New benzylidenethiazolidinediones as antibacterial agents

Article abstract of DOI:10.1016/j.bmcl.2003.07.010

A novel benzylidenethiazolidinedione has been discovered with antimicrobial activity. Here, we present the results of a structure-activity study on this compound with respect to its antimicrobial activity.

Full text of DOI:10.1016/j.bmcl.2003.07.010

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3771–3773
New Benzylidenethiazolidinediones as Antibacterial Agents
Dirk A. Heerding,a,* Lisa T. Christmann,a Tammy J. Clark,a David J. Holmes,b
Stephen F. Rittenhouse,b Dennis T. Takataa and Joseph W. Venslavskya
aMedicinal Chemistry Department, Microbial, Musculoskeletal and Proliferative Diseases,
GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Road, Collegeville, PA 19426, USA
bMicrobial Genetics and Biochemistry Department, Microbial, Musculoskeletal and Proliferative Diseases,
GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Road, Collegeville, PA 19426, USA
Received 8 October 2002; accepted 31 July 2003
Abstract—A novel benzylidenethiazolidinedione has been discovered with antimicrobial activity. Here, we present the results of a
structure–activity study on this compound with respect to its antimicrobial activity.
# 2003 Elsevier Ltd. All rights reserved.
Wide spread resistance to many commercially available
antibiotics is emerging and it is predicted that resistance
to these agents will only increase.1 There are now
examples of both Gram-positive and Gram-negative
infections which are resistant to all known commercial
agents.2 The discovery of novel antibacterial agents
working through an unexploited mechanism of action
are less likely to be compromised by pre-existing resis-
tance mechanisms to currently used antibiotics.3 As part
of our effort to identify such new antibiotic agents,4 we
have screened our proprietary compound collection for
whole cell activity against Staphylococcus aureus. Hits
were further profiled to identify compounds with at
least a Gram positive spectrum of activity (MIC values
<16 mg/mL) with a mechanism of action other than
general non-specific cytotoxicity.5 Compound 1 was
identified as meeting our criteria for further study.
Herein we present the structure–activity relationships
developed around 1.
described herein were prepared in a similar manner.
Analogues racemic at the secondary alcohol were pre-
pared using epichlorohydrin instead of (2R)-(À)-glyci-
dyl 3-nitrobenzenesulfonate. Compound 2 was prepared
in a similar manner using (2S)-(À)-glycidyl 3-nitro-
benzenesulfonate. Using 1,3-dichloropropane in place
of (2R)-(À)-glycidyl 3-nitrobenzenesulfonate gave the
des-hydroxy analogue 3. Ketone 4 was prepared by
oxidation of 1 using Dess–Martin periodinane.6 Reduc-
tive amination with ammonia furnished the primary
amine 5.
Table 1. Effect of varying the secondary hydroxyl group on anti-
bacterial activity
Compound 1 was prepared as shown in Scheme 1. The
cesium salt of 4-hydroxybenzaldehyde was condensed
with (2R)-(À)-glycidyl 3-nitrobenzenesulfonate to give
the corresponding epoxyaldehyde 21. Compound 21
was then condensed with the cesium salt of phenol 22 to
give the secondary alcohol 23. A Knoevenagel con-
densation with 2,4-thiazolidinedione then furnished the
final compound 1. The majority of the compounds
Compd
X
MICa (mg/mL)
SAURb
EFAEc
SPNEd
1
2
3
4
5
(S) CH(OH)
(R) CH(OH)
CH2
C(O)
(rac) CH(NH2)
2
1
>64
>64
16
4
64
>64
>64
32
2
1
>64
>64
2
aMinimal inhibitory concentration.
bS. aureus Oxford.
cE. faecalis 7.
dS. pneumoniae ERY2.
*Corresponding author. Tel.: +1-610-917-7944; fax: +1-610-917-
4206; e-mail: dirk_a_heerding@sbphrd.com
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.07.010

