Synthesis and antibacterial activity of dendritic architectures

Article abstract of DOI:10.1055/s-2006-926275

Synthesis of dendrimers with pentanone as core unit and m-terphenyl as surface end group has been achieved. The inhibitory activity of pentanone and its dendrimers against human pathogenic bacteria is well-documented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926275

528
PAPER
Synthesis and Antibacterial Activity of Dendritic Architectures
S
ynthesis and
e
A
ntibacteri
r
al Activi
u
ty of Dendrit
m
ic
A
rchitectures al Rajakumar,*a Kilivelu Ganesan,a S. Jayavelu,b K. Murugesanb
a
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, India
Fax +91(44)22352494; E-mail: perumalrajakumar@hotmail.com
Center for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai 600025, India
b
Received 17 August 2005; revised 24 August 2005
O
Abstract: Synthesis of dendrimers with pentanone as core unit and
m-terphenyl as surface end group has been achieved. The inhibitory
activity of pentanone and its dendrimers against human pathogenic
bacteria is well-documented.
R
O
O
R
1a R = H
1b R = OMe
Key words: pentanone, m-terphenyl, bactericidal screening, En-
terococcus faecalis, Klebsiella pneumoniae, Escherichia coli
Dendrimers are used as carrier macromolecules for drug
delivery, gene transfer, and as catalyst in homogeneous as
well as heterogeneous catalysis.1 Dendrimers offer innu-
merable applications in pharmaceutical, biological and
biomedical fields. Due to the presence of suitable func-
tional group at the core and surface, dendrimers find ap-
plication as multivalent bioconjugates, antibacterial and
antiviral agents.2–4 Hybrid dendrimers such as glycoden-
drimers exhibits potential application in medical field.5
Covalent attachment of drugs through various degradable
linkers such as lactosaminylated and galactosylated hu-
man serum albumin has allowed the targeted delivery of
antiinflammatory agents such as Naproxen.6,7 Synthesis
of permanent fluorescence sensing hyperbranched den-
dritic architectures8 as well as bactericidal efficacy of
novel dendrimers9 and axially chiral enantiopure
dendrimers10 were reported from our laboratory recently.
The pentanone nucleus is present in various natural
products11,12 and is known to be a very important precur-
sor to many potentially bioactive compounds.13 However
the synthesis and biological activity of pentanone core
based m-terphenyl hyperbranched dendritic architecture
are yet to be investigated. We report herein the synthesis
of pentanone core based dendritic architecture (1a–3a,
1b–3b, Figure 1) and their antibacterial activity against
Enterococcus faecalis, Klebsiella pneumoniae and Es-
cherichia coli bacteria.
O
R
O
O
O
O
O
O
R
2a R = H
2b R = OMe
O
O
O
O
R
O
O
O
O
O
O
R
O
O
O
O
O
3a R = H
3b R = OMe
Figure 1
5¢-Methyl-1,1¢:3¢,1¢¢-terphenyl (4) was prepared by the
application of the Hart reaction14 from 3,5-dibromo-4-io-
dotoluene. Radical bromination of 4 with N-bromosuccin-
imide in tetracholoromethane in the presence of Bz2O2
afforded 5¢-bromomethyl-1,1¢:3¢,1¢¢-terphenyl (5) in 84%
yield.15 Reaction of the pentanone core unit 6a/6b16 de-
rived from cyclopentanone and 4-hydroxybenzaldehyde/
3-methoxy 4-hydroxybenzaldehyde with 2.1 equivalents
of 5¢-bromomethyl-1,1¢:3¢,1¢¢-terphenyl in DMF in the
presence of K2CO3 gave the dendrimers 1a/1b in 73% and
70% yields, respectively (Scheme 1). The pentanone core
unit 6a/6b could be also obtained using
iodotrimethylsilane17 or Yb(OTf)318 as catalyst for cross-
aldol condensation.
1
The H NMR spectrum of dendrimer 1a displayed a sin-
glet at d = 3.04 for the methylene protons of cyclopen-
tanone moiety and another sharp singlet at d = 5.20 for
OCH2 protons in addition to olefinic and aromatic pro-
tons. In 13C NMR spectrum CH2, OCH2 and C=O carbon
appeared at d = 36.5, 70.2 and d = 196.4 in addition to ten
aromatic carbons. The appearance of a molecular ion peak
SYNTHESIS 2006, No. 3, pp 0528–0532
x
x
.
x
x
.2
0
0
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Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926275; Art ID: Z15605SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis and Antibacterial Activity of Dendritic Architectures
529
I
Br
dendritic alcohol 11 (G1)-CH2OH as described under the
synthesis of 2a/2b.
