In vitro activity of salicylamide derivatives against vancomycin-resistant enterococci

Article abstract of DOI:10.1016/j.bmcl.2018.05.011

A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199–25 μM) comparable to or more potent than ampicillin and ciprofloxacin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the highest potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotoxicity of the most effective compounds was performed using human monocytic leukemia THP-1 cells, and based on LD₅₀ values, it can be stated that the compounds have insignificant toxicity against human cells.

Full text of DOI:10.1016/j.bmcl.2018.05.011

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
In vitro activity of salicylamide derivatives against vancomycin-resistant
enterococci
Sarka Pospisilova a,b, , Hana Michnova a,b, Tereza Kauerova c, Karel Pauk d, Peter Kollar c,
⇑
Jarmila Vinsova e, Ales Imramovsky d, Alois Cizek b, Josef Jampilek a,
⇑
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia
b Department of Infectious Diseases and Microbiology, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic
c Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic
d Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
e Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of
vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality stan-
dard. The minimum inhibitory concentration was determined by the broth microdilution method with
subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinet-
ics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were
used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacterio-
static activity against VRE (0.199–25 mM) comparable to or more potent than ampicillin and ciproflox-
acin. In addition, these compounds were tested for synergistic effect with vancomycin, ciprofloxacin
and tetracycline, while 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide showed the high-
est potency as well as synergistic activity with vancomycin against VRE 368. Screening of the cytotox-
icity of the most effective compounds was performed using human monocytic leukemia THP-1 cells,
and based on LD50 values, it can be stated that the compounds have insignificant toxicity against
human cells.
Received 11 April 2018
Revised 3 May 2018
Accepted 4 May 2018
Available online xxxx
Keywords:
Salicylamides
Enterococcus
Time-kill assay
Cytotoxicity
Antibacterial activity
Ó 2018 Elsevier Ltd. All rights reserved.
Enterococcus is the 3rd most common nosocomial pathogen.1
The role of enterococci in nosocomial infection increases, because
they are still more resistant to clinically used antibacterial drugs.2,3
Vancomycin-resistant Enterococcus (VRE) was first isolated in
France, UK and USA at the end of the 1980s.4,5 Prevalence of VRE
in the world is very heterogeneous; e.g., it has tripled in Canadian
hospitals between 2007 and 2013 from 1.8 to 6%.6 The incidence of
hospitalizations with infections caused by VRE increased from 4.60
to 9.48 hospitalizations per 100.000 population in the USA from
2000 to 2006.7 On the other hand, the prevalence of VRE in Europe
is not so high in general, but it is different between countries. Data
from the European Antimicrobial Resistance Surveillance Network
showed that the highest prevalence of VRE in Europe is in Ireland
(44.0%), Portugal (23.3%), Greece (17.1%) and Germany (16.2%). On
the other hand, Denmark, the Netherlands and France had very low
number of VRE (0–2%).8 Nevertheless, the increasing number of
VRE is problematic not only due to complicated treatment,
especially of immunocompromised patient,9 or higher risk of mor-
tality,10–13 but it is also an economic problem.14
Problems with increasing resistance could be solved by devel-
oping new antibacterial drugs or using combinations of newly syn-
thetized compounds with convenient antibacterial agents.
Salicylamide derivatives/analogues seem to be one of the most
promising groups. This group of anti-infectious agents is known
by its wide range of pharmacological effects, such as antiviral,15
antibacterial/antimycobacterial,16–28 antifungal,8,18 antiparasitic,29
anthelminthic30 and in addition, noteworthy photosynthesis-
inhibiting activity.23–26,31–34 Thus, salicylamide-based compounds
can be considered as typical multi-target compounds, for which
it is difficult to propose the exact mechanism of action responsible
for overall biological activities. They are able to inhibit the
two-component regulatory systems of bacteria, inhibit bacterial
⇑
Corresponding authors at: Department of Pharmaceutical Chemistry, Faculty of
Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia
(S. Pospisilova).
E-mail address: josef.jampilek@gmail.com (J. Jampilek).
https://doi.org/10.1016/j.bmcl.2018.05.011
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pospisilova S., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.05.011

