Semi-synthesis, antibacterial activity, and molecular docking study of novel pleuromutilin derivatives bearing cinnamic acids moieties

Article abstract of DOI:10.1002/ardp.201800266

To develop new antibiotics owning a special mechanism, we used the molecular assembly method to synthesize a series of novel pleuromutilin derivatives containing a cinnamic acid scaffold at the C-14 side chain. We evaluated their antibacterial activity an

Full text of DOI:10.1002/ardp.201800266

Received: 5 September 2018
Revised: 1 November 2018
Accepted: 4 November 2018
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DOI: 10.1002/ardp.201800266
FULL PAPER
Semi-synthesis, antibacterial activity, and molecular docking
study of novel pleuromutilin derivatives bearing cinnamic
acids moieties
Yu Deng1
Da Tang1
Qiu-ru Wang2
Sheng Huang1
Li-zhi Fu1
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Cheng-hong Li1
1 Institute of Veterinary Sciences and
Pharmaceuticals, Chongqing Academy of
Animal Sciences, Rongchang, China
Abstract
To develop new antibiotics owning a special mechanism, we used the molecular
assembly method to synthesize a series of novel pleuromutilin derivatives containing a
cinnamic acid scaffold at the C-14 side chain. We evaluated their antibacterial activity
and used in silico molecular docking to study their binding mode with the target. The
structure–activity relationship (SAR) study suggested that compounds with NO2 (13e),
OH (13u), and NH2 (13y) appeared more active (0.0625–2 µg/mL) in vitro against
several penicillin-resistant Gram-positive bacteria and the position of the substituent
on the benzene ring would affect the activity. The in vivo efficacy investigation of 13e,
13u, and 13y with once daily intragastric (i.g.) administration at 40 mg/kg for 3
consecutive days in a mouse systemic infection model showed that 13u had equal
activity as valnemulin providing the mice with 60% survival, while 13e and 13y gave 30
and 40% survival, respectively. The molecular docking studies indicated that π–π
stacking and hydrogen bond formation played important roles in improving the
antibacterial activity.
2 West China School of Medicine, Sichuan
University, Chengdu, China
Correspondence
Cheng-hong Li, Institute of Veterinary
Sciences and Pharmaceuticals, Chongqing
Academy of Animal Sciences, Rongchang
402460, China.
Email: lchong_cqaa@hotmail.com
Funding information
Chongqing Basic Scientific Research Project,
Grant number: 16438; Chongqing
Agricultural Development Fund,
Grant number: 17412
K E Y W O R D S
antibiotics, cinnamic acid, molecular assembly, pleuromutilin, structure−activity relationship
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1
INTRODUCTION
antibiotics with novel mechanisms of action and minimal cross-
resistance. For example, the members of Mur ligase family MurC to
The dramatic increasing appearance of multidrug-resistant bacteria
has threatened the public health in the whole world.[1] Among these
multidrug-resistant Gram-positive bacteria, methicillin-resistant
Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus
pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE) are
the major control objectives. The grim situation has caused people's
high vigilance and concern, which prompts scientists to develop new
MurF that are involved in the intracellular biosynthesis stage of
bacterial peptidoglycans, have emerged as attractive targets for
antibiotics design and some progress has been achieved.[2,3] A recent
research reported two synthetic retinoid antibiotics discovered
through high-throughput screening displayed excellent activity against
Gram-positive bacteria by disrupting cell lipid bilayers.[4] All of these
urged us to focus on some effective molecules to develop new
antibacterial agents, for instance, pleuromutilin.
Pleuromutilin 1 (Figure 1) is a natural product with moderate
antibacterial activity first isolated from the fungi Pleurotusmutilus (now
Yu Deng and Da Tang contributed equally to this work.
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Arch Pharm Chem Life Sci. 2018;e1800266.
wileyonlinelibrary.com/journal/ardp
© 2018 Deutsche Pharmazeutische Gesellschaft
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FIGURE 1 The structures of pleuromutilin and related drugs
called Clitopilusscyphoides).[5] The mechanism studies have confirmed
that pleuromutilin derivatives selectively target bacterial 50S ribosome
subunit and display no cross-resistance with antibiotics in clinical
utilization.[6–8] Since its unique action mode, pleuromutilin has
attracted growing attention in the development of novel antibacterial
agents for the therapy of multi-drug resistant bacterial infections.[9]
veterinary medicine while the progress of human use was very limited.
