One-pot synthesis of 3,4-dihydro-3-hydroxyisochroman-1-one and evaluation of acetal derivatives as antibacterial and antifungal agents

Article abstract of DOI:10.1515/hc-2014-0136

A one-pot synthesis of 3,4-dihydro-3-hydroxyisochroman-1-one (lactol) 3 by oxidation of indene using tungstic acid-hydrogen peroxide is reported. The synthesized lactol was converted into acetal derivatives 5a-h, which were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Streptococcus pyogenes (Gram-positive), Escherichia coli, Pseudomonas aeruginosa (Gram-negative) strains, and antifungal activity against Candida albicans and Aspergillus niger by broth dilution method. The compounds show potent activity against S. aureus in comparison with ampicillin and exhibit modest antifungal activity.

Full text of DOI:10.1515/hc-2014-0136

Heterocycl. Commun. 2014; 20(5): 299–303
Gautam M. Patel and Pradeep T. Deota*
One-pot synthesis of 3,4-dihydro-3-hydroxyiso-
chroman-1-one and evaluation of acetal derivatives
as antibacterial and antifungal agents
Abstract: A one-pot synthesis of 3,4-dihydro-3-hydroxy- various reagents like sodium metaperiodate [11], aqueous
isochroman-1-one (lactol) 3 by oxidation of indene using potassium hydroxide [13], trifluoroacetic acid [14], and
tungstic acid-hydrogen peroxide is reported. The synthe- ozonolysis [15] in several steps. Schöpf and Kühne [16]
sized lactol was converted into acetal derivatives 5a–h, have been the first to report the synthesis of lactol 3 in four
which were evaluated for their in vitro antibacterial activ- steps. Abe and colleagues [17–19] have also synthesized
ity against Staphylococcus aureus, Streptococcus pyogenes lactol 3 by photooxygenation in three steps from indene,
(Gram-positive), Escherichia coli, Pseudomonas aerugi- and its crystal structure has been subsequently reported
nosa (Gram-negative) strains, and antifungal activity by Valente et al. [20].
against Candida albicans and Aspergillus niger by broth
Earlier, our group has demonstrated the synthetic
dilution method. The compounds show potent activ- utility of tungstic acid-hydrogen peroxide in t-butanol to
ity against S. aureus in comparison with ampicillin and furnish the corresponding trans-diol of (Z,Z)-cycloocta-
exhibit modest antifungal activity.
1,5-diene in 65% yield [21]. The treatment of endo-dicy-
clopentadiene with this reagent combination in t-butanol
Keywords: acetals; antibacterial; antifungal; 3,4-dihydro- unexpectedly resulted in the formation of polycyclic
3-hydroxyisochroman-1-one; lactol.
oxetanes [22]. Our continued interest in the dihydroxy-
lation of olefins prompted us to explore the reaction
of indene (1) with a tungstic acid-hydrogen peroxide
mixture in order to prepare its trans-diol, which is an
important intermediate for indinavir (Crixivan), an HIV
protease inhibitor [23]. However, this reaction resulted in
the formation of not only racemic indan-trans-1,2-diol 2
but also racemic lactol 3 (Scheme 1). This serendipitous
formation of lactol encouraged us to further investigate
DOI 10.1515/hc-2014-0136
Received June 24, 2014; accepted September 8, 2014
Introduction
The lactol scaffold is a core structural unit in various bio- this reaction.
logically active compounds such as callipeltoside A [1],
ginkgolides [2, 3], dysidiolide [4], cladocorans A and B
[5], acuminolide [6], spongianolide A [7], manoalide [8],
cacospongionolide B2 [9], and peniolactol [10]. Lactols Results and discussion
are also employed as important synthetic precursors to
several compounds such as illudalic acid [11], benzo- Because certain 4- and 5-oxoacids exist as cyclic lactols
pyran-1-ones [12], caronaldehyde [13], mevalonate, and or pseudoacids [20], it is clear that 3 is formed as a result
mevaldate [14].
