Synthesis and antibacterial activity of linezolid analogues

Article abstract of DOI:10.1016/S0960-894X(02)00043-4

Several new compounds of oxazolidinone class were designed and synthesized referring to the structure-activity relationship studies and the synthesis of Linezolid, and their antibacterial activity was studied.

Full text of DOI:10.1016/S0960-894X(02)00043-4

Bioorganic & Medicinal Chemistry Letters 12 (2002) 857–859
Synthesis and Antibacterial Activity of Linezolid Analogues
Du Yu and Guo Huiyuan*
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Peking Union Medical College,
Beijing 100050, China
Received 2 November 2001; accepted 28 December 2001
Abstract—Several new compounds ofoxazolidinone class were designed and synthesized referring to the structure–activity relationship
studies and the synthesis ofLinezolid, and their antibacterial activity was studied. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
synthesized (1a–d) and we also prepared some U-100766
for contrast (Fig. 1, 1e).
The increasing incidence ofmultidrug resistance among
Gram-positive bacterial pathogens represents one of
the major challenges in the 1990s for health care
researchers. This growing problem has recently rekindled
Chemistry
interest in the search for new antibiotic structural classes
that inhibit or kill by novel mechanisms. Clearly there is
an urgent need for the discovery and development of
new agents effective against the emerging and currently
problematic Gram-positive pathogens MRSA, methicillin-
resistant coagulase-negative staphylococci, VRE, and
penicillin-resistant pneumococci, as well as the perceived
looming threat ofa vancomycin-resistant Staphylo-
coccus aureus.
The synthesis route ofthese compounds is shown in
Figure 1. Commencing with 3,4-difluoronitrobenzene,
nucleophilic aromatic displacement with excess sub-
stituted piperazine (RH) selectively gave the p-sub-
stituted nitrobenzene (2). Reduction of 2 was followed
by attachment ofbenzyl chloroformate activating group
to the arylamine 3 giving 4. Carbamate 4 was deproto-
nated with n-BuLi (THF, À78 ꢀC), and then (R)-glycidyl
butyrate was added and the mixture was kept at À78 ꢀC
for about 1.5 h, then slowly allowed to warm to room
temperature and stirred overnight. This sequence pro-
vided directly the (5R)-(hydroxy methyl)-2-oxazolidinone
5 in >55% yield. 5 was reacted with 4-nitrobenzene-
sulfonyl chloride and gave 6. 6 then reacted with NH3 in
methyl alcohol, and gave 7. 7 was not purified but just
The oxazolidinones are a new class oftotally synthetic
antibacterial agents. They have a novel mechanism of
action that involves the inhibition ofbacterial protein
synthesis at a very early stage, prior to chain initiation.1
Linezolid (U-100766) is a successful agent of this class,
and has already gained the permission ofthe FDA and
come into the market.
handled with water, solution ofcitric acid and CH Cl2.
2
Then the mixture (made pH>8.5) was reacted with
acetic anhydride at 40 C for 2 h, and gave 1.
ꢀ
Referring to the structure–activity relationship
studies3À7 and the synthesis ofLinezolid,
In total, we have synthesized four target compounds
and 16 intermediates; all ofthem are not reported yet.
The structures ofall the target compounds were proved
by H NMR, MS and HRMS (data shown in Table 1
and ref8).
2
we have
designed some new compounds ofoxazolidinone class
in order to investigate the relationship ofantibacterial
activity and the increasing lipophilicity ofgroup R
(Fig. 1). These compounds all belong to piperazinyl
series. Figure 1 shows several compounds already
1
Biological Results and Discussion
Using U-100766 and Norvancomycin as control, we
tested the antibacterial activity in vitro ofthe target
*Corresponding author. Fax: +86-10-6304-7865; e-mail: hyguo@
public.fhnet.cn.net
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00043-4

858
D. Yu, G. Huiyuan / Bioorg. Med. Chem. Lett. 12 (2002) 857–859
Figure 1. Synthesis route.
Table 1. 1H NMR, MS and HRMS data oftarget compounds
Compound data
1a
1b
1c
1d
1e
1H NMR(CDCl3) d (ppm): 2.03 (3H, s, –COCH3), 3.20–3.34 (8H, m, piperizine), 3.78 (3H, s, –OMe), 3.58–4.06 (4H, m, 2Â –CH2–), 4.75–4.78
(1H, m, –CH–), 5.96 (1H, br, –NH–), 6.87–7.10 (6H, m, ArH), 7.45–7.50 (1H, m, ArH); MS-EI (m/z): 442 (M+), 398 (M+ÀCO2), 135
(C8H9N1O1); HRMS C23H27N4O4F, calc. (M): 442.201634; meas.: 442.201948
1H NMR (CDCl3) d (ppm): 2.03 (3H, s, –COCH3), 3.24–3.27 (8H, m, piperizine), 3.61–4.06 (4H, m, 2–CH2–), 4.72–4.80 (1H, m, –CH–),
6.00 (1H, br, –NH–), 6.95–7.11 (6H, m, ArH), 7.44–7.48 (1H, m, ArH); MS-EI (m/z): 430 (M+), 386 (M+ÀCO2), 150 (C9H9N1F1), 123
(C7H6N1F1); HRMS C22H24N4O3F2, calc. (M): 430.181647; meas.: 430.182161
1H NMR (CDCl3) d (ppm): 2.05 (3H, s, –COCH3), 3.25–3.39 (8H, m, piperizine), 3.56–4.06 (4H, m, 2Â –CH2–), 4.75–4.79 (1H, m, –CH–),
5.99 (1H, br, –NH–), 6.96–7.10 (5H, m, ArH), 7.30–7.50 (3H, m, ArH); MS-EI (m/z): 412 (M+), 368 (M+ÀCO2), 105 (C7H7N); HRMS
C22H25N4O3F, calc. (M): 412.191069; meas.: 412.193418
1H NMR (CDCl3) d (ppm): 2.02 (3H, s, –COCH3), 2.47–2.67 (4H, m, piperizine), 2.98–3.10 (4H, m, piperizine), 3.53–4.03 (4H, m, 2Â
–CH2–), 4.29 (1H, s, –CH–), 4.71–4.79 (1H, m, –CH–), 5.97 (1H, br, –NH–), 6.89–7.45 (13H, m, ArH); MS-EI (m/z): 502 (M+), 459 (MH+
ÀCO2), 336 (MH+Àph2CH), 195 (C14H13N1), 167 (ph2CH); HRMS C29H31N4O3F, calc.(M): 502.238019; meas.: 502.236347
1H NMR(CDCl3) d (ppm): 2.02 (3H, s, –COCH3), 3.04–3.07 (4H, m, (CH2)2N), 3.86–3.88 (4H, m, (CH2)2O), 3.59–4.05 (4H, m, 2Â –CH2–),
4.73–4.81 (1H, m, –CH–), 6.34 (1H, br, –NH–), 6.94 (1H, t, J=9.0 Hz, ArH), 7.04–7.08 (1H, dd, J1=2.1 Hz, J2=8.8 Hz, ArH), 7.41–7.46
(1H, dd, J1=3.0 Hz, J2=14.7 Hz, ArH); MS-EI (m/z): 337 (M+), 293 (M+ÀCO2), 234 (C13H15N2OF); HRMS C16H20N3O4F, calc. (M):
337.143785; meas. 337.144878

