Novel Chiral Skeletons for Drug Discovery: Antibacterial Tetramic Acids

Article abstract of DOI:10.1111/j.1747-0285.2011.01133.x

Modification of the ring nucleus of tetramic acids derived from serine gives chiral heterocyclic libraries that exhibit antibacterial activity, and correlation with various physicochemical parameters indicates that chiral tetramic acids may provide a potentially valuable non-aromatic skeleton for fragment-based drug discovery. Chiral tetramates are useful chiral fragments which may be used to generate libraries with antibacterial activity.

Full text of DOI:10.1111/j.1747-0285.2011.01133.x

ª 2011 John Wiley & Sons A/S
doi: 10.1111/j.1747-0285.2011.01133.x
Chem Biol Drug Des 2011; 78: 229–235
Research Article
Novel Chiral Skeletons for Drug Discovery:
Antibacterial Tetramic Acids
tetramate system is nonetheless of interest because the skeleton
Chloe A. Holloway, Christopher J.
Matthews, Yong-Chul Jeong, Mark G.
Moloney*, Christine F. Roberts and
Muhammad Yaqoob
obeys the 'rule of three' (M < 300; number of H-bond donors £3
and acceptors £3; cLogP £3; number of rotatable bonds £3; polar
surface area £60 ꢀ2), which has been suggested to be optimal for
the construction of fragment libraries (24,25), and ring modification
giving natural product analogues might be envisaged which would
lead to the restoration of antibacterial activity. We report here
success in that regard and validation of the concept of the use of
natural products as lead structures for the identification of novel
enantiopure fragments suitable for antibacterial development;
the neglect of chiral centres has been recognized as a key defi-
ciency of drug discovery methodology (26), and the potential value
of this approach is highlighted by the recently reported difficulties
and inefficiencies of contemporary antibacterial drug development
(27).
Department of Chemistry, Chemistry Research Laboratory, University
of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
*Corresponding author: Mark G. Moloney,
mark.moloney@chem.ox.ac.uk
Modification of the ring nucleus of tetramic acids
derived from serine gives chiral heterocyclic
libraries that exhibit antibacterial activity, and
correlation with various physicochemical parame-
ters indicates that chiral tetramic acids may pro-
vide a potentially valuable non-aromatic skeleton
for fragment-based drug discovery.
Using Seebach's concept of self-regeneration of stereocentre reac-
tions (28), we have developed effective synthetic methodology for
the preparation of optically active tetramic acid analogues derived
from serine (16–18). This exploits the propensity of oxazolidines to
control both the chemoselectivity and stereoselectivity of intramo-
lecular Dieckmann reactions, giving an efficient cyclization leading
to enantiopure tetramate products. Thus, serine methyl ester 1 was
treated with pivaldehyde to give oxazolidine 2 (16) and acylated
with carboxylic acids to give malonamides 3a–c (Scheme 1). These
materials were readily closed by Dieckmann reaction to the product
tetramates 4a–c using our previously reported protocol (16), in
yields of 66–84%. Alkylation using benzyl bromide, 2-(bromometh-
yl)pyridine hydrobromide or 4-iodo-3,3-dimethylisoxazole, chosen for
their range of hydrophilicity values (vide supra), gave the O-alkyl
products 6a,b starting from tetramate 4a (R = H), or the C-alkyl
products 5f–h starting from phenyl substituted tetramate 4c, but a
mixture of the O-alkyl products 6d and the C-alkyl products 5e
starting from methyl tetramate 4b (Table 1). No C-alkyl products
were obtained in the reaction of 4a nor O-alkyl products in the
case of 4c. Yields, however, were variable and in some cases
remained low, and the most reliable conditions were found to be
sodium hydride in THF at 0 ꢀC followed by addition of the alkyl
halide at 40 ꢀC; the simplicity of the procedure, however, readily
provided ample material for evaluation. Interestingly, when these
conditions were applied to 4c, the decarboxylated material 7 was
obtained in 29% yield along with 5f (24%), but conducting the
alkylation reaction at )78 ꢀC gave only the desired product 5f in
fair yield (40%). Assignment of stereochemistry was easily achieved
by nOe experiments (Figure 1). Deprotection of both the tetramate
and enol ether products was achieved using the Corey–Reichard
conditions, and alcohols 8a–e and 9a–c were readily obtained in
Key words: drug design, molecular diversity, natural product
Received 17 February 2011, revised 13 April 2011 and accepted for pub-
lication 4 May 2011
Amongst a number of strategies applied to antibacterial drug devel-
opment, high-throughput (1) and diversity-oriented synthesis (2) have
emerged as valuable tools, but diverted total synthesis and natural
product–inspired synthesis provide valuable alternatives (3,4). In
fact, re-examination of the function and availability of natural prod-
ucts has proved to be a key impetus in recent innovation (5), and
natural product–inspired synthesis (6–8) and its potential for drug
development are gaining renewed acceptance (9,10). It has recently
been reported that the physicochemical characteristics of antibacte-
rial compounds differ from the property space of commonly avail-
able compound libraries (11) and that natural product libraries can
allow the identification of privileged structures that are suitable
leads for optimization in drug discovery (12), because they can be
Lipinski compliant (13).