CH3
Br
Br
iii
i, ii
Reaction of 2.1 equivalents of dendritic bromide 1220
(G2)-CH2Br with one equivalent of parent compound 6a/
6b gave the dendrimer 3a/3b in 44% and 38% yields, re-
spectively (Scheme 3).
84%
62%
CH3
4
5 ≡ (mt)-CH2Br
O
R
6a or 6b
CO2Me
OH
iv
CO2Me
(G2)-CH2OH
2.1 equiv
(G1)-CH2Br
9
ii
HO
R
1a (R = H; 73%)
1b (R = OMe; 70%)
11
94%
O
O
iii
43%
HO
OH
i, 62%
O
Scheme 1 Reagent and conditions: i) PhMgBr (3.1 equiv), THF, re-
flux, 12 h; ii) H3O+; iii) NBS, Bz2O2, CCl4, reflux; iv) K2CO3, DMF,
60 °C, 48 h.
O
(G2)-CH2Br
O
O
12
10 ≡ (G2)-CO2Me
i
6a or 6b
3a (R = H; 44%)
at m/z = 808 in the FAB mass spectrum also confirmed the
structure of the dendrimer 1a. The structure of the den-
drimers 1b was also confirmed based on the spectral and
analytical data.
3b (R = OMe; 38%)
Scheme 3 Reagent and conditions: i) K2CO3, DMF, 60 °C, 48 h; ii)
LiAlH4, THF, reflux, 12 h; iii) CBr4, PPh3, THF, r.t.
In order to synthesize the first-generation dendrimer 2a,
methyl 3,5-dihydroxybenzoate was reacted with the 5¢-
bromomethyl-1,1¢:3¢,1¢¢-terphenyl (5) to give compound 7
and was followed by the conventional functional-group
transformation19 which afforded the corresponding den-
dritic bromide 920 (G1)-CH2Br in 56% yield. Reaction of
2.1 equivalents of the dendritic bromide 9 (G1)-CH2Br
with one equivalent of the pentanone core unit 6a/6b in
the presence of K2CO3 in DMF gave dendrimer 2a/2b in
68% and 62% yields, respectively (Scheme 2).
Dendrimers 3a and 3b were characterized from the spec-
tral and analytical data.
Antibacterial Activity
The bactericidal activity of the parent compounds, den-
drimer 1a–3a and 1b–3b, were assayed against Entero-
coccus faecalis, Klebsiella pneumoniae and Escherichia
coli by disc diffusion method. Parent compound 6a/6b ex-
hibited significant activity towards Enterococcus faecalis
and Klebsiella pneumoniae and less significant activity
towards Escherichia coli. Dendrimers 1a–3a and 1b–3b
showed good inhibition against the test bacteria when
compared with the parent compounds 6a/6b. Dendrimer
3a/3b possessed higher inhibitory activity than all other
dendrimers and parent compounds. The standard antibiot-
ic disc (Streptomycin 10 mg/ disc) inhibited the growth of
Enterococcus faecalis by 14 mm, Klebsiella pneumoniae
by 15 mm and Escherichia coli by 12 mm, respectively.
The diameter of inhibition zone for each concentration
against all the test bacteria is depicted in Tables 1–3.
CO2Me
CO2Me
(G1)-CH2OH
ii
2.1 equiv 5
8
O
O
98%
i, 58%
56%
iii
HO
OH
7 ≡ (G1)-CH2Me
(G1)-CH2Br
9
2a (R = H; 68%)
2b (R = OMe; 62%)
6a or 6b
i
Scheme 2 Reagent and conditions: i) K2CO3, DMF, 60 °C, 48 h; ii)
LiAlH4, THF, reflux, 12 h; iii) CBr4, PPh3, THF, r.t.
1
Table 1 Inhibition Effects of Parent and Dendrimers on the Growth
of Enterococcus faecalis
The H NMR spectrum dendrimer 2a displayed a singlet
at d = 2.98 for the two identical CH2 protons of pentanone
moiety. Two sharp singlets for 4-H and 8-H were ob-
served at d = 5.06 and 5.17 for OCH2 protons in addition
to olefinic and aromatic protons. In the 13C NMR spec-
trum CH2, OCH2 and C=O carbon appeared at d = 36.5,
70.0, 70.2 and at d = 196.4 in addition to thirteen aromatic
carbons. The appearance of molecular ion peak at m/z =
1504 in the FAB mass spectrum also confirmed the struc-
ture 2a. Similarly structure of the dendrimer 2b was also
confirmed based on the spectral and analytical data.
