Synthesis, reactivity, and antimicrobial properties of boron-containing 4-ethyl-3-thiosemicarbazide derivatives

Article abstract of DOI:10.1139/cjc-2018-0108

The addition of 4-ethyl-3-thiosemicarbazide to benzaldehyde and boronic acid containing derivatives afforded the corresponding thiosemicarbazones (1-3) or benzodiazaborines (4-6) depending on the position of the boronic acid within the ring. All compounds

Full text of DOI:10.1139/cjc-2018-0108

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S
ynthesis, reactivity and antimicrobial properties of boron-
containing 4-ethyl-3-thiosemicarbazide derivatives
Ryan S. Scott, Alex J. Veinot, Darcie L. Stack, Patrick T. Gormley, B. Ninh
Khuong, Christopher M. Vogels, Jason D. Masuda, Felix J. Baerlocher, Tyson
J. MacCormack and Stephen A. Westcott
R.S. Scott, C.M. Vogels, P.T. Gormley, B.N. Khuong, T.J. MacCormack, S.A. Westcott.
Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB, E4L 1G8,
Canada.
A.J. Veinot, D.L. Stack, J.D. Masuda. Department of Chemistry, Saint Mary’s University,
Halifax, NS, B3H 3C3, Canada.
F.J. Baerlocher. Department of Biology, Mount Allison University, Sackville, NB, E4L 1G8,
Canada.
Corresponding author: Stephen A. Westcott (email: swestcott@mta.ca)
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Abstract: The addition of 4ꢀethylꢀ3ꢀthiosemicarbazide to benzaldehyde and
boronic
acidꢀcontaining
derivatives
afforded
the
corresponding
thiosemicarbazones (1ꢀ3) or benzodiazaborines (4ꢀ6) depending on the position
of the boronic acid within the ring. All compounds have been characterized
fully including an Xꢀray diffraction study of the methoxyꢀcontaining
benzodiazaborine 6. Attempts to coordinate thiosemicarbazones 2 and 3 to
palladium(II) acetate were unsuccessful, however, addition of the nonꢀboronꢀ
containing derivative 1 to palladium afforded complex 7 whose molecular
structure was determined by an Xꢀray diffraction study.
The initial
bioactivities of compounds 1ꢀ7 were examined against two fungi, Aspergillus
niger and Saccharomyces cerevisiae, and two bacteria, Bacillus cereus and
Pseudomonas aeruginosa.
Key
words:
antimicrobial,
benzodiazaborines,
boron,
palladium,
thiosemicarbazones.
2

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Introduction
There has been recent considerable interest in boronꢀcontaining molecules for
their use in pharmaceutical chemistry.1 Among the many types of boron
compounds being investigated for their therapeutic potential, diazaborines are
a privileged class of heterocyclic compounds that have been studied extensively
for their antimicrobial properties (Figure 1a).2 The mechanism of action of
diazaborines is believed to involve the inhibition of fatty acid biosynthesis in
Escherichia coli, where the boron compound inhibits maturation of rRNAs for
the large ribosomal subunit.2f,j Interestingly, while the bioactivities of related
acyclic thiosemicarbazides (Figure 1b) and thiosemicarbazones (Figure 1c) are
well known,3 relatively little is known about boronꢀcontaining derivatives of
these species.4 Indeed, Groziak and coꢀworkers2o along with our group2n,s have
shown that thiosemicarbazones containing boronic acid [ꢀB(OH)2] groups
display significant antimicrobial activities.
In order to expand our
understanding of these promising compounds, we have undertaken a study to
make boronꢀcontaining diazaborines and thiosemicarbazones derived from
readily available 4ꢀethylꢀ3ꢀthiosemicarbazide, the results of which are
presented herein.
[insert Figure 1]
Experimental
Materials and methods
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Reagents and solvents used were obtained from SigmaꢀAldrich. Compound 15
was synthesized as previously reported. Nuclear magnetic resonance (NMR)
11
spectra were recorded on a JEOL JNMꢀGSX400 FT NMR (1H: 400 MHz; B:
13
19
128 MHz; C: 100 MHz; F: 188 MHz) spectrometer. Chemical shifts (δ) are
reported in ppm (relative to residual deuterated solvent peaks (1H and 13C) and
.
external BF3 OEt2 (11B) or CF3CO2H (19F)). Multiplicities are reported as singlet
(s), doublet (d), triplet (t), quartet (q), 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 FTꢀIR
spectrometer in attenuated total reflections (ATR) mode and are described as
strong (s), medium (m), weak (w) or broad (br) and are reported in cmꢀ1.
Melting points were measured uncorrected with a Stuart SMP30 apparatus.
Elemental analyses for C, H, and N were carried out at Laboratoire d’Analyse
Élémentaire de l’Université de Montréal (Montréal, QC).
Synthesis
of
(E)-(3-((2-(ethylcarbamothioyl)hydrazono)methyl)phenyl)-
boronic acid (2)
To a stirred suspension of 4ꢀethylꢀ3ꢀthiosemicarbazide (500 mg, 4.19 mmol) in
H2O (25 mL) was added 3ꢀformylphenylboronic acid (629 mg, 4.19 mmol) and 1
drop of formic acid. The reaction mixture was heated at reflux for 2 h, at which
point the reaction was allowed to cool to RT. The resulting white precipitate
was collected by suction filtration and washed with Et2O (2 × 10 mL) to afford 2
as a white solid. Yield: 1.00 g (95%); mp: 200ꢀ202 °C. 1H NMR (400 MHz,
4