Synthesis, antibiotic activity and structure-activity relationship study of some 3-enaminetetramic acids

Article abstract of DOI:10.1016/j.bmcl.2014.03.013

The synthesis and evaluation of 3-enaminetetramic acids as antibacterial agents is reported; contrary to the analogous 3-acyltetramic acids, the enaminetetramic acid class of compound exhibits modest antibacterial activity against a limited spectrum of organisms, and even that activity is strongly dependent on the identity of the tetramate ring substituents. Moreover, these compounds appear to have a different mode of action to the analogous 3-acyltetramic acids, and appear to offer more limited opportunity for further elaboration in drug discovery.

Full text of DOI:10.1016/j.bmcl.2014.03.013

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1901–1906
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antibiotic activity and structure–activity relationship
study of some 3-enaminetetramic acids
⇑
Yong-Chul Jeong, Muhammad Anwar, Mark G. Moloney
Chemistry Research Laboratory, University of Oxford, Mansfield Rd, Oxford OX1 3TA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and evaluation of 3-enaminetetramic acids as antibacterial agents is reported; contrary to
the analogous 3-acyltetramic acids, the enaminetetramic acid class of compound exhibits modest anti-
bacterial activity against a limited spectrum of organisms, and even that activity is strongly dependent
on the identity of the tetramate ring substituents. Moreover, these compounds appear to have a different
mode of action to the analogous 3-acyltetramic acids, and appear to offer more limited opportunity for
further elaboration in drug discovery.
Received 20 January 2014
Revised 5 March 2014
Accepted 6 March 2014
Available online 14 March 2014
Keywords:
Tetramate
Antibacterial
Enamine
Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.
O
R1
R1
R1
O
OH
H
N
R1
O
O
NH
3
R5
R6
O
H
N
H
HO
O
R4
OH
R4
R3
O
R4
HO
N
H
O
O
O
HO
3
O
Cl
3
5
1
5
5
1
Cl
1
O
O
O
H
N
N
N
R3
N
R3
R2
1a
H
R2
1b
R2
1d
R2
1c
H
O
OH
HO
O
H
O
O
HO
H
N
Figure 2. 3-Acyltetramic acid 1a, 3-carboxamidotetramic acid 1b, piperidine-2,4-
dione one 1c and 3-enaminetetramic acid 1d skeletons.
N
H
HO
O
O
O
N
O
O
O
O
N
H
O
O
H2N
Biologically active natural products are a source of lead com-
pounds for structural optimization in drug discovery,1–4 and those
containing the 3-acyltetramic acid subunit are of considerable
interest since they possess diverse biological activities.5–14 Those
3-acyltetramates with antibiotic activity are known to possess a
range of modes of action, and include streptolydigin (bacterial
RNA polymerase inhibitory activity),12 kibdelomycin (bacterial
type II topoisomerase inhibitory activity)13 and signermycin B (his-
tidine kinase WalK inhibitory activity),14 but all have sufficiently
complex structures that their synthesis is challenging (Fig. 1).
However, appropriate modification of the core tetramate skeleton
of these natural products can provide rapid access to antibacterially
active small molecule libraries, and this includes derivatives of the
3-acyltetramic acid 1a, 3-carboxamidotetramic acid 1b and the
piperidine-2,4-dione one 1c skeletons (Fig. 2).15–18 In order to extend
the scope of this work, exploration of the synthesis, bioactivity and
structure–activity relationships (SARs) of 3-enaminetetramic acids
1d, derived by exchanging 3-acyl for 3-enamine functionality, is
reported here. Interestingly, unlike 3-acyltetramic acids, 3-ETs
are very rarely found in nature;8 fischerellin A (Fig. 1) is one
OH
O
streptolydigin (1a)
kibdelomycin (1b)
signermycin B (1c)
R1
R1
R2
NH
R1
R1
O
O
N
O
N
OH
R4
O
R4
R3
O
HO
R3
3
R5
R6
HO
5
1
N
O
O
N
O
N
R3
R4
1g
R2
R2
R2
1d
1e
1f
O
C5H11
N
N
H
O
fischerellin A (1h)
Figure 1. Tetramate-containing natural products.
⇑
Corresponding author. Tel.: +44 1865 275656.
E-mail address: mark.moloney@chem.ox.ac.uk (M.G. Moloney).
http://dx.doi.org/10.1016/j.bmcl.2014.03.013
0960-894X/Crown Copyright Ó 2014 Published by Elsevier Ltd. All rights reserved.

