Improved synthesis and in vitro study of antimicrobial activity of α,β-unsaturated and α-bromo carboxylic acids

Article abstract of DOI:10.2298/JSC111104016V

A series of α,β-unsaturated and α-bromo carboxylic acids were identified as potent antimicrobial agents. The antimicrobial activity was evaluated using the broth microdilution method. All acids 1-12 exhibited a significant activity against nine laboratory control strains of bacteria and two strains of yeast Candida albicans. The tested acids were efficiently prepared by optimized phase-transfer-catalyzed (PTC) reactions of ketones with bromoform and aqueous lithium hydroxide in alcoholic solvent with triethylbenzyl ammonium chloride (TEBA) as catalyst.

Full text of DOI:10.2298/JSC111104016V

J. Serb. Chem. Soc. 77 (6) 741–750 (2012) UDC 547.39+546.14+547-316+542.913:615.28–188
JSCS–4305 Original scientific paper
Improved synthesis and in vitro study of antimicrobial activity of
α,β-unsaturated and α-bromo carboxylic acids
1
#
2
3
*
VESNA D. VITNIK , MARINA T. MILENKOVIĆ , SANDA P. DILBER ,
ŽELJKO J. VITNIK4# and IVAN O. JURANIĆ1#
1Department of Chemistry ICTM, University of Belgrade, Studentski trg 12–16, 11000
Belgrade, Serbia, 2Department of Microbiology and Immunology, Faculty of Pharmacy,
University of Belgrade, Vojvode Stepe 450, 11221 Belgrade, Serbia, 3Department of
Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450,
11221 Belgrade, Serbia and 4Faculty of Chemistry, University of Belgrade,
Studentski trg 12–16, 11000 Belgrade, Serbia
(Received 4 November 2011, revised 16 January 2012)
Abstract: A series of α,β-unsaturated and α-bromo carboxylic acids were iden-
tified as potent antimicrobial agents. The antimicrobial activity was evaluated
using the broth microdilution method. All acids 1–12 exhibited a significant
activity against nine laboratory control strains of bacteria and two strains of
yeast Candida albicans. The tested acids were efficiently prepared by opti-
mized phase-transfer-catalyzed (PTC) reactions of ketones with bromoform
and aqueous lithium hydroxide in alcoholic solvent with triethylbenzyl ammo-
nium chloride (TEBA) as catalyst.
Keywords: antimicrobial activity; one-pot synthesis; ketones; bromoform.
INTRODUCTION
Fungal and bacterial infections are important problems in phytopathology,
agriculture, the food industry and especially in medicine. Bacterial resistance to
antimicrobial agents has become a serious problem worldwide, with resistance
mechanisms having been identified and described for all known antibiotics cur-
1
rently available for clinical use.
The development of new antimicrobial agents represents an important field
in medicinal chemistry, due to the increasing problem of the formation of resis-
tant strains of bacterial pathogenes. Natural products often represent important
lead structures for the development of new antibiotics.
*Corresponding author. E-mail: vesnak@chem.bg.ac.rs
# Serbian Chemical Society member.
doi: 10.2298/JSC111104016V
741
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VITNIK et al.
The potential antimicrobial activity of α,β-unsaturated carbonyl compounds
continues to receive attention, and several substances exhibiting this function, are
2
3
used in therapy, for example (Fig. 1), ciprofloxacin and minocycline are mem-
bers of the antibiotics group, and are commonly used to treat a variety of in-
4
fections. Helenalin, a sesquiterpene lactone with potent anti-inflammatory and
antitumor effects, can also reduce the severity of Staphylococcus aureus infection
in animals. Some α,β-unsaturated carbonyl compounds with different biological
5
activity are shown in Fig. 1. Etacrynic acid is a loop diuretic used to treat high
6
blood pressure. Digoxin is a cardiac glycoside used in the treatment of conges-
7
tive heart failure and cardiac arrhythmia. Risperidone, a second generation anti-
8
psychotic, is used to treat schizophrenia. Rofecoxib is a non-steroidal anti-in-
flammatory drug, which has now been withdrawn due to safety concerns. Dime-
9
thyl fumarate is used to treat psoriasis.
