Design, synthesis, and in vitro antibacterial screening of some novel 3-pentyloxy-1-hydroxyxanthone derivatives

Article abstract of DOI:10.1007/s00044-013-0653-x

A series of 3-pentyloxy-1-hydroxyxanthone derivatives were synthesized by four-step reactions: first cyclocondensation between salicylic acid and phloroglucinol in the presence of Eaton's reagents, then alkylation with 1,5-dibromopentane, followed by nucl

Full text of DOI:10.1007/s00044-013-0653-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0653-x
ORIGINAL RESEARCH
Design, synthesis, and in vitro antibacterial screening of some
novel 3-pentyloxy-1-hydroxyxanthone derivatives
•
Aparoop Das Md. Mutahar Shaikh
•
Srabanti Jana
Received: 24 March 2013 / Accepted: 25 May 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of 3-pentyloxy-1-hydroxyxanthone
derivatives were synthesized by four-step reactions: first
cyclocondensation between salicylic acid and phloroglu-
cinol in the presence of Eaton’s reagents, then alkylation
with 1,5-dibromopentane, followed by nucleophilic substi-
tution by different nucleophiles to obtain final compounds.
Molecular structures of the synthesized compounds were
elucidated by FT-IR, 1H NMR, 13C NMR, mass spectral data,
and elemental analysis. The in vitro antibacterial activity was
evaluated by MIC determination using broth dilution method
against representative three Gram-positive and three Gram-
negative bacterial strains with reference to ofloxacin. All the
synthesized compounds showed antibacterial activity;
besides the compounds 7f and 7g showed better Gram-
positive and Gram-negative antibacterial activities.
creates a pressing need for newer antibacterial agents
(Francis et al., 2004; Kruszewska et al., 2004). While
searching for compounds with potential antibacterial
activity, we directed our attention to the xanthone deriva-
tives, which show several beneficial heterogenous and
varied pharmacological properties: for example, analeptic
(Quintas et al., 2003), anticonvulsant (Marona et al., 2008),
antilipidemic (Gion et al., 1982), diuretic (Sato et al.,
1990), antitumor (Castanheiro et al., 2007; Varache-
Lembege et al., 2008), protein kinase C inhibitors (Saraiva
et al., 2003), antimycotics (Moreau et al., 2002), antima-
larial (Dodean et al., 2008), anti-inflammatory, antihyper-
tensive (Wang et al., 2002), a-glucosidase inhibitors (Liu
et al., 2007) and antioxidant (Lee et al., 2005). Fukai et al.
(2005) isolated some isoprenoid-substituted xanthones
from Cudrania cochinchinensis which had antimicrobial
activity against vancomycin-resistant enterococci.
Keywords Xanthone ꢀ Antibacterial ꢀ Zone of inhibition ꢀ
Phloroglucinol
As naturally occurring xanthones showed good antibac-
terial activity with low side effect, we consider the xanthone
scaffold for discovery of newer antibiotics. It was found that
3,6-bis-x-(N,N-diethylaminoalkoxy) xanthones have good
antimalarial activity (Kelly et al., 2002). In this article, we
report on the synthesis, structural characterization, and
preliminary evaluation of the antibacterial properties
of a number of novel 3-pentyloxy-1-hydroxyxanthone
derivatives.
Introduction
Currently, problems relating to multidrug-resistant micro-
organisms have reached an alarming level all over the
world. Resistance to a number of antimicrobial agents
(b-lactam antibiotics, macrolides, quinolones, and vanco-
mycin) among a variety of clinically significant species of
bacteria is becoming increasingly major global problem.
The continual emergence of bacterial resistance to most
classes of antibiotics is a cause for great concern and
Chemistry
As we were interested in analyzing the relationship
between structure and antibacterial activity, we synthesized
appropriate substituted 3-pentyloxy-1-hydroxyxanthones.
The general synthetic route used for the target xanthones is
illustrated in Scheme 1.
A. Das (&) ꢀ Md. M. Shaikh ꢀ S. Jana
Department of Pharmaceutical Sciences, Dibrugarh University,
Dibrugarh 786004, Assam, India
e-mail: dasaparoop@gmail.com
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Med Chem Res
Scheme 1 Schematic
O
O
OH
O
OH
representation of the synthesis
of 3-pentyloxy-1-
hydroxyxanthone derivatives
Eaton's reagent
at 70oC ,35 min
OH
+
OH
OH
OH
HO
3
2
1
K2CO3, Acetone
Br
Br
Refluxed for 4 h,
at 600C
4
O
O
OH
O
OH
RH
6a-j
O
O
Br
DMSO
O
R
RT, 24-26 h
5
7a-j
The procedure for preparing hydroxylated xanthones is
the cyclization reaction between phloroglucinols and
appropriate substituted salicylic acids, in the presence of a
mixture of phosphorus pentoxide–methanesulfonic acid
(Eaton’s reagent) as catalyst which gives higher yield
(Eaton et al., 1973). According to this method, 1,3-dihy-
droxyxanthone (3) was obtained by cyclization of salicylic
acid (1) and phloroglucinol (2) in the presence of Eaton’s
reagent. Then, 3-hydroxyl group of compound 3 was
alkylated by 1,3-dibromopentane (4) to produce 3-(5-
bromopentyloxy)-1-hydroxyxanthone (5) in the presence of
potassium carbonate. Due to hydrogen bond formation
between oxygen of 9-keto and 1-hydroxyl groups, the
1-hydroxyl group could not be alkylated. Finally, target
compounds (7a–j) were prepared by means of nucleophilic
substitution of bromine atom from compound 4 using
various nucleophilic reagents RH (6a–j).