of cleavage of indene followed by in situ cyclization of the
The lactol unit has been assembled via different routes intermediate 2-carboxyphenylethanal. To ascertain the
such as photosensitized oxygenation of furan, oxidative source of the lactol 3, the experiments were designed as
cleavage of olefins or diols, followed by cyclization using follows. Initially, it was thought that indan-trans-1,2-diol
2 could be oxidized to 3 via intermediacy of 2-carboxy-
phenylethanal, but the treatment of 2 with tungstic acid-
*Corresponding author: Pradeep T. Deota, Faculty of Technology
hydrogen peroxide at 30°C in t-butanol left it unchanged
and Engineering, Applied Chemistry Department, The Maharaja
even after 14 h. It was then contemplated that the cis-diol
Sayajirao University of Baroda, Vadodara 390001, India,
of indene could be the source of 3. Thus, indan-cis-1,2-diol
e-mail: deotapt@yahoo.com
4 was prepared by a reported method [24] and treated
Gautam M. Patel: Applied Sciences Department, ITM Vocational
University, Vadodara 391760, India
with tungstic acid-hydrogen peroxide. This reaction gave
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300ꢀ
ꢀG.M. Patel and P.T. Deota: 3,4-Dihydro-3-hydroxyisochroman-1-one and acetal derivatives
O
OH
1
H2WO4, H2O2
O
OH
or
tBuOH, 14 h, 30°C
OH
OH
2
3
yield from 1:
yield from 4:
39%
63%
16%
28%
OH
4
Scheme 1ꢂ
a mixture of lactol 3 and trans-diol 2 in 28% and 63% derivatives of lactol 5a–h were synthesized to examine
yields, respectively (Scheme 1). A similar conversion of 4 the effect of spacer groups on their biological potency.
to 2 in the presence of nickel at 60°C has been reported The catalyst quantity and the reaction temperature play
[25]. It should be noted that the present method (Scheme an important role in the formation of acetal derivatives. It
1) furnishes 2 from 4 in better yield (63%) under milder was observed that lactol 3 underwent dehydration to 6 by
conditions.
increasing either the temperature or the catalyst quantity
These observations also implied that 4 could be trans- (ꢀ> ꢀ12.5 mol%) (Scheme 2).
formed into lactol 3 via oxidative cleavage followed by
All synthesized compounds (2, 3, and 5a–h) were
cyclization under the reaction conditions. A similar cleav- tested for their in vitro antimicrobial activities. The
age of 2 does not take place during the reaction, perhaps minimum inhibitory concentration (MIC) of the com-
due to the trans geometry of the hydroxyl groups. To the pounds were recorded against two Gram-positive bacteria
best of our knowledge, this one-pot synthesis of 3,4-dihy- (Staphylococcus aureus and Streptococcus pyogenes),
dro-3-hydroxyisochroman-1-one 3 from indene 1 under two Gram-negative bacteria (Escherichia coli and
such mild conditions is described here for the first time.
Pseudomonas aeruginosa), and fungi (Candida albicans
Lactol derivatives show a wide variety of biologi- and Aspergillus niger) by broth dilution method [26, 27].
cal activities [4–11]. These interesting biological proper- Standard antibacterial drug ampicillin and antifungal
ties prompted us to prepare the acetal derivatives 5a–h drug griseofulvin were also screened under identical con-
(Scheme 2) and examine their antimicrobial activity. ditions for comparison. Individual MIC values of all the
The cyclic lactols are known to coexist with open-chain compounds and for the standards are listed in Table 1.
structures having free aldehyde functionality that can The results reveal that all compounds show significant
react with alcohols to form acetals [20]. Various acetal antibacterial activity. All compounds show good activity
against S. aureus (Gram-positive bacteria). Derivatives 5d
and 5e are potent against E. coli (MICꢀ= ꢀ62.5 μg/mL) and
P. aeruginosa (MICꢀ= ꢀ62.5 μg/mL), respectively.
O
O
The antifungal screening data show that a few com-
pounds are potent against fungal strains. Compounds 2,
5d, and 5e are equipotent against C. albicans in compari-
son with griseofulvin.
