Synthesis of platensimycin analogues and their antibiotic potency

Article abstract of DOI:10.1002/ardp.200700177

Platensimycin is a natural product isolated from various strains of Streptomyces platensis which exhibits antimicrobial activity against Gram positive bacteria, including vancomycin- and linezolide-resistant species. Analogues of platensimycin were synthesized from 3-aminobenzoic acid or other aniline derivatives and several alkyl- and aryl-carboxylic acids. The resulting compounds were tested in an agar diffusion assay against several bacteria and fungi.

Full text of DOI:10.1002/ardp.200700177

386
Arch. Pharm. Chem. Life Sci. 2008, 341, 386–392
Full Paper
Synthesis of Platensimycin Analogues and Their Antibiotic
Potency
Jꢀrgen Krauss, Veronika Knorr, Vera Manhardt, Stefanie Scheffels, and Franz Bracher
Pharmaceutical Chemistry, Department of Pharmacy – Center of Drug Research, LMU Munich, Munich,
Germany
Platensimycin is a natural product isolated from various strains of Streptomyces platensis which
exhibits antimicrobial activity against Gram positive bacteria, including vancomycin- and linezo-
lide-resistant species. Analogues of platensimycin were synthesized from 3-aminobenzoic acid or
other aniline derivatives and several alkyl- and aryl-carboxylic acids. The resulting compounds
were tested in an agar diffusion assay against several bacteria and fungi.
Keywords: Antibiotics / Natural products / Platensimycin /
Received: August 22, 2007; accepted: January 18, 2008
DOI 10.1002/ardp.200700177
cytotoxicity against human cell lines so far [1, 2]. In 2006,
Introduction
Nicolaou et al. developed the first total synthesis of the
compound in more than fifteen steps [3]. Nicolaou et al.
also published the synthesis and antimicrobial evalua-
tion of the platensimycin derivative adamanta platensi-
mycin in 2007 [4]. Thus, it is of great interest to find deriv-
atives which show equal or even higher antibiotic activ-
ity while being easier to synthesize. Recently, Singh et al.
reported on the chemistry of platensimycin and the syn-
thesis of various derivatives of this compound [5].
Platensimycin (Fig. 1) was isolated in 2006 by Wang et. al.
from a culture of Streptomyces platensis. The compound
showed significant antibiotic activity especially against
Gram positive species (MIC 0.5–1.0 lg/mL). The mecha-
nism of action is the inhibition of the bacterial FabF/B
enzyme complex which results in an impaired fatty acid
synthesis. As this is a completely new target, the sub-
stance showed no cross resistance with other antibiotics.
Moreover, platensimycin did not show any significant
Results and discussion
Chemistry
The core of platensimycin is the hydroxy anilide struc-
ture. Therefore, the first series of analogues was prepared
from 3-amino benzoic acid 1a and several alkyl- or aryl-
carboxylic acid chlorides 2 to give the resulting anilides 3
(Scheme 1). Chlorides which were not commercially
available were prepared from the corresponding acids
with oxalyl chloride or thionyl chloride.
In a second series, 3-fluoro aniline 1b, aniline 1c, and 3-
hydroxy aniline 1d were reacted with the same carbonic
acid chlorides 2 to give the resulting anilides 3
(Scheme 1).
In a third series (Scheme 2), 3-amino benzoic acid was
esterified either with methanol or ethanol in the pres-
ence of sulphuric acid or with benzyl alcohol using the
Figure 1. Chemical structure of platensimycin.
Correspondence: Jꢀrgen Krauss, Pharmaceutical Chemistry, Depart-
ment of Pharmacy
– Center of Drug Research, LMU Munich, Bute-
nandtstr. 5-13, D-81377 Mꢀnchen, Germany.
E-mail: hjkra@cup.uni-muenchen.de
Fax: +49 89 2180-77171
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2008, 341, 386–392
Platensimycin Analogues and Their Antibiotic Potency
387
Scheme 1. Synthesis of carbonic anilides and fluoro anilides 1a–d, 2a–h, and 3a–p.
Scheme 2. Synthesis of the esters 4a–c, 5b, and 5c.
Scheme 3. Synthesis route of the hydroxy amino benzoic acids.
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Table 1. Agar diffusion assay.
Compound
E. coli
Pseudomonas
antimicrobial equorum
Staphylococcus Streptococcus Yarrowia
Aspergillus
niger
Candia
glabrata
Hypopichia
burtonii
entericus
lipolytica
DSM
1b
3a
3b
3c
3d
3e
3f
426
0
8
11
0
nt
0
8
16
0
nt
0
8361
0
11
0
13 (GI)
nt
12
15
8
20675
0
11
0
11
nt
10
12
7
6
nt
0
14446
0
0
0
0
nt
9
9
6
0
nt
0
1345
0
0
0
0
nt
0
8
0
0
1988
0
0
0
0
nt
0
0
0
0
11226
0
0
0
0
nt
12
14
0
0
nt
0
70663
0
0
0
0
nt
0
0
0
0
3g
3h
3i
0
nt
0
nt
0
nt
0
nt
0
3j
3k
3l
0
0
0
0
0
0
0
0
0
8
0
0
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 [10 GI]
0 [14 GI]
0 [20 GI]
10
0
12
0
0
7 [10]
0
10
20
0
0
0
0
3m
3n
3o
3p
4a
4b
4c
28 (GI)
8 [10]
10
0
10
0
10 GI [12]
10
0
0
0
0
7
0
0
0
0
5b
5c
0
0
7
0
0
0
0
0
0
0
0
0
0
0
0
0
6a
6b
7a
7b
0
0
nt
0
0
0
0
0
0
nt
0
0
0
nt
0
32
0
0
0
nt
0
0
0
nt
0
0
0
nt
0
14
nt
14
24
45
8
nt
0
30
50
12
Tetracycline 30
Penicillin
Clotrimazol
20
17
30
10
0
14
0
20
0
28
18
Agar diffusion assay (50 lg/disc [100 lg/disc], diameter of inhibition [mm]); te: tetracycline; cl: clotrimazol (25 lg/disc); 0 mm: no
effect in test concentration. GI: growth inhibition; nt: not tested.