Results and discussion
All the spectral data obtained are exactly according to the
assumed structure of synthesized compounds. The elemental
analysis results were within 0.4 % of the theoretical values,
i.e., synthesized compoundswerefullypure. Theantibacterial
activities of all the synthesized compounds were observed,
and all of these show antibacterial activity in comparison with
ofloxacin. Besides these, three compounds (7b, 7d, and 7e)
displayed low-to-moderate activity against only Gram-
positive bacteria, while three compounds (7a, 7c, and 7h)
showed good susceptibility against only Gram-negative
bacterial strain, and other four compounds (7f, 7g, 7i, and 7j)
showed good activity against both Gram-positive and Gram-
negative bacteria strain. Compounds 3 and 5 showed negli-
gibleornoantibacterialactivityagainstusedmicroorganisms.
The zones of inhibition of 3-pentyloxy-1-hydroxyxanthone
derivatives against representative bacterial strains are repre-
sented in Table 2. The minimum inhibitory concentration
value of synthesized compounds was found to be in the range
of 4–32 lg ml-1, and these are given in Table 3. Most of the
newly synthesized compounds showed significant antibacte-
rial activity against B. subtilis, S. aureus, and P. aeruginosa.
The compound 7f showed broad spectrum activity, while
compound 7d showed activity against only B. subtilis. Two
compounds 7f and 7g showed better minimum inhibitory
concentration (MIC) value in comparison with others which
have an introduction of electron-withdrawing group or groups
containing primary aromatic amine.
Pharmacology
Antibacterial activity
The in vitro antibacterial potency of all the synthesized
compounds were evaluated against selected three repre-
sentative Gram-positive organisms, viz., Bacillus subtilis
(ATCC 6633, NCIM 2063), Bacillus cereus (ATCC 10876,
NCIM 2156), and Staphylococcus aureus (ATCC 6538,
NCIM 2079); and three Gram-negative organisms, viz.,
Escherichia coli (ATCC 8739, NCIM 2065), Proteus
mirabilis (NCIM 2241), and Pseudomonas aeruginosa
(ATCC 19429, NCIM 2036) along with ofloxacin as ref-
erence antibiotic. The microbial strains used for antibac-
terial study were procured from National Collection of
Industrial Micro-organisms (NCIM), Pune, India.
Conclusion
In conclusion, the series of novel 3-pentyloxy-1-hydro-
xyxanthones were synthesized and evaluated for in vitro
123

Med Chem Res
antibacterial activity. The simplicity of preparation and
better yield in significantly short reaction time can poten-
tially make this procedure as a useful and attractive alter-
native for the synthesis of newer antibacterial compounds.
The compounds 7f and 7g showed significant activity in
comparison with ofloxacin. Therefore, we can conclude that
an introduction of electron-withdrawing group or groups
containing primary aromatic amine in the 3-pentyloxy-1-
hydroxyxanthone at 50 position significantly increases the
antibacterial activity against both Gram-positive and Gram-
negative bacteria strains. We can consider these two com-
pounds (7f and 7g) for further investigation as newer anti-
biotics suitable for bacterial resistance. The 3-(x-substituted
alkoxy)xanthones are considered as a newer series of anti-
biotics by changing alkoxy chain instead of pentyloxy and
substitution attached.
(d, 1H arom., J = 2 Hz), 5.12 (s, 1H, OH), 5.06 (s, 1H, OH),
13C NMR (100 MHz, DMSO-d6): 182.25 (CO), 163.3,
163.28, 158.5, 155.7 (4 9 quat. arom. C), 132.21, 130.03,
121.6 (3 9 arom. CH), 121.02 (quat. arom. C), 117.2 (arom.
CH), 102.62 (quat. arom. C), 96.4, 97.52 (2 9 arom. CH),
mass (m/e): 228.2 [M?], calc. for: C13H8NO4: C, 68.42 and
H, 3.53 %, found: C, 68.47 and H, 3.54 %.
Synthesis of 3-(5-bromopentyloxy)-1-
hydroxyxanthone (5)
A mixture of 1,3-dihydroxyxanthone (0.2 mmol) and
1,3-dibromopentane (0.2 mmol) was dissolved in acetone,
and potassium carbonate (0.25 mmol) was added to neu-
tralize hydrobromic acid. The mixture was refluxed under
stirring at 60 °C for 4 h. After cooling, the mixture was fil-
tered and the filtrate was concentrated to obtain crude
product. By flash chromatography, pure compound 4 was
obtained as light yellow color solid, yield 72.39 %, m.p.