We have been interested in the tetramic acid nucleus, because it
occurs widely in antibacterial natural products (14), and have devel-
oped effective synthetic methodology for the rapid preparation of
enantiopure tetramic acid analogues derived from serine (15–18)
and threonine (19,20). Although a number of these analogues were
found to exhibit some antibacterial activity against Staphylococcus
aureus and Escherichia coli, we also showed recently that simple
tetramates possess little or no intrinsic antibacterial activity (21),
but that activity may be restored by hybridization with amide
mimics of the side chain of oxazolomycin (22,23). However, the
229

Holloway et al.
Table 1: Alkylation and deprotection reactions of tetramates
4a–c (see Scheme 1 and Figure 1 for side chain structure)
chemical genetic (phenotypic) screens in these cell-based systems
is that hits are automatically selected for their combination of activ-
ity and cell permeability properties, and without any bias or prese-
lection of the most optimal target of a pathway, although the
downside is that further optimization requires identification of tar-
get (35,36). Of significance is that the core tetramate skeletons
4a–c exhibited no antibacterial activity against both S. aureus and
E. coli, in keeping with other results which we have published, indi-
cating that the tetramate core possesses no intrinsic bioactivity
(21). However, examples of substituted tetramates with antibacterial
activity are well known (14), and although most compounds exam-
ined here were inactive against S. aureus, significant activity was
observed in the case of substituted tetramate 5g, with lesser activ-
ity for 8d,e and 11a,b, and of interest was the activity of the enol
ester 9a. Activity against E. coli was also observed for 6a and
8b–e, and notable was the activity of the deprotected compounds
8e and 9a–c. Furthermore, although the enones 11c and 12a,b
and epoxides 13a,b were inactive against S. aureus, several dis-
played considerable activity against E. coli, with 11b being the
most potent. Only compounds 8d, 8e, 9a and 11a were active
against both S. aureus and E. coli. The significantly lower cell wall
permeability of Gram-negative bacteria, as a result of the presence
of the lipopolysaccharide outer membrane, is well known, and this
makes the development of novel Gram-negative antibacterials par-
ticularly challenging (11), so the activity of the libraries of com-
pounds 7, 8, 9 and 10 is noteworthy. This outcome is of interest
because the equisetins, of which the libraries derived from tetra-
mates 4 could be considered to be mimics, display activity against
both S. aureus and E. coli.
Yield (%)
Alkylation
Deprotection
R1
R2
C-Alkyl 5
O-Alkyl 6
C-Alkyl 8
O-Alkyl 9
H
H
H
Me
Me
Me
Ph
Ph
Ph
Ph
H
–
5a (0)
5b (0)
–
5d (0)
5e (21)
–
5f (14)
5g (12)
5h (31)
–
6a (35)
6b (23)
–
6c (2)
6d (22)
–
6e (0)
6f (0)
6g (0)
8a (41)
–
PhCH2
C5H4NCH2
H
PhCH2
C5H4NCH2
H
PhCH2
C5H4NCH2
C5H6NOCH2
–
–
9a (72)
9b (75)
8b (66)
–
–
–
–
9c (46)
8c (59)
8d (79)
–
–
–
–
–
8e (63)
good yield to excellent yield (16) (Scheme 2); deprotection of lac-
tam 7 gave alcohol 10 in 62% yield (Scheme 3).
