Preliminary investigations into the synthesis and antimicrobial activities of boron-containing capsaicinoids

Article abstract of DOI:10.1139/cjc-2018-0193

This preliminary study reports on the synthesis of two new boron-capsaicin derivatives containing either a short or long chain aliphatic tail group using an iridium catalyzed hydroboration reaction with pinacolborane. The boronate ester groups reside on the terminal position of the tail group and are necessary for the bioactivity of these compounds. Indeed, both compounds showed considerable activity against two Gram-positive bacteria, including Vancomycin-resistant Enterococcus. Vancomycin is considered the last resort medication for the treatment of septicemia, and new antibacterial agents that can treat sepsis are of paramount importance. The more lipophilic boron compound with the longer aliphatic chain also showed antifungal activity against Saccharomyces cerevisiae.

Full text of DOI:10.1139/cjc-2018-0193

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1
ARTICLE
Preliminary investigations into the synthesis and antimicrobial
activities of boron-containing capsaicinoids
Sharwatie Ramsaywack, Allyson Bos, Christopher M. Vogels, Christopher A. Gray,
and Stephen A. Westcott
Abstract: This preliminary study reports on the synthesis of two new boron-capsaicin derivatives containing either a short or
long chain aliphatic tail group using an iridium catalyzed hydroboration reaction with pinacolborane. The boronate ester groups
reside on the terminal position of the tail group and are necessary for the bioactivity of these compounds. Indeed, both
compounds showed considerable activity against two Gram-positive bacteria, including Vancomycin-resistant Enterococcus.
Vancomycin is considered the last resort medication for the treatment of septicemia, and new antibacterial agents that can treat
sepsis are of paramount importance. The more lipophilic boron compound with the longer aliphatic chain also showed
antifungal activity against Saccharomyces cerevisiae.
Key words: antimicrobial, boron, capsaicin, hot peppers.
Résumé : Cette étude préliminaire fait état de la synthèse de deux nouveaux dérivés de la capaïcine à base de bore comprenant
un groupe « de queue », composé d’une chaîne aliphatique soit courte ou longue, au moyen d’une hydroboration avec le
pinacolborane catalysée par l’iridium. Les groupes d’esters boroniques se trouvent à la position terminale du groupe de queue
et sont nécessaires à la bioactivité de ces composés. En effet, les deux composés ont présenté une activité considérable contre
deux bactéries à Gram positif, dont un entérocoque résistant à la vancomycine. La vancomycine est considérée comme le
médicament de dernier recours pour traiter la septicémie, et les nouveaux agents antibactériens capables de traiter un sepsis
sont d’une importance capitale. Le composé de bore plus lipophile, doté de la chaîne aliphatique la plus longue, présente
également une activité antifongique contre Saccharomyces cerevisiae. [Traduit par la Rédaction]
Mots-clés : antimicrobien, bore, capsaïcine, piments forts.
Introduction
of diazaborines is believed to involve the inhibition of fatty acid
biosynthesis in Escherichia coli, where the boron compound inhib-
its maturation of rRNAs for the large ribosomal subunit.2 Al-
though no diazaborines have yet to reach clinical trials, another
small boron molecule, Kerydin (aka Tavaborole, Fig. 1 com-
Although ␣-aminoboronic acids have been known for several
decades to be potent inhibitors of serine proteases, boron-
f,2j
1
containing compounds have been largely ignored by the phar-
maceutical industry until the discovery that the boropeptide
Velcade (aka Bortezomib, Fig. 1 compound (a) with the ␣-
®
pound (d)), has been developed for the treatment of onychomy-
3
®
cosis, a fungal infection of the nail and nail bed. This simple
aminoboronic acid fragment shown in blue) showed significant
compound inhibits the essential fungal enzyme, leucyl-tRNA syn-
thetase, leading to termination of cell growth and ultimately cell
death, thus completely eradicating the fungal infection.
promise for the treatment of multiple myeloma (a cancer of the
1
a
plasma cells) and mantle cell lymphoma (a cancer of the lymph
1
b
nodes). Indeed, Velcade has been approved by the FDA as
®
As part of our ongoing program for generating bioactive boron
the first ever boron-containing pharmaceutical molecule. Since
this remarkable discovery, the second-generation derivative
2
o,2t,4
compounds,
we have begun to design new compounds based
on the structural motif of capsaicin. Capsaicin (8-methyl-
N-vanillyl-6-nonenamide) is the spicy and active ingredient in hot
chili peppers and its biological activities are well-known to in-
clude, but not limited to, anticancer and anti-inflammatory prop-
erties and show promise in the treatment of Alzheimer’s disease.5
The chemical structure of capsaicin consists of two major groups;
(i) an aromatic head group with an amide linkage, and (ii) an
aliphatic hydrocarbon tail (Fig. 2). In this preliminary study, we
have decided to prepare a small family of capsaicinoids in an
effort to incorporate a boronate ester fragment into the tail
group, with one representative short chain and one long chain
Ninlaro (aka Ixazomib citrate, Fig. 1 compound (b) with the
®
␣
-aminoboronic acid fragment shown in blue) has been approved
for the treatment of relapsed multiple myeloma. Although
Velcade must be administered by injection, Ninlaro has a
®
®
huge marketable advantage in that it can be taken orally.