The main reason is probably the features of pleuromutilin, such as
metabolic instability, lack of oral bioavailability, hepatotoxicity would
make the side-chain chemistry of it become challenging. Despite a
large number of synthetic pleuromutilin derivatives including mar-
keted drugs either for human or veterinary use, usually contain
thioether-type in the C14 side chain, other pleuromutilin compounds
with superior skeleton and groups in the side chain have been rarely
synthesized and evaluated their activity. To our knowledge, piperazine
ring is one of the 25 most common nitrogen heterocycles in approved
marketed drugs by the US FDA. From the perspective of pharmaceu-
tical chemistry design, this ring not only has a good three-dimensional
structure, but also compounds with this structure usually have
excellent pharmacokinetic property and can increase the water
solubility and metabolic stability of the compounds. In addition,
several approved drugs like aripiprazole 7,[16] ketoconazole 8,[17] and
levofloxacin 9[18] (Figure 2) containing piperazine structure encour-
aged us to link piperazine ring to the side chain of pleuromutilin.
Furtherly, cinnamic acid derivatives have been verified to own a wide
variety of biological activities such as antimicrobial,[19] antimycobac-
terium,[20] anti-cell proliferative,[21] etc. Moreover, piperazine ferulate
10, a kind of non-peptide endothelin receptor antagonists approved by
CFDA, has good therapeutic effect on kidney diseases.[22] Based on
these points, our study aimed to introduce piperazine ring at the C22 of
These researches resulted in the discovery of tiamulin
2 and
valnemulin 3[10] which were approved as veterinary medicines in
1979 and 1999, respectively. Further studies led to the development
of azamulin 4 which aimed at human use. However, the phase I clinical
studies showed that the azamulin has poor bioavailability and serious
CYP450 inhibition.[11] Subsequently, retapamulin 5 was initiated by
GlaxoSmithKline and approved for treating human skin infections and
soft tissues infection in 2007, but low clinical efficacy was also
observed in the treatment of patients with secondarily infected open
wound (SIOW) infections caused by MRSA.[12] Recently, Nabriva
Therapeutics reported their efforts in developing lefamulin (BC-3781)
6 as the first pleuromutilin analogue for the treatment of systemic
bacterial skin infections.[13] At present, this compound has gone to the
stage of community-acquired bacterial pneumonia phase III clinical and
acute bacterial skin and skin structure infections (ABSSSI) phase II
clinical trials.[14,15]
However, a fact that should be acknowledged that like almost all
classes of antibiotics, pleuromutilin derivatives were smoothly used as
FIGURE 2 Approved drugs containing piperazine

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1,4-dioxane at room temperature overnight to give compound 11.
Next, HATU was employed to promote the condensation of the
resulting salt 11 with cinnamic acid derivatives in DMF to yield 13a–d
and 13f–x. The messy and low yield of the condensation of 2-
nitrocinnamic acid (12e) and 4-aminocinnamic acid (12y) with 11 urged
us to choose another route. The reduction of compound 12q using Fe
powder and HCOOH gave compound 12y in 26% yield. 12e and 12y
were condensed with 1-boc-piperazine followed by deprotection with
6 N HCl in 1,4-dioxane to provide 15e and 15y in 76.5 and 61.2% yield
for two steps, respectively. The hybridization of 15e and 15y with
compound 10 offered 13e and 13y.
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2.2 In vitro antibacterial activity assay
The pathogens inhibition assay was performed to evaluate the in vitro
anti-bacterial activity of all prepared compounds employing valnemu-
lin as the positive control. The minimum concentration (MIC) values
were revealed as the range of three different clinical isolates for each
bacterium.
FIGURE 3 Design scheme of target compounds
pleuromutilin as a linker and integrate cinnamic acid derivatives and
pleuromutilin to form hybrids (Figure 3) to investigate the anti-
bacterial activity of pleuromutilin derivatives.