Table 2. Cytotoxicity of the tested compounds against HL 60 cell
line.
Mitsunobu reaction [6]. Both reactions convert the acid
quantitatively into the esters 4. The resulting esters were
reacted with octanoyl chloride or 3-phenyl propionic
acid chloride to the corresponding anilides 5b/5c.
Compound
IC50 (lM)
3e
3f
312
64
474
5
As in the first and second series, octanoyl amides
showed the highest activities. In a fourth series, benzoic
acid was replaced by hydroxy benzoic acid derivatives
(Scheme 3) to further increase the activity. Therefore,
commercially available 6-nitro salicylic acid was reacted
with methanol to give ester 4d. The nitro group of 4d was
reduced under a H2 atmosphere with Pd/C to the corre-
sponding amino ester 5d, which was then reacted with
one equivalent of octanoyl chloride to give the amide 6a.
Cleavage of the methyl ester with methanolic aqueous
KOH led to the carboxylic acid 7a. Compound 7b was
built up in a similar way. Therefore, commercially avail-
able 4-hydroxy-3-amino benzoic acid was esterified with
methanol to afford the methyl ester 5e. The following
reaction with one equivalent of octanoyl chloride gave
the anilide 6b. Subsequent hydrolysis of the methyl ester
gave the carboxylic acid 7b [9–13].
3n
Cisplatin
Almost all compounds were tested against Gram posi-
tive and Gram negative bacteria and some fungi in agar
diffusion assays (Table 1) [7, 8]. All cultures were ordered
from the German collection of microorganisms and cell
cultures (http://www.dsmz.de). The compounds showed
weak or partially no activities against Gram positive and
Gram negative bacteria and the fungi. Derivatives with an
octanoyl anilide structure showed weak antibiotic activ-
ities against some of the bacteria species.
The cytotoxicity of the most promising compounds 3e,
3f, and 3n was determined in an MTT assay on a human
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Arch. Pharm. Chem. Life Sci. 2008, 341, 386–392
Platensimycin Analogues and Their Antibiotic Potency
389
brown solid. Elemental analysis C15H14FNO (243.28). Calcd.: C:
74.06. H: 5.80. N: 5.76. Found: C: 74.16. H: 5.80. N: 5.33. Mp.:
81.18C. MS (CI): m/z (%) = 244 [M+ + 1] (100), 111 (10). HR-MS:
Calcd.: 243.1059. Found: 243.1033. 1H-NMR (CDCl3) d (ppm) =
2.63 (t, J = 7.7 Hz, 2 H, CH2), 2.99 (t, J = 7.7 Hz, 2 H, CH2), 6.75 (dd, J
= 10.4 Hz, J = 8.3 Hz, 1 H, aromat. CH), 7.07 (d, J = 7.2 Hz, 1 H, aro-
mat. CH), 7.17 (m, 4 H, 3 aromat. CH), 7.24 (m, 2 H, 2 aromat. CH),
7.40 (d, J = 10.4 Hz, 1 H, aromat. CH), 7.84 (s, 1 H, NH). 13C-NMR
(CDCl3) d (ppm) = 31.24 (CH2), 39.32 (CH2), 106.30 (d, J = 26 Hz, aro-
mat. CH), 109.85 (d, J = 22 Hz, aromat. CH), 114.00 (aromat. CH),
126.46 (aromat. CH), 128.34 (2 aromat. CH), 128.66 (2 aromat.
CH), 128.88 (d, J = 9.6 Hz, aromat. CH), 139.22 (quart. C), 140.41
(quart. C), 163.01 (d, J = 246 Hz, quart. C), 170.81 (CO).
leukaemia cell line (HL-60). The compounds showed no or
weak cytotoxicity against HL-60 cells [14] (Table 2).
Discussion
The resulting compounds showed only weak or no signif-
icant antimicrobial activities in the agar diffusion assay.
In order to investigate whether the antimicrobial effects
of 3e, 3f, and 3n were caused by an unspecific cytotoxic
mechanism, the cytotoxicity was evaluated in an MTT
assay on HL-60 cells. Only compound 3f showed a notable
cytotoxicity with an IC50 about 60 lM, thus 3e and 3n are
interesting leads. The poor solubility of the compounds
might be a limiting factor. Therefore, work is in progress
to build up more hydrophilic compounds.
3-(3-Phenyl-propionylamino)-benzoic acid 3b
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 1.26 g
(7.5 mmol) 3-phenyl propionic acid chloride to give 995 mg
(74%) of 3b. Elemental analysis C16H15NO3 (269.30). Calcd.: C:
71.36. H: 5.61. N: 5.20. Found: C: 67.60. H: 5.30. N. 4.69. H-NMR (d-
DMSO) d (ppm) = 2.66 (t, J = 7.8 Hz, 2 H, CH2), 2.99 (t, J = 7.8 Hz, 2
H, CH2), 7.25 (m, 5 H, 5 aromat. CH), 7.33 (dd, J = 7.9 Hz, J = 7.6 Hz,
5–H), 7.65 (d, J = 7.6 Hz, 1 H, aromat. CH), 7.89 (d, J = 7.9 Hz, 1 H,
aromat. CH), 8.16 (s, 1 H, 2-H), 9.90 (s, 1H, NH). 13C-NMR (d-DMSO)
d (ppm) = 30.72 (CH2), 37.91 (CH2), 119.79 (aromat. CH), 122.76
(aromat. CH), 123.72 (aromat. CH), 125.80 (aromat. CH), 128.11 (2
aromat. CH), 128.17 (2 aromat. CH), 128.55 (aromat. CH), 131.84
(quart. C), 139.22 (quart. C), 141.00 (quart. C), 167.26 (CO), 170.43
(CO).