Other small molecule boron compounds that do not contain
␣
-aminoboronic acid fragments have also shown promise for their
potential use as pharmaceuticals. For instance, diazaborines are a
privileged class of heterocyclic compounds that have potent anti-
microbial properties (a representative example of a thienodiaza-
2
borine is shown in Fig. 1 compound (c)). The mechanism of action
Received 6 May 2018. Accepted 6 July 2018.
S. Ramsaywack, C.M. Vogels, and S.A. Westcott. Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB E4L 1G8,
Canada.
A. Bos. Department of Biological Sciences, University of New Brunswick, Saint John, NB E2L 4L5, Canada.
C.A. Gray. Department of Biological Sciences, University of New Brunswick, Saint John, NB E2L 4L5, Canada; Department of Chemistry, University of
New Brunswick, Saint John, NB E2L 4L5, Canada.
Corresponding authors: Stephen A. Westcott (email: swestcott@mta.ca) and Christopher A. Gray (email: cgray@unb.ca).
Copyright remains with the author(s) or their institution(s). Permission for reuse (free in most cases) can be obtained from RightsLink.
Can. J. Chem. 00: 1–6 (0000) dx.doi.org/10.1139/cjc-2018-0193
Published at www.nrcresearchpress.com/cjc on 30 July 2018.

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Can. J. Chem. Vol. 00, 0000
Fig. 1. Structures of (a) Velcade , (b) Ninlaro , (c) a representative thienodiazaborine, and (d) Kerydin . [Colour online.]
®
®
®
Fig. 2. The molecular structure of capsaicin. [Colour online.]
KMnO stain. Reactions were performed in oven-dried glassware
4
under an inert atmosphere unless otherwise stated.
General procedure for the synthesis of acyl chlorides
Mixtures of excess SOCl (10 equivalents) and the unsaturated
2
carboxylic acid derivatives (5 mmol) were heated at reflux for 2 h
in THF (10 mL). Removal of excess SOCl under vacuum afforded
2
the corresponding acyl chloride compounds (as confirmed by
1
H NMR spectroscopy), which were used without further puri-
fication.
Synthesis of N-(4-(benzyloxy)-3-methoxybenzyl)pent-
4-enamide (1)
A solution of compound (4-(benzyloxy)-3-methoxyphenyl)
methanamine·HCl (160 mg, 0.57 mmol) and NEt3 (69 mg,
.68 mmol) in anhydrous CH Cl (10 mL) at 0 °C was treated with
0
2
2
example, to see if the boron group could augment biological ac-
tivities in these compounds, the results of which are presented
herein.
a solution of the appropriate acyl chloride (92 mg, 0.78 mmol) in
anhydrous CH Cl (5 mL). Aqueous workup, removal of solvents,
2
2
and column chromatography (silica gel, EtOAC/hexanes, 1:2 to 2:1)
gave compound 1 as a white solid following removal of the sol-
Experimental
vents under vacuum. Yield: 160 mg (86%); mp: 108–109 °C. R = 0.34
f
1
(
EtOAc/hexanes, 1:1). H NMR (CDCl , 400 MHz) ␦: 7.41 (d, J = 6.9 Hz,
3
Materials and methods
Reagents and solvents used were obtained from Sigma-Aldrich.