2
S. Pospisilova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
transglycosylase, sortase A, D-alanine–D-alanine ligase, mycobac-
terial isocitrate lyase and methionine aminopeptidase; they serve
as uncouplers of oxidative phosphorylation, inhibitors of
autophosphorylation of the KinA kinase in bacteria, inhibitors of
protein kinase epidermal growth factor receptor and also as selec-
tive inhibitors of interleukin-12p40 production.17,20,21,35
group C, only compound 3a showed bactericidal effect against van-
comycin-susceptible strain E. faecalis. No antibacterial activity
against VRE was observed.
All the compounds were substituted by R1 substituent in the
para- or meta-position of the salicylic ring, while chlorine is pre-
ferred for high potency. Replacing chlorine in the salicylic ring by
a nitro moiety caused the loss of antibacterial activity, as it is
shown in case of compound 1d. It is more advantageous to sub-
stitute the anilide ring by a lipophilic and electron-withdrawing
group, such as CF3 (compound 1a) or 3,4-Cl (compound 1c),
rather than only by an electron-withdrawing nitro moiety (com-
pound 1b). On the other hand, already the substitution by only
an electron-withdrawing moiety significantly increased potency
against all three VRE strains; compare compound 1b (R2 = 4-
NO2) and compound 1e (R2 = H). The activity is negatively influ-
enced by the substitution of the anilide ring by electron-donating
moieties.
This study is
a follow-up paper to recently published
results.19,20,22 The investigated compounds, see Scheme 1 and
Table 1, can be divided into three groups: starting salicylanilides-
2-hydroxy-N-phenylbenzamides 1a–e (group A), protected
salicylanilide amino acid esters
– 2-(phenylcarbamoyl)phenyl
N-[(benzyloxy)carbonyl]-L-valinates 2a–e (group B) and final
‘‘diamides” 2-hydroxy-N-[(2S)-3-methyl-1-oxo-1-(phenylamino)
butan-2-yl]benzamides 3a–c (group C). The synthesis and charac-
terization of these salicylamide derivatives was described previ-
ously.19 All the compounds were tested for their activity against
vancomycin-susceptible E. faecalis ATCC 29212 as a reference
strain and three isolates from American crows of vanA-carrying
vancomycin-resistant E. faecalis.36 Moreover, active compounds
were tested to their ability to cause synergy with clinically used
drugs such as vancomycin, ciprofloxacin and tetracycline. The
activities of compounds, see Table 1, were expressed as minimal
inhibitory concentrations (MICs) and minimal bactericidal concen-
trations (MBCs) and were determined according to the CLSI37 with
some modification.20 The time-kill assay was used for evaluation of
bactericidal activity identified by subcultivation of the aliquots.20
The investigation of synergistic activity was performed according
to the methodology.38 The method of fractional inhibitory concen-
tration (FIC) was used.39
4-Chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide
(1c)
was the most active compound against VRE. Only this compound
is substituted by Cl in position C(4) of the salicylic ring. The rest
of compounds (except 1d) are substituted by Cl in position C(5)
.
Similar results of antimicrobial investigations of activity against
different bacteria were reported also by Pauk et al.19
It was surprising that, based on the MICs values, bactericidal
activity was found only for derivative 5-chloro-2-hydroxy-N-(4-
nitrophenyl)benzamide (1b), the least effective compound
among three active derivatives 1a–c of group A. The time-kill
curve assay was used for testing the bactericidal effect of the
compounds, which indicated the possibility of bactericidal activ-
ity in the pre-test subcultivation aliquots on agar. If in this test
MBC was ꢀ4 ꢁ MIC, a compound was considered as potentially
bactericidal and consequently tested using the time-kill curve
assay.38,41 Unfortunately, despite compound 1b demonstrated
bactericidal activity against VRE 342B and VRE 725B when the
method of subcultivation aliquot on agar was used, the subse-
quent time-kill curve assay showed only bacteriostatic effect,
see Fig. 1A and 1B. The same situation was discovered with
MRSA in the previous study.20 It could be caused by the differ-
For all the wells of the microtitration plates that corresponded
P
to a MIC value, the sum of the FICs ( FIC) was calculated for each
P
well, using the equation
FIC = FICA + FICB = (CA/MICA) +
(CB/MICB), where MICA and MICB are the MICs of drugs A and B
alone, respectively, and CA and CB are the concentrations of the
drugs in combination, respectively.39,40 Synergy was defined as a
P
P
FIC ꢀ 0.5; additivity was defined as 0.5 < FIC < 1; indifference
P
was defined as 1 < FIC < 4; and antagonism was defined as
P
FIC > 4.38 As the FIC index was evaluated for every single wall
corresponding to the MIC value, the results are presented as a
range. Only the MIC values of vancomycin and tetracycline against
resistant strains were determined, because only these were needed
for tests of synergism.
ence
between
microtiter
broth
dilution
and
broth
macrodilution.20
In addition, synergistic activity with ciprofloxacin, tetracycline
and vancomycin was tested for three most active derivatives 1a–
c, see Table 2. No antagonism was detected. Synergistic effect of
ciprofloxacin was tested only against isolate VRE 725B, because
other isolates were ciprofloxacin-susceptible.37 The additivity of
combinations with compounds 1a–c was investigated. Combina-
tions of tetracycline showed only additive effect with 1b against
VRE 342B and VRE 368 and with 1a against VRE 368. The best
result was demonstrated by the combination of vancomycin and
Based on the results, see Table 1, it is evident that the com-
pounds of group A expressed the highest potency among all the
investigated compounds. Compounds 1a–c showed strong bacte-
riostatic activity against VRE; even they were more potent than
the used standards – ampicillin and ciprofloxacin. On the other
hand, salicylanilide esters (group B) showed antibacterial activities
against neither VRE nor vancomycin-susceptible strain E. faecalis,
although in a previous study, these compounds demonstrated only
little weaker antibacterial activity against methicillin-resistant Sta-
phylococcus aureus (MRSA) than salicylanilides of group A.19 Within
1a. This combination had synergistic effect against VRE 368 with
P
FIC = 0.375–1.064 and additive effect against VRE 342B with
P
low
FIC = 0.750–1.250. Vancomycin also showed additivity
Scheme 1. Synthesis of 2-hydroxy-N-phenylbenzamides 1a–e (group A), 2-(phenylcarbamoyl)phenyl N-[(benzyloxy)carbonyl]-L-valinates 2a–e (group B) and 2-hydroxy-N-
[(2S)-3-methyl-1-oxo-1-(phenylamino)butan-2-yl]benzamides 3a–c (group C). Individual R1 and R2 substituents are mentioned in Table 1. Reagents and conditions: (a) PCl3,
chlorobenzene, microwave irradiation; (b) N,N-dicyclohexylcarbodiimide, DMF; (c) HBr/AcOH, triethylamine, CHCl3.19
Please cite this article in press as: Pospisilova S., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.05.011