O
O
ROH
conc. H2SO4
dry toluene, rt
OR
OH
5a-h
3
5a: R = C2H5
5b
ROH
ROH
: R = n-C3H7
5c: R = n-C4H9
5d
conc. H2SO4
(> 12.5 mol%)
dry toluene
rt
conc. H2SO4
(12.5 mol%)
dry toluene
rt to ∆
or
: R = n-C5H11
Conclusion
5e: R = n-C8H17
5f: R = n-C12H25
5g
: R = n-C14H29
5h: R = n-C16 33
A one-pot synthesis of 3,4-dihydro-3-hydroxyisochroman-
1-one (lactol) 3 from indene 1 is reported along with its
probable route of formation. Various acetal derivatives
5a–h were prepared and tested for biological activity. All
products exhibit moderate to good antibacterial and anti-
fungal activity.
O
H
O
6
Scheme 2ꢂ
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G.M. Patel and P.T. Deota: 3,4-Dihydro-3-hydroxyisochroman-1-one and acetal derivativesꢂ
ꢂ301
Table 1ꢂResults of antibacterial and antifungal screening of compounds 2, 3, and 5a–h.
Compound
ꢁ
MIC (μg/mL)
E. coliꢁ
MTCC 443ꢁ
P. aeruginosaꢁ
MTCC 1688ꢁ
S. aureusꢁ
MTCC 96ꢁ
S. pyogenesꢁ
MTCC 442ꢁ
C. albicansꢁ
MTCC 227ꢁ
A. niger
MTCC 282
2
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
200ꢃ
125ꢃ
250ꢃ
200ꢃ
200ꢃ
62.5ꢃ
200ꢃ
200ꢃ
250ꢃ
250ꢃ
100ꢃ
–ꢃ
500ꢃ
250ꢃ
200ꢃ
250ꢃ
250ꢃ
100ꢃ
62.5ꢃ
200ꢃ
250ꢃ
200ꢃ
100ꢃ
–ꢃ
200ꢃ
100ꢃ
200ꢃ
100ꢃ
200ꢃ
200ꢃ
250ꢃ
250ꢃ
100ꢃ
250ꢃ
250ꢃ
–ꢃ
250ꢃ
100ꢃ
200ꢃ
100ꢃ
200ꢃ
200ꢃ
250ꢃ
250ꢃ
100ꢃ
250ꢃ
100ꢃ
–ꢃ
500ꢃ
ꢀ> ꢀ1000ꢃ
1000ꢃ
1000ꢃ
1000ꢃ
500ꢃ
ꢀ> ꢀ1000
500
ꢀ> ꢀ1000
1000
ꢀ> ꢀ1000
ꢀ> ꢀ1000
500
200
250
1000
–
100
3
5a
5b
5c
5d
5e
500ꢃ
5f
ꢀ> ꢀ1000ꢃ
ꢀ> ꢀ1000ꢃ
ꢀ> ꢀ1000ꢃ
–ꢃ
5g
5h
Ampicillin
Griseofulvin ꢃ
500ꢃ
MICs of ampicillin and griseofulvin are used as standards for comparison and hence are in bold.
