
N
O
N
O
O
O
10
5
Figure 1: Molecular structure of ester based piperazinophane forms macrocycles 1–10
Synthesis and characterization of piperazinophanes
The synthesis of ester based 1:1 oligomeric cyclophanes 1, 2, 3, 4 and 5 and 2:2
oligomeric cyclophanes 6, 7, 8, 9 and 10 is shown in scheme 1. Reaction of 2.2 equiv. of
propargyl alcohol, 21 with one equiv. of each 5ꢀnitroisophthaloyl chloride 11, phthaloyl
4

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chloride 12, isophthaloyl chloride 13, terephthaloyl chloride 14 and thiopheneꢀ2,5ꢀ
dicarbonyl dichloride 15 afforded the precyclophane ester 16, 17, 18, 19 and 20, in 76%,
80%, 82%, 78% and 70% yields, respectively (Scheme 1). The 1H NMR spectrum of the
precyclophane 16 showed the alkyne protons as a triplet at δ 2.59 and Oꢀmethylene
protons as a doublet at δ 5.02 in addition to the signals for the aromatic protons. The 13C
NMR spectrum of the precyclophane 16 displayed signals for the Oꢀmethylene and the
two acetylenic carbons at
δ 53.5, and 76.0, 76.7, and ester carbonyl carbon at δ 162.8 in
addition the signals for four aromatic carbons. In the mass spectrum the appearance of
molecular ion peak at m/z 287 [M+] also confirmed the structure of the precyclophane 16.
Further the elemental analysis also supported the composition of the precyclophane 16.
Similarly, the structure of the precyclophanes 17, 18, 19 and 20 was also confirmed from
spectral and analytical data. Diacid chlorides 11, 12, 13, 14 and 15 were obtained by the
reaction of the corresponding dicarboxylic acid and thionyl chloride by the usual
procedure, as reported earlier.
Coupling of 1.0 equiv. of each of the precyclophane 16, 17, 18, 19 and 20 with
1.0 equiv. of piperazine, and 2.0 equiv. of formaldehyde from 37ꢀ41% formalin solution
in the presence of 1.0 equiv. CuCl in dioxane at 90 °C for 2 h afforded the 1:1 oligomeric
ester functionalized piperazinophanes 1, 2, 3, 4 and 5 in 32%, 26%, 33%, 35% and 30%,
and 2:2 oligomeric piperazinophane esters 6, 7, 8, 9 and 10 in 23%, 28% , 30%, 32% and
30% yields, respectively. (Scheme 1)
1
The H NMR spectrum of 1:1 oligomeric macrocyclic ester 1 displayed three
sharp singlets at
δ 2.78, 3.37, 4.99 for eight protons of the piperazine, four protons of the
Nꢀmethylene and four protons of Oꢀmethylene group in addition to the signals for the
13
aromatic protons. The C NMR spectrum of 1:1 oligomeric macrocyclic ester 1 showed
five signals at δ 46.6, 51.4, 55.2 and 78.2, 84.7 for the piperazine, Nꢀmethylene,
5

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Scheme 1: Reagents and conditions: i) DMAP, DCM (dry), 24 h, 16 (76%);. 17 (80%);
18 (82%); 19 (78%); 20 (70%). ii) piperazine (1.0 equiv.), formaldehyde (2.0 equiv.)
from 37ꢀ41% formalin solution, CuCl (1.0 equiv.) 90 °C, 2 h. 1 (32%); 2 (26%); 3 (33%);
4 (35%); 5 (30%); 6 (23%); 7 (28%); 8 (30%); 9 (32%); 10 (30%)
6

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Oꢀmethylene and acetylenic carbons and the ester carbonyl carbon at
δ 163.4 in addition
to the signals for four aromatic carbons. The appearance of molecular ion peak at m/z 397
and also the elemental analysis supported the structure of the macrocyclic ester 1.
Similarly, the structure of 1:1oligomeric ester macrocycles 2, 3, 4 and 5 was confirmed
from spectral and analytical data as shown in SI.
1
The H NMR spectrum of 2:2 oligomeric cyclophane ester 6 displayed a sharp
singlet at
δ
2.80 for sixteen protons of the piperazine and the NꢀCH2 protons appeared as
a singlet at
δ
3.45, OꢀCH2 protons as a singlet at 5.04 and the aromatic protons
δ
appeared in the region at δ 8.99 to 9.06. The 13C NMR spectrum of the 2:2 oligomeric
cyclophane ester 6 showed signals at δ 46.9, 51.6, 54.0 and 78.7; 82.7and for piperazine,
Nꢀmethylene, OꢀCH2 and alkyne carbons and the aromatic carbons appeared in the region
at δ 128.6ꢀ148.5 the carbonyl carbon of the ester moiety appeared at δ 163.0. The mass
spectrum of the 2:2 oligomeric cyclophane ester 6 showed the molecular ion peak at m/z
794 [M+]. The structure of the 2:2 oligomeric cyclophane ester 6 was confirmed from
analytical data (Scheme 1). Similarly the structure of the 2:2 oligomeric cyclophane ester
7, 8, 9 and 10 was characterized from spectral and analytical data as shown in SI.
