Synthesis and antibacterial activities of pleuromutilin derivatives with thiazole-5-carboxamide and thioether moiety

Article abstract of DOI:10.3184/174751911X13057375208346

Seven novel pleuromutilin derivatives with thiazole-5-carboxamide and thioether moiety in the C₁₄ side chain were designed and synthesised. The antibacterial activities of the target compounds were tested via agar-well diffusion method in vitro. The results showed that three target compounds still had antibacterial activity against Staphylococcus aureus ATCC26112 and Staphylococcus aureus SC at a low concentration of 0.05 μg mL^-1.

Full text of DOI:10.3184/174751911X13057375208346

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 313
MAY, 313–316
Synthesis and antibacterial activities of pleuromutilin deriv-
atives with thiazole-5-carboxamide and thioether moiety
Liang Wanga, Fu-ying Daib, Jie Zhub, Kui-kui Donga, Yu-liang Wanga* and Tian Chenb
aFaculty of Chemistry, Sichuan University, Chengdu 610065, P. R. China
bDepartment of Pathogenic Biology, Chengdu Medical College, Chengdu 610083, P. R. China
Seven novel pleuromutilin derivatives with thiazole-5-carboxamide and thioether moiety in the C14 side chain were
designed and synthesised. The antibacterial activities of the target compounds were tested via agar-well diffusion
method in vitro. The results showed that three target compounds still had antibacterial activity against Staphylococ-
cus aureus ATCC26112 and Staphylococcus aureus SC at a low concentration of 0.05 µg mL−1.
Keywords: pleuromutilins, antibacterial activity, Gram-positive bacteria, agar-well diffusion
Pleuromutilin(Fig. 1, 1), a naturally occurring antibiotic, was
first isolated in 1951 by Kavanagh and co-workers from
several species of basidiomycetes including Pleurotus mutilus,
Pleurotus passeckerianus, and Drosophilia substrata.1,2 Early
research showed that this kind of antibiotic has modest activity
against Gram-positive pathogens and /or mycoplasmas in vitro
but weak in vivo while it is not sensitive to Gram-negative
pathogens.3,4 Pleuromutilin inhibits the formation of bacterial
protein through interaction with prokaryotic ribosomes and
does not bind to mammalian ribosomes.5 During the 1970s and
early 1980s, a Sandoz group synthesised a series of pleuromu-
tilin derivatives, and indicated that the modification of the C14
glycolic acid chain would offer better opportunities to obtain
pleuromutilin derivatives with optimum activity, and the
combinations of both the thioether group and the matrix moiety
(pleuromutilin) gave excellent bioactivity.6 Based on these
structure–activity relationships (SARs), large numbers of pleu-
romutilin derivatives had been designed and synthesised.7–15
As a result, tiamulin (Fig. 1, 2)7 and valnemulin (Fig. 1, 3)8
were developed as therapeutic agents for veterinary medicine
to treat diseases in pigs and poultry.9 Aiming at finding an
agent for human use by further chemical modifications of
pleuromutilin produced azamulin (Fig. 1, 4),10 which had good
antibacterial activity but was subject to its poor solubility in
Experimental
Melting points were recorded on XRC-1 melting point apparatus
(Sichuan University Instrument Inc., Chengdu, China) without being
1
corrected. H NMR spectra were run on a Varian INOVA-400 spec-
trometer (Varian Inc., Palo Alto, CA, USA) with CDCl3 as the solvent
and TMS as the internal standard. Mass spectra were recorded with
Agilent 6210 (DOF-MAS) spectrometer (Agilent Inc., Santa Clara,
CA, USA) using the electrospray ionisation (ESI) method. IR spectra
were recorded with Perkin-Elmer 16PC-FT instrument (Perkin-Elmer
Inc., Norwalk Conn, CA, USA). Compounds 3a, and 3b were com-
mercially available, compounds 4 and 5 were synthesised according to
the literature18 and compound 7 was synthesised according to the
literature.17
Synthesis of compounds 2c–g
SOCl2 (0.2 mol, 23.8 g) was added to a substituted benzoic acid
(0.020 mol) and the reaction mixture was refluxed for 2 h. After
removal of the excess SOCl2 under reduced pressure, the resulting
residue was cooled to room temperature and poured into a mixture of
NH3·H2O (0.8 mol) and ice. The white solid which formed was washed
with 2N NaOH to give a crude amide; yields: 62–69%.