160–164 °C; IR (KBr, v cm-1): 3535.64 (O–Hstretch),
2729.37 (C–Hstretch alkyl), 1618.33 (C=Ostretch), 1553.28 and
1488.36 (C=Cstretch Ar. ring), 1489.10 (O–Hbend), 1182.21
(C–Ostretch 6-member cyclic ether), 1008.80 (C–Ostretch alkyl
Experimental protocol
All the reagents were A.R grade and used without further
purification. Melting points were determined in open cap-
illaries using Veego melting point apparatus. The FT-IR
spectra were recorded using KBr pellets on SHIMADZU-
FT-IR spectrophotometer. The 1H NMR spectra were
recorded on Bruker Avance–II (400 MHz) spectrometer,
and 13C NMR on Bruker Avance–II (100 MHz) spec-
trometer was performed using dimethylsulfoxide (DMSO)-
d6 and D2O as solvent with TMSi as an internal standard.
The mass spectra were recorded on Water ZQ-4000 mass
spectrometer. Elemental analysis was performed using a
Perkin Elmer 2400 Series II CHN Analyzer.
1
ether), 663.53 (C–Brstretch), H NMR (400 MHz, DMSO-
d6): d 7.63 (dd, 1H arom., J = 8, 1.5 Hz), 7.4 (dd, 1H arom.,
J = 8, 1.5 Hz), 7.08 (dd, 1H arom., J = 8, 1.5 Hz), 7.01 (dd,
1H arom., J = 8, 1.5 Hz), 6.14 (dd, 1H arom., J = 8,
1.5 Hz), 6.06 (s, 1H arom.), 5.11 (s, 1H, OH), 3.49 (t, 2H,
J = 6.7 Hz, CH2 near O), 3.31 (t, 2H, J = 6.7 Hz, CH2 near
N), 1.8 (m, 2H, J = 6.3 Hz, CH2), 1.71 (m, 2H, J = 6.3 Hz,
CH2), 1.29 (m, 2H, J = 6.3 Hz, CH2), 13C NMR (100 MHz,
DMSO-d6): d 182.3 (CO), 162.53, 162.36, 157.71, 155.69
(4 9 quat. arom. C), 132.21, 130.06, 121.62 (3 9 arom. CH),
121.03 (quat. arom. C), 117.21 (arom. CH), 101.63 (quat.
arom. C), 96.63, 95.03 (2 9 arom. CH), 68.94 (CH2 nearest to
O), 33.7, 32.72, 28.8, 24.38 (4 9 CH2), mass (m/e): 376.04
[M?], 378.03 [(M?2)?] (97.3 %), calc. for: C18H17BrO4: C,
53.31 and H, 4.54 %; found: C, 53.35 and H, 4.53 %.
Synthesis of 1,3-dihydroxyxanthone (3)
Phosphorous pentoxide was dissolved in methane sulfonic
acid in the ratio 1:10 to produce Eaton’s reagent (Eaton et al.,
1973). Dehydrated phloroglucinol (60 mmol) and salicylic
acid (60 mmol)were mixed, and previouslyprepared 100 ml
of Eaton’s reagent was added slowly to it. Then, the mixture
was kept stirring at about 70 °C for 35 min. After cooling the
mixture to room temperature, the reaction mixture was
poured into crushed ice and stirred for about 2.5 h. The
resulting solid was collected, washed with distilled water,
and recrystallized from the afforded compound 3 as reddish-
brown color solid, yield 76.45 %, m.p. 120–122 °C, IR
(KBr, v cm-1): 3585.79 (O–Hstretch) 2951.19 (C–Hstretch Ar.),
1660.77 (C=Ostretch), 1563.75 and 1485.24 (C=Cstretch Ar.
ring), 1442.80 (O–Hbend), 1182.40 (C–Ostretch 6-member
Synthesis of 3-(5-substituted pentyloxy)-1-
hydroxyxanthone (7a–j)
The 3-(5-bromopentyloxy)-1-hydroxyxanthone (10 mmol)
and various selected nucleophilic reagents (10 mmol) were
dissolved in 20 ml of DMSO and stirred at room temper-
ature for 24–26 h. At the end of the reaction, the mixture
was poured into 50 ml of water and extracted with 50 ml of
ether three times. The mixed extracts were condensed and
collected as purified product using column chromatography
over silica gel.
1
cyclic ether), H NMR (400 MHz, DMSO-d6): d 7.66 (dd,
1H arom., J = 7.5, 2 Hz), 7.41 (dd, 1H arom., J = 7.5,
2 Hz), 7.1 (dd, 1H arom., J = 7.5, 7.5 Hz), 7.02 (dd, 1H
arom., J = 7.5, 7.5 Hz), 6.21 (d, 1H arom., J = 2 Hz), 6.13
All the synthesized compounds (Table 1) were charac-
terized by spectroscopic data as FT-IR, 1H NMR, 13C
NMR, Mass spectroscopy, and elemental analysis.
123

Med Chem Res
Table 1 Structure and physical data of the synthesized compounds
O
OH
O
O
R
Compound
–R
M.p.
Mol. formula
Mol. wt.