2
6
H, Ar), 7.35 (ov dd, J = 7.3, 6.9 Hz, 2H, Ar), 7.28 (t, J = 7.3 Hz, 1H, Ar),
.81 (d, J = 1.8 Hz, 1H, Ar), 6.80 (d, J = 8.2 Hz, 1H, Ar), 6.72 (dd, J = 8.2,
6
[
Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene), 4-(benzyloxy)-3-
1.8 Hz, 1H, Ar), 5.81 (ov ddt, J = 17.4, 10.1, 6.9 Hz, 1H, CH CH=CHH),
2
7
methoxybenzonitrile, and (4-(benzyloxy)-3-methoxyphenyl)
methanamine and its hydrochloride salt have been synthesized
previously. Nuclear magnetic resonance (NMR) spectra were re-
5
.70 (br s, 1H, NH), 5.13 (s, 2H, OCH Ph), 5.06 (d ov dt, J = 17.4, 1.8,
2
8
1
.4 Hz, 1H, CH CH=CHH), 4.98 (d ov dt, J = 10.1, 1.4, 1.4 Hz, 1H,
2
CH CH=CHH), 4.30 (d, J = 5.7 Hz, 2H, NHCH Ar), 3.86 (s, 3H, OMe),
2
2
1
11
corded on a JEOL JNM-GSX400 FT NMR ( H: 400 MHz; B: 128 MHz;
2
.40 (ov tddd, J = 7.8, 6.9, 1.8, 1.4 Hz, 2H, CH CH CH=CH ), 2.28 (td,
2 2 2
1
3
C: 100 MHz) spectrometer. Chemical shifts (␦) are reported in
13
1
J = 7.8, 0.9 Hz, 2H, C(O)CH CH ). C{ H} NMR (CDCl , 100 MHz) ␦:
2
2
3
1
13
ppm (relative to residual solvent peaks ( H and C) or external
1
72.1, 149.9, 147.6, 137.1, 137.0, 131.5, 128.7, 127.9, 127.3, 120.1, 115.8,
114.0, 111.7, 71.1, 56.1, 43.5, 36.0, 29.7. IR: 3297 (m), 2929 (w), 1638
m), 1511 (m), 1259 (s), 1226 (s), 1135 (s), 1005 (m), 916 (m), 855 (m),
96 (s). Anal. calcd for C20H NO (325.40 g/mol) (%): C 73.82, H 7.12,
1
1
BF ·OEt ( B)). Multiplicities are reported as singlet (s), doublet (d),
3
2
triplet (t), quartet (q), quintet (quint), multiplet (m), broad (br), or
overlapping (ov) with coupling constants (J) reported in hertz.
Fourier transform infrared (FTIR) spectra were obtained with a
Thermo Fisher Scientific Nicolet iS5 FTIR spectrometer in attenu-
ated total reflections (ATR) mode and are described as strong (s),
medium (m), or weak (w) and are reported in cm . Melting points
were measured uncorrected with a Stuart SMP30 apparatus. Ele-
mental analyses for C, H, and N were carried out at Laboratoire
d’Analyse Élémentaire de l’Université de Montréal (Montréal, QC).
Column chromatography was carried out using silica gel (230–
(
6
23
3
N 4.30; found: C 73.86, H 7.20, N 4.27.
Synthesis of N-(4-(benzyloxy)-3-methoxybenzyl)undec-
10-enamide (2)
Under ambient conditions, NaOH (1.20 mL of a 1.0 N solution,
1.20 mmol) was added to a solution of (4-(benzyloxy)-3-methoxyphenyl)
−
1
methanamine·HCl (0.33 g, 1.18 mmol) in H O (10 mL) at RT. The
2
resulting mixture was allowed to stir for 15 min before CHCl3
(20 mL) was added and the organic layer separated. The aqueous
layer was extracted with CHCl3 (2 × 20 mL) and the combined
organic extracts sequentially washed with distilled water and
4
00 mesh). Thin layer chromatography (TLC) used pre-coated
glass-backed plates covered with 0.25 mm silica gel containing
fluorescent indicator UV 254 nm; visualization by UV light or
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Ramsaywack et al.
3
brine and dried with anhydrous MgSO . The MgSO was separated
(s, 3H, OMe), 2.19 (t, J = 7.5 Hz, 2H, C(O)CH CH ), 1.64 (quint, J =
4
4
2
2
by gravity filtration and the solvent was removed under vacuum
to give free amine (4-(benzyloxy)-3-methoxyphenyl)methanamine
as a light yellow oil (0.25 g, 1.03 mmol, 87%), which was used in
the subsequent step without further purification. Under an inert
atmosphere, the corresponding acyl chloride (0.21 g, 1.04 mmol) in
7.5 Hz, 2H, C(O)CH CH CH ), 1.43 (quint, J = 7.5 Hz, 2H,
2 2 2
CH CH CH Bpin), 1.20 (s, 12H, pin), 0.78 (t, J = 7.5 Hz, 2H,
2
2
2
1
1
13
1
CH CH Bpin). B NMR (CDCl , 128 MHz) ␦: 33 (br). C{ H} NMR
2
2
3
(CDCl , 100 MHz) ␦: 172.9, 149.9, 147.5, 137.2, 131.7, 128.6, 127.9,
3
127.3, 120.1, 114.0, 111.7, 83.1, 71.1, 56.1, 43.4, 36.7, 28.4, 24.9, 23.7, 11 (br,
CB). IR: 3291 (w), 2924 (s), 2854 (s), 1728 (m), 1637 (m), 1459 (m), 1379 (m),
1223 (m), 1138 (m). Anal. calcd for C H NBO (453.38 g/mol) (%): C 68.88,
anhydrous CH Cl2 (5 mL) at 0 °C was added to an anhydrous
2
CH Cl2 (10 mL) solution of (4-(benzyloxy)-3-methoxyphenyl)
2
26 36
5
methanamine (0.25 g, 1.03 mmol) and NEt (0.11 g, 1.09 mmol).
