Dialkylamino-2,4-dihydroxybenzoic acids as easily synthesized analogues of platensimycin and platencin with comparable antibacterial properties

Article abstract of DOI:10.1002/chem.201002410

Function matters more than synthesis: Simple analogues of platensimycin, nanomolar inhibitors of bacterial FabF enzymes, are made in just two-flask reactions from commercially available aldehydes. These readily synthesized analogues are as effective as pl

Full text of DOI:10.1002/chem.201002410

DOI: 10.1002/chem.201002410
Dialkylamino-2,4-dihydroxybenzoic Acids as Easily Synthesized Analogues
of Platensimycin and Platencin with Comparable Antibacterial Properties
Jingxin Wang and Herman O. Sintim*[a]
Bacterial resistance to most antibiotics has presented an
enormous problem to solve for mankind. In the last decade,
there have been increased efforts to identify new antibiotic
targets or to develop novel chemical scaffolds to inhibit
known drug targets in bacteria. It is just over four years
since a group at Merck reported the identification of a
novel class of antibiotics called platensimycin[1] or platen-
cin,[2] which are FabF/H inhibitors and therefore inhibit the
synthesis of lipids used by bacteria to make cell membranes.
In only four years since the seminal report by the Merck
group, over 20 groups world-
group[28] as well as others,[22,32] have reported SAR studies of
platensimycin. These studies have revealed that although
the tetracyclic core of platensimycin is mainly solvent ex-
posed (see Figure 1), gross modification of this moiety usu-
ally abrogates the biological activity of the antibiotic. Lee
et al. showed that the addition of a phenyl or methyl sub-
stituent to the tetracyclic core of platensimycin increased its
antibiotic activity.[22] However, Leeꢀs analogues which have
enhanced antibiotic activities are not readily prepared and
are obtained after 15 total steps.
wide
have
reported
the
total[3–19] or enzymatic synthe-
ses[20,21] of platensimycin/platen-
cin or analogues[22–38] thereof,
and
about
12
papers[22,23,28–34,36–38] have report-
ed biological investigations of
these molecules. Several review
articles[39] on these molecules
have also been published, es-
tablishing the platensimycin
family of antibiotics as one of
the most intensely studied bio-
active molecules in the last
decade. Despite the intense re-
search efforts directed at dis-
covering newer analogues of
platensimycin and family, the
majority of the reported synthe-
ses of platensimycin or ana-
logues typically involve close to
Figure 1. Structure of platensimycin and platencin (left). The interaction between the benzoic acid moiety of
platensimycin and the residues of FabF (right; PDB 2GFX). The majority of the tetracyclic core of platensimy-
cin is solvent exposed.
twenty total steps, with the shortest linear steps being
around nine.[16] Most total syntheses of platensimycin or pla-
tencin produced only a few milligrams of material. As most
antibiotic pills used in the clinics typically contain about two
hundred milligrams of active substances, the current chemi-
cal syntheses of platensimycin or analogues reported so far
would not be economically viable. We,[34] the Nicolaou
Studies have shown that modifications on the 2,4-dihy-
droxybenzoic acid moiety of platensimycin diminish most of
the antibiotic activity.[28,33,34,38] This is in agreement with the
structural data (Figure 1) which reveals that the dihydroxy-
benzoic acid subunit engages the His-His-Cys catalytic triad
of the condensing enzymes (FabF/H).[1] It therefore appears
that efforts aimed at discovering simpler platensimycin ana-
logues have a higher chance of success if the essential dihy-
droxybenzoic acid moiety is kept intact or minimally modi-
fied.
[a] J. Wang, Prof. Dr. H. O. Sintim
Department of Chemistry and Biochemistry
University of Maryland, College Park, MD 20742 (USA)
E-mail: hsintim@umd.edu
Recently, several groups have focused their attention on
the replacement of the “difficult-to-synthesize” tetracyclic/
tricyclic core of platensimycin or platencin with moieties
that are relatively easy to chemically prepare. For example
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002410.
3352
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Chem. Eur. J. 2011, 17, 3352 – 3357