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D. A. Heerding et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3771–3773
Moraxella catarrhalis or Escherichia coli. The lack of
Gram-negative activity does not appear to be due to
enhanced efflux of the compound as no antimicrobial
activity was observed when 1 was tested in the presence
of a potent efflux inhibitor, MC-207,1109,10 as well as
being inactive against E. coli AcrAB-. This by no means
precludes the possibility that the target of 1 exists in
Gram-negative bacteria and that inactivity may simply
be due to lack of penetration into these organisms.
While the antibacterial activity against S. aureus and
Staphylococcus pneumoniae was not appreciably affected
by changing the absolute steroechemistry of the sec-
ondary hydroxyl group (1 and 2, Table 1), a 16-fold
drop in activity against Enterococcus faecalis was seen.
This cannot be readily explained at this time. It appears
that a proton or hydrogen bond donor is required at
this position as the des-hydroxy compound (3) and the
Table 2. Effect on variations around the thiazolidinedione moiety on
antibacterial activity
Compd
R1
R2
MICa
SAURb EFAEc SPNEd
Scheme 1. Preparation of 1, 4 and 5: (a) (i) CsF (3 equiv), DMF, rt,
1.5 h; (ii) (2R)-(À)-glycidyl 3-nitrobenzenesulfonate (1.02 equiv), rt, 18
h, 86%; (b) (i) CsF (3.1 equiv), DMA, rt, 1.5 h; (ii) 21 (0.7 equiv),
DMA, 150 ꢀC, 5 h, 52%; (c) 2,4-thiazolidinedione (1.75 equiv), piper-
idine (0.3 equiv), benzoic acid (0.2 equiv), toluene, reflux, 5 h, 39%; (d)
Dess–Martin reagent, 73%; (e) NH3, MeOH, NaCNBH3, 49%.
6
7
H
H
>64
>64
>64
16
16
32
8
H
H
H
4
>64
8
4
64
16
4
64
8
9
Scheme 2. Preparation of 9: (a) 3-(triphenyl-l5-phosphanyl)-pyrroli-
dine-2,5-dione (1 equiv), MeOH, rt, 16 h, 38%.
10e
The maleimide moiety of 9 was installed following the
method of Paternotte7 as shown in Scheme 2.
11
12
H
8
8
8
4
4
1
Whole-cell antimicrobial activity was determined by a
broth microdilution procedure.8 Compounds were tes-
ted in serial 2-fold dilutions ranging from 0.06 to 64 mg/
mL. The minimum inhibitory concentration (MIC) was
determined as the lowest concentration of compound
that inhibited visible growth.
H
aMinimal inhibitory concentration.
bS. aureus Oxford.
cE. faecalis 7.
Further characterization of the antibacterial activity of 1
revealed this compound to be a Gram-positive agent
only. No activity was seen against Hemophilus influenzae,
dS. pneumoniae ERY2.
ePrepared by catalytic reduction (H2, 1 atm, 10% Pd/C) of compound 1.