H 8.00, N 3.09; found: C 68.62, H 8.16, N 3.01.
3
Upon warming to room temperature, the reaction was allowed to
proceed for 4 h, at which point, the reaction was concentrated
under vacuum and purification by flash column chromatography
Synthesis of N-(4-(benzyloxy)-3-methoxybenzyl)-11-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)undecanamide (5)
(silica gel, EtOAc/hexanes, 1:1) gave 2 as a white solid after removal
A mixture of [Ir(cod)Cl] (10 mg, 0.015 mmol) and dppe (dppe =
2
of solvents. Yield: 0.33 g (78%); mp: 98–99 °C. R = 0.51 (EtOAc/hex-
1,2-bis(diphenylphosphino)ethane) (12 mg, 0.030 mmol) in THF
(2 mL) was stirred for 10 min, at which point, a THF (1 mL) solution
of 2 (98 mg, 0.24 mmol) and a THF (1 mL) solution of HBpin (46 mg,
0.36 mmol) were added sequentially. After 24 h, the reaction mix-
ture was concentrated and purified by flash column chromatog-
raphy (silica gel, EtOAc/hexanes, 1:1) to provide compound 5 as a
colourless waxy solid after removal of solvents. Yield: 120 mg
f
1
anes, 1:1). H NMR (CDCl , 400 MHz) ␦: 7.41 (d, J = 6.9 Hz, 2H, Ar),
3
7
.34 (ov dd, J = 7.3, 6.9 Hz, 2H, Ar), 7.29 (t, J = 7.3 Hz, 1H, Ar), 6.81 (d,
J = 1.8 Hz, 1H, Ar), 6.80 (d, J = 8.2 Hz, 1H, Ar), 6.72 (dd, J = 8.2, 1.8 Hz,
H, Ar), 5.79 (ov ddt, J = 16.9, 10.1, 6.4 Hz, 1H, CH CH=CHH), 5.64 (br
1
2
t, J = 6.0 Hz, 1H, NHCH Ar), 5.13 (s, 2H, OCH Ph), 4.97 (d ov dt, J =
2
2
1
6.9, 1.8, 1.4 Hz, 1H, CH CH=CHH), 4.91 (d ov dt, J = 10.1, 1.4, 1.4 Hz,
2
1
1
H, CH CH=CHH), 4.34 (d, J = 6.0 Hz, 2H, NHCH Ar), 3.86 (s, 3H,
(93%); mp: 74–76 °C. R = 0.53 (EtOAc/hexanes, 1:4). H NMR (CDCl ,
2
2
f
3
OMe), 2.17 (t, J = 7.5 Hz, 2H, C(O)CH CH ), 2.01 (ov td, J = 7.8, 6.4 Hz,
400 MHz) ␦: 7.41 (d, J = 7.3 Hz, 2H, Ar), 7.34 (ov dd, J = 7.3, 6.8 Hz, 2H,
Ar), 7.28 (t, J = 6.8 Hz, 1H, Ar), 6.81 (d, J = 1.8 Hz, 1H, Ar), 6.80 (d, J =
8.2 Hz, 1H, Ar), 6.72 (dd, J = 8.2, 1.8 Hz, 1H, Ar), 5.67 (br t, J = 5.5 Hz
1H, HNCH Ar), 5.13 (s, 2H, OCH Ph), 4.34 (d, J = 5.5 Hz, 2H,
2
2
2
H, CH CH=CH ) 1.63 (quint, J = 7.1 Hz, 2H, CH CH CH ), 1.36–1.24
2 2 , 2 2 2
1
3
1
2 5 3
(ov m, 10H, –(CH ) –). C{ H} NMR (CDCl , 100 MHz) ␦: 173.0, 149.9,
1
7
3
1
47.6, 139.3, 137.1, 131.6, 128.7, 127.9, 127.3, 120.1, 114.3, 114.0, 111.7,
1.1, 56.1, 43.5, 36.9, 33.9, 29.4 (3C), 29.2, 29.0, 25.9. IR: 3310 (m),
066 (w), 2926 (s), 2853 (m), 1637 (s), 1542 (m), 1516 (m), 1466 (m),
236 (m), 1138 (m), 1012 (w). Anal. calcd for C H NO (409.56 g/mol) (%):
2
2
NHCH Ar), 3.86 (s, 3H, OMe), 2.17 (t, J = 7.5 Hz, 2H, C(O)CH CH ),
2
2
2
1.62 (quint, J = 7.5 Hz, 2H, C(O)CH CH CH ), 1.37 (quint, J = 7.5 Hz,
2 2 2
2H, CH CH CH Bpin), 1.30–1.20 (ov m, 24H, -(CH ) - and pin), 0.74
26
35
3
2 2 2 2 6
1
1
C 76.25, H 8.61, N 3.42; found: C 76.36, H 8.61, N 3.43.