Synthesis of compounds 3c–g
Phosphoric sulfide (2.0 mmol) was added portionwise to a solution of
a substituted amide 2 (5.0 mmol) in ethyl ether at 0 °C, the solution
was stirred at room temperature overnight and then the solid was
filtered off and the solvent was removed under reduced pressure to
give a yellow solid; yields: 87–95%.
11
water. Later, researchers at GlaxoSmithKline reported the
novel pleuromutilin analogue retapamulin (Fig. 1, 5), which
exhibited excellent antibacterial activity in vitro and therefore
was applied as a topical antimicrobial agent for treatment
of human skin infections in 2007.12,13 Recently, Yoshimi
Hirokawa and co-workers designed and synthesised novel
thioether pleuromutilin derivatives (Fig. 1, 6) bearing a
purine ring at the C14 glycolic side chain. These pleuromutilin
analogues showed good solubility in water and excellent
antibacterial activity in vitro and in vivo. 13
Synthesis of compounds 5
Anhydrous magnesium sulfate (10.0 mmol) and ethyl 2-chloro-2-
formylacetate 4 (10.0 mmol) were added to a solution of a substituted
thioamide 3 (5.0 mmol) in toluene, the reaction mixture was stirred
at 100 °C for 2 h, then cooled to room temperature and filtered. The
solvent was removed under reduced pressure and the resulting residue
waspurifiedbychromatography(petroleumether/ethylacetate = 10:1)
to provide the desired compound as a brown oil; yields: 41–48%.
In our previous research, some pleuromutilin derivatives
containing substituent pyrazole rings (Fig. 1, 7)16 and phenyl
rings (Fig. 1, 8)17 binding to a carboxamide at the C14 side
chain were reported and it was found that the pleuromutilin
derivatives with a substituent heterocyclic carboxamide
exhibited excellent activity while derivatives with the substitu-
ent benzamide showed low activity. Here, for the purpose of
exploiting new antibacterial agents with high activity, a series
of novel pleuromutilin derivatives containing a substituent
thiazole ring and a thioether group at the C14 position in the
side chain have been designed and synthesised, and the
antibacterial activities of the target compounds have been
tested via the agar-well diffusion method in vitro. The results
showed that three target compounds had excellent antibacterial
activity against Staphylococcus aureus ATCC26112 and
Staphylococcus aureus SC.
Synthesis of compounds 619
The purified ester 7 (1.5 mmol) was refluxed for 1.5 h with sodium
hydroxide (4.0 equiv.), water (10 mL) and ethanol (20 mL), the result-
ing residue was dissolved in water (30 mL), after removal of the
solvent under reduced pressure, extracted with ethyl acetate
(10 mL×3), the water layer acidified to pH = 2–3 with 6N HCl,
extracted with ethyl acetate again (10 mL×3) and the organic layer
was evaporated in vacuo to afford a yellow solid; yields: 83–92%.
Synthesis of target molecules 8
SOCl2 (0.2 mol, 23.8 g) was added to the thiazole acid 6 (2.0 mmol),
the solution was heated to reflux whilst the temperature was main-
tained for 1.5 h, then the solution was cooled to room temperature.
After removal of the excess SOCl2 under reduced pressure, CH2Cl2
(25 mL) was added to the resulting residue at 0 °C, followed by
triethylamine (2.0 mmol). When the solution became clear, a catalytic
amount of pyridine (0.20 mmol) and compound 7 (1.80 mmol, 0.84 g)
were added at 0 °C respectively. The reaction mixture was allowed to
stir at room temperature for 1 h, more CH2Cl2 (25 mL) was added
to the mixture, which was washed with saturated sodium chloride
* Correspondent. E-mail: chemwang2000@163.com

314 JOURNAL OF CHEMICAL RESEARCH 2011
Fig. 1 Structures of pleuromutilin and pleuromutilin derivatives.
(10 mL×3) and water(10 mL×3), dried with anhydrous Na2SO4 over-
night and filtered. The CH2Cl2 layer was evaporated under reduced
pressure and the resulting residue was chromatographed on silica gel
(petroleum ester/ethyl acetate = 2:1) to give the target molecule;
yields: 71–80%.
cm−1) 3437, 3079, 2959, 2929, 1728, 1646, 1542, 1455, 1377, 1284,
1117, 1022, 982, 946, 916, 874, 803, 610, 402. HR-MS (ESI): Calcd
for C31H46N2O5S2 (M+H+): 591.2927. Found: 591.2927.