1902
Y.-C. Jeong et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1901–1906
Figure 3. 3-Enaminetetramic acids (21 analogues).
O
R2
HN
R1
N
O
C9H19
N
O
O
C6H13
N
H
HN
O
3a; R1 = Ph, R2 = C6H13
O
N
H
3b; R1 = 1-naphthyl, R2 = cy-Hexyl
3c; R1 = 1-naphthyl, R2 = benzyl
3d; R1 = C9H19, R2 = Ph
O
N
H
3f
3g
3e; R1 = C11H23, R2 = (CH2)3OCH(CH3)2
RHN
NHR
C11H23
O
N
HN
C13H27
HN
HN
O
O
O
O
O
N
C6H13
N
C6H13
3l
N
C6H13
3h; R = H
3j; R = H
3i; R = COCH2OCH2CO2H
3k; R = COCH2OCH2CO2H
X
Ph
R2
R
R1
O
N
N
OPh
N
C6H13
R
R1
HN
HN
N
O
O
N
H
O
O
O
N
H
H
O
O
O
O
O
N
N
N
N
N
O
C6H13
O
C3H7
C6H13
S
O
O
C3H7
O
4f
4e
4d
4a; R1 = R2 = H, X = O
4g; R = H
4h; R = Me
4b; R1 = Me, R2 = H, X = O
4c; R1 = H, R2 = Me, X = CH2
N
O
N
O
OPh
N
C5H11
O
C10H21
HN
O
O
N
H
O
NH
C11H23
O
O
N
H
O
N
O
O
O
N
N
H
S
O
S
N
H
O
Ph
O
5
4i
4j
4k
Figure 4. 3-Enaminetetramic acids (24 analogues).

Y.-C. Jeong et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1901–1906
1903
H2N
O
N
C6H13
O
CO2Me
N
C11H23
O
O
N
H
O
N
H
O
O
HN
O
N
O
N
N
O
t-Bu
6d
O
N
t-Bu
6a
O
6b
O
6c
N
R
O
R
N
N
N
N
H
O
C9H19
CO2Et
N
O
O
O
N
H
N
H
O
O
H
O
N
CO2Me
CO2Et
O
CO2Et
O
N
N
t-Bu
N
O
O
6f; R = H
O
t-Bu
6e
t-Bu
6h
6g; R = Me
t-Bu
6i
O
N
OPh
N
n
O
OPh
C6F13
R
O
N
H
N
O
CO2Me
O
N
H
O
H
O
CO2Me
N
CO2Me
O
O
N
N
t-Bu
6l; R = H, n = 1
6m; R = Me, n = 2
O
O
t-Bu
6j
t-Bu
6k
Figure 5. 3-Enaminetetramic acids (13 analogues).
R2
R2
R1
R1
R5
N
H
N
H
O
R4
HO
O
R4
(a)
N
(b)
O
R1
O
3i from 3h
3k from 3j
R1
R6
external
tautomeric
set one
R5
R4
3
R5
R4
O
5
O
1
N
R3
O
N
O
R3
N
N
R2
R2
R3
R3
1a
2-6
A
B
Scheme 1. Synthesis of 3-enaminetetramic acids; reaction conditions (a) NHR5R6
(1.1 equiv), toluene, reflux; (b) diglycolic anhydride (1.1 equiv), toluene, reflux.
R1
R1
R2
H
R2
O
O
R5
R4
external
tautomeric
set two
N
N
H
R5
R4
example and has antifungal and herbicidal activity.19 Moreover,
the biological activity of unnatural 3-ETs has been rarely reported
(examples include herbicidal and antifungal activities20 and bind-
ing to tubulin21) while their antibiotic activity has not been re-
ported, aside from some examples in our earlier work.15
O
O
N
N
R3
R3
C
D
endo-enol
Figure 6. Tautomerism of 3-enaminetetramic acids.
Ph
exo-enol
All of the 3-ETs 2–6 (Figs. 3–5) examined in this study were pre-
pared via direct nucleophilic attack of the required primary or sec-
ondary amines onto the corresponding 3-acyltetramic acids 1d
(Scheme 1) whose synthesis has been reported previously.15,16,20,22
Two types of analogues were prepared in order to be able to di-
rectly compare bioactivity of enamines 1d (Fig. 1) with the parent
3-acyl 1a and 3-carboxamido 1b systems, and to provide a range of
hydrophobic, hydrophilic and functionalised side chains. In the
first set, the moiety R1 was fixed as a methyl group, while the
amine substituent was held as a primary amine (R6 = H) giving
3-ETs 2a–u (Fig. 3) with the R5 group being varied across alkyl
2a–e, substituted alkyl 2f–2q, aryl 2r,s and substituted aryl 2t,u.
In the second set, the alkyl moiety R1 of 1d was varied, giving
monocyclic 3-ETs 3a–l, 4a–k (Fig. 4) and bicyclic 3-ETs 6a–m
(Fig. 5). R1 was varied across a spectrum of aryl (3a–c, 6a), alkyl
(3d–l, 4a–c, 4f–j, 6b–i), substituted alkyl (4d–e,k, 6j–m) groups,
while the amine substituent was again held as a primary amine
C8H17
C8H17
H
N
Ph
171.7
O
172.1
N
O
193.3
51.0
95.5
197.8
49.6
97.5
H
172.9
176.7
O
O
N
H
N
H
3d
tautomer B
3d tautomer D
Figure 7. HMBC correlation of 3ET 3d in CDCl3.
(R6 = H) but with the R5 group also being varied across substituted
alkyl, aryl and substituted aryl groups (Figs. 4 and 5). In two cases,