(t, J = 7.5 Hz, 2H, CH CH Bpin). B NMR (CDCl , 128 MHz) ␦: 33 (br).
2 2 3
1
3
1
C{ H} NMR (CDCl , 100 MHz) ␦: 173.0, 149.9, 147.6, 137.1, 131.6,
3
Synthesis of (E)-N-(4-(benzyloxy)-3-methoxybenzyl)but-
128.6, 127.9, 127.3, 120.1, 114.0, 111.7, 82.9, 71.1, 56.1, 43.5, 37.0, 32.5,
2
-enamide (3)
2
2
9.7, 29.6, 29.5, 29.4, 25.9, 24.9 (2C), 24.1, 11 (br, CB). IR: 3307 (m),
924 (s), 2854 (s), 1639 (w), 1462 (s), 1377 (m), 1145 (w). Anal. calcd for
A solution of compound (4-(benzyloxy)-3-methoxyphenyl)
methanamine·HCl (0.42 g, 1.50 mmol) and NEt (0.18 g, 1.78 mmol)
3
C H48NBO5 (537.54 g/mol) (%): C 71.50, H 9.00, N 2.61; found:
32
in anhydrous CH Cl (10 mL) was treated with a solution of the
2
2
C 71.52, H 9.06, N 2.57.
appropriate acyl chloride (0.18 g, 1.72 mmol) in anhydrous CH Cl
2
2
(5 mL). Aqueous workup, removal of solvents, and column chro-
Stability testing of compounds
matography (silica gel, EtOAC/hexanes, 1:2 to 2:1) gave compound
In NMR tubes, compounds 1–5 were dissolved in DMSO-d and
analyzed by H NMR spectroscopy. The solutions were stored at
37 °C for 2 d, at which point, the compounds were reanalyzed by
H NMR spectroscopy. No significant decomposition of the com-
6
1
3
as a white solid after removal of solvents under vacuum. Yield:
1
0.44 g (94%); mp: 122–123 °C. R = 0.38 (EtOAc/hexanes, 1:1). H NMR
f
1
(
CDCl , 400 MHz) ␦: 7.41 (d, J = 7.3 Hz, 2H, Ar), 7.34 (ov dd, J = 7.3,
3
6
.9 Hz, 2H, Ar), 7.29 (t, J = 6.9 Hz, 1H, Ar), 6.84 (ov dq, J = 15.1, 6.9 Hz,
pounds was observed over this time period.
1
6
H, HC=CHCH , 6.81 (d, J = 1.8 Hz, 1H, Ar), 6.80 (d, J = 8.2 Hz, 1H, Ar),
.72 (dd, J = 8.2, 1.8 Hz, 1H, Ar), 5.77 (dq, J = 15.1, 1.4 Hz, 1H,
3
General biological testing
Antibiotic susceptibility tests were performed using BBL Mueller
Hinton II cation adjusted broth (Becton Dickinson, Mississauga, ON)
for Staphylococcus aureus, methicillin-resistant Staphylococcus aureus
HC=CHCH ), 5.64 (br s, 1H, NHCH ), 5.13 (s, 2H, OCH Ph), 4.40 (d, J =
3
2
2
5
.5 Hz, 2H, NHCH Ph), 3.86 (s, 3H, OMe), 1.84 (dd, J = 6.9, 1.4 Hz, 3H,
2
1
1
3
CH=CHCH3). C{ H} NMR (CDCl , 100 MHz) ␦: 165.9, 149.8, 147.4,
3
(
MRSA), and Pseudomonas aeruginosa, Bacto Brain Heart Infusion
1
5
1
39.9, 137.1, 131.8, 128.6, 127.9, 127.3, 125.1, 120.1, 114.1, 111.8, 71.1,
6.0, 43.3, 17.7. IR: 3288 (m), 3035 (w), 2916 (w), 1671 (m), 1625 (s),
540 (m), 1511 (s), 1385 (m), 1224 (s), 1009 (m), 971 (m), 795 (s). Anal.