Mutilin 14-O-[1-(2-phenylthiazole carboxamide)-2-methylpropane-
1
2-yl] thioacetate (8c): Yellow solid; yield: 80%; m.p. 91–93 °C; H
Mutilin 14-O-[1-thiazole carboxamide-2-methylpropane-2-yl]
thioacetate (8a): Yellow solid; yield: 75%; m.p. 82–84 °C; H NMR
NMR spectrum (400 MHz; d1-CDCl3; TMS): δ (p.p.m.) = 0.74 (3H, d,
J = 6.8 Hz), 0.88 (3H, d, J = 6.8 Hz), 1.10–1.14 (1H, m), 1.17 (3H, s),
1.31 (3H, s), 1.33 (3H, s), 1.38–1.44 (2H, m), 1.47 (3H, s), 1.52–1.55
(1H, m), 1.61–1.70 (2H, m), 1.76–1.80 (1H, m), 2.05–2.20 (3H, m),
2.22–2.34 (3H, m), 3.17–3.31 (3H, m), 3.35 (1H, d, J = 6.4 Hz), 3.46–
3.51 (1H, m), 5.18 (1H, dd, J1 = 17.6 Hz, J2 = 1.2 Hz), 5.26 (1H, d,
J = 11.2 Hz), 5.77 (1H, d, J = 8.4 Hz), 6.48 (1H, dd, J1 = 17.6 Hz,
J2 = 10.8 Hz), 7.48–7.50 (3H, m), 7.77 (1H, s), 8.01–8.04 (2H, m),
8.41 (1H, s). IR (KBr, cm−1) 3439, 3082, 2929, 2860, 1728, 1649,
1544, 1455, 1416, 1380, 1286, 1147, 1118, 1021, 979, 916, 766, 691,
640. HR-MS (ESI): Calcd for C36H48N2O5S2 (M+H+): 653.3084.
Found: 653.3087.
1
spectrum (400 MHz; d1-CDCl3; TMS): δ (p.p.m.) = 0.73 (3H, d, J =
6.8 Hz), 0.89 (3H, d, J = 6.8 Hz), 1.10–1.15 (1H, m), 1.17 (3H, s),
1.31 (3H, s), 1.33 (3H, s), 1.37–1.43 (2H, m), 1.47 (3H, s), 1.53–1.56
(1H, m), 1.62–1.70 (2H, m), 1.77–1.80 (1H, m), 2.05–2.20 (3H, m),
2.22–2.33 (3H, m), 3.16–3.30 (3H, m), 3.36 (1H, d, J = 6.4 Hz), 3.42–
3.48 (1H, m), 5.17 (1H, d, J = 17.6 Hz), 5.22 (1H, d, J = 10.8 Hz),
5.75 (1H, d, J = 8.8 Hz), 6.46 (1H, dd, J1 = 17.2 Hz, J2 = 10.8 Hz),
7.97 (1H, s), 8.45 (1H, s), 8.94 (1H, s). IR (KBr, cm−1) 3442, 3083,
2930, 2860, 1727, 1651, 1545, 1459, 1414, 1379, 1286, 1145, 1118,
1020, 982, 917, 881, 812, 609. HR-MS (ESI): Calcd for C30H44N2O5S2
(M+H+): 577.2771. Found: 577.2763.