Alternative direct homologation of the tetramate nucleus 4a using
aldol-type chemistry was found to be feasible, using an extension
of literature methodology (29,30). Thus, reaction of benzaldehyde or
veratraldehyde under acidic conditions gave the corresponding prod-
ucts 11a,b in moderate yield (Scheme 1) without oxazolidine cleav-
age, as a 1:1 mixture of diastereomers. If this reaction was
conducted using dimethylformamide dimethyl acetal in DCM at
reflux using the literature method (31,32), the enamine 11c was
obtained in 96% yield as a 1:1 mixture of diastereomers. This latter
compound could be reacted with Grignard reagents PhMgBr, Me-
MgBr and C6H11MgBr (33) to give the alkene products 11a, and
12a,b in good yield (38%, 80% and 65%, respectively), all as 1:1
mixtures of (E,Z)-diastereomers. An attempt at the epoxidation of
enone 12a using alkaline hydrogen peroxide gave only a 5% yield
of the desired product 13a, but when 12b was epoxidized using
hydrogen peroxide at pH 9 in dichloromethane, the corresponding
epoxide 13b was obtained in good yield (54%) as a 4:2:1 ratio of
inseparable diastereomers (34).
Chemical informatics analysis is instructive (Table 2); cLogP values
confirm the lipophilic character of protected compounds 4a–c, 5e–
h, 6a–e, 7, 11a–c, 12a,b and 13a,b but the significantly more
hydrophilic character of the deprotected equivalents 8a–c, 9a–c,
10 and 14, as might be expected. The van der Waals molecular
surface area (MSA) is in the range of 250–650 ꢀ2 (37), as would
be expected from their common structural skeleton. The small num-
ber of S. aureus actives (8) appears to exhibit bimodal activity, with
six non-polar compounds possessing cLogP and %PSA values of
2.9 € 0.5 and 15.7 € 1.7, and two polar compounds values of
0.6 € 0.8 and 22.6 € 0.3, respectively. The larger number of E. coli
actives (16) similarly exhibited bimodal activity, with 10 non-polar
compounds possessing cLogP and %PSA values of 2.3 € 0.9 and
16.5 € 3.0 and six polar compounds values of )0.6 € 0.6 and
26.2 € 4.1. Activity of these compounds against E. coli is observed
across a much wider range of cLogP and MSA values than for
S. aureus; this can be graphically seen in Figure 2A, in which cLogP
values of S. aureus and E. coli active ⁄ inactives are plotted against
Bioassay of these compound libraries against S. aureus and E. coli
using the hole-plate methoda gave the results indicated in Table 2,
in which the inhibitory activity is measured as the diameter of the
inhibition zone obtained after overnight incubation of the substrate
with the relevant bacteria; although not giving quantitative MIC val-
ues, these assays were nonetheless suitable for our purpose, giving
active ⁄ not active outcomes enabling rapid assessment of the struc-
tural variations of the fragment modification. The value of forward
Figure 1: NOE Characterisation
of Tetramate Stereochemistry.
230
Chem Biol Drug Des 2011; 78: 229–235

Novel Chiral Skeletons for Drug Discovery
MeO2C
HN
MeO2C
R
CO2Me
OH
(i)
(ii)
O
EtO
N
O
71–74%
Cl-H3N+
84%
O
O
t-Bu
t-Bu
1
2
3a R = H (67%)
3b R = CH3 (82%)
3c R = Ph (82%)
(iii)
O
R
R
O
CO2Me
(vi)
4a only
CO2Me
O
N
O
N
O
O
t-Bu
t-Bu
4a R = H (66%)
4b R = CH3 (84%)
4c R = Ph (74%)
11a R = Ph (16%)
11b R = (MeO)3C6H2 (37%)
11c R= NMe2 (96%)
(iv)
(vii)
11c only
R2
R1
O
R2
O
R1
R
CO2Me
CO2Me
O
+
O
O
CO2Me
N
N
O
O
O
N
t-Bu
t-Bu
O
t-Bu
5e-h
6a-d
11a R = Ph (38%)
12a
R = CH3 (80%)
12b R = C6H11 (65%)
(v)
O
(v)
(viii) 12a,b only
R2
R1
O
R2
CO2Me
R
O
N
O
R1
CO2Me
CO2Me
O
O
N
N
H
O
H
HO
HO
9a-c
O
t-Bu
8a-e
13a R = CH3 (5%)
13b R = C6H11 (54%)
(i) Me3CCHO, petrol (40/60), reflux, 16-20h; (ii) DCCI, DMAP, EtO2CCH(R)CO2H, DCM, rt; (iii) KOt-Bu, t-BuOH,
reflux; (iv) NaH, R2CH2Br, THF, 0oC - 40oC; (v) HS(CH2)3SH, CF3CH2OH, HCl, r.t.; (vi) ArCHO, MeOH, HCl or
DMF.DMA; (vii) RMgBr, -40o then r.t.,THF; (viii) H2O2, CH2Cl2, pH 9 or H2O2, MeOH, NaOH
Scheme 1: Synthesis of tetra-
mate derived libraries.