The authors have declared no conflict of interest.
Experimental
Material and spectroscopy
IR-Spectra: Perkin-Elmer FT-IR Paragon 1000 (Perkin-Elmer, Nor-
walk, CT, USA); MS: Hewlett Packard MS-Engine, electron ionisa-
tion (EI) 70 eV, chemical ionisation (CI) with CH4 (300 eV) (Hew-
lett Packard, Palo Alto, CA, USA); NMR (400 MHz): Jeol GSX 400,
1H: 400 MHz (JEOL, Tokyo, Japan); 13C: 100 MHz: GLC-MS: Shi-
madzu GC 17 A (Shimadzu, Tokyo, Japan); flash column chroma-
tography (FCC): silica gel 60 (230–400 mesh, E. Merck, Darm-
stadt, Germany).
(E)-N-(3-Fluoro-phenyl)-3-phenyl-acrylamide 3c
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.2 g (7.5 mmol) phe-
nyl acryloyl chloride to give 970 mg (73%) of 3c. Elemental anal-
ysis C15H12FNO (241.27). Calcd.: C: 74.68. H: 5.01. N: 5.81. Found:
C: 74.20. H: 4.78. N: 5.79. MS (CI): m/z (%) = 242 [M+ + 1] (100), 131
(28). MS (EI): m/z (%) = 241 [M+] (30), 131 (100), 103 (72). 1H-NMR (d-
DMSO) d (ppm) = 6.85 (m, 2 H, 2 aromat. CH), 7.40 (m, 5 H, 5 aro-
mat. CH), 7.62 (m, 3 H, 3 aromat. CH), 7.76 (ddd, J = 11.6 Hz, J =
2.1 Hz, J = 2.1 Hz, 1 H, aromat. CH), 10.38 (s, 1H, NH). 13C-NMR (d-
DMSO) d (ppm) = 106.18 (d, J = 25 Hz, aromat. CH), 109.65 (d, J =
21 Hz, aromat. CH), 114.92 (quart. C), 121.88 (aromat. CH),
127.70 (2 aromat. CH), 128.89 (2 aromat. CH), 130.12 (d, J =
9.8 Hz, aromat. CH), 130.15 (aromat. CH), 140.67 (aromat. CH),
141.03 (d, J = 12 Hz, quart. C), 162.22 (d, J = 243 Hz, quart. C),
163.80 (CO).
Agar diffusion assay
The bacteria and fungi were cultivated on an AC agar (Sigma-
Aldrich, Munich, Germany), Aspergillus niger on a potato dex-
trose broth agar (Sigma). The substances were placed on 6 mm
paper discs on the agar each impregnated with 100 lg of the
tested compound or 50 lg of the reference drugs. The bacteria
media were incubated for 24 h at 328C, the fungi media for 48 h
at 288C and the diameter of the zone of inhibition [mm] was reg-
istered.
General procedure 1 for the preparation of amides
The aniline derivative (5.0 mmol) was dissolved in 20 mL dry tol-
uene and 7.5 mmol of the acid chloride and 5 mL EDMA were
added. The solution was stirred for 5 h at room temperature.
Then, it was quenched with 20 mL brine and extracted with
ethyl acetate (3630 mL). The combined organic layers were
dried over Na2SO4 and the solvent was evaporated. The residue
was purified by flash column chromatography (n-hexane/ethyl
acetate 1 : 1) or crystallization.
3-Octanoylamino benzoic acid 3e
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 1.2 g
(7.5 mmol) octanoyl acid chloride to give 1.2 g (93%) of 3e. Ele-
mental analysis C15H21NO3 (263.34). Calcd.: C: 68.42. H: 8.04. N:
5.32. Found: C: 68.94. H: 8.49. N: 4.95. MS (CI): m/z (%) = 264 [M+ +
1] (100). 1H-NMR (d-DMSO) d (ppm) = 0.86 (t, J = 7.0 Hz, 3 H, CH3),
1.28 (m, 8 H, 4 CH2), 1.60 (m, 2 H, CH2), 2.31 (t, J = 7.4 Hz, 2 H,
CH2), 7.41 (dd, J = 8.0 Hz, J = 8.0 Hz, 1 H, 5-H), 7.60 (ddd, J = 8.0 Hz,
J = 1.1 Hz, J = 1.1 Hz, 1 H, aromat. CH), 7.82 (ddd, J = 8.0 Hz, J =
1.1 Hz, J = 1.1 Hz, 1 H, aromat. CH), 8.23 (dd, J = 1.1 Hz, J = 1.1 Hz,
1 H, 2-H), 10.06 (s, 1 H, NH), 12.91 (s, 1 H, OH). 13C-NMR (d-DMSO) d
(ppm) = 13.93 (CH3), 22.07 (CH2), 25.05 (CH2), 28.32 (CH2), 28.60
(CH2), 31.16 (CH2), 36.39 (CH2), 119.74 (aromat. CH), 123.03 (aro-
N-(3-Fluoro-phenyl)-3-phenyl-propionamide 3a
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.26 g (7.5 mmol) 3-
phenyl propionic acid chloride to give 990 mg (82%) of 3a as a
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mat. CH), 123.73 (aromat. CH), 128.88 (aromat. CH), 131.29
(quart. C), 139.52 (quart. C), 167.21 (CO), 171.52 (quart. C).