Fig. 1. Structures of several significant α,β-unsaturated carbonyl compounds
currently used in medical therapy.
It is generally assumed and confirmed by experimental evidence that the ac-
tivity of this class of compounds is due to the alkylation of nucleophilic groups,
10
such as amino groups or sulfhydryls, of biomolecules. The reaction involves a
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ANTIMICROBIAL ACTIVITY OF α,β-UNSATURATED CARBOXYLIC ACIDS
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Michael-type addition of the nucleophile to the activated double bond of α,β-un-
saturated carbonyl compounds.
The synthesis of α,β-unsaturated carboxylic acids has gained considerable
11
attention because of the biologically important properties of these acids and
12
their use as precursors for the preparation of biologically active compounds.
These acids are known for their broad spectrum of activity, for example: anti-
13
fungal activity of derivatives of tiglic acid and cyclohex-1-enecarboxylic acid.
Derivatives of cyclohex-1-enecarboxylic acid are effective in controlling weeds
14
in rice paddies and in vegetable fields. The structural analogue of the anti-epi-
leptic drug sodium valproate (VPA, 2-propylpentanoic acid) possessing an α,β-
-unsaturated carboxyl group, is 1-cyclohept-1-enecarboxylic acid, which has very
15
low activity. Atropic acid and β,β-dimethylatropic acid are plant growth regu-
16
lators. Pyrethrins are natural organic compounds with potent insecticidal acti-
vity. Pyrethrin I and pyrethrin II are structurally related esters with a cyclopro-
pane core, (+)-trans-chrysanthemic acid in the case of pyrethrin I. Natural chemi-
cal pyrethrins produced by the flowers of pyrethrums (Chrysanthemum cinera-
riaefolium and C. coccineum) have the synthetic analog pyrethroid, which now
17
constitutes a major proportion of the synthetic insecticides. A large number of
known drugs arise from the reduction of appropriate precursors (α,β-unsaturated
18
carboxylic acids), for example, Ariflo, an orally active second-generation
phosphodiesterase type 4 inhibitor (PDE4) inhibitor for the treatment of asthma,
19
as well as non-steroidal anti-inflammatory drugs, such as ibuprofen and na-
20
proxen.
EXPERIMENTAL
Reagents and chemicals
All used chemicals were of analytical reagent grade, purchased from Aldrich, Fluka or
Merck, and were used without further purification.
Measurements
The NMR spectra for samples were recorded on a Varian Gemini 2000, 1H-NMR at 200
MHz, 13C-NMR at 50 MHz, in deuterated chloroform. Chemical shifts are expressed in ppm
using tetramethylsilane as the internal standard. The IR spectra were recorded on Nicolet 6700
FT instrument, and are expressed in cm-1. Melting points were determined on a Boetius PMHK
apparatus and are not corrected.
Typical procedure for the synthesis of cyclopent-1-enecarboxylic acid (8)
A flask was charged with LiOH solution (1.18 mol, 49.93 g, in 50 ml H2O), t-BuOH
(250 ml), cyclopentanone (0.059 mol, 5.0 g) and TEBA (0.029 mol, 6.8 g). The mixture was
stirred vigorously (large egg-shaped stirring bar) at 45–50 °C (water bath), while bromoform
(0.24 mol, 60 g) was added dropwise from a dropping funnel (≈60 min.). The stirring was con-
tinued for 24 h at room temperature. Then (0.12 mol, 30 g) of bromoform was added, and the
stirring continued for 12 h at room temperature; H2O (300 ml) was added and the organic
layer (lower one) discarded. The aqueous layer was extracted with toluene (2×70 ml), then
acidified with HCl (20 %) to pH around 1. The separated oil was extracted with toluene (3×70
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VITNIK et al.
ml), dried (anh. MgSO4), concentrated and crystallized from toluene. Cyclopent-1-enecarbo-
xylic acid was obtained as white crystals.