3,4-Dihydro-3-hydroxyisochroman-1-one (3)ꢀWhite crystalline
solid; mp 95°C; IR (νmax, cm-1): 3276, 2923, 1702, 1603, 1439, 1393, 1133,
1067, 735. 1H NMR: δH 1.70 (broad s, 1H, OH, exchanges with D2O), 3.15
(dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ 4.6 Hz), 3.35 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz,
J2 ꢀ= ꢀ 4.6 Hz), 5.95 (t, 1H, CH-OH, J ꢀ= ꢀ 4.8 Hz), 7.54 (m, 4H, aromatic H);
13C NMR: δC 34.2, 96.2, 124.7, 127.9, 128.6, 130.2, 134.5, 136.6, 165.5; MS
(EI): m/z 164 (M+). Anal. Calcd for C9H8O3: C, 65.85; H, 4.91. Found: C,
65.78; H, 4.84.
Experimental
IR spectra were obtained using KBr pellets on a Shimadzu 8400S
1
FTIR spectrometer. H NMR spectra (400 MHz) and 13C NMR spectra
(100 MHz) were determined on a Bruker-400 FT NMR spectrometer
in CDCl3. Mass spectra were obtained on a Shimadzu QP-5050 mass
spectrometer. Column chromatography was carried out using Acme’s
silica gel (60–120 mesh size) and eluting with light petroleum and
ethyl acetate mixtures. Thin-layer chromatography (TLC) was per-
formed using Acme’s silica gel for TLC and spots were visualized with
the iodine vapor.
Synthesis of indan-trans-1,2-diol (2) and 3,4-dihydro-
3-hydroxyisochroman-1-one (3) from cis-diol (4)
The reaction was conducted and the products isolated as described
above. Column chromatography furnished the indan-trans-1,2-diol
(2, 0.63 g, 63%) and 3,4-dihydro-3-hydroxyisochroman-1-one (3,
0.31 g, 28%).
Synthesis of indan-trans-1,2-diol (2) and 3,4-dihydro-
3-hydroxyisochroman-1-one (3)
To a stirred solution of indene (5 mL, 43 mmol) in t-butanol (25 mL)
was added a suspension of tungstic acid (0.5 g) and hydrogen per-
oxide (30%, 140 mmol). The mixture was stirred for 14 h at room
temperature (∼30°C). Afer completion of the reaction, as monitored
by TLC, the mixture was filtered through a celite pad to remove the
suspended catalyst. The filtrate was diluted with water (20 mL)
and extracted with ethyl acetate (4ꢀ× ꢀ25 mL). The combined organic
extracts were washed with water (15 mL), brine (10 mL), and dried
over anhydrous sodium sulfate. Removal of solvent and column chro-
matography of the residue furnished the indan-trans-1,2-diol (2, 2.10
g, 39%) and 3,4-dihydro-3-hydroxyisochroman-1-one (3, 0.90 g, 16%).
Prolonged reaction periods did not appreciably alter the product
ratio.
Synthesis of acetal derivatives 5a–h
To a mixture of the lactol 3 (3.05 mmol) and an alcohol (3.65 mmol) in
dry toluene (20 mL) was added concentrated H2SO4 (0.4 mL) at room
temperature under stirring for 5 h. Afer completion of the reaction
(TLC), the solvent was removed and the mixture was neutralized with
saturated solution of sodium bicarbonate and extracted with ethyl
acetate. The combined organic extracts were washed with water,
brine, and dried over anhydrous sodium sulfate. Removal of solvent
followed by chromatography of the residue furnished 5a–h.
3-Ethoxy-3,4-dihydroisochroman-1-one (5a)ꢀLight yellow liquid;
yield 72%; IR (νmax, cm-1): 2946, 2912, 2834, 1729, 1628, 1464, 1310, 1274,
1104, 1092, 738; 1H NMR: δH 1.20 (t, 3H, OCH2CH3, J ꢀ= ꢀ 6.9 Hz), 3.15 (dd,
1H, CH2, J1 ꢀ= ꢀ 16.2 Hz, J2 ꢀ= ꢀ 4.8 Hz), 3.35 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.2 Hz, J2 ꢀ= ꢀ 4.8
Hz), 3.70 (m, 1H, OCH2CH3), 3.98 (m, 1H, OCH2CH3), 5.55 (t, 1H, CH-OR,
J ꢀ= ꢀ 4 Hz), 7.52 (m, 4H, aromatic H); 13C NMR: δC 15.3, 33.7, 65.3, 101.1,
125.0, 127.7, 128.3, 129.9, 134.1, 136.6, 164.2; MS (EI): m/z 192 (M+). Anal.
Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.76; H, 6.23.
2,3-Dihydro1H-indan-trans-1,2-diol (2)ꢀWhite crystalline solid;
mp 156–160°C; IR (νmax, cm-1): 3226, 2911, 2849, 1559, 1477, 1458, 1354,
1057, 746, 645; 1H NMR: δH 2.74 (dd, 1H, CH2 geminal, J1 ꢀ= ꢀ 15.5 Hz, J2 ꢀ= ꢀ
7.5 Hz), 3.18 (dd, 1H, CH2 geminal, J1 ꢀ= ꢀ 15.5 Hz, J2 ꢀ= ꢀ 7.5 Hz), 4.25 (m, 1H,
CH-OH), 5.04 (d, 1H, Ar-CH-OH, J ꢀ= ꢀ 5.6 Hz), 4.88 and 4.86 (s, 2H, OH,
both exchange with D2O), 7.32 (m, 4H, aromatic H); 13C NMR: δC 3 7.7,
80.6, 81.1, 123.9, 124.3, 126.3, 127.4, 138.9, 143.1. MS (EI): m/z 150 (M+).
Anal. Calcd for C9H10O2: C, 71.98; H, 6.71. Found: C, 71.80; H, 6.74.
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302ꢀ ꢀG.M. Patel and P.T. Deota: 3,4-Dihydro-3-hydroxyisochroman-1-one and acetal derivatives
3,4-Dihydro-3-propoxyisochroman-1-one (5b)ꢀLight yellow liq-
(dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.62 (m, 1H, OCH2(CH2)12CH3),
uid; yield 78%; IR (νmax, cm-1): 2964, 2933, 2879, 1728, 1610, 1462, 1379, 3.95 (m, 1H, OCH2(CH2)12CH3), 5.56 (t, 1H, CH-OCH2(CH2)12CH3, J ꢀ= ꢀ 4.4
1
1271, 1016, 910, 731; H NMR: δH 0.88 (t, 3H, OCH2CH2CH3, J ꢀ= ꢀ 7.2 Hz), Hz), 7.52 (m, 4H, aromatic H); 13C NMR: δC 14.1, 22.7, 25.8, 29.3, 29.3,
1.60 (m, 2H, OCH2CH2CH3), 3.12 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.3 Hz, J2 ꢀ= ꢀ 4.4 Hz), 29.3, 29.5, 29.5, 29.5, 29.6, 29.6, 29.7, 31.9, 33.4, 69.7, 101.0, 124.9, 127.5,
3.31 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.3 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.59 (m, 1H, OCH2CH2CH3), 128.1, 129.9, 133.9, 136.4, 164.1. MS (EI): m/z 360 (M+). Anal. Calcd for
3.91 (m, 1H, OCH2CH2CH3), 5.57 (t, 1H, CH-OCH2CH2CH3, J ꢀ= ꢀ 4.4 Hz), C23H36O3: C, 76.62; H, 10.06. Found: C, 76.58; H, 10.10.