calcd for C H NO (311.37 g/mol) (%): C 73.29, H 6.80, N 4.50;
broth (Becton Dickinson, Mississauga, ON) for Enterococcus faecium
and vancomycin-resistant Enterococcus faecium (VRE), Difco Sab-
ouraud Dextrose broth (Becton Dickinson, Mississauga, ON) for
Candida albicans, and Difco Yeast Mold broth (Becton Dickinson,
Mississauga, ON) for Saccharomyces cerevisiae in nontissue culture
treated 96-well microtitre plates. Optical densities (OD) were mea-
sured using a Molecular Devices Emax microplate reader with a
600 nm filter.
1
9
21
3
found: C 73.29, H 6.82, N 4.48.
Synthesis of N-(4-(benzyloxy)-3-methoxybenzyl)-5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pentanamide (4)
A solution of [Ir(cod)Cl]2 (12 mg, 0.018 mmol) and 1,2-bis
(diphenylphosphino)ethane (16 mg, 0.040 mmol) in THF (2 mL)
was stirred for 10 min and to this mixture was sequentially added
a THF (2 mL) solution of 1 (100 mg, 0.31 mmol) and a THF (2 mL)
solution of HBpin (95 mg, 0.74 mmol). After 24 h, the reaction
mixture was concentrated and the mixture purified by flash col-
umn chromatography (silica gel, EtOAc/hexanes, 1:1) to provide
Antibiotic susceptibility screening assay
Antibacterial activity against S. aureus (ATCC 29213), MRSA
(ATCC 33591), E. faecium (ATCC 35667), VRE (ATCC 51559), and
P. aeruginosa (ATCC 10145) and antifungal activity against C. albicans
(ATCC 14053) and S. cerevisiae (ATCC 9763) were evaluated using
a microbroth dilution antibiotic susceptibility assay modified
4
as a colourless waxy solid after removal of solvents. Yield:
1
9
132 mg (94%); mp: 74–75 °C. R = 0.23 (EtOAc/hexanes, 1:1). H NMR
from McCulloch et al. Stock solutions of the test compounds
f
(
6
6
1
CDCl , 400 MHz) ␦: 7.41 (d, J = 6.9 Hz, 2H, Ar), 7.34 (ov dd, J = 7.3,
.9 Hz, 2H, Ar), 7.28 (t, J = 7.3 Hz, 1H, Ar), 6.81 (d, J = 1.8 Hz, 1H, Ar),
.79 (d, J = 8.2 Hz, 1H, Ar), 6.71 (dd, J = 8.2, 1.8 Hz, 1H, Ar), 5.77 (br s,
(10 mmol/L) were prepared with sterile-filtered DMSO, stored at
4 °C, and used within 1 week of preparation. Immediately prior to
use, stock solutions (40 ␮L) were diluted with the appropriate
nutrient broth (960 ␮L), and the resulting test solutions (100 ␮L)
3
H, NH), 5.12 (s, 2H, OCH Ph), 4.30 (d, J = 5.5 Hz, 2H, NHCH Ar), 3.86
2
2
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Can. J. Chem. Vol. 00, 0000
Scheme 1. Synthesis of unsaturated amides 1–3.
were transferred to nonperipheral wells of a 96-well microtitre
plate in triplicate. Wells were then inoculated with suspensions
droboration of unsaturated amides using pinacolborane. We
therefore designed a small family of compounds of unsaturated
amides with two short aliphatic chains and one longer lipophilic
derivative to see if the corresponding borocapsaicinoid products
would display any appreciable antimicrobial activity. Compounds
1–3 were prepared via initial reduction of the nitrile group of
a protected 4-hydroxy-3-methoxybenzonitrile derivative using
of the appropriate microbial strain (100 ␮L) of cell density 5 ×
5
1
0 colony-forming units (CFU)/mL. To reduce evaporation from
the plates, sterile water (200 ␮L) was added to perimeter wells.