Pleuromutilin/cinnamic acid hybrids containing both electron
withdrawing and donating groups were introduced to explore the SAR,
as shown in Table 1. The MICs data showed that compounds bearing
electron-donating groups, e.g., 4-CH3 (13r) or 4-OCH3 (13s), displayed
similar potency to compound 13a that was more effective against
methicillin sensitive bacteria than against methicillin-resistant patho-
gen. The presence of 4-OH in 13u and 4-NH2 in 13y substantially
increased in vitro activity against all strains compared with that of 13r
and 13s and even showed superior to that of valnemulin. The 4-Cl and
4-Br substituted derivatives, namely 13c and 13d, were slightly more
active than 13a but not as good as 13n (4-F) whose MICs ranged from
0.125 to 1 µg/mL. Surprisingly, 13q with strong electron-withdrawing
group 4-NO2 presented enhanced anti-bacterial activity compared to
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2
RESULTS AND DISCUSSION
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2.1 Synthesis
The synthesis of our target compounds is showed in Scheme 1. The
commercial available pleuromutilin 1 was reacted with p-toluene
sulfonylchloride (TsCl) using NaOH as the base to give 14-O-(p-
toluenesulfonyloxyacetyl) mutilin 10. Then compound 10 was reacted
with 1-boc-piperazine in the presence of K2CO3 and 2 mol% NaI in
acetonitrile. The obtained crude product was treated with 6 N HCl in
SCHEME 1 The synthesis of target compounds 13a–y. Reagents and conditions: (a) TsCl, NaOH, H2O, t-butyl methyl ether, reflux, 1 h; (b)
(i) K2CO3, 2 mol% NaI, CH3CN, 85°C, 4 h; (ii) HCl/1,4-dioxane, rt, 2 h; (c) HATU, Et3N, DMF, rt, 3 h. (d) HCl/1,4-dioxane, 45°C, overnight; (e)
Fe/HCOOH, 60°C, overnight

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TABLE 1 Antibacterial activity (MIC, µg/mL) of pleuromutilin derivatives containing cinnamic acid in vitro
MICa (µg/mL)
Compound
13a
MSSAb
0.5–1
0.25
MRSAb
2–4
MSSEb
0.25–2
0.5
MRSEb
4
PSSPb
1–2
0.5
PRSPb
4
E. coli
64
13b
0.25–0.5
0.5–1
1–2
1–2
1
1–4
2–4
1
>64
>64
>64
64
13c
0.5
0.5
1-2
13d
0.5
0.5–1
0.125–0.5
1–2
0.5–1
0.25
2
0.5
13e
0.0625
1–2
0.0625–0.25
2
0.25–1
1–4
0.5–1
1–2
1
0.25–1
2
13f
32
13g
0.125
0.5–1
0.5
0.25–0.5
0.5–1
0.5–1
1
0.25–0.5
1
0.25–1
1–2
2
1–2
4
64
13h
64
13i
1–2
2
64
13j
0.5
0.5
1
1
2
64
13k
0.25–1
0.125–0.5
0.125–0.25
0.25
0.5-2
0.25
1
0.5–1
0.5
2
32
13l
0.5–1
0.25
0.5
1–2
0.5
1–2
0.5–1
1
32
13m
13n
0.125–0.5
0.5
0.5–1
0.5
32
0.25–0.5
0.5–2
1–2
0.5–1
1
>64
32
13o
13p
0.25–0.5
0.5–1
0.0625
1–2
0.5–1
0.5
0.5
1–2
1–2
0.5–1
2
0.5–1
0.5
0.5
32
13q
0.125–1
1–4
0.125
0.5–2
1
0.5–1
0.5
32
13r
4
64
13s
2
2–4
2
1
1
64
13t
0.5
1–2
1
1–2
0.25–0.5
0.5–2
0.25–2
2–4
0.0625–1
0.5–2
0.5
1–4
0.25–2
2–8
2
32
13u
0.0625
0.25–0.5
0.125–1
1–2
0.125
0.25–1
0.5–1
1–4
0.125
0.5
0.25–1
1
16
13v
64
13w
13x
0.25–0.5
0.5–2
0.0625–0.125
0.125–0.5
1–2
0.25–2
0.25–0.5
0.25–1
64
4
32
13y
0.0625–0.125
0.0625
0.0625–1
0.25–0.5
0.25–1
0.5–1
32
Valnemulin
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aAbbreviations are as follows: MIC, minimum inhibitory concentration; MSSA, methicillin-sensitive Staphylococcus aureus, three strains; MRSA, methicillin-
resistant Staphylococcus aureus, three strains; MSSE, methicillin-sensitive Staphylococcus epidermidis, three strains; MRSE, methicillin-resistant
Staphylococcus epidermidis, three strains; PSSP, methicillin-sensitive Streptococcus pneumoniae, three strains; PRSP, penicillin-resistant Streptococcus
pneumoniae, three strains; E.coli, Escherichia coli.