In vitro antibacterial activity
The antimicrobial activity was evaluated using nine laboratory control strains of bacteria,
i.e., the Gram-positive Staphylococcus aureus (ATCC 25923), Staphylococcus epidermidis
(ATCC 12228), Micrococcus luteus (ATCC 9341), Micrococcus flavus (ATCC 10240), Еnte-
rococcus faecalis (ATCC 29212), Bacillus subtilis (ATCC 6633) and the Gram-negative Esche-
richia coli (ATCC 25922), Klebsiella pneumoniae (NCIMB 9111), Pseudomonas aeruginosa
(ATCC 27853), and two strains of yeast Candida albicans (ATCC 10231 and ATCC 10259).
A broth microdilution method was used to determine the minimal inhibitory concentrations
(MICs) of tested compounds according to the Clinical and Laboratory Standards Institute
(CLSI 2005).21
All tests were performed in Müller–Hinton broth for the bacterial strains and in Sabour-
aud dextrose broth for the Candida albicans. Overnight broth cultures of each strain were pre-
pared, and the final concentration in each well was adjusted to 2×106 CFU ml-1 for the bac-
teria and 2×107 CFU ml-1 for the yeasts. The investigated acids were dissolved to 1 % in di-
methyl sulfoxide (DMSO) and then diluted to the highest test concentration. Serial doubling
dilutions of the compounds were prepared in 96-well micotiter plates over the concentration
range 31.25–1000 μg ml-1. In the tests, triphenyltetrazolium chloride (TTC) (Aldrich, USA)
was also added to the culture medium as a growth indicator. The final concentration of TTC
after inoculation was 0.05 %. The microbial growth was determined after 24 h incubation at
37 °C for the bacteria and at 25 °C after 48 h for the fungi. The MIC is defined as the lowest
concentration of a compound at which the microorganism does not demonstrate visible growth.
All determinations were performed in duplicate and two positive growth controls were included.
RESULTS AND DISCUSSION
Herein, an optimized, convenient synthesis of α,β-unsaturated and α-bromo
carboxylic acids, by phase-transfer-catalyzed reactions of ketones with bromo-
form and aqueous lithium hydroxide in an alcoholic solvent is reported.
Chemistry
As a part of efforts to synthesize various novel α,β-unsaturated carboxylic
acids, a substantially improved and modified synthesis of them has been deve-
22
loped. It also provides access to numerous other conjugated acids.
All the investigated acids (Fig. 2) were synthesized in one-pot phase-transfer
reactions of ketones with bromoform (Scheme 1). The acids 1–7, 11 and 12 were
22
synthesized in satisfactory yields, as is reported in a previous paper. The acids
8–10 were obtained in the improved synthesis in the present work (Scheme 2).
In a previous study, conjugated acids 1–10 were obtained from the corres-
ponding cyclic or aromatic ketones. Bromo acids, 4-bromo-piperidine-1,4-dicar-
boxylic acid mono-tert-butyl ester 11 and 4-bromo-piperidine-1,4-dicarboxylic
acid monoethyl ester 12 were obtained from 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester and 4-oxo-piperidine-1-carboxylic acid ethyl ester. The published
syntheses of the cyclic carboxylic acids 8–10 suffered from low yields (35–75
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ANTIMICROBIAL ACTIVITY OF α,β-UNSATURATED CARBOXYLIC ACIDS
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%).22 In general, ketones with larger ring size (cycloheptanone and cyclododeca-
none) were found to be much less reactive than the model ketone (cyclohexa-
22
none). Due to steric hindrance, the reaction is slow. Various solvents and re-
agents were tested, usually resulting in lower yields or giving various side pro-
ducts. Their synthesis presented herein was accomplished in one-step, starting
from cyclic ketones, Scheme 2. In this research, the reaction conditions were op-
timized regarding the reaction temperature, molar ratio of the reactants and the
catalyst. Optimal molar proportion of the reagents was found to be 6 eq. of CHBr
3
and 20 eq. of LiOH per 1 eq. of ketone, with solvents (t-BuOH/H O) and the
2
phase-transfer catalyst TEBA. Lower ratios diminished the yields while higher
proportions did not lead to further improvements.