Antibacterial activity:
There is always need to search for alternative antibacterial drugs for two reasons.
The microorganism may develop immunity towards the existing drug and the drug itself
can have side effects which will be seen only after long time usage. Antibacterial drugs
could be of natural or semi synthetic or synthetic in origin. However, the synthetic drugs
are more preferred because structural modification can be carried out from docking
studies and structure activity relationship can be studied. Antibacterial activity of
carbazolophane amides against Escherichia coli, Klebsiella pneumoniae, Staphylococcus
aureus and Staphylococcus pyogens bacteria has been reported from our laboratory
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earlier20 and the reported carbazolophanes have shown remarkable antibacterial activity
only against Staphylococcus aureus. Though, we have shown that imino cyclophane21
exhibited good antibacterial activity against Escherichia coli, Klebsiella pneumoniae and
Staphylococcus aureus bacteria, the synthesis and the yields are challenging. Hence,
recently we have synthesized various sulphonophanes22 and tested their antibacterial
activity towards Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus bacteria
and we have observed that their antibacterial activity is comparable to that of the
piperazinophanes reported herein. In fact the antibacterial activity expressed as MIC
values of some of the sulphonophanes reported earlier from our research group lies in the
range of 10 ꢁg/mL to 20 ꢁg/mL and in the present study, the synthesized
piperazinophanes shows the MIC values in the range of 12.5 ꢁg/mL to 25 ꢁg/mL for the
three pathogens viz against Escherichia coli, Klebsiella pneumoniae and Staphylococcus
aureus. The antibacterial activity of the compounds S1 (piperazinophane 1) to S10
(piperazinophane 10) is tested by resazurin reduction method. The four test bacteria
chosen are Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and
Staphylococcus pyogens and streptomycin is employed as the standard. Table 1 shows the
MIC values expressed in micromoles (ꢁM) for all the synthesized compounds 1-10
against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and
Streptococcus pyogens bacteria with streptomycin as the standard drug of choice. 1:1
Oligomeric cyclophane esters S1 to S5 show antibacterial activity against the human
pathogens Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and
Streptococcus pyogens which is less than that of reference drug viz streptomycin. The 2:2
oligomeric cyclophane esters exhibit nil activity towards the two micro organism viz
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Escherichia coli, Klebsiella pneumoniae, however they inhibit the growth of
Staphylococcus aureus and Streptococcus pyogens to some extent. The ester based 2:2
oligomeric cyclophane S10 is inactive towards all the tested pathogens. Piperazinophane
S1 show better activity in controlling the growth of Escherichia coli than cyclophanes S3
and S4 which are structurally similar. Surprisingly, the ortho isomer i.e. compound S2 is
less active than the piperazinophanes S3 and S4, when tested with Escherichia coli
bacteria. Cyclophanes S2 and S4 show similar activity towards the inhibition of the
growth of Klebsiella pneumoniae and Staphylococcus aureus. Compounds S2, S4 and S8
show better activity than other piperazinophanes towards the inhibition of the growth of
Streptococcus pyogens. In conclusion 2:2 oligomeric piperazinophanes S7, S8, S9 and
S10 are inactive against gram negative bacteria and except piperazinophane S10 all of the
other piperazinophanes (1-9) show moderate activity against gram positive bacteria.
Hence, based on the MIC values piperazinophanes S2 and S4 would be the better choice
as antibacterial agent for the pathogen Klebsiella pneumoniae, Staphylococcus aureus
and Streptococcus pyogens where as piperazinophane S1 would be the better choice for
the Escherichia coli bacteria when compared with all other synthesized cyclophanes.
Dimethyl sulfoxide was used as the control and exhibits nil activity with reference to all
the tested bacteria.
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Table 1: Minimum Inhibitory Concentration of test compounds by resazurin
reduction assay:
MIC (micromoles ꢁM)
Bacterial pathogens
Samples /
Cyclophanes
Escherichia
coli
Klebsiella
Staphylococcus Streptococcus
pyogens
0.126
pneumoniae aureus
S1/1
0.031
0.142
0.071
0.071
0.279
0.126
NA
0.126
0.036
0.071
0.036
0.279
NA
0.126
S2/ 2
0.071
0.142
0.071
0.139
0.126
0.142
0.142
0.142
NA
0.071
0.142
0.071
0.279
0.126
0.142
0.071
0.142
NA
S3/3
S4/4
S5/5
S6/6
S7/7
NA
S8/8
NA
NA
S9/9
NA
NA
S10/10
Streptomycin
Control (DMSO)
NA= Nil activity
NA
NA
0.001
NA
0.005
NA
0.005
NA
0.001
NA
The antibacterial activity of the synthesized compounds were tested by resazurin
reduction method as shown in Figure 2.