COMMUNICATION
the Metzler-Nolte group recently reported the synthesis and
biological evaluation of bioorganometallic analogues of pla-
tensimycin/platencin whereby the tetracyclic/tricyclic cores
of these antibiotics were replaced with a h6-arylCr(CO)3
moiety.[31] Although the synthesis of the organometallic ana-
logues of platensimycin took a total of nine linear steps
from pentamethylbenzyl chloride, which was significantly
shorter than the chemical synthesis of the parent platensi-
mycin antibiotic, the MIC (minimum inhibitory concentra-
tion) of these analogues were close to two orders of magni-
tude higher than platensimycin. Recently, Mulzer reported a
new analogue that took only seven linear steps to make,
starting from perillaldehyde and which showed antibiotic ac-
tivity profile that is similar to those of platensimycin or pla-
tencin.[38]
We rationalized that since FAS enzymes utilize substrates
with long alkyl chains to make fatty acids[40] there ought to
be a hydrophobic pocket at or near the active site of these
enzymes. It is also known that dihydroxybenzoic acids bind
to the catalytic triad in FAS enzymes.[1] In fact, other FAS
inhibitors such as cerulenin,[41] thiolactomycin[41] or alkyl di-
sulfide[42] analogues contain hydrophobic alkyl or alkenyl
side chains. Therefore we wondered if a combinatorial strat-
egy whereby dihydroxybenzoic was coupled to a variety of
commercially available alkyl chains would yield an active
analogue of platensimycin (Figure 2).
minal amino group could be synthesized on the gram-scale.
A simple reductive amination with commercially available
aldehydes (Scheme 1) or reactions with acid chlorides or sul-
fonyl chlorides would then furnish myriads of easily accessi-
ble platensimycin/platencin analogues (see Figures 3 and 4).
These analogues can be obtained in up to 69% yield, start-
ing from compound 3, after column chromatography or re-
crystallization.
Screening of our first-generation analogues, compounds
6–13 (Table 1), revealed that compound 8 (a myrtenal deriv-
ative) was the most potent amongst the molecules tested
with MIC values of 4, 16 and 8 mgmLÀ1 against B. subtilis
(3160), methicillin-resistant S. aureus (MRSA) and vanco-
mycin-resistant Enterococci (VRE), respectively (Tables 1
and 2). The MIC of compound 8 against B. subtilis
(4 mgmLÀ1) compared favorably with the MIC of platensi-
mycin against B. subtilis (2 mgmLÀ1) and was smaller than
that of cerulenin (see Table 1). The other dialkylamino ana-
logues in Figure 3 were inactive and this goes to show that
Figure 2. Function-oriented synthesis (FOS) of platensimycin.
Figure 3. First-generation analogues with hydrophobic side chains of dif-
ferent shapes and sizes.
En route to our reported synthesis of oxazolidinyl platen-
simycin,[34] we demonstrated the facile synthesis of amine 3
(Scheme 1). This 2,4-dihydroxybenzoic acid ester with a ter-
the antibiotic activity of compound 8 is not just due to
“greasiness” but is rather related to a specific architecture
obtained with two myrtenyl groups. Of note, compounds 10
and 11, which are structurally similar to compound 8, as
both also contain six-membered rings, were found to be in-
active. In line with earlier observation by the Merck group
that platensimycin/platencin were ineffective against gram-
negative bacteria,[1,2] our new analogue 8 was also ineffec-
tive against E. coli K12 (1655) (Table 1).
We chose compound 8 as the lead structure and designed
a second set of structurally related compounds (Figure 4;
compounds 16–23). Compounds 16 and 17 tested the impor-
tance of the carboxylic acid moiety by either deleting it or
modifying it to its methyl ester. Methyl esters can usually
Scheme 1. A general pathway to generate dialkylamino-2,4-dihydroxy-
benzoic acid analogues.
Chem. Eur. J. 2011, 17, 3352 – 3357
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3353

H. O. Sintim and J. Wang
Table 1. MIC values of compounds 6–23 against B. subtilis (3160).[a]
signed to investigate if both the benzoic acid moiety or the
myrtenyl unit alone had antibacterial activity. Compound
20, which does not contain the olefin unit, was designed to
probe the importance of the alkene unit in 8 for biological
activity. Compound 21 is the enantiomer of the lead com-
pound 8 whereas compound 22 contained only one (À)-myr-
tenyl group and was designed to test if both alkyl groups on
the nitrogen in 8 were needed for biological activity. The
starting aldehydes used to make compounds 8, 20 and 21
were greater than 97% ee, leading to products that have
enantiopurities greater than 97% ee. (À)-Myrtenal (>97%
ee) used to make compounds 8 was commercially obtained
from Sigma–Aldrich. (À)-Myrtanol (99% ee, from Sigma–
Aldrich) was oxidized to make the aldehyde intermediate
for synthesizing compound 20. And (+)-myrtenal (>99%
ee) used to make compound 21 was prepared from commer-
cially available (+)-pinene (99% ee, from Sigma–Aldrich).
Both NMR and HPLC analyses of analogues 8, 20 and 21
indicated predominately single compounds, in line with the
use of an almost enantiopure starting materials, which do
not racemize under the experimental conditions used to pre-
pare the analogues. The MIC values of the second-genera-
tion compounds 16–22 against S. aureus and B. subtilis are
summarized in Table 1. From these results, we conclude that
both the carboxylic acid moiety and the dimyrtenyl groups
but not the alkene unit are important for the antibiotic ac-
tivity of compound 8. In B. subtilis, compounds 19 and 23
were not as active as 8 (see Table 1 for MIC values), indicat-
ing that the benzoic acid and myrtenyl units in 8 are both re-
quired to impact the antibacterial activity of compound 8.
Others have also shown that platensic acid, an analogue of
platensimycin that lacks the benzoic acid core, only has
modest antibiotic activity.[28] Interestingly, the antibiotic ac-
tivities of enantiomers (À)-8 and (+)-21 are similar (see
Tables 1 and 2). Adding one
Compounds
MIC [mgmLÀ1
]
platensimycin (1)
cerulenin
2
8
6
>256
7
128
8
4
9
>256
>256
>256
>256
>256
>256
>256
>256
>256
8
128
2
4
>256
>256
10
11
12
13
14
15
16
17
18
19
20
21
22
23
[a] The MIC values of compounds 6–22 against E. coli K12 (1655) were>
256 mgmLÀ1
.
hydrolyze in vivo to produce carboxylic acids but we and
others have previously shown that methyl esters of platensi-
mycin are not good pro-drugs and do not hydrolyze into car-
boxylic acids under in vivo conditions.[33,34] This is not sur-
prising because the presence of two phenolic hydroxyls on
the benzoic acid core of platensimycin is expected to reduce
the reactivity of the ester carbonyl towards hydrolysis. Com-
pound 18 had one extra methylene group in the linker
region between the benzoic acid core and the myrtenyl
moiety and was designed to test the importance of the
length of the linker unit. Compounds 19 and 23 were de-
carbon length between the ben-
zoic acid moiety and the dimyr-
tenyl amino moiety (see com-
pound 18) did not change the
MIC value significantly. How-
ever, analogue 22 which had
only one myrtenyl group at-
tached to the nitrogen atom
was inactive. The ineffective-
ness of platensimycin/platencin
against gram-negative bacteria
has been ascribed to efflux
pumps in gram negatives. It is
thought that these pumps
reduce the intracellular concen-
trations of the platensimycin/
platencin class of antibiotics.[43]
Consequently,
co-administra-
tion of the efflux pump inhibi-
tor, Phe-Arg-b-naphthylamide
dihydrochloride (PAbND), po-
tentiated the effects of our new
Figure 4. Second-generation analogues based on lead compound 8.
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Chem. Eur. J. 2011, 17, 3352 – 3357