PhCH2
O
O
Me2N
PhCH2
Ph
O
HS(CH2)3SH,
CF3CH2OH,
HCl, r.t., 3 days
Ph
O
CO2Me
(i)
H
(ii)
H
4c
O
11c
O
N
N
H
N
H
(99%)
O
HO
HO
t-Bu
14
7
10
(i) NaH, PhCH2Br, THF, 0oC - 40oC (29%) ; (ii) HS(CH2)3SH, CF3CH2OH, HCl, r.t. (62%)
Scheme 3: Deprotection of a tetramate.
Scheme 2: Synthesis and deprotection of fully substituted tet-
ramates.
118.7, 84.9 and 100.6. The notable activity of pyridyl-substituted
5g is likely to be the result of its high basicity (pKa = 6). Activity
against E. coli is observed across a much wider range of %PSA val-
ues and at higher %PSA than for S. aureus, as seen in Figure 2B,
in which %PSA of S. aureus and E. coli active ⁄ inactives is plotted
against PSA. Overall, the data in Figure 2 indicate that E. coli anti-
bacterial activity is observed for compounds of greater hydrophilicity
than for S. aureus activity.
MSA. The polar surface area parameter (PSA), which correlates the
presence of polar atoms with membrane permeability and therefore
gives an indication of drug transport properties (38), has been
reported to have an optimal value of 70 < PSA < 120 ꢀ2 for a non-
CNS orally absorbable drug (39), and of interest is that the most
active compound 5g against S. aureus possessed a PSA value of
86 ꢀ2, and for those against E. coli (8e, 9a and 11b), values of
Chem Biol Drug Des 2011; 78: 229–235
231

Holloway et al.
Moreover, recently reported ADMET rules of thumb (40) indicate that
the compounds described herein, with MW < 400 and cLogP < 4
predominantly as neutral molecules, are likely to exhibit average val-
ues for a variety of indicators (including solubility, bioavailability,
plasma protein binding, P-gp efflux and in vivo clearance) and there-
fore provide good library starting points. It has also recently been
established using a random forest statistical analysis that lipophilici-
ty strongly correlates with adverse toxicity in vivo, with a signifi-
cantly higher probability of an adverse indication if cLogP and PSA
are >3 and <75 ꢀ2, respectively, than if they are <3 and in the range
of 100–130, respectively (41); although the compounds reported
herein do not fulfil both of these criteria precisely, they are in most
cases close to these values and in any case allow scope for adjust-
ment, as would be required in any lead optimization process.
)0.1, 165 and 42, respectively (11). In terms of these property
values, the bioactive tetramates reported in this work most nearly
resemble the fluoroquinolones, which have average values of
molecular weight (371), cLogP(1.3), PSA(82) and %PSA(25), H-
donors (2.1) and H-acceptors (6.5). However, we have no data
related to their mode of action, although tetramate systems are
known to exhibit RNA polymerase (42), UPPS (43) and LuxR
(44,45) inhibitory activity.