Mutilin 14-O-[1-(2-p-tolylthiazole carboxamide)-2-methylpropane-
1
Mutilin 14-O-[1-(2-methylthiazole carboxamide)-2-methylpropane-
2-yl] thioacetate (8d): Yellow solid, yield: 79%, m.p. 96–98 °C; H
1
2-yl] thioacetate (8b): Yellow solid; yield: 73%; m.p. 72–73 °C; H
NMR spectrum (400 MHz; d1-CDCl3; TMS): δ (p.p.m.) = 0.74 (3H, d,
J = 6.8 Hz), 0.88 (3H, d, J = 6.8 Hz), 1.10–1.14 (1H, m), 1.17 (3H, s),
1.31 (3H, s), 1.33 (3H, s), 1.36–1.43 (2H, m), 1.47 (3H,s), 1.51–1.55
(1H, m), 1.61–1.70 (2H, m), 1.77–1.80 (1H, m), 2.05–2.17 (3H, m),
2.18–2.27 (3H, m), 2.42 (3H, s), 3.17–3.30 (3H, m), 3.35 (1H, d,
J = 6.4 Hz), 3.45–3.51 (1H, m), 5.18 (1H, d, J1 = 17.6 Hz), 5.26 (1H,
d, J = 11.2 Hz), 5.77 (1H, d, J = 8.4 Hz), 6.48 (1H, dd, J1 = 17.2 Hz,
J2 = 10.8 Hz), 7.28 (2H, d, J = 10.0 Hz), 7.67 (1H, s), 7.90 (2H, d,
NMR spectrum (400 MHz; d1-CDCl3; TMS): δ (p.p.m.) = 0.73 (3H, d,
J = 6.8 Hz), 0.89 (3H, d, J = 7.2 Hz), 1.10–1.15 (1H, m), 1.17 (3H, s),
1.29 (3H, s), 1.31 (3H, s), 1.37–1.44(2H, m), 1.46(3H,s), 1.53–1.57
(1H, m), 1.62–1.68 (2H, m), 1.76–1.80 (1H, m), 2.05–2.20 (3H, m),
2.22–2.35 (3H, m), 2.76 (3H, s), 3.15–3.29 (3H, m), 3.36 (1H, d,
J = 6.8 Hz), 3.41–3.46 (1H, m), 5.15–5.24 (2H, m), 5.76 (1H, d,
J = 8.4 Hz), 6.42–6.49 (1H, m), 7.57 (1H, s), 8.16 (1H, s). IR (KBr,

JOURNAL OF CHEMICAL RESEARCH 2011 315
Scheme 1 The synthetic route to compound 8a–g.
J = 8.0 Hz), 8.37 (1H,s). IR (KBr, cm−1) 3431, 3079, 2928, 2866,
1729, 1650, 1540, 1498, 1458, 1426, 1286, 1148, 1118, 1019, 980,
916, 819, 747, 640, 588, 482. HR-MS (ESI): Calcd for C37H50N2O5S2
(M+H+): 667.3240. Found: 667.3242.
1117, 1028, 980, 917, 836, 801, 605. HR-MS (ESI): Calcd for
C37H50N2O6S2 (M+H+): 683.3189. Found: 683.3193.
Mutilin 14-O-[1-(2-(3, 5-dimethoxyphenyl) thiazole carboxamide)
-2-methylpropane- 2-yl] thioacetate (8g):White solid, yield: 71%,
m.p. 87–90 °C; 1H NMR spectrum (400 MHz; d1-CDCl3; TMS):
δ (p.p.m.) 0.73 = (3H, d, J = 7.2 Hz), 0.88 (3H, d, J = 7.2 Hz), 1.10–
1.15 (1H, m), 1.16 (3H, s), 1.32 (3H, s), 1.34 (3H, s), 1.37–1.43 (2H,
m), 1.47 (3H, s), 1.51–1.55 (1H, m), 1.61–1.70 (2H, m), 1.76–1.80
(1H, m), 2.05–2.17 (3H, m), 2.22–2.34 (3H, m), 3.17–3.30 (2H, m),
3.35 (1H, d, J = 6.4 Hz), 3.45–3.53 (1H,m), 3.92 (6H, d, J = 7.2 Hz),
5.17 (1H, d, J = 17.6 Hz), 5.22 (1H, d, J = 11.2 Hz), 5.77 (1H, d,
J = 8.4 Hz), 6.47(1H, m ), 6.65 (1H, s), 7.50 (1H, s), 7.76 (1H, s), 8.46
(1H, s). IR (KBr, cm−1) 3435, 3084, 2924, 2854, 1729, 1650, 1597,
1539, 1460, 1407, 1288, 1205, 1156, 1118, 1064, 1020. 983, 920, 818,
683, 587, 482, 405. HR-MS (ESI): Calcd for C38H52N2O7S2 (M-H+):
