Synthesis and antimicrobial activities of monoindolyl- and bisindolyloximes

Article abstract of DOI:10.1016/S0223-5234(99)80049-X

Six monoindolyl- and bisindolyloximes structurally related to protein kinase C inhibitors bisindolylmaleimides were synthezised. They did not have protein kinase C inhibitory properties but exhibited interesting antimicrobial activities. Their antibacterial activities against several strains of pathogenic and non-pathogenic Gram-positive and Gram-negative bacteria are described. The bisindolyl monooxime isomers exhibited a marked activity against the three strains of Staphylococcus aureus tested and against Escherichia coli 1507E.

Full text of DOI:10.1016/S0223-5234(99)80049-X

Eur. J. Med. Chem. 34 (1999) 161−165
© Elsevier, Paris
161
Short communication
Synthesis and antimicrobial activities of monoindolyl- and bisindolyloximes
Michelle Prudhommea*, Martine Sancelmea, Alain Bonnefoyb, Doriano Fabbroc, Thomas Meyerc
aSynthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, Université Blaise Pascal, CNRS – UMR 6504,
63177 Aubière, France
bHoechst Marion Roussel, 102 route de Noisy, 93235 Romainville, France
cNovartis K-125-409, CH-4002 Bâle, Switzerland
(Received 25 June 1998; accepted 17 September 1998)
Abstract – Six monoindolyl- and bisindolyloximes structurally related to protein kinase C inhibitors bisindolylmaleimides were synthezised.
They did not have protein kinase C inhibitory properties but exhibited interesting antimicrobial activities. Their antibacterial activities against
several strains of pathogenic and non-pathogenic Gram-positive and Gram-negative bacteria are described. The bisindolyl monooxime isomers
exhibited a marked activity against the three strains of Staphylococcus aureus tested and against Escherichia coli 1507E. © Elsevier, Paris
indolyl oximes / antimicrobial activity / pathogenic bacteria
1. Introduction
problem which led to the development of series of
analogues of the known drugs as well as the research for
new drugs owning quite different structures.
The ever increasing incidence of infection resulting
from bacteria resistant to currently available therapy has
prompted the continuing need to develop new antibacte-
rial agents [1–3]. The different antibacterial agents may
act via various mechanisms [4, 5]. They can be inhibitors
of cell wall synthesis (â-lactam antibiotics including
penicillins, cephalosporins, monobactams, carbapenems
or others such as vancomycin), inhibitors of protein
synthesis (macrolides such as erythromycin, aminoglyco-
sides, tetracyclines, chloramphenicol, oxazolidinones),
inhibitors of nucleic acid synthesis with four different
modes of action: by direct interaction with DNA, by
inhibition of DNA topoisomerases (quinolones,
2-pyridones), by inhibition of DNA synthesis or inhibi-
tion of RNA synthesis (fluoroquinolones, rifamycins,
coumarin antibiotics). They can also target other essential
cellular metabolic functions like membrane transport,
fatty acid synthesis, lipopolysaccharide biosynthesis,
folic acid metabolism (sulfonilamides, trimethoprim).
Emergence of bacterial resistance to a number of
antimicrobial agents such as â-lactam antibiotics, mac-
rolides, quinolones, and vancomycin [6, 7] is a crucial
In the course of search for new protein kinase C
inhibitors structurally related to bisindolyl maleimides
(figure 1) [8–10] and interacting with the ATP binding
site of the enzyme, we synthezised mono-indolyl and
bisindolyloximes. Compounds 1–6 (figure 2), as already
observed for amides [11] in which the rigid upper hetero-
cycle was missing, were found to be inactive toward
protein kinase C. However, except compound 4, they
exhibited strong antimicrobial properties against Gram-
positive bacteria Bacillus cereus and Streptomyces char-
treusis. Compound 4 was active against Gram-negative
bacterium Escherichia coli. These results prompted us to
test their antimicrobial activities against bacterial patho-
gens. In this paper, we describe the synthesis and the
antimicrobial activities of indolyloximes 1–6.