D. A. Heerding et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3771–3773
3773
Table 3. Terminal aryl ring variation and antibacterial activity
We have discovered a new series of Gram-positive anti-
bacterial agents. The promising level of antibacterial
activity seen with this series of compounds has promp-
ted further investigation into the mode of action of this
class of compounds. These studies will be reported in
due course.
Compd
R1
R2
R3
R4
MICa (mg/mL)
References and Notes
SAURb
EFAEc
SPNEd
1. Bush, K.; Macielag, M. Curr. Opin. Chem. Biol. 2000, 4,
433.
2. Bax, R.; Mullan, N.; Verhoef, J. Int. J. Antimicrob. Agents
2000, 16, 51.
3. Wendler, P. A.; Silverman, J. A. Curr. Opin. in Anti-Infec-
tive Invest. Drugs 2000, 2, 125.
13
14
15
16
17
18
19
H
Me
Et
nPr
nPr
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
H
H
Cl
H
H
>64
64
16
16
8
>64
>64
>64
>64
32
>64
8
64
32
16
2
4
>64
64
H
Cl
Cl
Cl
>64
>64
Cl
4. Holmes, D. J.; Throup, J. P.; Wallis, N. G.; Burnham,
M. K. R.; Zalacain, M.; Biswas, S.; Chalker, A. F.; Ingraham,
K. A.; Marra, A.; Bryant, A.; Woodnutt, G.; Warren, P. V.;
Brown, J. R.; Rosenberg, M. Focus Biotechnol. 2001, 1, 23.
5. The cytotoxicity of the compounds was evaluated by mea-
suring cell viability in a human type II lung cell line (A549
cells). Cell viability was colorimetrically estimated by measur-
ing the metabolism of XTT to its formazan derivative.
6. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
7. Paternotte, I.; Fan, H. J.; Screve, P.; Claesen, M.; Tulkens,
P. M.; Sonveaux, E. Bioorg. Med. Chem. 2001, 9, 493.
8. Compounds in DMSO were diluted 1:10 with water giving
a 256 ug/mL solution. This solution (50 mL) was serially dilu-
ted into cation adjusted Mueller Hinton broth. A 50 mL ali-
quot of bacteria (ca. 1Â106 cfu/mL) was added to each well.
Inoculated plates were incubated at 35 C for 24 h. Minimum
inhibitory concentration (MIC)=the lowest concentration of
compound that inhibited visible growth.
9. Barrett, J. F. Curr. Opin. Investig. Drugs 2001, 2, 212.
10. Lomovskaya, O.; Warren, M. S.; Lee, A.; Galazzo, J.;
Fronko, R.; Lee, M.; Blais, J.; Cho, D.; Chamberland, S.;
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aMinimal inhibitory concentration.
bS. aureus Oxford.
cE. faecalis 7.
dS. pneumoniae ERY2.
corresponding ketone (4) are inactive whereas the amine
(5) retains Gram-positive antibacterial activity.
Next, we investigated the role of the thiazolidinedione
moiety (Table 2). Having an N–H at the 3-position of
the five-membered ring is a minimum requirement for
activity. Although the thiazolidinedione moiety can be
considered as a carboxylic acid isostere,11À13 no corre-
lation was seen between the calculated pKa values of this
group and antibacterial activity. A heteroatom at the 1-
position of the five-membered ring is also needed for
antibacterial activity (9 vs 1, 7 or 8). A sulfur or nitro-
gen atom appears to confer slightly better antibacterial
activity than oxygen at this position. There also appears
to be improved activity for the benzylidene thiazolidi-
nedione over the benzyl thiazolidinedione and for this
group to be located para with respect to the ether sub-
stituent (10 and 11). A carbonyl or thiocarbonyl group
at the 2-position is equivalent with respect to anti-
bacterial activity (1 and 12).
12. Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown,
K. K.; Cobb, J. E.; Collins, L.; Harrington, W. W., Jr.;
Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, A.;
Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard,
J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A.;
Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.; Szewc-
zyk, J. R.; Willson, T. M. J. Med. Chem. 1998, 41, 5020.
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Coyle, P. J.; Dean, D. K.; Faller, A.; Haigh, D.; Hindley,
R. M.; Jefcott, L. J.; Lister, C. A.; Pinto, I. L.; Rami, H. K.;
Smith, D. G.; Smith, S. A. Bioorg. Med. Chem. Lett. 1996, 6,
2121.
Finally, the effect of variations on the terminal aromatic
ring were examined (Table 3). An alkyl group at R2
appears to be a minimum requirement for activity with
a slight preference for a propyl group (14, 15, and 16).
In addition to the propyl group, chlorination of the ring
improves antibacterial activity (17), however, chlorina-
tion alone is not sufficient for antibiotic activity (18 and
19). The antimicrobial activity of this series of com-
pounds appears to be optimized with the combination
of functional groups found in 1.