711.3137. Found: 711.3145.
Mutilin 14-O-[1-(2-m-tolylthiazole carboxamide)-2-methylpro-
pane-2-yl] thioacetate (8e): Yellow solid, yield:75%; m.p. 87–88 °C;
1H NMR spectrum (400 MHz; d1-CDCl3; TMS): δ (p.p.m.) 0.74 = (3H,
d, J = 6.8 Hz), 0.88 (3H, d, J = 6.8 Hz), 1.10–1.14 (1H, m), 1.17 (3H,
s), 1.32 (3H, s), 1.34 (3H, s), 1.37–1.43 (2H, m), 1.47 (3H, s), 1.51–
1.55 (1H, m), 1.61–1.70 (2H, m), 1.76–1.80 (1H, m), 2.05–2.17 (3H,
m), 2.19–2.34 (3H, m), 2.44 (3H, s), 3.17–3.31 (3H, m), 3.35 (1H, d,
J = 6.4 Hz), 3.46–3.51 (1H, m), 5.18 (1H, d, J = 17.6 Hz), 5.26 (1H,
d, J = 11.2 Hz), 5.77 (1H, d, J = 8.4 Hz), 6.48 (1H, dd, J1 = 17.2 Hz,
J2 = 10.8 Hz), 7.31 (1H, d, J = 7.2 Hz), 7.37 (1H, t, J = 7.6 Hz), 7.72
(1H, s), 7.81 (1H, d, J = 7.6 Hz), 7.85 (1H, s), 8.40 (1H, s). IR (KBr,
cm−1) 3431, 2929, 2867, 1728, 1650, 1541, 1458, 1418, 1388, 1287,
1147, 1118, 1019, 982, 916, 790, 692, 648, 586. HR-MS (ESI): Calcd
for C37H50N2O5S2 (M-H+): 665.3082. Found: 665.3095.
Biological assay
Mutilin 14-O-[1-(2-(4-methoxyphenyl) thiazole carboxamide)-2-
methylpropane-2-yl] thioacetate (8f): White solid, yield: 78%; m.p.
93–94 °C; 1H NMR spectrum (400 MHz; d1-CDCl3; TMS): δ (p.p.m.)
0.74 = (3H, d, J = 6.8 Hz), 0.88 (3H, d, J = 6.8 Hz), 1.10–1.14 (1H,
m), 1.17 (3H, s), 1.31 (3H, s), 1.33 (3H, s),1.36–1.43 (2H, m), 1.47
(3H, s), 1.51–1.55 (1H, m), 1.61–1.70 (2H, m), 1.76–1.80 (1H, m),
2.05–2.17 (3H, m), 2.18–2.34 (3H, m), 3.17–3.30 (3H, m), 3.35 (1H,
d, J = 6.4 Hz), 3.45–3.51 (1H, m), 3.88 (3H, s), 5.18 (1H, d,
J = 17.6 Hz), 5.26 (1H, d, J = 11.2 Hz), 5.76 (1H, d, J = 8.4 Hz), 6.47
(1H, dd, J1 = 17.2 Hz, J2 = 10.8 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.67
(1H, s), 7.96 (2H, d, J = 8.8 Hz), 8.33(1H, s) IR (KBr, cm−1) 3431,
3079, 2931, 2860, 1728, 1647, 1539, 1459, 1410, 1299, 1256, 1149,
Two pathogenic bacterial strains were used in the studies: wild
Staphylcoccus aureus SC and standard Staphylcoccus aureus
ATCC26112. The wild Staphylcoccus aureus SC were isolated from
Sichuan Province in China. The standard Staphylcoccus aureus
ATCC26112 were obtained from the Basic Medical and Forensic
College Sichuan University. McF was used to evaluate the bacteria
count and 0.5 McF (amount of bacteria: about 1.5 × 108 colony-
forming unit (cfu)/mL) was formulated according to the conditions:
0.048 M BaCl2 0.5 mL, 0.36 N H2SO4 99.5 mL.
The antibacterial activities of the target compounds in vitro were
tested via an agar-well diffusion method20,21
.

316 JOURNAL OF CHEMICAL RESEARCH 2011
1. Preparation of bacteria solution: The Staphylococcus aureus
ATCC26112 and Staphylococcus aureus SC were inoculated in LB
(Luria Bertani) culture medium respectively and then kept at 37 °C for
18 h after they were both recovered. Later, the bacteria solution was
corrected to 0.5 McF (amount of bacteria: about 108 colony-forming
units (cfu)/mL) with saline.