bMIC values are obtained as the range of different strains of the same type. Single number represents the same MIC value for three different strains. Each
strain was repeated three times. All of the strains were isolated from the clinical bacteria in Chongqing Daping Hospital and reserved in Veterinary &
Veterinary Drug Research Institute, Chongqing Academy of Animal Sciences.
13n except for PSSP and PRSP, whereas the activity of the 4-CF3
substituted derivative 13t was lower than other 4-substituted
cinnamic acid derivatives embodying electron-withdrawing groups.
Identical trends were observed in 2-substituted cinnamic acid
derivatives. 13e with 2-NO2 presented the most strong potency against
MSSA, MRSA, MSSE, and MRSE, which showed two- to eightfold higher
activity than its 3-position regioisomer 13k. Compounds bearing
electron-withdrawing groups like 13b (2-F), 13c (2-Cl), and 13d (2-Br)
showed improved anti-bacterial activities in comparison with 13f
owning 2-CH3 but were less effective than 13g possessing 2-OCH3.
The investigation of 3-substituted cinnamic acid derivatives gave
different trends compared to other two kinds of substituted
derivatives. The electron-donating groups substituted compounds
such as 13l (3-CH3) and 13m (3-OCH3), inhibited the growth of tested
bacteria more effectively than those compounds with halogen (13h–
13j) as well as nitro (13k). The results indicate that the position of
substituent had a notable effluence on the activity.
The inspection of compounds 13v and 13w against the listed
strains showed that MICs of multi-halogen substitutions were equal or
close to that of single-halogen substitution (13v vs. 13b and 13p, 13w
vs. 13b and 13h). 13x bearing a CH3 substituent in the α-position of
cinnamic acid lowered a bit of activity compared to 13a.
The antibacterial activity against Gram-negative bacterium of
13a–y were also tested. 13u and valnemulin possessed the same

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the oxygen atom of carbonyl on C-21 interacted with residue G2044
exhibited another hydrogen bond. It was also found that the NO2 of
13e and the benzene ring of 13u had a π–π stacking with residue
A2045, respectively. The calculation showed that the binding energy
of 13e with ribosome was −7.09 kcal/mol while that of 13u reduced to
−7.19 kcal/mol.
The molecular docking of 13y bearing 4-NH2 displayed five
hydrogen bonds (Figure 7). Three hydrogen bonds were formed by the
interaction between OH and residue G2484 as well as carbonyl on C-
21 and residue G2044. The NH2 on the benzene ring formed other two
hydrogen bonds with the phosphate of C2420. The binding energy of
13y was −7.57 kcal/mol and lower than that of both 13e and 13u. The
docking result may explain why 13y exhibited better in vitro
antibacterial activity and suggested that the introduction of NH2 to
the C14 side chain would be an effective tactic for the design of
pleuromutilin derivatives.
FIGURE 4 Docking mode of tiamulin in the active site of 50s
ribosome subunit: blue indicates the conformation of tiamulin in the
crystal structure; yellow indicates the conformation after redock;
green indicates surrounded residue
The docking research of the positive control compound valne-
mulin was also made to compare its binding mode with that of above
docking compounds. The result showed valnemulin formed four
hydrogen bonds with the 50S ribosome subunit and rendered a similar
docking mode to that of 13y in general (Figure 8). The main difference
was that the amide of valnemulin formed one hydrogen bond with
C2046 residue and another hydrogen bond interaction was found
between the NH2 and U2564 residue. The calculated binding free
energy of valnemulin was −7.94 kcal/mol, being lower than that of 13e,
13u, and 13y. However, the in vitro antibacterial activity of valnemulin
was equal or even lower than that of these three compounds.
moderate potency against Escherichia coli (MIC = 16 µg/mL) while MIC
values of other compounds were more than 32 µg/mL. The testing
result showed that none of this class of compounds were effective
against E. coli, which were consistent with other pleuromutilin
derivatives.