2. Chemistry
Monooximes 1 and 2 and dioxime 3 were prepared in
two steps from commercial indole-glyoxalyl chloride:
reaction with indolylmagnesium bromide, leading to
bis-3-indolylglyoxal [12], followed by treatment with
hydroxylamine hydrochloride (1 eq. for 1 and 2, 10 eq.
*Correspondence and reprints

162
154.4 ppm in compound 1, which is in agreement with
anti configuration for 1 and syn configuration for 2 [13].
Compound 4 was prepared in two steps from bis-(3-
indolylglyoxal): N-methylation of both indole nitro-
gens [14] followed by reaction with hydroxylamine hy-
drochloride (1 eq.). Two isomers were obtained but they
could not be separated by chromatography since syn
isomer was converted to anti isomer on the silicagel
chromatography column. Oximes 5 and 6 were prepared
from 3-indoleglyoxylic acid. Esterification was per-
formed using sulfuric acid in methanol, reaction of the
methyl ester with hydroxylamine hydrochloride (1 eq.)
yielded isomers 5 and 6 which could be isolated indepen-
dently. In the 13C NMR spectra, the signal of the
quaternary carbon (C=N) was observed at 148.0 ppm for
anti isomer 5 and at 144.2 ppm for syn isomer 6.
Figure 1.
for 3) in ethanol in the presence of pyridine (figure 2).
Both isomers 1 and 2 could be easily separated by
chromatography. Their structures were assigned from 13
C
NMR spectra. The signals of the quaternary carbon
(C=N) were observed at 105.4 ppm in compound 2 and
Figure 2.

163
a
Table I. In vitro growth inhibitory effect of compounds 1–6 against different microorganisms.
Compounds
B. cereus ATCC 14579
S. chartreusis NRRL 11407
E. coli ATCC 11303
C. albicans IP 444
1
2
3
4
5
6
++
+++
+
–
+
+++ sp ++++
++++ sp ++++
++ sp ++
– sp ++++
+++
–
±
–
++
+
–
–
–
–
–
–
–
+++
–
a The size of zones of growth inhibition was 13–15 mm (++++), 10–12 mm (+++), 8–9 mm (++), 6–7 mm (+); sp (inhibition of sporulation):
++++ (28–35 mm), ++: 12 mm.
3. Biological results and discussion
membrane. Among the cytoplasmic steps, four ADP-
forming ligases catalyse the assembly of the peptide
moiety by successive additions of L-alanine, D-glutamate,
a diaminoacid (most frequently diaminopimelate or
lysine) and D-alanyl-D-alanine to UDP-N-acetylmuramic
Antibiogram tests were performed on a Gram-negative
bacterium E. coli, a yeast Candida albicans and two
Gram-positive bacteria B. cereus, S. chartreusis. The
inhibition of sporulation of S. chartreusis was examined
(table I). None of the compounds 1–6 tested had any
activity against C. albicans. Surprisingly, oxime 4 exhib-
ited a non-negligible antimicrobial activity against Gram-
negative E. coli without any growth inhibition toward
Gram-positive bacteria B. cereus and S. chartreusis.
Oxime 2 was weakly active against E. coli. Oximes 1, 2,
3 and 5 were active against the two Gram-positive
bacteria tested, 6 was only active against S. chartreusis.
Compound 2 had the strongest antibacterial activity
against both B. cereus and S. chartreusis.