Positive controls consisted of an appropriate antibiotic tested in
triplicate (0.625 ␮g/mL, erythromycin for S. aureus; 5 ␮g/mL,
vancomycin for MRSA; 0.625 ␮g/mL, tetracycline for E. faecium and
VRE; 1.25 and 10 ␮g/mL, and P. aeruginosa, respectively; 2.5 ␮g/mL,
nystatin for C. albicans; and 2.5 ␮g/mL, amphotericin B for S. cerevisiae)
as 4% DMSO solutions in the appropriate nutrient broth inocu-
lated with suspensions of the appropriate pathogen (100 ␮L). In
addition to test and positive control wells, each plate contained
three untreated controls [4% DMSO in the appropriate nutrient
broth (100 ␮L) inoculated with suspensions of the appropriate
pathogen (100 ␮L)] and three uninoculated blanks (200 ␮L of 2%
DMSO in the appropriate nutrient broth). The optical densities of
the wells were measured before and after a 24 h incubation period
12
LAH, which resulted in the corresponding benzylamine (Scheme 1).
This amine could be isolated as the HCl salt in 81% as a white
8
solid. Further reaction of this amine with readily prepared acyl
chlorides (derived from three commercially available unsaturated
carboxylic acids) in the presence of base afforded the desired un-
saturated capsaicinoids (1–3) in good yields (78%–94%). It is impor-
tant to note at this point that both compounds 1 and 2 have a
terminal alkene with varying chain lengths (1 has a short chain
and 2 contains a considerably longer lipophilic tail) and that com-
pound 3 has an internal alkene.
The transition metal catalyzed hydroboration reaction is a
powerful synthetic methodology for introducing boryl groups
(37 °C), and the change in optical density (⌬OD) was calculated by
subtracting the initial optical density from the final optical den-
sity of corresponding wells. The ⌬OD values were corrected for
background absorbance of the media by subtracting the mean
13
(
BR ) into unsaturated compounds. In this study, we have found
2
that [IrCl(cod)] /2 dppe (cod = 1,5-cyclooctadiene; dppe = 1,2-bis
2
(
diphenylphosphino)ethane) can be employed (6 mol%) to cata-
⌬OD readings of the blanks from the mean ⌬OD readings of the
lyze the addition of pinacolborane (HBpin: pin = O C Me )
2
2
4
control and test compound wells. The percentage inhibition of
bacterial or fungal growth was then defined as [1 – (mean test or
positive control ⌬OD/mean negative control ⌬OD)] × 100.
to 1 and 2 to give selective formation of the corresponding
terminal hydroboration products 4 and 5, respectively (Scheme 2).
Compounds 4 and 5 have been characterized using multinuclear
NMR and FTIR spectroscopy, melting point determination and
Determination of minimum inhibitory concentration (MIC)
1
1
elemental analysis. A broad peak at 33 ppm in the B NMR spectra
for both complexes confirms that the Bpin group has been incor-
porated into the capsaicinoid and the boron atom lies in a three
and median lethal concentration (IC50
)
MIC and IC50 values were determined for test compounds that
exhibited >20% growth inhibition at a concentration of 200 ␮mol/L
in the initial screening assays. Assays were performed as described
previously on two-fold serial dilutions of active compounds in
triplicate. All compounds were tested at a minimum of 7 and
maximum of 17 concentrations obtained from two-fold dilution
series (400–3.125 and 300–1.172 ␮mol/L) for median lethal concen-
trations against susceptible bacteria and fungi. The MIC of a com-
pound was considered to be the lowest assay concentration at
which it inhibited microbial growth by more than a mean value of
1
4
coordinate environment. Unfortunately, all attempts to affect
the hydroboration of 3 to give a branched boron-containing prod-
uct using [IrCl(cod)] /2 dppe and a number of other late metal
2
catalysts proved unsuccessful, including the ones developed by
Smith and Takacs for amide-direction hydroborations.1 It
should also be noted that a number of catalyst systems have been
developed that facilitate the isomerization/hydroboration of in-
ternal alkenes to give the corresponding terminal linear boronate
3d
1
3c
esters, which can alternatively be prepared using the method-
ology developed herein using a terminal unsaturated acyl chloride.
1
0
9
0%. Absolute IC50 values were estimated by fitting a four param-
eter logistic curve to the microbial growth data (percent inhibi-
tion) using Prism 6.0 (GraphPad).11
Biological activity
With two representative boron-containing capsaicinoid deriva-
tives in hand, one with a short aliphatic tail and the other with a
longer lipophilic chain, we decided to conduct preliminary anti-
microbial tests on these boron compounds, along with the unsat-
urated starting materials using capsaicin as a natural products
Results and discussion
Chemistry
In this preliminary study, we have incorporated the boron
group into the aliphatic group via the iridium-catalyzed hy-
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Ramsaywack et al.
5
Scheme 2. The iridium-catalysed hydroboration of unsaturated amides 1 and 2 to give boronate ester derivatives 4 and 5.