383.44
Yield (%)
69.78
7a
236–238
224–226
C22H25NO5
N
O
7b
C24H29NO4
395.49
64.35
HN
7c
7d
7e
146–148
152–154
178–180
C23H28N2O4
C23H22N2O4
C23H23NO5
396.48
390.43
393.43
74.67
78.56
71.23
N
N
N
CH3
HN
HN
O
7f
Cl
212–214
164–166
C24H21ClFNO4
441.88
434.44
77.47
79.48
HN
F
7g
C24H22N2O6
HN
NO2
7h
7i
219–221
167–169
C23H27NO4
C21H20N2O4
381.46
364.39
78.36
75.67
N
N
N
7j
143–145
C24H31NO4
397.51
73.84
N
(C–Nstretch), 1128.36 (C–Ostretch ether), 1H NMR
(400 MHz, DMSO-d6): d 7.68 (d, 1H arom., J = 6.8 Hz,
H8), 7.46 (t, 1H arom., J = 6.8 Hz, H6), 7.12 (t, 1H arom.,
J = 6.8 Hz, H7), 7.01 (d, 1H arom., J = 6.8 Hz, H5), 6.1
(s, 1H arom., H4), 6.05 (s, 1H arom., H2), 5.53 (s, 1H,
OH), 3.96 (t, 2H, J = 5.7 Hz, CH2 near O), 3.67 (2 9 t,
2H, J = 12.5 Hz, cyclic CH2 near O), 2.4 (2 9 t, 2H,
1-Hydroxy-3-(5-morpholinopentyloxy)-9H-xanthen-
9-one (7a)
The compound 5 with morpholine (6a) was yielded as a
brown solid, IR ((KBr, vmax cm-1): 3512.19 (O–Hstretch),
3094.0 (C–Hstretch Ar), 2955.04 (C–Hstretch), 1666.56
(C=Ostretch), 1599.04 and 1553.28 (C=Cstretch Ar), 1404.22
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Med Chem Res
J = 12.5 Hz, CH2 near N of morpholine), 2.34 (t, 2H,
J = 5.7 Hz, CH2 near N), 1.72 (m, 2H, J = 5.9 Hz, CH2),
1.39 (m, 2H, J = 5.9 Hz, CH2), 1.29 (m, 2H, J = 5.9 Hz,
CH2), 13C NMR (100 MHz, DMSO-d6): d 182.3 (CO),
162.61, 162.36, 157.81, 155.86 (4 9 quat. arom. C),
132.23, 130.06, 121.64 (3 9 arom. CH), 121.02 (quat.
arom. C), 117.23 (arom. CH), 101.61 (quat. arom. C),
96.02, 95.01 (2 9 arom. CH), 68.97, 66.82 (3 9 CH2
nearest to O), 54.42, 53.71 (3 9 CH2 nearest to N), 29.41,
28.5, 23.72 (3 9 CH2), mass (m/e): 383.2 [M?], calc. for:
C22H25NO5: C, 68.91, H, 6.57, N, 3.65 %; found: C, 68.87,
H, 6.53, N, 3.62 %.
CH2 near of O), 2.46 (4 9 t, 2H, J = 14.4 Hz, CH2 of
piperazine), 2.35 (t, 2H, J = 7.21 Hz, CH2 near N), 2.27
(s, 3H, CH3), 1.71 (m, 2H, J = 7.28 Hz, CH2), 1.44 (m, 2H,
J = 7.28 Hz, CH2), 1.29 (m, 2H, J = 7.28 Hz, CH2), C13
NMR (100 MHz, D2O): d 182.29 (CO), 162.52, 162.31,
157.69, 155.7 (4 9 quat. arom. C), 132.19, 130.02, 121.61
(3 9 arom. CH), 121.58 (quat. arom. C), 117.21 (arom.
CH), 101.6 (quat. arom. C), 96.02, 94.91 (2 9 arom. CH),
68.9 (CH2 near of O), 55.72, 55.21, 54.13 (5 9 CH2 near of
N), 43.11 (CH3), 29.41, 28.4, 23.72 (3 9 CH2), mass (m/e):
396.6 [M?]. Calc. for C23H28N2O4: C, 69.67; H, 7.12; N,
7.07 %; found: C, 69.71; H, 7.15; N, 7.05 %.
3-[5-(Cyclohexylamino) pentyloxy]-1-hydroxy-
9H-xanthen-9-one (7b)
1-Hydroxy-3-[5-(pyridin-2-ylamino)-pentyloxy]-9H-
xanthen-9-one (7d)
The compound 5 with cyclohexylamine (6b) was yielded
as a light brown solid, FT-IR (KBr, vmax cm-1): 34412.19
(O–Hstretch), 3092.42 (C–Hstretch Ar), 3236.66 (N–Hstretch
NH), 2955.04 (C–Hstretch alkyl), 1666.55 (C=Ostretch),
1504.34 and 1404.22 (C=Cstretch Ar. ring), 1128.36
(C–Ostretch ether), H1 NMR (400 MHz, DMSO-d6): d 7.76
(d, 1H arom., J = 7.43 Hz, H), 7.43 (t, 1H arom.,
J = 7.24 Hz, H6), 7.1 (t, 1H, J = 7.24 Hz, H7), 7.01
(d, 1H arom., J = 8.0 Hz, H5), 6.63 (s, 1H arom., H4),
6.51 (s, 1H arom., H2), 5.36 (s, 1H, OH), 4.32 (t, 2H,
J = 2.17 Hz, CH2 near O), 2.57 (m, 1H, J = 2.4 Hz, CH
near N), 2.4 (t, 2H, J = 2.14 Hz, CH2 near N), 2.3 (q, 1H,
J = 2.1 Hz, NH), 1.81 (m, 2H, J = 6.9 Hz, CH2), 1.64 (m,
2H, J = 6.9 Hz, CH2), 1.57 (m, 2H, J = 6.9 Hz, CH2),
1.46–1.26 (m, 2H, J = 6.9 Hz, CH2), C13 NMR (100 MHz,
DMSO-d6): d 182.2 (CO), 162.5, 162.31, 157.7, 155.69
(4 9 quat. arom. C), 132.2, 129.98, 121.6 (3 9 arom. CH),
121.02 (quat. arom. C), 117.24 (arom. CH), 101.6 (quat.