Calcd.: 207.0895. Found: 207.0895. 1H-NMR (CDCl3) d (ppm) =
0.93 (t, J = 7.5 Hz, 3 H, CH3), 1.63 (tq, J = 7.5 Hz, J = 7.5 Hz, 2 H,
CH2), 2.30 (t, J = 7.5 Hz, 2 H, CH2), 7.39 (dd, J = 7.6 Hz, J = 8.7 Hz, 1
H, H-5), 7.60 (d, J = 7.6 Hz, 1 H, aromat. CH), 7.83 (d, J = Hz, 8.7 Hz,
1 H, aromat. CH), 8.22 (s, 1 H, H-2), 10.02 (s, 1 H, OH). 13C-NMR
(CDCl3) d (ppm) = 13.58 (CH3), 18.49 (CH2), 38.31 (CH2), 119.82 (aro-
mat. CH), 123.02 (aromat. CH), 123.69 (aromat. CH), 128.69 (aro-
mat. CH), 139.44 (quart. C), 168.92 (CO), 171.27 (CO).
Octanoic acid (3-fluoro-phenyl)amide 3f
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.2 g (7.5 mmol) octa-
noyl chloride to give 745 mg (63%) of 3f. Elemental analysis
C14H20FNO. Calcd.: C: 70.86. H: 8.49. N: 5.90. Found: C: 70.13. H:
8.74. N. 5.21. MS (CI): m/z (%) = 238 [M+ + 1] (100), 111 (55). 1H-NMR
(CDCl3) d (ppm) = 0.88 (t, J = 7.1 Hz, 3 H, CH3), 1.29 (m, 8 H, 4 CH2),
1.72 (tt, J = 7.5 Hz, J = 7.5 Hz, 2 H, CH2), 2.35 (t, J = 8.0 Hz, 2 H,
CH2), 6.78 (ddd, J = 1.7 Hz, J = 8.3 Hz, J = 8.3 Hz, 1 H, aromat. CH),
7.20 (m, 2 H, 2 aromat. CH), 7.52 (d, J = 11.6 Hz, 1 H, aromat. CH),
7.70 (s, 1 H, NH). 13C-NMR (CDCl3) d (ppm) = 14.07 (CH3), 22.61
(CH2), 25.54 (CH2), 28.97 (CH2), 29.11 (CH2), 29.22 (CH2), 31.68
(CH2), 114.84 (aromat. CH), 110.60 (d, aromat. CH), 107.04 (d, aro-
mat. CH), 129.95 (d, aromat. CH), 139.70 (d, quart. C), 163.00 (d,
quart. C), 171.71 (CO).
N-(3-Fluorophenyl)acetamide 3j
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 590 mg (7.5 mmol)
acetyl chloride to give 424 mg (55%) of 3j. Elemental analysis
C8H8FNO (153.16). Mp.: 81.18C. MS (CI): m/z (%) = 154 [M+ + 1]
(100). HR-MS: Calcd.: 153.0590. Found: 153.0581. 1H-NMR (CDCl3)
d (ppm) = 2.16 (s, 3 H, CH3), 6.78 (dd, J = 8.2 Hz, J = 8.2 Hz, J =
1.9 Hz, 1 H, aromat. CH), 7.18 (dd, J = 7.0 Hz, J = 8.2 Hz, 1 H, aro-
mat. CH), 7.22 (dd, J = 1.6 Hz, J = 7.0 Hz, 1 H, aromat. CH), 7.48
(ddd, J = 11.1 Hz, J = 1.9 Hz, J = 1.6 Hz, 1 H, aromat. CH), 8.31 (s, 1
H, NH). 13C-NMR (CDCl3) d (ppm) = 24.55 (CH3), 107.35 (d, J =
27.4 Hz, 1 H, aromat. CH), 110.95 (d, J = 20.2 Hz, 1 H, aromat. CH),
115.04 (aromat. CH), 130.05 (m, aromat. CH), 139.50 (d, J = 9.0 Hz,
quart. C), 162.99 (d, J = 243.1 Hz, quart. C), 168.72 (CO).
3-Undec-10-enoylamino benzoic acid 3g
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 1.5 g
(7.5 mmol) undec-10-enoyl chloride to give 833 mg (55%) of 3g.
Elemental analysis C18H25NO3 (303.40). MS (CI): m/z (%) = 304 [M+ +
1] (12), 200 (100), 182 (24), 138 (26). HR-MS: Calcd.: 303.1834.
Found: 303.1834. 1H-NMR (d-DMSO) d (ppm) = 1.27 (m, 10, 5 CH2),
1.58 (m, 2 H, CH2), 2.00 (m, 2 H, CH2), 2.30 (t, J = 7.3 Hz, 2 H, CH2),
4.96 (m, 2 H, =CH2), 5.78 (ddt, J = 6.5 Hz, J = 10.5 Hz, J = 17.3 Hz, 1
H, -CH=), 7.40 (dd, J = 7.6 Hz, J = 7.8 Hz, 1 H, aromat. CH), 7.59 (d, J
= 7.6 Hz, 1 H, aromat. CH), 7.81 (d, J = 7.8 Hz, 1 H, aromat. CH),
8.22 (s, 1 H, 2-H), 10.04 (s, 1 H, NH), 12.86 (s, 1 H, OH). 13C-NMR (d-
DMSO) d (ppm) = 24.98 (CH2), 28.19 (CH2), 28.42 (CH2), 28.56 (CH2),
28.64 (CH2), 28.68 (CH2), 33.10 (CH2), 36.34 (CH2), 114.59 (=CH2),
119.71 (aromat. CH), 123.04 (aromat. CH), 123.69 (aromat. CH),
131.18 (quart. C), 138.78 (-CH=), 139.50 (quart. C), 167.15 (CO),
171.50 (CO).