1904
Y.-C. Jeong et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1901–1906
Table 1
In vitro antibiotic activity (MIC,
l
g/ml) of 3-enaminetetramic acids 2–6a–e
S1
S26
S4
S2
E1
E2
P1
P9
P9B
H3
H4
16
16
32
<0.06
32
8
2ce
2d
2j
2m
2p
2s
3e
3g
3h
3i
3k
3l
4a
4b
4c
4h
4j
>64
>64
64
>64
>64
64
4
>64
64
>64
16
4
>64
>64
>64
>64
>64
64
>64
16
>64
>64
16
64
>64
16
>64
>64
>64
8
>64
64
>64
>64
64
>64
>64
64
4
>64
64
16
16
2
16
>64
>64
>64
>64
64
>64
16
>64
>64
16
>64
>64
8
>64
>64
2
1
>64
8
4
>64
2
8
2
>64
>64
1
1
>64
8
4
16
8
16
2
2
64
16
32
>64
4
16
16
4
>64
>64
2
2
>64
8
>64
>64
>64
4
>64
>64
>64
64
8
8
1
c
—
>64
64
64
>64
32
8
8
1
64
16
16
16
16
32
16
32
64
>64
64
64
32
32
>64
8
>64
>64
16
32
>64
16
2
>64
16
2
4
4
64
32
>64
>64
>64
16
8
32
4
8
8
4
>64
16
8
>64
>64
>64
>64
>64
64
>64
16
>64
>64
16
>64
>64
>64
>64
>64
64
>64
8
>64
>64
16
>64
>64
>64
>64
>64
64
>64
16
>64
>64
16
16
>64
>64
>64
>64
64
>64
8
>64
>64
8
32
>64
16
2
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
>64
16
2
64
16
32
>64
8
>64
>64
4
32
>64
16
1
5
6b
6e
6f
32
>64
32
32
>64
16
64
>64
32
32
>64
32
16
>64
8
6i
6k
Linee
Ciproe
8
4
2
2
2
2
2
0.5
0.5
0.12
0.5
0.12
16
1
32
1
1
1
0.5
60.06
a
Abbreviation: S1; S. aureus 1, ATCC13709 in vivo (methicillin sensitive), S26; S. aureus 26, ATCC25923 (vancomycin susceptible), S4; S. aureus 4, Oxford, S2; S. aureus 2,
MRSA in vivo (methicillin resistant), E1; E. faecalis 1, ATCC29212 VanS (vancomycin susceptible), E2; E. faecium 1, VanA (vancomycin resistant), P1; S. pneumonia 1,
ATCC49619 (erythromycin susceptible), P9; S. pneumonia 9, PenR (penicillin and erythromycin resistant), P9B; S. pneumonia 9 in presence of 2.5% horse blood, H3; H.
influenzae 3, ATCC31517 MMSA, H4; H. influenzae 4, LS2 Efflux knock-out, line; linezolid, cipro; ciprofloxacin.
b
All analogues are inactive against E. coli 1, ATCC25922 (non Pathogenic strain), E. coli 50, Ec49 No Efflux and P. aeruginosa 1, ATCC27853 (MIC > 32 lg/ml).
Not determined.
c
d
e
Analogues 2a,b,e–i,k,l,n,o,q,r,t,u, 3a–d,f,j, 4d–g,i,k, and 6a,c,d,g,h,j,l were inactive against all strains (MIC > 32
lg/ml).
The activity of analogues 2a,c,d,r was reported in our previous paper and is included here for comparison.15
(197.8 ppm) and the carbon on C(2) (172.9 ppm) were assigned
to tautomer B (as compared to tautomer D, 193.3 and 176.7 ppm,
respectively). In cases when there was only a single set of signals
(e.g. tert-amines 2i, 3g and 6d), the favoured exo-enol form B or
D could not be assigned.
The antibacterial activity of 58 of 3-ETs 2–6 shown in Figures 3–5
was assessed (Table 1). The existence of activity against the
Gram-negative Haemophilus influenzae (H3) and efflux-negative
Haemophilus influenzae (H4) and Gram-positive Staphylococcus aur-
eus (S1, S26, S4 and S2), Enterococcus faecalis (E1), E. faecium (E2)
and S. pneumonia (P1 and P9) strains critically depended on the