arom. C), 96.02, 94.93 (2 9 arom. CH), 68.89 (CH2
nearest to O), 56.3, 47.7 (2 9 CH2 nearest to N), 34.31,
30.92, 29.43, 27.98, 23.4, 23.2 (8 9 CH2), mass (m/e):
395.7 [M?], calc. for C24H29NO4: C, 72.89, H, 7.39, N,
3.54 %, found: C, 72.91, H, 7.36, N, 3.51 %.
\The compound 5 with 2-amino pyridine (6d) was yielded as a
gray solid, IR (KBr, vmax cm-1): 3512.53 (O–Hstretch),
3264.89 (N–Hstretch), 3096.34 (C–Hstretch Ar), 1674.21
(C=Ostretch), 1591.27 (N–Hbend), 1545.32 and 1489.05
(C=Cstretch Ar. ring), 1392.61 (O–Hbend), 1321.24 (C–Nstretch),
1128.09 (C–Ostretch ether), H1 NMR (400 MHz, DMSO-d6): d
8.11 (d, 1H arom., J = 5.36 Hz), 7.66 (d, 1H arom.,
J = 5.36 Hz), 7.44 (t, 1H arom., J = 5.36 Hz), 7.4 (t, 1H
arom., J = 5.36 Hz), 7.12 (t, 1H arom., J = 5.36 Hz), 7.04
(d, 1H arom., J = 5.36 Hz), 6.7 (d, 1H arom., J = 5.36 Hz),
6.6 (t, 1H arom., J = 5.36 Hz), 6.1 (s, 1H arom.), 6.06 (s, 1H
arom.), 5. 53 (s, 1H, OH), 4.06 (t, 1H, J = 2.24 Hz, NH), 3.94
(t, 2H, J = 4.8 Hz, CH2 near O), 3.06 (q, 2H, J = 6.8 Hz,
CH2 near N), 1.72 (m, 2H, J = 6.8 Hz, CH2), 1.52 (m, 2H,
J = 6.8 Hz, CH2), 1.29 (m, 2H, J = 6.8 Hz, CH2), C13 NMR
(100 MHz, DMSO-d6):d182.21(CO), 162.53, 162.3,158.62,
157.71, 157.7 (5 9 quat. arom. C), 148.23 138.3, 132.2,
130.02, 121.6 (5 9 arom. CH), 121.01 (quat. arom. C), 117.2,
113.32, 109.9 (3 9 arom. CH), 101.61 (quat. arom. C), 96.01,
94.92 (2 9 arom. CH), 68.92 (CH2 near of O), 45.12 (CH2
near of N), 30.2, 29.4, 23.41 (3 9 CH2), mass (m/e): 389.5
[M?], calc. for C23H22N2O4: C, 70.75; H, 5.68; N, 7.17 %;
found: C, 70.73; H, 5.70; N, 7.14 %.
1-Hydroxy-3-[5-(4-methylpiperazin-1-yl)pentyloxy]-9H-
xanthen-9-one (7c)
3-[5-[(Furan-2-ylmethyl) amino] pentyloxy]-1-hydroxy-
9H-xanthen-9-one (7e)
The compound 5 with methyl piperazine (6c) was yielded
as a brown solid, IR (KBr, vmax cm-1): 3425.35
(O–Hstretch), 3094.32 (C–Hstretch Ar), 2906.73 (C–Hstretch
alkyl), 1678.32 (C=Ostretch), 1583.56 and 1465.90
(C=Cstretch Ar. ring), 1354.21 (C–Nstretch), 1128.36
(C–Ostretch ether) H1 NMR (400 MHz, D2O): d 7.74 (d, 1H
arom., J = 6.49 Hz, H8), 7.39 (t, 1H arom., J = 7.64 Hz,
H6), 7.12 (t, 1H arom., J = 12.8 Hz, H7), 6.92 (d, 1H
arom., J = 12.8 Hz, H5), 6.09 (s, 1H arom., H4), 6.02
(s, 1H arom., H2), 5.24 (s, 1H, OH), 3.94 (t, 2H, J = 7.21 Hz,
The compound 5 with furan-2-ylmethyl amine (6e) was
yielded as a brown solid, IR(KBr, vmax cm-1): 3489.43
(O–Hstretch), 3249.46 (N–Hstretch), 3093.57 (C–Hstretch, Ar),
2904.80 (C–Hstretch, alkyl), 1651.07 (C=Ostretch), 1593.20
(N–Hbend), 1552.14 and 1487.12 (C=Cstretch, Ar. ring),
1409.96 (O–Hbend), 1373.32 (C–Nstretch), 1127.83
(C–Ostretch, ether); H1 NMR (400 MHz, D2O): d 7.66 (d,
1H arom., J = 8.02 Hz), 7.52 (t, 1H arom., J = 8.02 Hz),
7.29 (d, 1H arom., J = 8.02 Hz), 7.09 (t, 1H arom.,
J = 8.02 Hz), 7.0 (d, 1H arom, J = 8.02 Hz), 6.28 (t, 1H
123

Med Chem Res