7.54 (m, 4H, aromatic H); 13C NMR: δC 15.3, 22.6, 33.4, 71.1, 101.0, 124.9,
127.5, 128.1, 129.9, 133.9, 136.5, 164.2; MS (EI): m/z 206 (M+). Anal. Calcd 3-(Hexadecyloxy)-3,4-dihydroisochroman-1-one
(5h)ꢀWhite
for C12H14O3: C, 69.88; H, 6.84. Found: C, 69.79; H, 6.88.
crystalline solid; yield 78%; IR (νmax, cm-1): 3090, 2941, 2837, 1720,
1637, 1487, 1251, 1045, 794, 688; 1H NMR: δH 0.89 (t, 3H, OCH2(CH2)14CH3,
J
ꢀ= ꢀ 6.9 Hz), 1.26 (m, 26H, OCH2CH2(CH2)13CH3), 1.57 (m, 2H,
3-Butoxy-3,4-dihydroisochroman-1-one (5c)ꢀLight yellow liquid;
yield 74%; IR (νmax, cm-1): 2958, 2935, 2874, 1728, 1610, 1460, 1379, 1271,
OCH2CH2(CH2)13CH3), 3.11 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.30
(dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.61 (m, 1H, OCH2(CH2)14CH3),
3.96 (m, 1H, OCH2(CH2)14CH3), 5.56 (t, 1H, CH-OCH2(CH2)14CH3, J ꢀ= ꢀ 4
Hz), 7.54 (m, 4H, aromatic H); 13C NMR: δC 14.1, 22.7, 25.7, 25.8, 29.3,
29.3, 29.4, 29.4, 29.5, 29.5, 29.6, 29.6, 29.7, 31.9, 32.8, 33.4, 69.7, 101.0,
124.9, 127.5, 128.1, 129.9, 133.9, 136.5, 164.1; MS (EI): m/z 388 (M+). Anal.
Calcd for C25H40O3: C, 77.27; H, 10.38. Found: C, 77.22; H, 10.30.
1
1128, 1053, 732, 692; H NMR: δH 0.89 (t, 3H, OCH2CH2CH2CH3, J ꢀ= ꢀ 7.2
Hz), 1.30 (m, 2H, OCH2CH2CH2CH3), 1.60 (m, 2H, OCH2CH2CH2CH3), 3.11
(dd, 1H, CH2, J1 ꢀ= ꢀ 18.2 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.30 (dd, 1H, CH2, J1 ꢀ= ꢀ 18.2 Hz, J2 ꢀ= ꢀ
4.4 Hz), 3.62 (m, 1H, OCH2CH2CH2CH3), 3.97 (m, 1H, OCH2CH2CH2CH3),
5.56 (t, 1H, CH-OCH2CH2CH2CH3, J ꢀ= ꢀ 4.1 Hz), 7.52 (m, 4H, aromatic H);
13C NMR: δC 13.7, 19.0, 31.3, 33.4, 69.3, 101.0, 124.9, 127.5, 128.1, 129.9,
133.9, 136.4, 164.2; MS (EI): m/z 220 (M+). Anal. Calcd for C13H16O3: C,
70.89; H, 7.32. Found: C, 70.81; H, 7.26.
1H-Isochromen-1-one (6) [28]ꢀWhite crystalline solid; mp 46°C; IR
(νmax, cm-1): 2962, 1732, 1610, 1462, 1246, 1008, 731; H NMR: δH 6.52
1
(d, 1H, CHꢀ= ꢀCH-O, J ꢀ= ꢀ 5.6 Hz), 7.28 (d, 1H, CHꢀ= ꢀCH-O, J ꢀ= ꢀ 5.2 Hz), 7.62
(m, 4H, aromatic H); 13C NMR: δC 107.0, 121.8, 125.5, 128.6, 129.7, 134.8,
136.4, 144.7, 162.2.