S. Pospisilova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
with other salicylanilides, specifically with 1b against VRE 368 and
with 1a against VRE 342B. It is important to note that synergistic
effect with ampicillin was not tested, because all strains are sus-
ceptible to ampicillin.36
The cytotoxicity of chosen compounds 1a–e was determined
using a LDH assay kit as described previously.42 For the discussed
compounds, the cytotoxicity was evaluated as the LD50 value
(LD50 – lethal dose causing death in at least 50% of the cell popula-
tion) using the human monocytic leukaemia THP-1 cells. The tox-
icity values of the tested compounds were compared with
camptothecin (LD50 = 0.161 0.071
indexes were calculated as a rate of LD50 and MIC [
l
M) as a standard. Selectivity
M] values of
l
VRE 342B as a representative of resistant isolates. Results are
shown in Table 1. Based on these observations, it can be concluded
that all tested compounds 1a–e can be considered as insignificant
toxic agents for mammalian cells in subsequent design of novel
therapeutic agents.
In the previous study20, diamides 3a and 3c showed strong bac-
tericidal activity against MRSA. In general, the antibacterial activity
of salicylanilides is predominantly bacteriostatic; nevertheless, it
can be hypothesized that the bactericidal activity of both diamides
is caused by the presence of two amide bonds. In fact the whole
structure of these diamides mimics structural features of ‘‘three-
cycles salicylanilides” that were described by Cheng et al. as agents
able to inhibit transglycosylation in cell wall synthesis of S.
aureus.17 As the inhibition of cell wall biosynthesis is characteristic
for bactericidal agents, it is possible that the inhibition of transgly-
cosylation is responsible for the bactericidal activity of salicylic
diamides against MRSA.14,20
The difference in activity against MRSA and VRE can be
explained just by the resistance to vancomycin. Vancomycin is a
glycopeptide antibiotic that inhibits transglycosylation. Entero-
cocci carrying gen vanA synthetize D-ala-D-lac instead of D-ala-
D-ala, to which vancomycin has 100ꢁ lower affinity. All VRE
strains in this study carried gen vanA, and their MICs for van-
comycin were 512–2046 mg/ml, although MRSA strains used in
the previous study19,20 were vancomycin-susceptible. It is possi-
ble that salicylic diamides interact with a step of the enzymatic
reaction participating in the synthesis of peptidoglycan, and their
interaction with this target is disabled by the presence of vanA in
VRE. This theory could be supported by the activity of salicylic
diamides against the reference vancomycin-susceptible strain E.
faecalis ATCC 29212.
The difference between the activities of compounds 3a and 3c
against E. faecalis could be caused by the different position of Cl
on the salicylic ring and the presence of the CF3 group on the ani-
lide ring of compound 3a. Concerning antimicrobial activity, it was
0
observed that the substitution of C(4) by the CF3 moiety is prefer-
able to that by Br.16,18–20,22–29 Simultaneously it can be expected
that the mechanism of action of salicylanilides is different from
that of salicylic diamides, because salicylanilides were active
against VRE.
Summarizing, it can be concluded that tested compounds 4-
chloro-N-(3,4-dichlorophenyl)-2-hydroxybenzamide
chloro-2-hydroxy-N-[4-(trifluoromethyl)phenyl]benzamide (1a)
and 5-chloro-2-hydroxy-N-(4-nitrophenyl)benzamide (1b)
(1c),
5-
showed strong bacteriostatic activity against VRE, and at the same
time, compound 1a showed synergistic effect with vancomycin
against VRE 368. The anti-VRE activity significantly depends on
compound lipophilicity and strong electron-withdrawing proper-
ties of the substituent on the anilide ring. Moreover, the most
potent compounds can be considered as insignificant toxic agents.
Based on the obtained results and the previous study, it can be sta-
ted that salicylanilides and their derivatives are promising candi-
dates for the study of novel antibacterial drugs against
multiresistant strains.
Please cite this article in press as: Pospisilova S., et al. Bioorg. Med. Chem. Lett. (2018), https://doi.org/10.1016/j.bmcl.2018.05.011