arom., J = 8.02 Hz), 6.1 (s, 1H arom.), 6.06 (s, 1H arom.),
6.02 (d, 1H arom.), 4.8 (s, 1H, OH), 3.94 (t, 2H,
J = 6.8 Hz, CH2 near of O), 3.66 (d, 2H, J = 6.8 Hz, CH2
between N and furan), 2.55 (q, 2H, J = 6.8 Hz, CH2 near
of N), 2.13 (m, 1H, J = 6.8 Hz, NH), 1.71 (m, 2H,
J = 6.8 Hz, CH2), 1.41 (m, 2H, J = 6.8 Hz, CH2), 1.28
(m, 2H, J = 6.8 Hz, CH2), C13 NMR (100 MHz, D2O): d
182.21 (CO), 162.51, 162.32, 157.72, 155.7, 148.8
(5 9 quat. arom. C), 142.11, 132.21, 130.02, 121.63
(4 9 arom. CH), 121.6 (quat. arom. C), 117.21, 110.6,
106.7 (3 9 arom. CH), 101.61 (quat. arom. C), 96.02, 94.9
(2 9 arom. CH), 68.9 (CH2 near of O), 50.21, 47.11 (CH2
near of N), 30.01, 29.4, 23.41 (3 9 CH2), mass (m/e):393.7
[M?], calc. for C23H23NO5: C, 70.21; H, 5.89; N, 3.56 %,
found: C, 70.24; H, 5.91; N, 3.54 %.
1487.12 (C=Cstretch Ar. ring), 1390.68 (C–Nstretch nitro),
1129.08 (C–Ostretc ether), H1 NMR (400 MHz, DMSO-d6):
d 7.97 (2 9 d, 1H arom. near NO2, J = 9.56 Hz), 7.69 (d,
1H arom., J = 9.56 Hz), 7.43 (t, 1H arom., J = 9.56 Hz),
7.09 (t, 1H arom., J = 9.56 Hz), 7.02 (d, 1H arom.,
J = 9.56 Hz), 6.69 (2 9 d, 1H arom., J = 9.56 Hz), 6.1 (s,
1H arom.), 6.04 (s, 1H arom.), 5.06 (s, 1H, OH), 4.14 (t,
1H, J = 3.49 Hz, NH), 3.98 (t, 2H, J = 6.4 Hz, CH2 near
O), 3.07 (q, 2H, J = 6.4 Hz, CH2 near N), 1.73 (m, 2H,
J = 6.4 Hz, CH2), 1.53 (m, 2H, J = 6.4 Hz, CH2), 1.28
(m, 2H, J = 6.4 Hz, CH2), C13 NMR (400 MHz, DMSO-
d6): d 182.21 (CO), 162.51, 162.32, 157.73, 155.72, 153.7,
136.81 (6 9 quat. arom. C), 132.23, 130.02, 121.9, 121.63
(5 9 arom. CH), 121.02 (quat. arom. C), 117.21, 114.42
(3 9 arom. CH), 101.63 (quat. arom. C), 96.01, 94.93
(4 9 arom. CH), 68.9 (CH2 near of O), 45.11 (CH2 near of
N), 31.2, 29.4, 23.41 (3 9 CH2), mass (m/e): 335.6 [M?],
calc. for C24H22N2O6: C, 66.35; H, 5.10, N, 6.45 %, found:
C, 66.32, H, 5.11, N, 6.48 %.
3-[5-(3-Chloro-4-fluoro-phenylamino)-pentyloxy]-1-
hydroxy-9H-xanthen-9-one (7f)
The compound 5 with 3-chloro-4-fluoro-phenylamine (6f)
was yielded as a brown solid, IR (KBr, vmax cm-1):
3419.55 (O–Hstretch), 3264.89 (N–Hstretch), 3092.48
(C–Hstretch Ar), 1629.85 (C=Ostretch), 1591.27 (N–Hbend),
1548.68 and 1489.05 (C=Cstretch Ar. ring), 1392.61
(O–Hbend), 1155.36 (C–Fstretch), 1127.96 (C–Ostretch ether),
746.45 (C–Clstretch), H1 NMR (400 MHz, DMSO-d6): d
7.67 (d, 1H arom., J = 9.8 Hz), 7.43 (t, 1H arom.,
J = 9.8 Hz), 7.16 (t, 1H, J = 9.8 Hz), 7.12 (d, 1H arom.,
J = 9.8 Hz), 6.69 (d, 1H arom., J = 9.8 Hz), 6.42 (s, 1H
arom.), 6.29 (d, 1H arom., J = 9.8 Hz), 6.12 (s, 1H arom.),
6.06 (s, 1H arom.), 5.53 (s, 1H, OH), 4.12 (t, 1H,
J = 2.6 Hz, NH), 3.96 (t, 2H, J = 7.32 Hz, CH2 near O),
3.07 (q, 2H, J = 7.32 Hz, CH2 near N), 1.71 (m, 2H,
J = 7.32 Hz, CH2), 1.53 (m, 2H, J = 7.32 Hz, CH2), 1.31
(m, 2H, J = 7.32 Hz, CH2), C13 NMR (400 MHz, DMSO-
d6): d 182.19 (CO), 162.51, 162.32, 157.72, 155.69
(4 9 quat. arom. C), 151.2 (arom. CF), 144.6 (quat. arom.