Compounds 1–6 were tested against six strains of
pathogenic Gram-positive bacteria (Staphylococcus au-
reus SG511, SG 285 and Exp54146, Streptococcus pyo-
genes A561 and 77A, Enterococcus faecium M78L) and
eleven strains of pathogenic Gram-negative bacteria (Ser-
ratia RG 2532, Proteus mirabilis A235, Proteus vulgaris
A232, Escherichia coli UC1894, 078, TEM, 1507E, DC0
and DC2, Salmonella typhimurium MZ11 and Klebsiella
pneumoniae 52145). The MICs were determined. Only
the bisindolylmonooximes 1 and 2 exhibited a noticeable
activity against S. aureus SG511, 285 and S. aureus
Exp54146 as well as against E. coli 1507E (table II).The
syn oxime 2 was weakly active against E. faecium M78L.
The anti oxime 1 was weakly active against S. pyogenes
A561 and E. coli DC2.
acid [15].
UDP-N-acetylmuramoyl-L-alanine:D-gluta-
mate ligase (Mur D) is responsible for the addition of
D-glutamic acid to UDP-N-acetylmuramic acid and
therefore can be a potential target for new antibacterial
agents. Since several structurally related indolocarba-
zoles were found to be Mur D inhibitors (unpublished
results), the antimicrobial potencies of compounds 1 and
2 could be due, at least partially, to this enzyme inhibi-
tion. We are now investigating this hypothesis. Moreover,
the major problem with compounds in these series is their
insolubility. Their antimicrobial properties could be
markedly increased by introducing on the indole moieties
substituents that are known to facilitate membrane cross-
ing such as hydroxy groups. To conclude, oximes 1 and 2
represent new structures able to exhibit interesting anti-
microbial activities especially against S. aureus. Chemi-
cal investigations have to be extended in this field.
Table II. In vitro antimicrobial activities against six strains of
pathogenic Gram-positive bacteria (MICs in µg/mL reading after
24 h) compared to those of the known antibiotic Ofloxacine
determined in identical conditions.
Strains
MIC µg/mL
1
2
Ofloxacine
The main interest of the work is the antimicrobial
activity of the monooximes 1 and 2 toward S. aureus. To
have an insight into the mode of action of these com-
pounds, we tested their inhibitory potencies against
protein kinase C (PKCα). The IC50 observed were >
100 mg/mL. Therefore the antibacterial activity cannot be
due to PKC inhibition.
Peptidoglycan is an essential constituent of the cell wall
of eubacteria. Its biosynthesis is a complex process
involving many steps, both in the cytoplasm and in the cell
S. aureus SG511
S. aureus 285
S. aureus Exp54146 160
S. pyogenes A561
S. pyogenes 77A
E. faecium M78L
E. coli TEM
E. coli 1507E
E. coli DC0
20
40
20
40
40
> 160
> 160
160
> 160
40
0.15
0.15
0.30
1.20
2.50
0.60
0.15
0.15
0.60
0.30
160
> 160
> 160
> 160
80
> 160
160
> 160
> 160
E. coli DC2

164
4. Experimental protocols
4.1.2. 1,2-bis(3-indolyl)-1,2-bis(hydroxyimino)-ethane
3
A mixture of 1,2-bis(3-indolyl)-glyoxal (2.585 g,
4.1. Chemistry
8.97 mmol), NH2OH, HCl (6.23 g, 89.70 mmol), pyri-
dine (13 mL) and absolute ethanol (65 mL) was refluxed
for 6 h. After idendical work-up as described above, 1
was obtained as a white powder (2.0125 g, 6.32 mmol,
71% yield). M.p. 189–192 °C. HRMS (FAB+) M+ Calc.
for C18H14N4O2 318.1116 Found 318.1115. IR (KBr):
νC=N 1640 cm–1, νNH,OH 3200–3600 cm–1. 1H-NMR (400
MHz, acetone-d6) δ: 7.15 (2H, t, J = 7.2 Hz), 7.19 (2H,
s), 7.22 (2H, t, J = 7.0 Hz), 7.44 (2H, d, J = 7.9 Hz), 8.21
(2H, d, J = 7.7 Hz), 10.65 (2H, s), 11.32 (2H, s).