Recently, there has been interest not only in the identification of
novel but synthetically tractable heterocyclic systems (46) but also
of increasing molecular complexity by moving away from planar sys-
tems in the process of drug discovery (47,48). Furthermore, the
changing role of organic chemistry in drug discovery and the need
for synthesis design to respond to multiparametric inputs have been
noted (49). Our work demonstrates that enantiopure skeletons,
which might be considered to be simpler mimics of natural
products, with several points of diversity, are available in <3 syn-
thetic steps and that further simple modification gives structures
that exhibit bioactivity properties akin to that of the parent natural
product. Moreover, these systems, despite their three-dimensional
complexity, offer favourable values of MW, PSA and numbers of
rotatable bonds, H-bond acceptors and H-bond donors, while leav-
Of interest is that O'Shea and Moser (11) note that Gram-negative
bacteria are intrinsically more resistant to antibacterials as a
result of a more impermeable outer cell membrane, and particu-
larly efficient efflux pumps; for this reason, the mean compound
property values of Gram-negative and Gram-positive active anti-
bacterials differ. Thus, molecular weight, cLogP, PSA and %PSA
for Gram-positive active antibacterials are 813, 2.1, 243 and 30,
respectively, but for Gram-negative active antibacterials are 414,
Table 2: Bioassay and cheminformatic data for tetramates 4–14
Bioactivity2
Staphylococcus aureus
Zone diameter ⁄ mm
Escherichia coli Zone
diameter ⁄ mm
Compound
LogP1
PSA1
%PSA1
MSA1
4a
1.29
1.83
2.96
2.62
5.10
3.75
3.79
2.61
1.47
1.61
3.00
5.1
)1.36
)0.81
0.32
2.45
1.15
)0.04
)1.17
)0.78
2.45
3.34
2.87
1.33
2.12
3.73
1.54
3.29
)1.32
72.9
72.9
72.9
85.8
72.9
85.8
98.9
65.1
78.0
65.1
65.1
46.6
92.7
92.7
92.7
92.7
118.7
84.9
97.8
97.8
66.4
72.9
100.6
76.2
72.9
72.9
85.4
85.4
95.9
18.8
17.8
14.9
15.5
11.6
13.8
15.1
12.6
15.4
14.8
11.9
8.4
36.9
33.1
22.7
18.8
22.8
22.4
26.3
24.2
15.8
14.8
15.7
16.1
17.5
13.5
19.4
15.2
28.5
386.0
414.7
488.9
553.7
626.7
621.7
656.4
514.0
506.9
439.1
545.4
557.6
251.4
279.7
408.7
491.9
520.6
378.3
371.2
403.3
421.0
492.1
642.4
472.1
417.3
540.1
439.3
561.3
337.0
Inactive
Inactive
Inactive
13
Inactive
25
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
15
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
14
Inactive
Inactive
Inactive
Inactive
Inactive
16
4b
4c
5e
5f
5g
5h
6a
6b
6c
6d
7
8a
8b
8c
14
18
19
19
18
15
14
18
8d
8e
14
15
Inactive
Inactive
12
9a
9b
9c
10
11a
11b
11c
12a
12b
13a
13b
14
15
15
19
18
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
13
12
16
14
1LogP, polar surface area parameter (PSA) and MSA calculated using Marvinb; %PSA = (PSA ⁄ MSA) · 100%.
2Hole-plate bioassay using 100 ll of a 4 mg ⁄ ml (DMSO) with inhibition zone diameter quoted in mm (€1 mm).a
232
Chem Biol Drug Des 2011; 78: 229–235

Novel Chiral Skeletons for Drug Discovery
6
5
6
5
A
Active S
Active E
Inactive S
Inactive E
4
4
3
3
2
2
1
1
0
0
–1
–2
–1
–2
200
300
400
500
600
700
200
300
400
500
600
700
MSA
MSA
40
35
30
25
20
15
10
5
40
B
% PSA active E
Active S
Inactive S
% PSA inactive E
35
30
25
20
15
10
5
40 50 60 70 80 90 100 110 120
40 50 60 70 80 90 100 110 120
PSA
PSA
Figure 2: Plots of bioassay and cheminformatic data from Table 2 for Staphylococcus aureus (S) and Escherichia coli (E) active ⁄ inactives
(A) cLogP against MSA; (B) %PSA against PSA.
ing ample scope for ADMET optimization in the drug discovery pro-
cess using the Lipinski parameters. They therefore offer viable skel-
etons for application in fragment-based drug design (50), in which
there is significant current interest (51). There is no doubt therefore
that 'escaping from flatland' (47) is possible and that the proposed
benefits of such liberation may be more accessible than has hith-
erto been assumed.
tion Grant funded by the Korean Government (MOEHRD) (KRF-2006-
352-C00044) (YJ).
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Notes
aBioassay of penicillin products: Microbiological assays were per-
formed by the hole- plate method with the test organism Staphylo-
coccus aureus N.C.T.C. 6571 or E. coli X580. Solutions (100 ll) of
the compounds to be tested (4 mg ⁄ ml) were loaded into wells in
bioassay plates, and incubated overnight at 37 ꢀC. The diameters
of the resultant inhibition zones were measured (€1 mm).
bMarvin was used for drawing, displaying and characterizing chemi-
cal structures, substructures and reactions, Marvin 5.2.1, 2009,
ChemAxon (http://www.chemaxon.com). Calculator Plugins were
used for structure property prediction and calculation, Marvin
5.2.5.1, 2009, ChemAxon (http://www.chemaxon.com).
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