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Figure 2: Antibacterial activity of the synthesized piperazinophanes by resazurin
reduction method
Figure keys:
C4 ꢀControl ꢀ dye + Staphylococcus aureus+ without compound
S10 – Compound + dye + Escherichia coli
S1b to S5b – Compound + dye + Staphylococcus aureus
P3 – Streptomycin + dye + Staphylococcus aureus
Structure activity relationship studies:
The in vitro antibacterial activity reveals that the ester and diyne functionality
along with piperazine ring (1-5) show better antibacterial activity as compared to other
piperazinophanes. Among the 1:1 oligomers the inhibitory activity depend on the nature
of the substituents. Electron withdrawing group such as ester, when placed in the pꢀ
position of the intra annular cavity as in the piperazinophane S4 show better activity than
all other piperazinophanes. The 1:1 oligomer showed better antibacterial activity because
of high solubility in polar solvents and hence can be easily applied to a substrate and also
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has low molecular weight. Piperazinophane 1 shows better antibacterial activity against
Escherichia coli may be due to the presence of the nitro functionality and rigid smaller
cavity. Though cyclophane 6 also has nitro group, the cavity is bigger and hence shows
nil activity against Escherichia coli bacteria. Similarly cyclophane 4 shows better
antibacterial activity against Klebsiella pneumoniae however the corresponding 2:2
oligomer 8 shows nil activity due to larger cavity size. Further, with respect to the
bacteria Staphylococcus aureus and Streptococcus pyogens both cyclophanes 2 and 4
show similar activity. Hence the cavity size and the presence of functional group at the
intraanular position control the antibacterial activity. In conclusion, 1:1 oligomers
provide better antibacterial activity against both gramꢀpositive and gramꢀnegative
bacteria than high molecular weight 2:2 oligomeric piperazinophanes. Further, structure
activity studies report that ester cyclophane S5 having alkyl and thiophene ring show less
inhibitory activity. Thus, the nature of the aromatic unit, the ester and diyne skeleton
attached to piperazine has a strong influence on the extent of antibacterial activity.
Molecular docking studies:
The molecular docking study helps to find the binding of the tested compounds
(ligand) with protein of interest (target). Molecular docking study has shown that in
general compound binds well at the active site of protein biotin carboxylase (PDB ID:
2V59). The coꢀcrystal ligand interacts with the residues GLUꢀ201, LYSꢀ202, LEUꢀ204
and LYSꢀ159 with the glide score of 11.742 and glide energy of ꢀ57.232 kcal/mol as
evident from Fig 20 given in SI. Among the ten synthesized compounds, cyclophane S1,
S2 and S4 showed binding with the target protein and the remaining compounds did not
dock with the active pocket of the protein due to the incompatibility of their structures to
the active site. Among S1, S2 and S4 cyclophane, S4 showed the best binding affinity to
the biotin carboxylase with a glide score and glide energy comparable to the coꢀcrystal
12

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ligand. S2 also showed interaction with LYSꢀ159, coꢀcrystal active site. Compound S1
showed hydrogen bond interaction with the HISꢀ236 with the glide score of 5.721 and
glide energy of ꢀ49.417kcal/mol as evident from Fig 21 given in SI. Compound S2
showed interactions with the TYRꢀ203 and LySꢀ159 with the glide score of 8.212 and
glide energy of 46.669 kcal/mol respectively as evident from Fig 22 given in SI. The
compound S4 showed hydrogen bond interaction with the residue LEUꢀ204 with the
glide score of 7.622 and glide energy of ꢀ40.772kcal/mol (Figure 3).
Figure 3: Molecular Docking of Compound S4 in the active pocket of Protein (PDB IDꢀ
2V59)
Conclusions
In conclusion, efficient oneꢀpot synthesis of the novel ester based 1:1 and 2:2
oligomeric piperazinophanes 1-10 has been successfully achieved under mild conditions
and their in vitro antibacterial activity against four human pathogens Escherichia coli,
Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pyogens revealed that
piperazinophane 4 exhibited excellent antibacterial activity than all other synthesized
piperazinophanes, which is also supported by molecular docking studies. All the 1:1
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oligomeric piperazinophanes show better antibacterial activity against Escherichia coli,
Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pyogens than 2:2
oligomeric piperazinophanes. The structure activity relationship also reveals that the ester
functionality on the benzene ring at the pꢀposition in the intra annular cavity and diyne
skeleton attached to the piperazine molecule has a strong influence on the antibacterial
activity.