3-Acetylamino benzoic acid 3k
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 590 mg
(7.5 mmol) acetyl chloride to give 537 mg (60%) of 3k as brown
solid. Elemental analysis C9H9NO3 (179.18). MS (CI): m/z (%) = 180
[M+ + 1] (100). HR-MS: Calcd.: 179.0582. Found: 179.0590. 1H-NMR
(d-DMSO) d (ppm) = 2.05 (s, 3 H, CH3), 7.40 (dd, J = 7.8 Hz, J =
8.3 Hz, 1 H, 5-H), 7.60 (d, J = 7.8 Hz, 1 H, aromat. CH), 7.80 (d, J =
8.3 Hz, 1 H, aromat. CH), 8.21 (s, 1 H, 2-H), 10.11 (s, 1 H, NH),
11.87 (s, 1 H, OH). 13C-NMR (d-DMSO) d (ppm) = 23.37 (CH3), 119.10
(aromat. CH), 122.42 (aromat. CH), 123.17 (aromat. CH), 128.25
(aromat. CH), 130.61 (quart. C), 138.89 (quart. C), 166.57 (CO),
167.57 (CO).
Undec-10-enoic acid (3-fluoro-phenyl)amide 3h
Octanoic acid phenyl amide 3l
The compound was prepared following general procedure 1
from 550 mg (5 mmol) 3-fluoro aniline and 1.5 g (7.5 mmol)
undec-10-enoyl chloride to give 830 mg (60%) of 3h. Elemental
analysis C17H24FNO (277.39). Calcd.: C: 73.61. H: 8.72. N: 5.05.
Found: C: 73.23. H: 8.89. N. 4.60. MS (CI): m/z (%) = 278 [M+ + 1]
The compound was prepared following general procedure 1
from 930 mg (10 mmol) aniline and 1.63 g (10.0 mmol) octanoyl
chloride to give 2.07 g (94%) of 3l as white solid. Elemental anal-
ysis C14H21NO (219.33). MS (CI): m/z (%) = 220 [M+ + 1] (100). HR-MS:
1
1
(100), 111 (38). HR-MS: Calcd.: 277.1842. Found: 277.1838. H-
Calcd.: 219.1623. Found: 219.1584. H-NMR (d-DMSO) d (ppm) =
NMR (CDCl3) d (ppm) = 1.32 (m, 12 H, 6 CH2), 1.70 (m, 2 H, CH2),
2.03 (m, 2 H, CH2), 2.35 (t, J = 7.8 Hz, 2 H, CH2), 4.93 (m, 1 H, =CH2),
4.99 (m, 1 H, =CH2), 5.80 (ddt, J = 17.2 Hz, J = 10.5 Hz, J = 6.8 Hz, 1
H, -CH=), 6.78 (ddd, J = 8.3 Hz, J = 8.3 Hz, J = 1.7 Hz, 1 H, aromat.
C), 7.19 (m, 1 H, aromat. CH), 7.23 (m, 1 H, aromat. CH), 7.51 (d, J
= 11.2 Hz, 1 H, 2-H), 7.87 (s, 1 H, NH). 13C-NMR (CDCl3) d (ppm) =
25.58 (CH2), 28.89 (CH2), 29.07 (CH2), 29.12 (CH2), 29.33 (CH2),
30.95 (CH2), 33.78 (CH2), 37.72 (CH2), 106.06 (aromat. CH), 109.41
(aromat. CH), 112.91 (=CH2), 128.63 (aromat. CH), 138.00 (=CH-),
138.41 (quart. C), 163.00 (d, J = 245 Hz, quart. C), 171.95 (CO).
0.88 (t, J = 6.7 Hz, 3 H, CH3), 1.31 (m, 8 H, 4 CH2), 1.72 (m, 2 H,
CH2), 2.35 (t, J = 7.4 Hz, 2 H, CH2), 7.09 (dd, J = 7.4 Hz, J = 7.4 Hz, 1
H, aromat. CH), 7.31 (dd, J = 7.7 Hz, J = 8.2 Hz, 2 H, 2 aromat. CH),
7.52 (d, J = 8.3 Hz, 2 H, 2 aromat. CH).13C-NMR (d-DMSO) d (ppm) =
14.09 (CH3), 22.62 (CH2), 25.66 (CH2), 29.05 (CH2), 29.24 (CH2),
31.69 (CH2), 37.86 (CH2), 119.75 (2 aromat. CH), 124.14 (aromat.
CH), 128.98 (2 aromat. CH), 137.98 (quart. C), 171.47 (CO). The
compound is also described in Lit. [12, 13].
Octanoic acid (3-hydroxyphenyl)amide 3m
The compound was prepared following general procedure 1
from 1.09 g (10 mmol) 3-hydroxy aniline and 1.63 g (10.0 mmol)
octanoyl chloride to give 330 mg (14%) of 3m as brown solid. Ele-
mental analysis C14H21NO2 (235.33). MS (EI): m/z (%) = 235 [M+] (8),
151 (10), 109 (100).13C-NMR (d-DMSO) d (ppm) = 14.00 (CH3), 22.35
(CH2), 25.52 (CH2), 28.83 (CH2), 29.02 (CH2), 31.46 (CH2), 37.03
(CH2), 106.77 (aromat. CH), 110.30 (aromat. CH), 110.32 (aromat.
3-Buturylamino benzoic acid 3i
The compound was prepared following general procedure 1
from 685 mg (5 mmol) 3-amino benzoic acid and 795 mg
(7.5 mmol) butyryl chloride to give 670 mg (65%) of 3i. Elemental
analysis C11H13NO3 (207.23). MS (EI): m/z (%) = 207 [M+] (16), 137
(100), 71 (18). MS (CI): m/z (%) = 208 [M+ + 1] (100), 137 (16). HR-MS:
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Arch. Pharm. Chem. Life Sci. 2008, 341, 386–392
Platensimycin Analogues and Their Antibiotic Potency
391
CH), 129.07 (aromat. CH), 140.21 (quart. C), 157.56 (quart. C),
171.62 (COOH). The compound is also described in Lit [11].
aromat. CH), 7.37 (dd, J = 2.4 Hz, J = 2.5 Hz, 1 H, aromat. CH), 7.44
(ddd, J = 0.8 Hz, J = 1.1 Hz, J = 7.9 Hz, 1 H, aromat. CH). 13C-NMR
(CDCl3) d (ppm) = 14.32 (CH3), 60.89 (CH2), 115.84 (aromat. CH),
119.41 (aromat. CH), 129.23 (aromat. CH), 131.50 (quart. C),
146.29 (quart. C), 166.81 (CO). The compound is also described in
Lit [9].