3,4-Dihydro-3-(pentyloxy)isochroman-1-one (5d)ꢀLight yellow
liquid; yield 71%; IR (νmax, cm-1): 2956, 2933, 2872, 1732, 1620, 1460,
1383, 1271, 1136, 1072, 732; 1H NMR: δH 0.86 (t, 3H, OCH2(CH2)3CH3, J ꢀ= ꢀ6.4
Hz), 1.28 (m, 4H, OCH2CH2(CH2)2CH3), 1.56 (m, 2H, OCH2CH2(CH2)2CH3),
3.10 (dd, 1H, CH2, J1 ꢀ= ꢀ 17.4 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.29 (dd, 1H, CH2, J1 ꢀ= ꢀ 17.4 Hz,
J2 ꢀ= ꢀ 4.4 Hz), 3.60 (m, 1H, OCH2(CH2)3CH3), 3.94 (m, 1H, OCH2(CH2)3CH3), Antibacterial assay
5.55 (t, 1H, CH-OCH2(CH2)3CH3, J ꢀ= ꢀ 4 Hz), 7.48 (m, 4H, aromatic H); 13
C
NMR: δC 12.3, 22.5, 27.9, 29.0, 34.2, 69.6, 101.0, 123.4, 127.5, 128.1, 129.9,
133.9, 136.5, 164.2; MS (EI): m/z 234 (M+). Anal. Calcd for C14H18O3: C,
71.77; H, 7.74. Found: C, 71.68; H, 7.71.
Compounds 2, 3, and 5a–h were screened for their antibacterial
activity against Gram-positive bacteria [S. aureus (MTCC-96) and S.
pyogenes (MTCC-442)] and Gram-negative bacteria [Escherichia coli
(MTCC-443) and P. aeruginosa (MTCC-1688)]. All MTCC cultures were
collected from the Institute of Microbial Technology, Chandigarh,
India. The activity of compounds was determined as per National
Committee for Clinical Laboratory Standards (NCCLS) protocol using
Mueller Hinton broth (Becton Dickinson, Franklin Lakes, NJ, USA).
Compounds were screened for their antibacterial activity as primary
screening in five sets against S. aureus, S. pyogenes, E. coli, and P.
aeruginosa at different concentrations of 1000, 500, and 250 μg/
mL. The compounds found to be active in primary screening were
similarly diluted to obtain 200, 125, 100, 62.5, 50, 25, and 12.5 μg/
mL concentrations for secondary screening to test in a second set
of dilution against all microorganisms. Inoculum size for test strain
was adjusted to 106 colony forming unit (CFU)/mL by comparing the
turbidity (turbidimetric method). Mueller Hinton broth was used as
nutrient medium to grow and dilute the compound suspension for
test bacteria. DMSO (2%) was used as a diluent/vehicle to obtain
the desired concentration of synthesized compounds and standard
drugs to test against standard microbial strains. The compounds
were diluted to 2000-μg/mL concentration as a stock solution. The
control tube containing no antibiotic was immediately subcultured
(before inoculation) by spreading a loopful evenly over a quarter of
plate of medium suitable for the growth of test organisms. The tubes
were then put for incubation at 37°C for 24 h for bacteria. Suspen-
sions (10 μg/mL) were further inoculated on an appropriate media,
3,4-Dihydro-3-(octyloxy)isochroman-1-one (5e)ꢀLight yellow liq-
uid; yield 76%; IR (νmax, cm-1): 3018, 2928, 1723, 1612, 1464, 1320, 1244,
1045, 794, 689; 1H NMR: δH 0.86 (t, 3H, OCH2(CH2)6CH3, J ꢀ= ꢀ 6.4 Hz), 1.25
(m, 10H, OCH2CH2(CH2)5CH3), 1.55 (m, 2H, OCH2CH2(CH2)5CH3), 3.09
(dd, 1H, CH2, J1 ꢀ= ꢀ 17.1 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.28 (dd, 1H, CH2, J1 ꢀ= ꢀ 17.1 Hz,
J2 ꢀ= ꢀ 4.4 Hz), 3.59 (m, 1H, OCH2(CH2)6CH3), 3.93 (m, 1H, OCH2(CH2)6CH3),
5.54 (t, 1H, CH-OCH2(CH2)6CH3, J ꢀ= ꢀ 3.6 Hz), 7.52 (m, 4H, aromatic H);
13C NMR: δC 14.0, 22.6, 25.8, 29.1, 29.2, 29.2, 31.7, 33.4, 69.6, 101.0, 124.9,
127.5, 128.1, 129.8, 133.8, 136.5, 164.0; MS (EI): m/z 276 (M+). Anal.