Compound
Zone of Inhibition (mm)
30 mg/mL
3.0
50 mg/mL
4.0
70 mg/mL
5.5
Parent 6b
Dendrimer 1a
Dendrimer 1b
Dendrimer 2a
Dendrimer 2b
Dendrimer 3a
4.2
5.6
6.8
4.8
6.4
7.2
5.0
6.5
7.5
5.8
7.2
8.4
With a view to synthesize the second-generation dendrim-
ers 3a/3b methyl 3,5-dihydroxybenzoate was reacted with
2.1 equivalents of dendritic bromide 9 (G1)-CH2Br to give
the methyl carboxylate 10 (G2)-CO2Me, which was con- Dendrimer 3b
verted to the dendritic bromide 12 (G2)-CH2Br through
7.2
8.4
10.5
11.2
7.6
8.8
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530
P. Rajakumar et al.
PAPER
ic extracts were washed with brine and dried over MgSO4. Evapo-
ration of organic layer gave a residue, which was chromatographed
over SiO2 using hexane–CHCl3 as eluent.
Table 2 Inhibition Effects of Parent and Dendrimers on the Growth
of Klebsiella pneumoniae
Compound
Zone of Inhibition (mm)
Dendritic Ester [G1]-CO2Me (7)
Yield: 5.4 g (58%); mp 148 °C; eluent: hexane–CHCl3 (1:1).
1H NMR (CDCl3): d = 3.83 (s, 3 H), 5.11 (s, 4 H), 7.15–7.68 (m, 29
H).
13C NMR: d = 52.3, 70.3, 107.2, 108.4, 125.3, 125.9, 127.2, 127.5,
128.8, 132.1, 137.4, 140.7, 142.2, 159.7, 166.7.
30 mg/mL
3.0
50 mg/mL
4.0
70 mg/mL
5.5
Parent 6b
Dendrimer 1a
Dendrimer 1b
Dendrimer 2a
Dendrimer 2b
Dendrimer 3a
Dendrimer 3b
4.2
5.8
6.6
4.6
6.2
7.2
MS (EI): m/z = 652.
4.8
6.4
7.4
Anal. Calcd for C46H36O4: C, 84.66; H, 5.52. Found: C, 84.03; H,
5.32.
5.0
6.8
7.8
6.2
7.6
10.2
10.8
Dendritic Ester [G2]-CO2Me (10)
Yield: 1.30 g (62%); mp 95–98 °C; eluent: hexane–CHCl3 (1:2).
1H NMR (CDCl3): d = 3.85 (s, 3 H), 4.99 (s, 4 H), 5.12 (s, 8 H),
7.21–7.73 (m, 61 H).
7.4
8.4
13C NMR: d = 52.2, 70.1, 101.1, 106.4, 107.1, 108.3, 125.3, 127.2,
Table 3 Inhibition Effects of Parent and Dendrimers on the Growth
of Escherichia coli
127.5, 128.7, 137.7, 138.9, 140.7, 142.1, 159.6, 160.1, 166.6.
MS (FAB): m/z = 1380.
Compound
Zone of inhibition (mm)
Anal. Calcd for C98H76O8: C, 85.21; H, 5.51. Found: C, 85.19; H,
5.48.
30 mg/mL
2.5
50 mg/mL
3.5
70 mg/mL
5.0
Synthesis of Dendritic Alcohol 8/11; General Procedure
To a solution of dendritic ester 7/10 (1.0 mmol) in anhyd THF (100
mL) was added LiAlH4 (5.0 mmol) portionwise at r.t. The reaction
mixture was stirred at reflux for 12 h and slowly poured into
Na2SO4·10H2O (10 g) and stirred. It was then digested on a steam
bath for 20 min and filtered. The inorganic residue was further ex-
tracted (Soxhlet) with THF (100 mL). The combined organic layer
on evaporation gave the corresponding alcohol.
Parent 6b
Dendrimer 1a
Dendrimer 1b
Dendrimer 2a
Dendrimer 2b
Dendrimer 3a
Dendrimer 3b
3.6
4.4
5.4
4.0
5.6
6.6
4.4
6.2
7.2
5.2
6.6
7.6
5.6
7.2
8.2
Dendritic Alcohol [G1]-CH2OH (8)
Yield: 5.10 g (98%); mp 62–65 °C; eluent: CHCl3.