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2.3 In silico molecular docking
Since their excellent anti-bacterial activity, compounds 13e, 13u, 13y
and valnemulin were selected to study molecular docking. The X-ray
structure of ribosome-tiamulin (PDB 1D: 1XBP) was employed to
construct the initial model (Figure 4). The docking method was
validated by the redock of tiamulin, with the root mean square
deviations (RMSD) of tiamulin in crystal structure relative to tiamulin in
the redock model being 0.35 Å, which confirmed the approach was
appropriate.
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2.4 In vivo efficacy of compounds 13e, 13u, and 13y
Due to their excellent activity in vitro against MRSA, the investigation
of the in vivo efficacy of compounds 13e, 13u, and 13y were also
conducted in a panel of mice infected by lethal S. aureus (MRSA), with
once daily intragastric (i.g.) administration with 40 mg/kg for 3
consecutive days. The results in Figure 9 show that compound 13u
and valnemulin displayed equivalent in vivo potency with 60% survival
while 13e and 13y provided the infectious mice with 30 and 40%
survival, respectively, though 13e and 13y exhibited superior
Specifically, 13e and 13u displayed the same interaction mode. As
shown in Figures 5 and 6, 13e and 13u were found to form two strong
hydrogen bonds with 50S ribosome. The interaction between the OH
on C-11 and the phosphate of G2484 formed one hydrogen bond and
FIGURE 5 Docking mode of 13e in the active site of the 50S ribosome subunit

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FIGURE 6 Docking mode of 13u in the active site of the 50S ribosome subunit
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effectiveness in vitro than both 13u and valnemulin. The ADME
properties as well as the better aqueous solubility and higher melt
point of compounds 13u and valnemulin would explain why they
proffered relative better efficacy in vivo than that of 13e and 13y.
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EXPERIMENTAL
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4.1 Chemistry
The synthesis route and conditions are described in the Supporting
Information, which also provides the spectroscopic characterization
and the original spectra of the synthesized compounds. The InChI
codes of the investigated compounds together with some biological
activity data are also provided as Supporting Information.
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CONCLUSIONS
In summary, a series of novel pleuromutilin derivatives bearing
cinnamic acid scaffold and piperazine have been reported. The
investigation of these prepared compounds against clinical bacteria
demonstrated that most of them owned moderate to good antibacte-
rial activity against Gram-positive bacteria. The SAR study revealed
that halogen substitution in the 2-position of cinnamic acid had the
same activity as the 3-position and 4-postion regioisomers while
compounds with OCH3 and CH3 at the 3-position were more active
than other two position regioisomers, especially against MSSA and
MRSA. Pleuromutilin modifications embracing 2-NO2 or 4-NO2
substitutions both exhibited approximate fourfold compared to 3-
NO2 substituted compounds. The MIC values of 13y were less than
that of valnemulin and the excellent in vivo potency of 13u indicates
that 13y and 13u could be researched deeply in future to find a hit and
a promising lead compound for the development of new antibacterial
agents.
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4.2 Minimum inhibition concentration testing
The minimum inhibitory concentrations (MICs) of target compounds
against bacteria were determined by an agar dilution method in
accordance with the methods of the National Committee for Clinical
Laboratory Standards (NCCLS) and valnemulin was employed as the
positive control. Target compounds were dissolved in 30% aqueous
solution of DMSO to prepare stock solutions with an initial
concentration of 640 µg/mL. A series of twofold dilutions were
prepared from the stock solutions using sterile water followed by a 10-
fold dilution with Muller–Hinton (MH) agar medium to provide
concentrations ranging from 64 to 0.05 µg/mL. MH broth was
employed to culture the tested organisms at 37°C for 12 h, which
were detected via OD values to adjust their concentrations to 106
FIGURE 7 Docking mode of 13u in the active site of the 50S ribosome subunit

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FIGURE 8 Docking mode of valnemulin in the active site of the 50S ribosome subunit
CFU/mL. The bacterial suspensions were inoculated onto the 96-well
plates filled with varying concentrations of drugs which were 64, 32,
16, 8, 4, 2, 1, 0.5, 0.25, 0.125 µg/mL from well 1 to well 10 using a
multipoint inoculator and incubated at 37°C for 24 h. Each well
contained 100 µL bacterial suspension and 100 µL compound solu-
tion. Each concentration of testing compounds embraced three
parallels for each bacterium.