13C-NMR (100 MHz, acetone-d6) δ: 109.8, 124.3, 136.9
(C quat. arom.), 111.7, 119.9, 121.9, 122.0, 127.3 (C tert.
arom.), 149.4 (C=N).
IR spectra were recorded on a Perkin-Elmer 881
spectrometer (ν in cm–1), NMR spectra on a Bruker AC
400 (1H: 400 MHz, 13C: 100 MHz) (chemical shifts δ in
ppm, the following abbreviations are used: singlet (s),
doublet (d), triplet (t), multiplet (m), tertiary carbons (C
tert.), quaternary carbons (C quat.)). Mass spectra (EI)
and (FAB+) were determined at Cesamo (Talence) on a
high-resolution Fisons Autospec-Q spectrometer. Chro-
matographic purifications were performed with a flash
Geduran SI 60 (Merck) 0.040–0.063 mm column.
4.1.1. Anti 1,2-bis(3-indolyl)-2-(hydroxyimino)-ethan-
1-one 1 and Syn 1,2-bis(3-indolyl)-2-(hydroxyimino)-
ethan-1-one 2
4.1.3. Anti 1,2-bis(3-N-methylindolyl)-2-(hydroxy-
imino)-ethan-1-one 4
A mixture of 1,2-bis[3-(N-methyl-indolyl)]-glyoxal
(283 mg, 0.89 mmol), NH2OH, HCl (62 mg, 0.89 mmol),
pyridine (1.5 mL) and absolute ethanol (7.5 mL) was
refluxed for 6 h. After idendical work-up as described
above, 4 was obtained as an off-white powder (176 mg,
0.53 mmol, 60% yield). M.p. 255–256 °C. IR (KBr)
νC=O,C=N 1610, 1620 cm–1, νOH 3300–3550 cm–1. HRMS
(EI) M+ Calc. for C20H17N3O2: 331.1320. Found:
A mixture of 1,2-bis(3-indolyl)-glyoxal (300 mg,
1.04 mmol), NH2OH, HCl (72 mg, 1.04 mmol), pyridine
(1.5 mL) and absolute ethanol (7.5 mL) was refluxed for
6 h. After removal of the solvent, the residue was
dissolved in EtOAc and washed with brine. The organic
phase was dried over MgSO4. After removal of the
solvent, the residue was purified by flash chromatography
(eluent, cyclohexane–EtOAc 5:5) to give 1 (170 mg,
0.56 mmol, 54% yield) and 2 (121 mg, 0.40 mmol, 38%
yield) as white powders.
1
331.1320. H NMR (400 MHz, DMSO-d6): 3.76 (3H, s,
NCH3), 3.88 (3H, s, NCH3), 7.24 (1H, dt, J1 = 7.9 Hz, J2
= 0.8 Hz), 7.31 (1H, dt, J1 = 8.3 Hz, J2 = 1.2 Hz), 7.33
(1H, s), 7.36 (1H, dt, J1 = 7.4 Hz, J2 = 1.0 Hz), 7.38 (1H,
dt, J1 = 7.2 Hz, J2 = 1.7 Hz), 7.51 (1H, d, J = 8.2 Hz),
7.60 (1H, dd, J1 = 6.8 Hz, J2 = 1.9 Hz), 8.02 (1H, s), 8.21
(1H, d, J = 7.8 Hz), 8.30 (1H, d, J = 6.9 Hz), 10.82 (1H,
s, N=OH). 13C NMR (100 MHz, DMSO-d6): 32.5, 33.1
(NCH3); 108.0, 114.2, 124.7, 125.5, 137.2, 137.6 (C quat.
arom.); 110.1, 110.9, 120.5, 121.2, 122.1, 122.2, 122.5
(2C), 123.2, 131.2 (C tert. arom.); 154.0 (C=N); 187.4
(C=O).