4
S. Pospisilova et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
Fig. 1. Time-kill curve of compound 1b against VRE 342B (A) and against VRE 725B (B).
Table 2
Combined effect of most potent salicylamide derivatives and ciprofloxacin (CPX), tetracycline (TET) and vancomycin (VAN).
Isolate
Combination of
compounds
Separate MIC
g/ml]
FIC index
Concentration [
causing synergistic effect
l
g/ml]
Concentration [lg/ml]
causing additive effect
[
l
VRE 725B
1a/CPX
0.25/128
0.532–1.125
–
0.125/32
0.008/64
–
1b/CPX
1c/CPX
1.00/64
0.125/64
1.000–1.250
0.756–1.250
–
–
0.032/32
VRE 342B
VRE 368
1a/TET
1b/TET
1c/TET
0.5/64
1.00/64
0.063/64
1.008–1.5
0.75–1.25
1.016–1.508
–
–
–
–
0.5/16
–
1a/TET
1b/TET
1c/TET
0.5/64
2.00/64
0.125/64
0.625–1.25
0.75–1.25
1.016–1.504
–
–
–
0.25/8
1.00/16
–
VRE 725B
VRE 342B
1a/TET
1b/TET
1c/TET
0.5/64
1.00/64
0.125/64
1.032–1.500
1.032–2.125
1.016–1.504
–
–
–
–
–
–
1a/VAN
1b/VAN
1c/VAN
1.00/1024
1.00/512
0.125/512
0.750–1.250
1.00–2.250
0.629–1.128
–
–
–
0.5/256
–
0.063/64
0.032/256
VRE 368
1a/VAN
0.5/1024
0.375–1.064
0.125/128
0.25/32
0.063/512
0.25/256
–
1b/VAN
1c/VAN
2/512
0.5/512
0.625–1.250
1.00–1.25
–
–
VRE 725B
1a/VAN
1b/VAN
1c/VAN
0.25/1024
1.00/1024
0.063/1024
1.000–1.250
1.063–1.500
1.031–2.234
–
–
–
–
–
–
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This study was supported by the grant of the Comenius Univer-
sity in Bratislava No. UK/229/2018, grant of the Faculty of Phar-
macy of Comenius University in Bratislava FaF UK/9/2018, by
project No. 18-03847S of the Grant Agency of the Czech Republic,
by IGA VFU Brno 303/2018/FaF and by SANOFI-AVENTIS Pharma
Slovakia, s.r.o.
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