1H NMR (CDCl3): d = 4.42 (s, 2 H), 4.92 (s, 4 H), 7.18–7.58 (m, 29
H).
6.8
7.4
8.4
13C NMR: d = 65.5, 70.1, 102.2, 108.2, 125.9, 127.2, 127.5, 128.7,
All dendrimers other than the parent compound signifi-
cantly inhibited the growth of Enterococcus faecalis,
Klebsiella pneumoniae and Escherichia coli. Dendrimers
1a–3a and 1b–3b could be used as potential compounds
to ward off diseases caused by the bacteria, especially
pneumonia.
137.5, 139.8, 140.7, 142.1, 160.0.
MS (FAB): m/z = 624.
Anal. Calcd for C45H36O3: C, 86.53; H, 5.76. Found: C, 86.43; H,
5.72.
Dendritic Alcohol [G2]-CH2OH (11)
Yield: 94%; mp 98–100 °C; eluent: CHCl3.
1H NMR (CDCl3): d = 4.58 (s, 2 H), 4.98 (s, 4 H), 5.14 (s, 8 H),
Dichloromethane was distilled from P2O5 and stored over 4 Å mo-
lecular sieves; THF was distilled from sodium prior to use. Materi-
als used were purchased from Lancaster chemicals. H NMR and
7.25–7.77 (m, 61 H).
1
13C NMR: d = 65.3, 70.0, 70.2, 101.7, 105.8, 106.5, 128.4, 126.0,
127.4, 127.6, 128.9, 140.2, 160.1 160.2.
13C NMR spectra were obtained on a Jeol 500 spectrometer operat-
ing at 500 MHz and 125 MHz respectively. The FAB-mass spectral
data were recorded on a Jeol SX 102/DA-6000 mass spectrometer
using p-nitrobenzyl alcohol (NBA) as matrix, MALDI-TOF mass
spectra on a Voyager–DE PRO mass spectrometer using a-cyano-
4-hydroxycinnamic acid as (CHCA) matrix and EI-mass spectra on
a Jeol DX-303 mass spectrometer. Elemental analyses were deter-
mined on a Perkin-Elmer 240B elemental analyzer.
MS (FAB): m/z = 1352.
Anal. Calcd for C97H76O7: C, 71.74; H, 5.62. Found: C, 71.68; H,
5.58.
Synthesis of Dendritic Bromide 9/12; General Procedure
To a solution of the dendritic alcohol 8/11 (1.0 mmol) in THF (30
mL), a solution of CBr4 (2 × 1.2 mmol) and PPh3 (2 × 1.2 mmol) in
THF (20 mL) was added during 10 min. Upon complete addition,
the mixture turned bright yellow and was subsequently quenched by
the addition of H2O, and extracted with CH2Cl2 (3 × 150 mL). The
combined organic layers were dried with MgSO4 and evaporated to
Synthesis of Dendritic Esters 7/10; General Procedure
Mixture of methyl 3,5-dihydroxybenzoate (1.0 mmol) and dendritic
bromide 5/9 (2.1 mmol) was stirred with K2CO3 (5 mmol) in DMF
(20 mL) at 60 °C for 48 h. The reaction mixture was poured into
H2O and extracted with CH2Cl2 (3 × 150 mL). The combined organ-
Synthesis 2006, No. 3, 528–532 © Thieme Stuttgart · New York

PAPER
Synthesis and Antibacterial Activity of Dendritic Architectures
531
dryness and the residue was purified by column chromatography
(SiO2).
Anal. Calcd for C99H84O7: C, 85.83; H, 6.06. Found: C, 85.80; H,
6.62.
Dendritic Bromide [G1]-CH2Br (9)
Yield: 2.2 g (56%); mp 142–145 °C; eluent: hexane–CHCl3 (2:1).
Dendrimer 2b
Yield: 110 mg (62%); mp 114–116 °C; eluent: CHCl3.
1H NMR (CDCl3): d = 4.41 (s, 2 H), 5.12 (s, 4 H), 7.20–7.75 (m, 29
H).
1H NMR (500 MHz, CDCl3): d = 2.98 (s, 4 H), 3.89 (s, 6 H), 5.16
(s, 4 H), 5.18 (s, 8 H), 6.88–8.02 (m, 66 H).
13C NMR: d = 33.5, 70.1, 102.2, 108.2, 125.9, 127.2, 127.5, 128.7,
13C NMR (125 MHz, CDCl3): d = 36.5, 56.0, 70.2, 70.8, 101.7,
106.1, 115.2, 125.4, 126.0, 127.4, 127.6, 128.9, 137.8, 139.4, 140.9,
142.2, 149.4, 160.3, 196.4.