Table 1. Antibacterial activities (IC50 values in ␮mol/L) of compounds 1–5, PBA, and capsaicin.
E. faecium
VRE
S. aureus
MRSA
Compound
IC50 (95% CI)
IC50 (95% CI)
IC50 (95% CI)
IC50 (95% CI)
1
Inactive
Inactive
Inactive
Inactive
2
Inactive
Inactive
Inactive
Inactive
3
Inactive
Inactive
Inactive
Inactive
4
5
Inactive
228.6 (215.5, 242.6)
Inactive
Inactive
276.7 (262.4, 291.8)
Inactive
105.9 (80.7, 138.9)
279.5 (248.1, 314.8)
Inactive
107.1 (75.4, 152.2)
244.7 (198.9, 301.1)
169.6 (125.4, 229.5)
Inactive
PBA
Capsaicin
Inactive
Inactive
Inactive
Note: No compound inhibited the growth of any test organism by 90% or greater at the highest test concentration
400 ␮mol/L), and therefore, accurate MICs could not be determined. Less than 20% inhibition in initial screening
200 ␮mol/L) was considered inactive. IC50, median lethal concentration; 95% CI, 95% confidence interval (n = 3); PBA,
(
(
phenylboronic acid.
Table 2. Antifungal activities (IC50 and MIC values in ␮mol/L) of
compounds 1–5, PBA, and capsaicin.
Conclusions
In this preliminary study, we have prepared two new boron-
capsaicin derivatives containing either a short or long chain
aliphatic tail group using an iridium-catalyzed hydroboration
reaction with pinacolborane. The boronate ester groups reside on
the terminal position of the tail groups, and it appears, in these
initial studies, that it is necessary for the bioactivity of these com-
pounds. Indeed, both compounds showed considerable activity
against two Gram-positive bacteria, including Vancomycin-resistant
Enterococcus. Vancomycin is considered the last resort medication
for the treatment of septicemia and new antibacterial agents that
can treat sepsis are of paramount importance. The more lipo-
philic boron compound with the longer aliphatic chain also
showed antifungal activity against S. cerevisiae. Encouraged by
these initial results, we are now developing a more exhaustive
family of aliphatic compounds loosely based on the capsaicin scaf-
fold that incorporate boron groups within the molecule, the re-
sults of which will be reported in due course.
C. albicans
S. cerevisiae
Compound
IC50 (95% CI)
IC50 (95% CI)
MIC
1
2
3
4
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
150.6 (126.8, 178.9)
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
400
5
PBA
Capsaicin
Inactive
Inactive
Note: Less than 25% inhibition in initial screening (200 ␮mol/L) was consid-
ered to be inactive. MIC is defined as the lowest testing concentration that
inhibited growth by a mean value of >90%. IC50, median lethal concentration;
95% CI, 95% confidence interval (n = 3); PBA, phenylboronic acid.
control and phenylboronic acid (PBA). PBA was chosen as an organo-
boronic acid control in these antimicrobial studies. Antibacterial
studies were conducted on Gram-positive Enterococcus faecium,
Vancomycin-resistant Enterococcus faecium (VRE), Staphylococcus
aureus, and Methicillin-resistant Staphylococcus aureus (MRSA)
Supplementary data
Supplementary data are available with the article through the
journal Web site at http://nrcresearchpress.com/doi/suppl/10.1139/
cjc-2018-0193.
(Table 1). Not surprisingly, the unsaturated capsaicinoids (as well
as capsaicin) did not show any appreciable activity against these
1
5
bacteria. We were pleased to observe, however, that the short-
chain aliphatic derivative 4 showed activity against both S. aureus
and MRSA, although no activity was observed against E. faecium
and VRE. However, the more lipophilic boron-derivative 5 showed
significant activity against all bacterial cell lines. These results are
significant as Vancomycin is considered the last resort medication
for the treatment of septicemia and several other infections
Acknowledgements
Thanks are gratefully extended to Mount Allison University and
the University of New Brunswick. SAW and CAG acknowledge
support from the Natural Sciences and Engineering Research
Council of Canada. We also thank Dethumb Durant (Mount Allison
University) for his expert technical assistance, and anonymous re-
viewers are thanked for their helpful comments.
caused by Gram-positive bacteria.1
6,17
Encouraged by these re-
sults, we then examined all new compounds for potential antifun-
gal activity against Candida albicans and Saccharomyces cerevisiae.
Remarkably, only the long chain boron-containing compound 5
showed any activity against one of these fungi, S. cerevisiae (Table 2).
These results are quite promising and suggest that both the boron
group and the increased length of the aliphatic chain are necessary
for pronounced bioactive efficacy in these compounds.
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