Fig. 2. Investigated acids 1–12, synthesized in a one-pot phase-transfer
reaction of ketones with bromoform.
Scheme 1. One-pot reaction of ketones with bromoform.22
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VITNIK et al.
Although these kinds of reaction of cyclohexanone and analogs are usually
22
performed at 20 °C, it was found that subsequent heating at 40–50 °C for the
first hour of reaction was necessary to achieve nearly quantitative yields, as given
in Scheme 2. Finally, acceptable yields and purity of acids 8–10 were obtained
using lithium hydroxide (20 eq.), heated t-BuOH/H O (40–50 °C) with the gra-
2
dual addition of bromoform (4 eq., 1 h). After 24 h, the addition of two further
equivalents of CHBr dramatically improved the yields and the reaction rate. A
3
number of solvent systems were examined (PhMe/H O, DMSO, CH Cl /H O,
2
2
2
2
THF/H O, i-PrOH/H O, t-BuOH/H O and t-PentOH/H O). The optimal yields,
2
2
2
2
purity and reaction rate were achieved in a t-BuOH/H O mixture (5:1), in the
2
presence of ≈0.5 eq. of TEBA. The products were isolated and recrystallized
from toluene. All the synthesized compounds were fully characterized by instru-
mental methods, and the purity confirmed by GC, TLC, and MS.
Scheme 2. Optimized one-pot reaction of cyclic ketones with bromoform.
It should be stressed that the reaction protocol presented herein is applicable
to a variety of ketones.
Characterization data of the compounds
Cyclopent-1-enecarboxylic acid (8). Yield: 5.7 g, 87 %; m.p: 120–121 °C
23
−1
(lit. 121 °C ); IR (KBr, cm ): 3100–3150 (O−H stretching of COOH group),
2967 (=C−H stretching of vinyl group), 2863 (−C−H stretching of CH group),
2
1724 (C=O stretching of COOH group), 1429 (C=C stretching of vinyl group ),
1294 (C−O stretching of COOH group), 952 (C=CH bending of vinyl group);
1
H-NMR (200 MHz, CDCl , δ / ppm): 11.08 (1H, s), 6.94 (1H, t, J = 2 Hz), 2.49
3
13
(4H, m), 2.06 (2H, m); C-NMR (50 MHz CDCl , δ / ppm): 171.02 (CO),
3
147.07 (CH), 136.07 (C), 33.54 (CH ), 30.88 (CH ), 23.07 (CH ).
2
2
2
Cyclohept-1-enecarboxylic acid (9). Yield: 5.0 g, 85 %; m.p: 53 °C (lit. 51
23
−1
°C ); IR (KBr, cm ): 3150–3200 (O−H stretching of COOH group ), 2932
(=C−H stretching of vinyl group), 2860 (−C−H stretching of CH group), 1703
2
(C=O stretching of COOH group), 1450 (C=C stretching of vinyl group), 1288
1
(C−O stretching of COOH group), 951 (C=CH bending of vinyl group); H-NMR
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ANTIMICROBIAL ACTIVITY OF α,β-UNSATURATED CARBOXYLIC ACIDS
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(200 MHz, CDCl , δ / ppm): 12 (1H, s), 7.2 (1H, t, J = 7 Hz), 2.6 (2H, m), 2.25
3
13
(2H, m), 1.8 (2H, m), 1.6 (4H, m); C-NMR (50 MHz, CDCl , δ / ppm): 174.04
3
(CO), 147.46 (CH), 135.89 (C), 31.93 (CH ), 28.93 (CH ), 26.82 (CH ), 26.06
2
2
2
(CH ), 25.55 (CH ).