identity of the ring substituents R1, R2, R5 and R6. Of interest is that
3-ETs 2–6 tended to be significantly weaker in activity than their
corresponding analogues 1a–c.15–17 By way of illustration, the
magnitude of this activity loss can be seen by comparing com-
pounds 2d and 6g with their analogues 7a,b (Fig. 8); both 2d and
6g are almost devoid of all activity, while 7a has MIC values against
Me
O
Me
NH
O
O
O
Me
O
CO2Et
O
N
N
O
O
t-Bu
t-Bu
7a
7b
Figure 8. Examples of active acyl and amide analogues.
secondary amines were included (3g, 6d). In the case of formation
of 3-ET 5b, by-product 3-ET 5 was also obtained, indicating that
the N-acyl moiety can also be attacked by nucleophiles. 3-ETs 3i
and 3k were synthesized from 3-ETs 3h and 3j, respectively, using
diglycolic anhydride.
3-ETs 1g, like the analogous 3-acyltetramic acid 1d and 3-carb-
oxamidotetramic acid 1f systems, may exist as tautomeric forms
A–D (Fig. 6).15–17,22 In their 1H and 13C NMR spectra, two clear sets
of signals generally appeared as a 1:1 ratio, although for 3-ETs 3h,
4e,i and 6c,e,f,g,i and tert-amine derivatives 2i, 3g and 6d, the sig-
nals were broad (see Experimental section in Supporting informa-
tion for details). In order to determine the relevant tautomeric
form, HMBC NMR spectra of representative analogues were also
determined and as an example, HMBC correlation of 3-ET 3d is
shown in Fig. 7 (see S-Fig. 1 in Supporting information for other
analogues). Similarly to previous literature reports,20,23 3-ETs were
found to exist as exo-enol tautomers B and D rather than endo-enol
tautomers A and C. In the assignment of NMR spectra, chemical
shifts of carbonyl carbons on C(2) and C(4) were key, with the
expected chemical shifts of keto-carbonyls for tautomers B and D
rather than enol-carbonyls for C(4) in tautomer A and C(2) in
tautomer C. In 3-ET 3d, the chemical shift of the carbon on C(4)
all organisms in the assay panel not worse than 2
lg/ml and 7b is
similar but has some MIC values as low as 0.5
l
g/ml.15 The activi-
ties of enamines 2–6 indicates that the identity of the functionality
at C(3) of 1d is similarly crucial to the observance of antibiotic
activity, and appears to be more important than N(1) and C(5)).
Interestingly, the activity profile among Gram-positive strains de-
creases in the order S. pneumonia > E. faecalis and E. faecium >> S.
aureus; in particular, 3-ETs 3e,g,h, 4j and 6e–g are the most active.
3-ET ( )-2m exhibited a broad spectrum of activity, especially
against resistant and susceptible strains such as vancomycin
susceptible (VSSA) and methicillin resistant (MRSA) S. aureus,
vancomycin susceptible E. faecalis (VSE), vancomycin resistant
E. faecium (VRE) and multi-drug resistant S. pneumonia (MDRSP).
Moreover, none of 3-ETs 2–6 proved to be active against
Gram-negative Pseudomonas aeruginosa and both efflux-positive
and -negative Escherichia coli (data not shown in Table 1). It has