D. Yu, G. Huiyuan / Bioorg. Med. Chem. Lett. 12 (2002) 857–859
859
Table 2. Antibacterial activity
Acknowledgements
Strain
MIC (mg/mL)
1e Linezolid 1a 1b 1c 1d Norvancomycin
The authors would like to thank the National Research
Center ofDrug and Metabolite Analysis of r measuring
the data of H NMR, MS and HRMS, and we also
want to thank the Pharmacology Laboratory of
Institute ofMedicinal Biotechnology ofr testing the
antibacterial activity.
1
S. pneumoniae 9753
S. pneumoniae 9757
S. pneumoniae 9798
Streptococcus A 29
Streptococcus A 44
S. pyogenes 102
S. pyogenes 114
E. faecalis 50
E. faecalis 68
S. aureus 975
S. aureus 9616
S. aureus 9721
S. aureus 9776
S. aureus 966
S. epidermidis 975
S. epidermidis 9753
S. epidermidis 9759
0.5
0.5
0.5
0.25
0.5
0.5
0.5
0.5
1
1
1
1
1
1
1
2
1
2
1
1
1
1
2
1
1
1
1
1
1
1
1
1
2
1
0.5
0.25
1
0.5
2
1
1
1
2
4
4
8
0.25
0.25
0.25
0.5
0.5
0.5
2
4
32
32
16
8
32
4
1
2
References and Notes
4
0.25
1
0.5
2
1
1
1
1
0.5 0.5
1
1
1
1
1
2
1
1
0.5
1
1
2
1
1
1
8
16
8
8
8
0.5
0.5
0.5
0.5
0.25
0.5
1. (a) Eustice, D. C.; Feldam, P. A.; Zajic, I., et al. Anti-
microb. Agents Chemother. 1988, 32, 1218. (b) Lin, A. H.;
Murray, R. W.; Vidmar, T. J., et al. Antimicrob. Agent Che-
mother. 1997, 41, 2127.
2. Bricker, S. J.; Hutchinson, D. K.; Barbachyn, M. R., et al.
J. Med. Chem. 1996, 39, 673.
4
16
1
3. Seneci, P.; Caspani, M.; Ripamenti, F., et al. J. Chem. Soc.,
Perkin Trans. 1 1994, 2345.
compounds with several clinical separated pathogens,
several quality control strains and several standard
strains. The target compounds 1a–d were dissolved in
DMSO and we tested MICs with double dilution
method. The results are shown in Table 2. The activity
of 1d is very poor. The activity ofthe other three com-
pounds is equal to or less than U-100766 and Norvan-
comycin. Because we only get a certain number of
compounds, we cannot discuss the SAR in depth now.
Here, we just report the synthesis and antibacterial
activity ofthese analogues and more analogues will be
prepared for this purpose soon.
4. Gregory, W. A.; Brottelli, D. R.; Wang, C. L. J., et al.
J. Med. Chem. 1989, 32, 1673.
5. Park, C. H.; Brittelli, D. R.; Wang, C. L. J., et al. J. Med.
Chem. 1992, 35, 1156.
6. (a) WO 09.103 1993; Chem. Abstr. 1993, 119, 160265u. (b)
WO 14684, 1995; Chem. Abstr. 1995, 123, 314020g.
7. Gregory, W. A.; Brottelli, D. R.; Wang, C. L. J., et al.
J. Med. Chem. 1990, 33, 2569.
8. Physical constants: 1a: mp: 226–230 ꢀC; [a]D27 (ꢀ): À6 (c
0.63, DMSO). 1b: mp: 222–226 ꢀC; [a]D27 (ꢀ): À2.7 (c 0.76,
27
ꢀ
CHCl3). 1c: mp: 206–209 C; [a]D (ꢀ): À12 (c 2.03, CHCl3).
1d: [a]2D7 (ꢀ): À7 (c 5.52, CHCl3). 1e: mp: 181–183 C; [a]D (ꢀ):
27
ꢀ
À11 (c 5.10, CHCl3).