2
2
Cyclododec-1-enecarboxylic acid (10). Yield: 4.61 g, 80 %; m.p: 121–122
24
−1
°C (lit. 120–123 °C ); IR (KBr, cm ): 2958, 2865 (−C−H stretching of CH
2
group), 1682 (C=O stretching of COOH group), 1424 (C=C stretching of vinyl
group), 1280 (C−O stretching of COOH group), 932 (C=CH bending of vinyl
1
group); H-NMR (200 MHz, CDCl , δ / ppm): 10.47 (1H, s), 7.14 (1H, t, J = 8 Hz),
3
13
2.45 (2H, m), 1.9 (2H, m), 0.95 (16H, m); C-NMR (50 MHz, CDCl , δ / ppm):
3
173.13 (CO), 143.22 (CH), 129.56 (C), 43.09 (CH ), 34.92 (CH ), 32.42 (CH ),
2
2
2
32.06 (CH ), 27.69 (CH ), 27.40 (CH ), 27.06 (CH ), 25.1 (CH ), 23.4 (CH ),
2
2
2
2
2
2
21.76 (CH ).
2
Characterization data of compounds (1–7, 11 and 12) are given in a previous
22
paper.
Biological results and discussion
The antimicrobial activity of α,β-unsaturated and α-bromo-carboxylic acids was
tested against ATCC strains of bacteria and two strains of yeast Candida al-
bicans. As a standard for the comparison with the synthesized compounds, a
well-known drug ampicillin was used. The inhibitory properties of the acids were
–1
observed within the concentration range 0.10 to 1.0 mg ml . Minimal inhibitory
concentrations (MICs) of tested acids are presented in Table I. The maximum ac-
tivity was exhibited by the acids 8–10. The Gram-positive bacteria were more
sensitive to the tested acids than the Gram-negative bacteria. The most resistant
bacterial strain was the Gram-negative P. aeruginosa, which is known to have a
high level of intrinsic resistance to virtually all known antimicrobials and anti-
biotics, due to its very restrictive outer membrane barrier, which is highly resis-
25
tant even to synthetic drugs.
From the biological data (Table I), it was observed that cyclohex-1-enecar-
boxylic acid 1 was almost inactive against all the tested strains. As can be seen in
Table I, most of the conjugated acids 2–10 generally showed antifungal and anti-
bacterial activity against all the tested fungal and bacterial strains. The activities
of compounds 3 and 5 were higher in comparison to those of compounds 2 and 4
because of the steric hindrance (tert-butyl and phenyl group) in the series of the
substituted cyclohex-1-enecarboxylic acids. The cyclic acids 8–10 showed good
inhibitory effects against all the Gram-positive bacteria and the two strains of
yeast C. albicans. Furthermore, the aromatic acids 6 and 7 showed good antibac-
terial and antifungal activities. The acids 11 and 12, the activities of which are
unknown in the literature, showed good antifungal activity with an MIC value of
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VITNIK et al.
–1
0.1 mg ml . It is evident that the studied compounds exhibit much lower anti-
bacterial activities than ampicillin.
22
In a previous study, undesirable cytotoxic effects of the investigated com-
pounds were determined on immune competent cells, the normal peripheral blood
mononuclear cells. All the compounds examined in this work did not affect proli-
feration of healthy human blood peripheral mononuclear cells (PBMC and PBMC
+ PHA), IC > 200 μM; hence, they could be safely used as potential antibiotics.
50
TABLE I. Antimicrobial activity of the tested α,β-unsaturated and α-bromo-carboxylic acids
(n.t. – not tested)
MIC / mg ml-1
Microorganism
1
2
3
4
5
6
7
8
9
10 11 12 Ampicillin
S. aureus
>1.0 0.5 0.5 0.2 1.0 1.0 1.0 0.5 0.5 0.5 1.0 >1.0 0.0005
ATCC 25923
S. epidermidis 0.2 0.5 0.2 1.0 0.2 0.5 0.5 0.1 0.2 0.2 1.0 0.5 0.0002
ATCC 12228
M. luteus
ATCC 9341
M. flavus
>1.0 1.0 0.2 0.5 1.0 n.t. n.t. 0.2 0.2 0.2 n.t n.t.