Acknowledgements
The authors acknowledge UGC, New Delhi, India for financial support and DST,
New Delhi for NMR facility under DSTꢀFIST programme to the Department of
Organic Chemistry, University of Madras. SS thanks to DST PURSE Phase II for
providing fellowship in the form of JRF.
References and Notes
1. Taskos, M.; Schaffert, S. E.; Clement, L.; Villadsen, L. N.; Poulsen, B. T., Nad.
Prod. Rep., 2015, 32, 605ꢀ632.
2. Morisaki, Y.; Chujo, Y.; Prog.Polym. Sci, 2008, 33, 346ꢀ364.
3. Gilles, V.; Vieira, A. M.; Lacerda, V.; Castro, R. V. E.; Santos, B. R.; Orestes, E.;
Carneiro, W.M.; Greco, J.S.; J. Braz. Chem. Soc., 2015, 26, 74ꢀ83.
4. Araujo, R.; Casal, M..; Paulo, C; Biocatalyst and Biotransformation, 2008, 26,
332ꢀ349.
5. Tao, Y.; Ping, Y.G.; Fei, P.L.; Xia, L. X.; Jing, Y.S.; Ming, Z.L;
Chem.Res.Chinese universities, 2012, 28, 53ꢀ56.
6. Johnson, D. W.; Hills, J. E.; Lubricants, 2013, 1, 132ꢀ148.
7. Hubinger, H.C.; J. Cosmet. Sci., 2010, 61, 457ꢀ465.
14

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View Article Online
DOI: 10.1039/C6NJ01956K
8. Bang, Y. D.; I. K. Lee, Lee, B. M.; Toxicol.Res., 2011, 27, 191ꢀ203.
9. Frank.G.H.; Stadelhofer, J. W.; Fourth edition, Industrial Aromatic Chemistry,
2013.
10. Fathima, N.; Mamatha, T.; Qureshi, H.; Anitha, N.; Vengateswar Rao, J.; Journal
of Applied Pharmaceutical Science, 2011, 1, 66ꢀ71.
11. Zhang, P.; Yang, B.; Fang, X.; Cheng, Z.; Yang, M.; J. Braz. Chem. Soc., 2012,
23, 1771ꢀ1775.
12. Arunachalam, M.; Ravikumar, I.; Ghosh, P.; J. Org. Chem. 2008, 73, 9144ꢀ9147.
13. Chen, P.; Jakle, F.; J. Am. Chem. Soc. 2011, 133, 20142ꢀ20145.
14. Rajakumar, P.; Padmanabhan, R.; Tetrahedron Lett. 2010, 51, 1059ꢀ1063.
15. Rajakumar, P.; Abdul Rasheed, A. M.; Rabia, A. I.; Chamundeeswari, D.; Bioorg.
Med. Chem. Lett. 2006, 16, 6019ꢀ6023.
16. Sharghi, H.; Khoshnood, A.; Khalifeh, R., IJST, 2012, A1, 25ꢀ35.
17. Raatikainen, K.; Beyeh, K.N.; Rissanen, K.; Chem. Eur. J., 2010, 16, 14554ꢀ
14564.
18. Raatikainen, K.; Huuskonen, J.; Lahtinen, M.; Metrangolo, P.; Chem. Commun,
2009, 2160ꢀ2162.
19. Baumann, M.; Baxendale, R.I.; Beilestein J. Org. Chem, 2013, 9, 2265ꢀ2319.
20. Rajakumar, P.; Sekar, K.; shanmugaiah, V.; Mathivanan, N.; European Journal of
Medicinal Chemistry, 2009, 44, 3040ꢀ3045.
21. Rajakumar, P.; Padmanabhan, R.; Ramprasath, C; Mathivanan, N.; Silambarasan,
V.; Velmurugan, D.; Aust. J. Chem, 2013, 66, 84ꢀ92.
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22. Satheeshkumar, C.; Ravivarma, M.; Rajakumar, P.; Mathivanan, N.;
Silambarasan, V.; Velmurugan, D.; Canadian Chemical Transactions, 2014, 02,
248ꢀ257.
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New Journal of Chemistry
Synthesis and antibacterial activity of some novel Piperazinophanes with intra annular ester functionality
Sivasamy Selvarani and Perumal Rajakumar*
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai-600 025, India.
E-mail: perumalrajakumar@gmail.com
Fax: +91 044 22300488; Tel: +91 044 22351269 ext. 213
Graphical Abstract
Ester based 1:1 and 2:2 oligomeric piperazinophanes were synthesized by multicomponent reactions (MCR) technique and assessed for
their antibacterial activity and further supported by molecular docking studies.