C), 132.21, 130.02 (2 9 arom. CH), 121.6 (arom. CCl),
121.58 (arom. CH), 121.04 (quat. arom. C), 117.71, 117.2,
115.52, 113.2 (4 9 arom. CH), 101.63 (quat. arom. C),
96.06, 94.92 (2 9 arom. CH), 68.9 (CH2 near O), 45.12
(CH2 near N), 30.21, 29.4, 23.4 (3 9 CH2), mass (m/e):
441.1 [M?], 443.11[M?2]? (32.1 %), calc. for
C24H21ClFNO4: C, 65.23; H, 4.79; N, 3.1 %, found: C,
65.21; H, 4.82; N, 3.20 %.
1-Hydroxy-3-[5-(piperidin-1-yl) pentyloxy]-9H-
xanthen-9-one (7h)
The compound 5 with piperidine (6h) was yielded as a brown
solid, IR (KBr, vmax cm-1): 3473.31 (O–Hstretch), 3091.46
(C–Hstretch Ar), 2947.24 (C–Hstretch, Alkyl), 1646.56
(C=Ostretch), 1602.32 and 1569.12 (C=Cstretch Ar), 1406.03
(C–Nstretch,), 1127.32 (C–Ostretch ether), H1 NMR (400 MHz,
DMSO-d6): d 7.66 (d, 1H arom, J = 7.2 Hz), 7.42 (t, 1H
arom, J = 7.2 Hz), 7.09 (t, 1H arom, J = 7.2 Hz), 7.03 (d,
1H arom, J = 7.2 Hz), 6.1 (s, 1H arom.), 6.04 (s, 1H arom.),
5.32 (s, 1H, OH), 3.28 (t, 2H, J = 6.4 Hz, CH2 near of O),
2.36 (t, 2H, J = 6.4 Hz, CH2 near of N), 2.25 (t, 2H,
J = 6.4 Hz, CH2 near of N), 1.7 (m, 2H, J = 6.4 Hz, CH2),
1.51 (m, 2H, J = 6.4 Hz, CH2), 1.39 (m, 2H, J = 6.4 Hz,
CH2), 1.29 (m, 2H, J = 6.4 Hz, CH2), C13 NMR (400 MHz,
DMSO-d6): d 182.21 (CO), 162.5, 162.31, 157.74, 155.72
(4 9 quat. arom. C), 132.23, 131.02, 121.62 (3 9 arom.
CH), 121.03 (quat. arom. C), 117.21 (arom. CH), 101.62
(quat. arom. C), 96.01, 94.9 (2 9 arom. CH), 68.91 (CH2
near of O), 54.63, 54.42 (3 9 CH2 near of N), 29.4, 28.41,
25.93, 25.5, 23.71 (6 9 CH2), mass (m/e): 381.19 [M?],
calc. for C23H27NO4: C, 72.42, H, 7.13, N, 3.67 %, found: C,
72.38, H, 7.18, N, 3.65 %.
3-[5-(1H-Imidazol-1-yl) pentyloxy]-1-hydroxy-9H-
xanthen-9-one (7i)
1-Hydroxy-3-[5-(4-nitro-phenylamino)-pentyloxy]-9H-
xanthen-9-one (7g)
The compound 5 with imidazole (6i) was yielded as a yellow
solid, IR (KBr, vmax cm-1): 3474.65 (O–Hstretch), 3094.67
(C–Hstretch Ar), 2948.14 (C–Hstretch alkyl), 1666.39
(C=Ostretch), 1563.65 and 1507.24 (C=Cstretch Ar), 1408.43
(C–Nstretch), 1123.16 (C–Ostretch ether), H1 NMR (400 MHz,
The compound 5 with 4-nitro-phenylamine(6g) was yiel-
ded as a yellow solid, IR (KBr, vmax cm-1): 3481.51
(O–Hstretch), 3361.93 (N–Hstretch), 3070.68 (C–Hstretch Ar.),
1629.85 (C=Ostretch), 1593.20 (N–Hbend), 1553.43 and
123

Med Chem Res
DMSO-d6): d 7.6 (d, 1H arom., J = 3.31 Hz), 7.56 (s, 1H
arom.), 7.42 (t, 1H arom., J = 9.76 Hz), 7.09 (t, 1H arom.,
J = 9.76 Hz), 7.06 (d, 1H arom., J = 9.76 Hz), 7.01 (d, 1H
arom., J = 9.76 Hz), 6.96 (d, 1H arom., J = 9.76 Hz), 6.09
(s, 1H arom.), 6.05 (s, 1H arom.), 5.24 (s, 1H, OH), 3.98 (t,
2H, J = 1.9 Hz, CH2 near O), 3.68 (t, 2H, J = 1.9 Hz, CH2
near N), 1.79 (m, 2H, J = 2.3 Hz, CH2), 1.73 (m, 2H,
J = 2.3 Hz, CH2), 1.27 (m, 2H, J = 2.3 Hz, CH2), C13
NMR (400 MHz, DMSO-d6): d 182.21 (CO), 162.5, 162.3,
157.71, 155.72 (4 9 quat. arom. C), 136.82, 132.22, 130.03,
128.1, 121.62 (5 9 arom. CH), 121.02 (quat. arom. C),
120.73, 117.22 (2 9 arom. CH), 100.62 (quat. arom. C),
96.01, 94.92 (2 9 arom. CH), 68.91 (CH2 near of O), 52.43
(CH2 near of N), 31.1, 29.4, 23.5 (3 9 CH2), mass (m/e):
364.14 [M?], calc. for C21H20N2O4: C, 69.22, H, 5.53, N,
7.69 %, found: C, 69.23, H, 5.50, N, 7.67 %.