1.0 >1.0 0.5 0.1 1.0 n.t. n.t. 0.2 0.2 0.2 n.t. n.t.
0.002
0.003
ATCC 10240
E. faecalis
ATCC 29212
B. subtilis
ATCC 6633
E. coli
>1.0 >1.0 1.0 >1.0 1.0 0.2 1.0 0.1 0.2 0.2 >1.0 >1.0 0.0005
1.0 1.0 0.2 0.2 0.5 0.2 >1.0 0.2 0.2 0.2 >1.0 1.0 n.t.
>1.0 1.0 1.0 >1.0 >1.0 >1.0 >1.0 0.2 0.5 0.5 >1.0 >1.0 0.002
ATCC 25922
K. pneumoniae >1.0 >1.0 >1.0 >1.0 >1.0 >1.0 >1.0 0.2 0.2 0.5 >1.0 1.0
ATCC 13883
P. aeruginosa >1.0 1.0 >1.0 >1.0 >1.0 >1.0 >1.0 1.0 0.5 1.0 >1.0 1.0
ATCC 27853
0.004
0.003
n.t.
C. albicans
>1.0 1.0 0.5 >1.0 >1.0 0.1 0.2 0.5 0.2 0.5 0.1 0.1
ATCC 10259
CONCLUSIONS
The tested compounds exhibited significant antimicrobial and antifungal
activities and could be considered as the potential antimicrobial agents. Previous
22
cytotoxicity studies revealed low toxicity of these compounds, which renders
them as harmless drugs against various microbial and micro-fungal strains.
Further studies are planned to elucidate the possible mechanism/mechanisms of
action of these compounds.
Acknowledgements. This work was financially supported by the Ministry of Education
and Science of the Republic of Serbia, under Grant Nos. 172035, 172041 and 173021.
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И З В О Д
ОПТИМИЗАЦИЈА СИНТЕЗЕ И IN VITRO ПРОУЧАВАЊЕ АНТИМИКРОБНОГ ДЕЈСТВА
α,β-НЕЗАСИЋЕНИХ И α-БРОМКАРБОКСИЛНИХ КИСЕЛИНА
ВЕСНА Д. ВИТНИК1, МАРИНА Т. МИЛЕНКОВИЋ2, САНДА П. ДИЛБЕР3,
ЖЕЉКО Ј. ВИТНИК4 и ИВАН О. ЈУРАНИЋ1
1
2
IHTM – Centar za hemiju, Univerzitet u Beogradu, Studentski trg 12–16, 11000 Beograd, Institut za
mikrobiologiju i imunologiju, Farmaceutski fakultet, Univerzitet u Beogradu, Vojvode Stepe 450, 11221
3
Beograd, Institut za organsku hemiju, Farmaceutski fakultet, Univerzitet u Beogradu, Vojvode Stepe
4
450, 11221 Beograd i Hemijski fakultet, Univerzitet u Beogradu, Studentski trg 12–16, 11000 Beograd
У овом раду је приказано in vitro испитивање антимикробног дејства серије α,β-неза-
сићених и α-бромкарбоксилних киселина и показано је да су оне потенцијално добри анти-
микробни агенси. Све киселине 1–12 показале су значајну активност према девет сојева бак-
терија и два соја гљивица Candida albicans. Испитиване киселине синтетисане су у оптими-
зованој реакцији кетона са бромоформом и литијум-хидроксидом у смеси растварача (terc-
-бутанол/вода). Као катализатор за пренос између фаза употребљен је триетилбензиламо-
нијум-хлорид (ТЕБА).
(Примљено 4. новембра 2011, ревидирано 16. јануара 2012)
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