3-(2-Bicyclo[2.2.1]hept-2-yl-acetylamino)benzoic acid 3n
The compound was prepared following general procedure 1
from 631 mg (4.6 mmol) 3-amino benzoic acid and 794 mg
(4.6 mmol) 2-norbornylethanoyl chloride to give 0.8 g (64%) of
3n as pale brown solid after crystallization from methanol /
water. Elemental analysis C16H19NO3 (273.33). MS (CI): m/z (%) =
274 [M+ + 1] (38), 210 (82), 155 (94), 137 (100). HR-MS: Calcd.:
3-Amino benzoic acid benzyl ester 4c
3-Amino benzoic acid (1.37 g; 10 mmol), 1.2 g (11 mmol) benzyl
alcohol 3.1 g (12 mmol) triphenylphosphine were dissolved in
dry toluene. 2.4 g (12 mmol) DIAD (diisopropylazodicarboxylate)
were added dropwise and the solution was stirred for 5 h. The
organic solvent was evaporated and the residue was separated
by flash column chromatography (hexane/ethyl acetate 1 : 1) to
give 1.97 g (87%) of 4c as a pale yellow oil. Elemental analysis
C14H13NO2 (227.27). 1H-NMR (CDCl3) d (ppm) = 5.29 (s, 2 H, CH2O),
7.62 (m, 9 H, 9 aromat. CH). 13C-NMR (CDCl3) d (ppm) = 65.16
(CH2O), 114.36 (aromat. CH), 116.74 (aromat. CH), 118.55 (aro-
mat. CH), 128.61 (2 aromat. CH), 131.92 (aromat. CH), 133.00
(quart. C), 131.52 (2 aromat. CH), 136.27 (quart. C), 148.18 (quart.
C), 165.45 (CO). The compound is also described in Lit [10].
1
273.1365. Found: 273.1359. H-NMR (d-DMSO) d (ppm) = 1.22–
2.03 (m, 3 CH, 5 CH2), 7.39 (dd, J = 8.0 Hz, J = 8.0 Hz, 1 H, H-5), 7.58
(d, J = 8.0 Hz, 1 H, aromat. CH), 7.80 (d, J = 8.0 Hz, 1 H, aromat.
CH), 8.22 (s, 1 H, H-2), 10.04 (s, 1 H, NH), 12.68 (s, 1 H, OH). 13C-
NMR (d-DMSO) d (ppm) = 32.96 (CH2), 34.07 (CH2), 39.38 (CH2),
40.83 (CH), 41.72 (CH2), 43.27 (CH), 45.14 (CH), 48.08 (CH2), 119.77
(aromat. CH), 123.08 (aromat. CH), 123.78 (aromat. CH), 128.92
(aromat. CH), 131.23 (quart. C), 139.51 (quart. C), 167.22 (CO),
170.87 (CO).
3-(2-Cyclohexyl-acetylamino)benzoic acid 3o
The compound was prepared following general procedure 1
from 1.37 g (10 mmol) 3-amino benzoic acid and 1.6 g (10 mmol)
2-phenyl acetyl chloride to give 1.9 g (73%) of 3o as white solid.
Elemental analysis: C15H19NO3 (261.32). MS (CI): m/z (%) = 262 [M+
+ 1] (100). HR-MS: Calcd.: 261.1365. Found: 261.1360. 1H-NMR (d-
DMSO) d (ppm) = 0.98 (m, 2 H, CH2), 1.19 (m, 3 H, CH2, CH), 1.69
(m, 6 H, 3 CH2), 2.20 (d, J = 6.8 Hz, 1 H, H-2'), 7.40 (dd, J = 7.6 Hz, J =
8.2 Hz, 1 H, 5-H), 7.60 (d, J = 7.6 Hz, 1 H, aromat. CH), 7.82 (d, J =
8.2 Hz, 1 H, aromat. CH), 8.24 (s, 1 H, H-2), 10.04 (s, 1 H, NH),
12.92 (s, 1 H, OH). 13C-NMR (d-DMSO) d (ppm) = 25.58 (2 CH2),
25.79 (CH2), 32.47 (2 CH2), 34.76 (CH), 44.27 (CH2), 119.77 (aromat.
CH), 123.04 (aromat. CH), 123.70 (aromat. CH), 128.66 (aromat.
CH), 131.14 (quart. C), 139.40 (quart. C), 167.15 (CO), 170.67 (CO).
3-(3-Phenylpropionylamino)benzoic acid ethyl ester 5b
The compound was prepared following general procedure 1
from 825 mg (5 mmol) 4b and 1.26 g (7.5 mmol) phenyl pro-
pionyl acid chloride to give 1.43 g (96%) of 5b as a brown oil. Ele-
mental analysis C18H19NO3 (297.36). MS (EI): m/z (%) = 297 [M+]
(30), 252 (16), 165 (100). HR-MS: Calcd.: 297.1365. Found:
297.1357. 1H-NMR (CDCl3) d (ppm) = 1.38 (t, J = 7.1 Hz, 3 H, CH3),
2.69 (t, J = 7.7 Hz, 2 H, CH2), 3.07 (t, J = 7.7 Hz, 2 H, CH2), 4.36 (q, J =
7.1 Hz, 2 H, CH2), 7.27 (m, 6 H, 6 aromat. CH), 7.77 (d, J = 7.6 Hz. 1
H, aromat. CH), 7.88 (d, J = 7.9 Hz, 1 H, aromat. CH), 7.92 (s, 1 H,
aromat. CH). 13C-NMR (CDCl3) d (ppm) = 14.26 (CH3), 31.48 (CH2),
39.17 (CH2), 61.15 (CH2), 115.72 (aromat. CH), 120.77 (aromat.