(m, 2H, J = 4.37 Hz, CH2), 1.39 (m, 2H, J = 4.37 Hz,
CH2), 1.26 (m, 2H, J = 4.37 Hz, CH2), 1.08 (4 9 d, 12H,
J = 1.18 Hz, CH3), C13 NMR (400 MHz, DMSO-d6): d
182.21 (CO), 162.52, 162.3, 157.73, 155.7 (4 9 quat.
arom. C), 132.23, 129.9, 121.61 (3 9 arom. CH), 121.02
(quat. arom. C), 117.21 (arom. CH), 101.62 (quat. arom. C),
96.03, 95.01, 68.92 (CH2 near of O), 49.12 (3 9 CH2 near
of N), 29.4, 29.01, 23.72 (3 9 CH2), 22.91 (4 9 CH3),
mass (m/e): 381.19 [M?], calc. for C24H31NO4: C, 66.35; H,
5.10, N, 6.45 %, found: C, 66.32, H, 5.11, N, 6.48 %.
Antibacterial activity
Preparation of seed of organisms
About 13.0 g of nutrient broth medium was suspended in
1,000 ml distilled water. Then, it was boiled to dissolve the
medium completely and filtered from 5 l sintered glass fil-
ter. A set of test tubes with nutrient broth (5 ml) was capped
with cotton plugs and sterilized by autoclaving at 15 psig
pressure (121 °C) for 15 min. Then, after cooling, a loop of
various organisms were inoculated into liquid broth and
incubated at 37 1 °C and used within 12 h. The inoculums
size for test strain was adjusted to 108 CFU/ml (colony
forming unit per milliliter) by comparing the turbidity.
3-[5-(Diisopropylamino) pentyloxy]-1-hydroxy-9H-
xanthen-9-one (7j)
The compound 5 with diisopropylamine (6j) was yielded as
a gray solid, IR (KBr, vmax cm-1): 3473.31 (O–Hstretch);
3098 (C–Hstretch Ar.), 2939.49 (C–Hstretch Alkyl), 1646.56
(C=Ostretch), 1589.12 (C=Cstretch Ar. ring), 1406.03
(C–Nstretch), 1125.52 (C–Ostretch ether); H1 NMR
(400 MHz, DMSO-d6): d 7.61 (d, 1H arom., J = 7.1 Hz),
7.36 (t, 1H arom., J = 7.1 Hz), 7.09 (t, 1H arom.,
J = 7.1 Hz), 7.01 (d, 1H arom., J = 7.1 Hz), 6.1 (s, 1H
arom.), 6.07 (s, 1H arom.), 5.13 (s, 1H, OH), 3.97 (t, 2H,
J = 0.6 Hz, CH2 near O), 2.97 (2 9 m, 1H, J = 1.2 Hz,
CH(CH3)2), 2.37 (t, 2H, J = 4.37 Hz, CH2 near N), 1.72
Determination of zone of inhibition
The zones of inhibition of all the synthesized compounds
(7a–j) were determined preliminarily for antibacterial
Table 2 The zone of inhibition of synthesized compounds
Zone of inhibition (mm)a,b
Compound
Gram-positive organisms
Gram-negative organisms
B. subtilis
B. cereus
S. aureus
E. coli
P. aeruginosa
P. mirabilis
c
7a
–
–
10 0.372
11 0.421
13 0.37
–
15 0.35
7b
12 0.25
–
–
–
–
7c
–
–
19 0.3
11 0.315
–
–
7d
10 0.34
–
–
–
–
–
–
7e
9
–
0.257
–
12 0.39
14 0.254
19 0.37
–
–
–
7f
16 0.341
11 0.421
16 0.247
10 0.34
11 0.421
11 0.421
21 0.362
19 0.352
7g
18 0.35
–
–
–
7h
–
11 0.421
–
–
7i
11 0.421
10 0.34
20 0.32
–
10 0.34
11 0.421
21 0.4
–
7j
11 0.421
23 0.25
10 0.34
22 0.4
–
Ofloxacin
24 0.274
a
DMSO as negative control
b
c
Data are mean of three replications
No inhibition was observed
123

Med Chem Res
seeds of organisms were incubated into various previously
prepared broths with drugs. At the end of the incubation
period (37 1 °C for 24 h), the MIC values were deter-
mined which are presented in Table 3.
Table 3 Minimum inhibitory concentration (MIC) of synthesized
compounds
MIC (lg ml-1 a
)
Compound Gram-positive
organisms
Gram-negative organisms
B.
B.
S.
subtilis cereus aureus
E. coli P. P.
aeruginosa mirabilis
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