Table 2 The antibacterial activity of the target compounds
(8a–c) at different concentrations towards S. aureus ATCC26112
and S. aureus SC (isolated from Sichuan, China)
Diameter of inhibition zone (mm)
S. aureus ATCC26112
2* 1* 0.5* 0.2* 0.05*
19 18 12 12 10
S. aureus SC
2. Dispensing of drugs: Every sample (1000 µg) was dissolved with
ethanol (1 mL) and diluted to 5 µg mL−1 with ethanol in a super clean
bench; Later, 8a, 8b and 8c were diluted to 2 µg mL−1, 1 µg mL−1,
0.5 µg mL−1, 0.2 µg mL−1 and 0.05 µg mL−1 for further testing.
3. Antibacterial activity testing: The LB culture medium (with
2.2% agar) was calmed down at about 55 °C after sterilisation by
autoclave. 1 mL of bacterial solution (0.5 McF) was added into the
LB culture medium (100 mL) [the amount of bacteria: about 106
colony-forming units (cfu/mL)], and the resulting mixture was shaken
up until it was well-distributed, then the mixture was poured into three
plates (20 mL for each). Five wells (6 mm) were made in each
plate using a sterile cork borer when the mixture became curdled.
A 50 µL solution of each compound (target compounds or reference
compounds) were injected into the corresponding well and then the
plates were incubated at 37 °C for 24 h.
Compound
2* 1* 0.5* 0.2* 0.05*
8a
21 19 16 15 13
17 15 14 15 12
17 15 14 15 12
8b
18 14 10
15 13 10
8
8
6
10
10
6
8c
Pleuromutilin
6
6
6
7
7
7
7
7
Diameter of the wells in each plate: 6 mm.
*Different concentrations of the compounds.
Pictures of the inhibition zone are available in the Electronic
Supplementary Information.
designed and synthesised. The antibacterial activity results
indicated that three target compounds displayed excellent
activity against S. aureus ATCC26112 and S. aureus SC at the
concentration of 0.05 µg mL−1. This exploration has further
proved the SAR of pleuromutilin derivatives we put forward,
showing that the heterocyclic carboxamide group was essen-
tial to enhance bioactivity with a thioether moiety in the
C14 side chain of pleuromutilin.15 It will be helpful for us in
designing more potent pleuromutilin derivatives.
Results and discussion
Since pleuromutilin has modest activity against Gram-positive
bacteria while it lacks activity against Gram-negative bacteria,
two Gram-positive bacteria, S. aureus ATCC26112 and
S. aureus SC were chosen to test the antibacterial activities of
the target compounds. The results showed that all the target
compounds exhibited better antibacterial activity than pleuro-
mutilin at the concentration of 5 µg mL−1 and therefore, three
target compounds (8a, 8b, 8c) were chosen to test the antibac-
terial activity again at another five concentrations (2 µg mL−1,
1 µg mL−1, 0.5 µg mL−1, 0.2 µg mL−1 and 0.05 µg mL−1). These
three chosen compounds displayed good antibacterial activity
even if they were diluted to 0.05 µg mL−1.
We appreciate the financial support from the National Science
Foundation of China (No. 21072135), the antibacterial activity
test by Jie Zhu who is a 2008 grade student in the School of
1
Biomedical Science of Chengdu Medical College and the H
NMR analysis by Sichuan University Analytical and Testing
Center.
It can be seen from the tables that S. aureus SC was more
sensitive than S. aureus ATCC26112 to the target compounds
and the target compounds without the substituent phenyl ring
binding to the thiazole ring (8a, 8b) exhibited better biological
activity than the compounds with a substituent phenyl ring
(8d, 8e, 8f, 8g).
Received 22 February 2011; accepted 18 April 2011
Paper 1100584 doi: 10.3184/174751911X13057375208346
Published online: 1 June 2011
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Table 1 The antibacterial activity of the target compounds
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Compound
Diameter of inhibition zone/mm
S. aureus ATCC26112
S. aureus SC
8a
28
19
18
13
13
14
11
12
6
30
26
17
16
14
15
12
13
6
8b
8c
8d
8e
8f
8g
Pleuromutilin
Ethanol
Concentration of pleuromutilin: 5.0 µg mL−1; negative control:
ethanol; positive control: pleuromutilin; diameter of the well in
each plate: 6 mm.
20 J.O. Moody, O.A. Adebiyi and B.A. Adeniyi, J. Ethnopharmacol., 2004,
92, 57.
21 S.Y. Zheng, Q.H. Liu and G.Q. Zhang, Acta Biochim. Pol., 2010, 57, 43.

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