CH), 124.52 (aromat. CH), 125.11 (aromat. CH), 126.31 (aromat.
CH), 128.33 (2 aromat. CH), 128.46 (aromat. CH), 128.59 (2 aro-
mat. CH), 129.01 (quart. C), 129.22 (quart. C), 133.99 (quart. C),
166.38 (CO), 171.06 (CO).
Octanoic acid 3-octanoylamino phenyl ester 3p
The compound was isolated as by-product by the synthesis of 3m
as a pale brown oil: 780 mg (22%). Elemental analysis: C22H35NO3
(361.53). MS (CI): m/z (%) = 362 [M+ + 1] (100). HR-MS: Calcd.:
361.2617. Found: 361.2589. 1H-NMR (d-DMSO) d (ppm) = 0.89 (m,
6 H, 2 CH3), 1.31 (m, 16 H, 8 CH2), 1.74 (m, 4 H, 2 CH2), 2.29 (t, J =
7.5 Hz, 2 H, CH2), 2.51 (t, J = 7.4 Hz, 2 H, CH2), 6.79 (d, J = 8.1 Hz, 1
H, NH), 7.23 (m, 3 H, 2 aromat. CH), 7.49 (m, 2 H, 2 aromat. CH).
13C-NMR (d-DMSO) d (ppm) = 14.08 (2 CH3), 22.64 (CH2), 24.92
(CH2), 25.53 (CH2), 28.94 (CH2), 29.07 (CH2), 29.08 (2 CH2), 29.23
(CH2), 31.66 (CH2), 31.69 (CH2), 34.39 (CH2), 37.70 (CH2), 113.28
(aromat. CH), 116.75 (aromat. CH), 116.99 (aromat. CH), 129.49
(aromat. CH), 139.20 (quart. C), 151.06 (quart. C), 171.53 (CO),
172.50 (CO).
3-Octanoylamino benzoic acid benzyl ester 5c
The compound was prepared following general procedure 1
from 600 mg (2.6 mmol) 4c and 650 mg (4 mmol) octanoic acid
chloride to give 650 mg (71%) of 5c. Elemental analysis
C22H27NO3 (353.47) MS (CI):m/z (%) = 354 [M+ + 1] (100), 210 (54). 1H-
NMR (CDCl3) d (ppm) = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.28 (m, 8 H, 4
CH2), 1.72 (tt, J = 7.4 Hz, J = 7.4 Hz, 2 H, CH2), 2.36 (t, J = 8.2 Hz, 2
H, CH2), 5.35 (s, 2 H, CH2O), 7.39 (m, 4 H, 4 aromat. CH), 7.44 (d, J =
6.9 Hz, 2 H, 2 aromat. CH), 7.80 (d, J = 8.3 Hz, 1 H, aromat. CH),
7.96 (s, 1 H, aromat. CH), 8.01 (d, J = 7.8 Hz, 1 H, aromat. CH). 13C-
NMR (CDCl3) d (ppm) = 14.07 (CH3), 22.57 (CH2), 25.51 (CH2), 29.04
(CH2), 29.20 (CH2), 30.96 (CH2), 31.65 (CH2), 66.89 (CH2O), 120.52
(aromat. CH), 124.51 (aromat. CH), 125.31 (aromat. CH), 128.26 (2
aromat. CH), 128.31 (aromat. CH), 128.62 (2 aromat. CH), 129.23
(aromat. CH), 130.79 (quart. C), 135.91 (quart. C), 138.23 (quart.
C), 166.03 (CO), 171.68 (CO).
3-Aminobenzoic acid ethyl ester 4b
3-Amino benzoic acid (5.0 g) were dissolved in 50 mL dry ethanol
and 5 mL sulphuric acid (98%) were added. The mixture was
heated for 2 h, the solvent was evaporated and the residue was
suspended in 50 mL aqueous NaOH (10%). The aqueous layer was
extracted with ethyl acetate (3650 mL) and the combined
organic layers were dried over Na2SO4. The solvent was evapo-
rated to give 4b as a pale yellow oil without further purification.
1H-NMR (CDCl3) d (ppm) = 1.38 (t, J = 6.9 Hz, 3 H, CH3), 3.35 (s, 2 H,
NH2), 4.35 (q, J = 6.9 Hz, 2 H, CH2), 6.86 (ddd, J = 0.8 Hz, J = 2.5 Hz,
J = 8.1 Hz, 1 H, aromat. CH), 7.21 (dd, J = 8.1 Hz, J = 7.9 Hz, 1 H,
2-Hydroxy-3-octanoylamino benzoic acid methyl ester 6a
The compound was prepared following general procedure 1
from 835 mg (5 mmol) 5d and 813 mg (5 mmol) octanoic acid
1
chloride to give 454 mg (31%) of 6a. H-NMR (CDCl3) d (ppm) =
0.88 (t, J = 7.1 Hz, 3 H, CH3), 1.29 (m, 8 h, 4 CH2), 1.74 (tt, J = 7.8 Hz,
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392
J. Krauss et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 386–392
J = 7.8 Hz, 2 H, CH2), 2.42 (t, J = 7.8 Hz, 2 H, CH2), 3.96 (s, 3 H, CH3),
6.89 (dd, J = 8.2 Hz, J = 8.2 Hz, 1 H, aromat. CH), 7.53 (dd, J =
8.2 Hz, J = 1.4 Hz, 1 H, aromat. CH), 7.81 (s, 1 H, NH), 8.59 (dd, J =
8.2 Hz, J = 1.4 Hz, 1 H, aromat. CH), 11.28 (s, 1 H, OH). 13C-NMR
(CDCl3) d (ppm) = 14.07 (CH3), 22.62 (CH2), 25.59 (CH2), 29.04
(CH2), 29.19 (CH2), 29.71 (CH2), 31.68 (CH2), 52.52 (CH3), 111.61
(quart. C), 127.52 (quart. C), 119.22 (aromat. CH), 123.50 (aromat.