1: M.p. 110–113 °C. IR (KBr): νCO,
1610,
1620 cm–1, νNH,OH 3200–3380 cm–1. HRMS (CF=ANB+) M+
1
Calc. for C18H13N3O2 303.1007 Found 303.1005. H-
NMR (400 MHz, DMSO-d6) δ: 7.19 (1H, t, J = 7.3 Hz),
7.25 (1H, t, J = 7.3 Hz), 7.30 (2H, m), 7.49 (1H, d, J = 7.8
Hz), 7.58 (1H, m), 7.95 (1H, s), 8.19 (1H, d, J = 7.8 Hz),
8.29 (1H, m), 10.75 (1H, s), 11.47 (1H, s), 12.10 (1H, s).
13C-NMR (100 MHz, DMSO-d6) δ: 111.9, 112.5, 120.3,
121.0, 121.9, 122.1, 122.4, 123.1, 127.3, 136.6 (C tert.
arom.), 108.9, 115.3, 124.3, 124.9, 136.8, 136.9 (C quat.
arom.), 154.4 (C=N), 188.0 (C=O).
4.1.4. Methyl 2-indolyl-2-oxo-ethanoate
2: M.p. 195–198 °C. IR (KBr): νCO,
1610,
Commercial indolyl-glyoxylic acid (1 g, 5.28 mmol)
was added to a solution of concentrated H2SO4 (1.6 mL)
in methanol (6.2 mL). The mixture was refluxed for 3 h.
After neutralization with NaOH and extraction with
EtOAc, the organic phase was washed with brine, dried
over MgSO4. After removal of the solvent, the residue
was purified by flash chromatography (eluent, EtOAc) to
give methyl 2-indolyl-2-oxo-ethanoate as a yellow solid
(934 mg, 4.57 mmol, 87% yield). M.p.: 218–220 °C. IR
(KBr) νC=O 1730, 1740 cm–1, νNH 3240 cm–1. HRMS
(FAB+) (M + H)+ Calc. for C11H10NO3: 204.0661.
1620 cm–1, νNH,OH 3100–3380 cm–1. HRMS (CF=ANB+) M+
1
Calc. for C18H13N3O2 303.1007 Found 303.1006. H-
NMR (400 MHz, DMSO-d6) δ: 6.93 (1H, t, J = 7.5 Hz),
7.12 (1H, t, J = 7.5 Hz), 7.32 (3H, m), 7.49 (1H, d, J = 8.0
Hz), 7.58 (1H, m), 8.13 (1H, s), 8.36 (1H, m), 8.42 (1H,
s), 11.55 (3H, broad s, 2NH + OH). 13C-NMR (100 MHz,
DMSO-d6) δ: 111.8, 112.5, 119.6, 120.4, 121.4, 121.5,
122.2, 123.2, 131.4, 137.2 (C tert. arom.), 105.0, 116.0,
124.9, 125.8, 135.2, 136.8 (C quat. arom.), 150.4 (C=N),
186.8 (C=O).

165
1
Found: 204.0647. H NMR (400 MHz, DMSO-d6): 3.95
was placed on Petri dishes. Growth inhibition was exam-
ined after 24 h incubation at 27 °C.
(3H, s, OCH3), 7.35 (2H, t, J = 7.5 Hz), 7.60 (1H, d, J =
7.5 Hz), 8.20 (1H, d, J = 7.5 Hz), 8.50 (1H, s), 12.45 (1H,
s, Nindole–H). 13C NMR (100 MHz, DMSO-d6): 52.5
(CH3), 112.7, 121.1, 122.8, 123.8, 138.3 (C tert. arom.),
112.4, 125.4, 136.7 (C quat. arom.), 163.9, 178.6 (C=O).
MICs were determined by a two-fold microdilution
method in Mueller–Hinton broth (Diagnostic Pasteur).
The medium was supplemented with 4% globular extract
(Diagnostic Pasteur) to support the growth of strepto-
cocci. The MIC was defined as the lowest concentration
which prevents the growth after 24 h incubation at 37 °C
in ambient atmosphere.