Calcd for C17H24O3: C, 73.88; H, 8.75. Found: C, 73.82; H, 8.78.
3-(Dodecyloxy)-3,4-dihydroisochroman-1-one (5f)ꢀLight yellow
liquid; yield 78%; IR (νmax, cm-1): 2968, 2931, 2868, 1728, 1637, 1487, 1251,
1045, 792, 688; 1H NMR: δH 0.89 (t, 3H, OCH2(CH2)10CH3, J ꢀ= ꢀ 6.8 Hz), 1.26
(m, 18H, OCH2CH2(CH2)9CH3), 1.60 (m, 2H, OCH2CH2(CH2)9CH3), 3.12
(dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ 4.8 Hz), 3.31 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ
4.8 Hz), 3.62 (m, 1H, OCH2(CH2)10CH3), 3.96 (m, 1H, OCH2(CH2)10CH3),
5.56 (t, 1H, CH-OCH2(CH2)10CH3, J ꢀ= ꢀ 4 Hz), 7.54 (m, 4H, aromatic H); 13C
NMR: δC 14.1, 22.6, 25.7, 29.3, 29.4, 29.4, 29.5, 29.5, 29.6, 29.6, 31.8, 32.7,
62.9, 107.0, 125.5, 128.5, 129.5, 134.8, 136.4, 144.6, 162.2; MS (EI): m/z
332 (M+). Anal. Calcd for C21H32O3: C, 75.86; H, 9.70. Found: C, 75.78;
H, 9.66.
3,4-Dihydro-3-(tetradecyloxy)isochroman-1-one
(5g)ꢀWhite and growth was noted afer 24 and 48 h. The highest dilution (lowest
crystalline solid; yield 80%; IR (νmax, cm-1): 3020, 2938, 1720, concentration) preventing appearance of turbidity was considered as
1637, 1487, 1330, 1251, 1045, 794, 688; 1H NMR: δH 0.89 (t, 3H, MIC (μg/mL), i.e., the amount of growth from the control tube before
OCH2(CH2)12CH3, J ꢀ= ꢀ 6.8 Hz), 1.28 (m, 22H, OCH2CH2(CH2)11CH3), 1.58 (m, incubation (which represents the original inoculum) was compared.
2H, OCH2CH2(CH2)11CH3), 3.12 (dd, 1H, CH2, J1 ꢀ= ꢀ 16.6 Hz, J2 ꢀ= ꢀ 4.4 Hz), 3.31 A set of tubes containing only seeded broth and solvent controls were
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G.M. Patel and P.T. Deota: 3,4-Dihydro-3-hydroxyisochroman-1-one and acetal derivativesꢂ
ꢂ303
maintained under identical conditions to ensure that the solvent had [11] Shen, J.; Ling, Q.; Huang, Y.; Zhou, Y.; Cai, Z.; Xiong, B.;
no influence on strain growth. The result was greatly affected by the
size of the inoculum. The test mixture should contain 106 CFU/mL
organisms. The standard drug used in the present study was ampicil-
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Antifungal assay
Compounds 2, 3, and 5a–h were also tested for antifungal activity
in primary screening in five sets against C. albicans and A. niger at
various concentrations of 1000, 500, and 250 μg/mL. Compounds
found to be active in the primary screening were similarly diluted to
obtain 200-, 125-, 100-, 62.5-, 50-, 25-, and 12.5-μg/mL concentrations
for a secondary screening to test in a second set of dilution against
all microorganisms. For fungal growth, in the present protocol, Sab-
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h. Griseofulvin was used as a standard drug for antifungal activity.
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Acknowledgments: G.M.P. thanks UGC, New Delhi, India,
for the award of a research fellowship under the RFSMS
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