137.5, 139.8, 140.7, 142.1, 160.0.
MS (FAB): m/z = 687.
MS (FAB): m/z = 1384.
Anal. Calcd for C46H35O2Br: C, 78.60; H, 5.09. Found: C, 78.58; H,
5.02.
Anal. Calcd for C101H88O9: C, 83.93; H, 6.09. Found: C, 83.88; H,
6.64.
Dendritic Bromide [G2]-CH2Br (12)
Yield: 1.25 g (43%); mp 95–98 °C; eluent: hexane–CHCl3 (2:2).
Dendrimer 3a
Yield: 90 mg (44%); mp 126–130 °C; eluent: CHCl3.
1H NMR (500 MHz, CDCl3): d = 2.94 (s, 4 H), 4.98 (s, 4 H), 5.06
(s, 8 H), 5.17 (s, 16 H), 6.97–8.04 (m, 132 H).
13C NMR (125 MHz, CDCl3): d = 36.5, 68.1, 70.0, 70.2, 101.8,
106.4, 115.2, 125.4, 126.0, 127.4, 127.7, 128.9, 137.8, 140.9, 142.3,
159.6, 160.3, 196.4.
1H NMR (CDCl3): d = 4.24 (s, 2 H), 4.85 (s, 4 H), 5.03 (s, 8 H),
6.51–7.64 (m, 61 H).
13C NMR: d = 69.9, 70.1, 101.7, 106.4, 108.1, 125.3, 125.8, 127.2,
127.5, 128.7, 137.7, 140.7, 142.1, 160.1.
MS (FAB): m/z = 1419
Anal. Calcd for C91H75O6Br: C, 82.17; H, 5.29. Found: C, 82.10; H,
5.22.
MS (MAL–TOF): m/z = 2960.
Anal. Calcd for C213H164O15: C, 86.35; H, 5.54. Found: C, 86.30; H,
5.40.
Synthesis of Enone Based Dendrimers; General Procedure
A mixture of pentanone 6a/6b (1.0 mmol) and the bromide 5/9/12
(2.1 mmol) was stirred with K2CO3 (5.0 mmol) in DMF (20 mL) at
60 °C for 48 h. The reaction mixture was then poured into H2O and
extracted with CH2Cl2 (3 × 150 mL). The combined organic extract
was washed with brine and dried over MgSO4. Evaporation of the
organic layer gave a residue, which was chromatographed over
SiO2 using hexane–CHCl3 to give the corresponding dendrimers.
Dendrimer 3b
Yield: 130 mg (38%); mp 136–140 °C; eluent: CHCl3.
1H NMR (500 MHz, CDCl3): d = 2.93 (s, 4 H), 3.87 (s, 6 H), 4.96
(s, 4 H), 5.06 (s, 8 H), 5.17 (s, 16 H), 6.97–8.04 (m, 130 H).
13C NMR (125 MHz, CDCl3): d = 36.5, 56.0, 68.1, 70.1, 70.2, 101.7,
106.5, 114.8, 125.4, 126.0, 127.4, 127.6, 128.9, 137.8, 139.4, 140.9,
142.2, 160.2, 160.3, 196.4.
Dendrimer 1a
Yield: 176 mg (73%); mp 88–90 °C; eluent: CHCl3.
MS (MAL–TOF): m/z = 3020.
1H NMR (500 MHz, CDCl3): d = 3.04 (s, 4 H), 5.20 (s, 4 H), 7.02–
8.01 (m, 36 H).
Anal. Calcd for C215H168O17: C, 85.43; H, 5.56. Found: C, 85.38; H,
5.42.
13C NMR (125 MHz, CDCl3): d = 36.5, 70.2, 115.2, 125.3, 126.1,
127.4, 127.7, 128.9, 132.6, 140.8, 142.3, 159.7, 196.4.
Acknowledgment
MS (FAB): m/z = 808.
PR and KG thanks CSIR, New Delhi for financial assistance and
RSIC, CDRI, Lucknow for spectral data.
Anal. Calcd for C57H44O5: C, 84.65; H, 5.44. Found: C, 84.60; H,
5.40.
Dendrimer 1b
Yield: 250 mg (70%); mp 74–78 °C; eluent: CHCl3.
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Yield: 128 mg (68%); mp 94–98 °C; eluent: CHCl3.
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(s, 8 H), 6.97–8.04 (m, 68 H).
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