CH), 125.04 (aromat. CH), 171.15 (CO), 171.59 (CO).
The combined organic layers were dried over Na2SO4, the solvent
was evaporated and residue was purified by flash column chro-
matography (n-hexane/ethyl acetate 1 : 1) to give 148 mg of 7b
1
(76%). MS (CI): m/z (%) = 280 [M+ + 1] (82), 262 (34), 236 (80). H-
NMR (d-DMSO) d (ppm) = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 1.29 (m, 4 H,
2 CH2), 1.61 (m, 2 H, CH2), 2.40 (t, J = 7.9 Hz, 2 H, CH2), 6.90 (d, J =
8.4 Hz, 1 H, aromat. CH), 7.56 (d, J = 8.4 Hz, 1 H, aromat. CH), 8.39
(s, 1 H, aromat. CH), 9.21 (s, 1 H, OH), 10.59 (s, 1 H, OH), 12.33 (s, 1
H, OH). 13C-NMR (d-DMSO) d (ppm) = 13.80 (CH3), 22.01 (CH2),
25.15 (CH2), 28.43 (CH2), 28.64 (CH2), 31.12 (CH2), 35.95 (CH2),
115.14 (aromat. CH), 121.37 (quart. C), 123.47 (aromat. CH),
126.23 (aromat. CH), 126.00 (quart. C), 151.68 (quart. C), 167.03
(CO), 171.96 (CO).
4-Hydroxy-3-octanoylamino benzoic acid methyl ester 6b
The compound was prepared following general procedure 1
from 835 mg (5 mmol) 5e and 813 mg (5 mmol) octanoic acid
chloride to give 351 mg (24%) of 6b as pale brown solid. Mp.:
122–1288C. Elemental analysis C16H23NO4 (293.37). MS (CI): m/z
(%) = 294 [M+ + 1] (100), 167 (20). HR-MS: Calcd.: 293.1627. Found:
293.1622. 1H-NMR (CDCl3) d (ppm) = 0.88 (t, J = 6.8 Hz, 3 H, CH3),
1.28 (m, 8 H, 4 CH2), 1.74 (tt, J = 6.8 Hz, J = 6.8 Hz, 2 H, CH2), 2.48
(t, J = 7.3 Hz, 2 H, CH2), 3.86 (s, 3 H, CH3), 7.01 (d, J = 8.1 Hz, 1 H,
aromat. CH), 7.77 (dd, J = 8.6 Hz, J = 1.8 Hz, 1 H, aromat. CH), 7.80
(s, 1 H, aromat. CH), 8.07 (s, 1 H, NH). 13C-NMR (CDCl3) d (ppm) =
14.03 (CH3), 22.56 (CH2), 25.69 (CH2), 28.93 (CH2), 29.08 (CH2),
31.59 (CH2), 36.88 (CH2), 52.07 (OCH3), 119.62 (aromat. CH),
121.82 (quart. C), 124.18 (aromat. CH), 125.76 (quart. C), 128.73
(aromat. CH), 153.39 (quart. C), 166.73 (CO), 174.32 (CO).
References
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2-Hydroxy-3-octanoylamino benzoic acid 7a
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Compound 6a (200 mg; 0.7 mmol) was dissolved in 20 mL meth-
anolic aqueous KOH and stirred under N2 atmosphere for 12 h.
The solvent was evaporated, the residue dissolved in 20 mL 10%
aqueous HCl and extracted with ethyl acetate (3620 mL). The
combined organic layers were dried over Na2SO4, the solvent was
evaporated and the residue was purified by flash column chro-
matography (n-hexane / ethyl acetate 1 : 1) to give 156 mg (80%)
of 7a. 1H-NMR (CDCl3) d (ppm) = 0.81 (t, J = 7.1 Hz, 3 H, CH3), 1.22
(m, 6 H, 3 CH2), 1.69 (m, 2 H, CH2), 2.39 (t, J = 7.5 Hz, 2 H, CH2),
6.87 (dd, J = 8.1 Hz, J = 8.0 Hz, 1 H, 5-H), 7.56 (dd, J = 8.1 Hz, J =
1.5 Hz, 1 H, aromat. CH), 7.78 (s, 1 H, OH), 8.55 (dd, J = 8.0 Hz, J =
1.5, 1 H, aromat. CH). 13C-NMR (CDCl3) d (ppm) = 13.05 (CH3),
21.59 (CH2), 24.63 (CH2), 27.80 (CH2), 28.15 (CH2), 30.64 (CH2),
37.00 (CH2), 110.10 (quart. C), 118.43 (aromat. CH), 123.68 (aro-
mat. CH), 125.00 (aromat. CH), 126.30 (quart. C), 149.81 (quart.
C), 171.15 (CO), 172.87 (CO).
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4-Hydroxy-3-octanoylamino benzoic acid 7b
An amount of 200 mg (0.7 mmol) of 6b was dissolved in 20 mL
methanolic aqueous KOH and stirred under N2 atmosphere for
12 h. The solvent was evaporated, the residue dissolved in 20 mL
10% aqueous HCl and extracted with ethyl acetate (3620 mL).
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www.archpharm.com