Y.-C. Jeong et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1901–1906
1905
(B)
(A)
6
4
2
0
-2
300
600
MSA
900
6
4
(C)
2
3-Enamine tetramic acids
Active Mild
3-Acyltetramic acids
Active Mild
Inactive
Inactive
0
-2
3-Carboxamide tetramic acids
Active Mild Inactive
300
600
900
MSA
Figure 9. Plot of ClogD7.4 against MSA of 3-enamines 2–6 along with the 3-acyls 1a,c and 3-carboxamides 1b reported in our previous papers against (A) MRSA, (B) H.
influenzae 3 and (C) efflux-negative H. influenzae 4. Active, mild and inactive mean that the values are MIC 6 4 lg/ml, 4 lg/ml < MIC 6 32 lg/ml and MIC > 32 lg/ml,
respectively.
been found that tetramic acids either without any pendant func-
tional groups24 or with mono-, di-alkyl25,26 or cyano27 groups on
C(3), have no or only weak antibiotic activity, while 3-acyl 1a
and 3-carboxamide tetramic acids 1b generally exhibit excellent
antibiotic activity.13–18,27 Unfortunately, the antibacterial activity
of the few actives decreased in the presence of 2.5% horse blood
(P9B); a similar effect has been found for 3-acyl and 3-carboxamid-
etetramic acids.15–17 Additionally, 3-ETs 2a–c,e,h–j,r, 3h and
Overall, 3-ETs 2–6 were easily prepared from 3-acyltetramic
acids 1a and found to exist predominantly in the exo-enol form
in solution. However, unlike the parent 3-acyl and 3-carboxamide
TAs which exhibited excellent antibacterial activity with novel
mode of actions as inhibitors of RNA polymerase and UPPS,15–17
the antibacterial activity of 3-ETs tended to be poorer and with
unclear modes of action. This result suggests that the carbonyl
oxygen in the 3-acyl 1a and 3-carboxamide 1c TA systems
(Fig. 2), giving systems with ClogP ꢀ 4.5, ClogD7.4 ꢀ 3, MSA ꢀ 600,
rel-PSA > 10, and ClogP ꢀ 1.5, ClogD7.4 ꢀ À1.0, MSA ꢀ 600, rel-
PSA > 10 respectively, are critical for sizeable antibacterial biologi-
cal activity.15 Moreover, the parameters for the 3-carboxamide 1c
compound class more nearly overlap with those seen for other
antibacterial agents, being relatively more polar, and may there-
fore be the most suitable for further optimisation.28
6a,b,d,e,i,l were inactive against RNA polymerase (IC50 > 100
although 3ETs 6j,h exhibited mild RNA polymerase activity
(IC50 = 26.0 M) and 3-ETs 2a,c–e,j,r were inactive against undeca-
prenyl pyrophosphate synthase (UPPS, IC50 > 10 M), suggesting
lM,
l
l
that the mode of action of active 3-ETs is different to 3-acyltetram-
ic acids and 3-carboxamidotetramic acids, systems known to
exhibit inhibition of RNA polymerase and UPPS.15,16
Physicochemical properties of 3-enamines 2–6 were compared
with 3-acyls 1a,c and 3-carboxamides 1b,15–17 for which the plots
of ClogD7.4, ClogP, polar surface area (PSA) and relative-PSA (rel-
PSA = PSA/MSA X100) against molecular surface area (MSA) are
shown in Figure 9 and S-Figures 2–4 in the Supporting information,
Acknowledgments
We are particularly grateful for valuable input by Drs. Phil Dud-
field and John Lowther, and for funding by Galapagos SASU
(France).
respectively (see also S-Table
1 in Supporting information).
Noteworthy is that almost all active 3-ETs are relatively lipophilic
(ClogP > 3, ClogD7.4>2, rel-PSA < 10, MSA > 600), and since they
have a high molecular weight (MW > 400 Da) and a larger number
of rotatable bonds (RB > 10), they are already placed at a disadvan-
tage for further optimization. By contrast, active 3-acyls 1a,c are
clustered at more polar values of ClogD7.4 and MSA (2–4 and
550–700, respectively); active 3-carboxamides 1b are even more
tightly clustered (À2–0 and 550–650, respectively) (Fig. 9 and
S-Fig. 2). It is worth noting that most known antibacterial
compounds are relatively polar, and this might account for the
general lack of activity in the relatively lipophilic enamine com-
pound class.28
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.03.
013.
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3. Danishefsky, S. Nat. Prod. Rep. 2010, 27, 1114.

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