4.1.5. Anti Methyl-2-hydroxyimino-2-(3-indolyl)-
5 and Syn Methyl-2-hydroxyimino-2-(3-
indolyl)-ethanoate 6
ethanoate
A
mixture of methyl 2-indolyl-2-oxo-ethanoate
4.3. Protein kinase C inhibition
(275 mg, 1.355 mmol), NH2OH, HCl (94 mg,
1.355 mmol), pyridine (2.3 mL) and absolute ethanol
(10 mL) was refluxed for 6 h. After idendical work-up as
described for 1, 5 (142 mg, 0.651 mmol, 48% yield) and
6 (100 mg, 0.460 mmol, 34% yield) were obtained as
off-white powders.
Protamine sulphate was from Merck (Darmstadt, Ger-
many). Unless specified, chemicals were from Sigma (St.
Louis, MO). [γ-33P] ATP (1000–3000 Ci/mmol) was
obtained from Amersham. Recombinant baculoviruses
from protein kinase C subtypes were supplied by Dr.
Silvia Stabel, Köln, Germany.
Expression and partial purification of PKCs together
with measurements of activities were carried out as
previously described [16].
5: M.p.: 134–135 °C. IR (KBr) νC=N 1610 cm–1, νC=O
1720 cm–1, νOH,NH 3340, 3440 cm–1. HRMS (EI) M+
1
Calc. for C11H10N2O3: 218.0691. Found: 218.0692. H
NMR (400 MHz, DMSO-d6): 3.89 (3H, s), 7.17 (1H, dt,
J1 = 7.8 Hz, J2 = 0.7 Hz), 7.25 (1H, dt, J1 = 8.2 Hz, J2 =
1.3 Hz), 7.51 (1H, d, J = 8.1 Hz), 7.54 (1H, d, J = 2.5 Hz),
8.02 (1H, d, J = 7.8 Hz), 11.26 (1H, s), 11.65 (1H, s). 13
C
References
NMR (100 MHz, DMSO-d6): 52.1 (OCH3); 107.0, 123.9,
136.9 (C quat. arom.); 112.8, 121.2, 121.4, 122.7, 127.4
(C tert. arom.); 148.0 (C=N); 164.7 (C=O).
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3853–3874.
1710 cm–1, νOH,NH 3200–3500 cm–1. HRMS (EI) M+
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Calc. for C11H10N2O3: 218.0691. Found: 218.0691. H
NMR (400 MHz, DMSO-d6): 3.86 (3H, s), 7.10 (1H, dt,
J1 = 7.9 Hz, J2 = 1.0 Hz), 7.19 (1H, dt, J1 = 8.2 Hz, J2 =
1.2 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.1 Hz),
8.13 (1H, d, J = 2.8 Hz). 13C NMR (100 MHz, DMSO-
d6): 52.3 (OCH3); 111.9, 119.9, 120.0, 121.6, 130.6 (C
tert. arom.); 103.7, 124.8, 135.3 (C quat. arom.); 144.2
(C=N); 165.5 (C=O).
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Five strains were tested, three Gram positive bacteria
(B. cereus ATCC 14579, S. chartreusis NRRL 11407, S.
griseus ATCC 23345), a Gram negative bacterium (E.
coli ATCC 11303) and a yeast (Candida albicans 444
from Pasteur Institute). Antimicrobial activity was deter-
mined by the conventional paper disk (Durieux No. 268,
6 mm in diameter) diffusion method using the following
nutrient media: Mueller–Hinton (Difco) for B. cereus and
E. coli, Sabouraud agar (Difco) for C. albicans and
Emerson agar (0.4% beef extract, 0.4% peptone, 1%
dextrose, 0.25% NaCl, 2% agar, pH 7.0) for the Strepto-
myces strains. Products 1–6 were dissolved in DMSO and
a paper disk containing each of the products (300 mg)
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