removed. Addition of hydrogens, merger of nonpolar hydrogens to the
atom to which they were attached. The PTC model was established
comprising residues within a spherical cut of 10 Å around the PTC
binding site of 1XBP. Molecular docking was implemented by
AutoDock 4.2.6 program.[25] The docking sites were determined
according to tiamulin in 1XBP and the specific parameters were listed
below: the coordinates of the center point of the interface pocket were
(55.425, 124.162, 113.592) and the number of grid points was
60 × 60 × 60 as well as the grid spacing was 0.375 Å. The lattice energy
of the interface pocket area was calculated by AutoGrid program. The
conformation search strategy adopted the Lamarckian genetic
algorithm (LGA) and the key parameters were as follows: number of
GA Runs was set to be 100 and the maximum number of evaluations
was 25000000, and the rest parameters used default values. PyMOL
was employed to achieve docking visualization. The molecular docking
results were optimized 1000 steps using the Amber force field in
Chimera.
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4.3 Molecular docking
The energy minimization was performed in the GAFF force field to
optimize the docking compounds using AmberTools 14, with the
steepest descent method to optimize 2000 steps followed using the
conjugate gradient method to optimize 1000 steps furtherly. The
AM1-BCC charge was added to the optimized structures and finally
stored as a mol2 file for subsequent docking.
AutoDockTools 1.5.6[23] was used to prepare the peptidyl
transferase center (PTC) mode based on the crystal structure of
Deinococcus radiodurans in complex with tiamulin (PDB ID:1XBP).[24]
Co-crystallized ligands and crystallographic water molecules were
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4.4 MRSA infection model
4.4.1 Clinical isolate of MRSA
Kunming mice (female, Chongqing Tengxin Bill Experimental
Animal Sales Co. Ltd.) weighing 22 2 g were treated with neutropenic
for intraperitoneal treatment with 150 mg/kg cyclophosphamide
4 days before infection and with 100 mg/kg 1 day prior to infection.
The neutropenic mice were treated with 0.5 mL bacterium suspension
via intraperitoneal injection. One hour after infection, the infected
mice were conducted intragastric administration with the test
compounds 13e, 13u, 13y and valnemulin at doses of 40 mg/kg for
3 consecutive days.The protocol for this study was reviewed and
approved by Chongqing Academy of Animal Sciences.
ACKNOWLEDGMENTS
This work was supported by Chongqing Basic Scientific Research
Project (No. 16438) and Chongqing Agricultural Development Fund
(No. 17412).
FIGURE 9 Efficacy of compounds 13e, 13u, 13y and valnemulin
in the mouse systemic infection model

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CONFLICT OF INTEREST
[13] W. T. Prince, Z. Ivezic-Schoenfeld, C. Lell, K. J. Tack, R. Novak, F.
Obermayr, G. H. Talbota, Antimicrob. Agents Chemother. 2013, 57,
2087.
The authors have declared no conflict of interest.
[14] S. Paukner, R. Riedl, Cold Spring Harb. Perspect. Med. 2017, 7,
a027110.
ORCID
[15] Lefamulin Evaluation Against Pneumonia (LEAP 2) Phase 3 Topline
Results, https://investors.nabriva.com/static-files/5c34b447-99cc-
4739-b9d6-d4ea4c7d13b9, accessed 2018/10/26.
[16] M. A. Grady, T. L. Gasperoni, P. Kirkpatrick, Drug Discov. 2003, 2, 427.
[17] J. Heeres, L. J. J. Backx, J. H. Mostmans, J. Van Cutsem, J. Med. Chem.
1979, 22, 1003.
Cheng-hong Li
http://orcid.org/0000-0002-5621-4409
[18] Y. Wang, W. K. Law, J. S. Hu, H. Q. Lin, T. M. Ip, D. C. C. Wan, J. Chem.
Inf. Model. 2014, 54, 3046.
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