Natural Products
COMMUNICATION
analogues on E. coli. In the presence of PAbND at
128 mgmLÀ1, the MICs of compound 8 and analogues 20 and
21 were 4, 2 and 8 mgmLÀ1 respectively. Interestingly, these
MICs were even lower than that of platensimycin in the
presence of PAbND (see Table 2). PAbND did not kill bac-
teria at 128 mgmLÀ1.
lated lower binding energies of 7.4 and 6.7 kcalmolÀ1, re-
spectively (Table 3).
Table 3. Calculated binding affinities and experimental MICs of platensi-
mycin (1), compounds 10, 20 and 23.
Platensi-
mycin (1)
(À)-Myrta-
mycin (20)
10
23
Binding affinity
[kcalmolÀ1
MIC to B. subtilis
[mgmLÀ1
9.0
8.7
7.4
6.7
Table 2. MIC value of compounds 8, 20 and 21.
]
Compounds
MIC [mgmLÀ1
]
2
2
>256
>256
S. aureus
AHCTUNGTRENGN(UN MRSA)
Enterococcus
faecium
E. coli +
PAbND
A
]
AHCTUNGTERG(NNUN VRE)
platensimycin (1)
1 (0.5,[1] 4[22]
)
1 (0.1,[1] 1[22]
)
>32
(À)-myrtemycin (8)
(À)-myrtamycin (20)
(+)-myrtemycin (21)
16
32
16
8
32
16
4
2
8
In the last few decades, there has been a growing appreci-
ation that almost every complex bioactive molecule can be
prepared in the laboratory. Despite these great strides made
in organic chemistry, the practical synthesis of complex nat-
ural products is still in its infancy. Most syntheses of com-
plex bioactive natural products are not yet practical and the
commercial production of complex natural products such as
taxol, erythromycin and vancomycin mainly use biosynthe-
sis.[45–47] Recently, there has been a call to medicinal chemists
to focus more on function-oriented synthesis (FOS) rather
than on the total synthesis of complex molecules, and sever-
al excellent examples by the Wender group[48] and
others[49–51] have highlighted that FOS is a viable and some-
times even better approach[52] to the discovery of new medi-
cines. In this paper, we illustrate that the biological function
of platensimycin can be replicated with moieties which are
easier to install but which would not have been predicted
based on structure homology modeling. Significantly, we
report new analogues that are exceptionally simple to make
(two-flask reactions from commercial materials) yet they
maintain biological activity
To gain some insights into the probably mechanism
whereby the analogues described this paper achieve their
antibiotic effects, we used Autodock Vina[44] to dock platen-
simycin (1), (À)-myrtamycin (20) and compounds 10 and 23
into the platensimycin binding site in FabF (PDB 2GFX). It
has been suggested that platensimycin achieves its antibacte-
rial effect via the inhibition of FabF.[1] Our docking results
reveal that the binding modes of platensimycin and our
active analogue, (À)-myrtamycin (20) are similar and that
the carboxylic acid moiety in both compounds contacts
His303 and His340 in the active site of FabF (see Figure 5).
Moreover, the calculated binding affinities of platensimycin
(1) and myrtamycin (20) to FabF are similar (9.0 and
8.7 kcalmolÀ1 respectively, see Table 1). Compounds 10 and
23, which were inactive antibiotics bind to FabF with calcu-
which are comparable to the
natural compounds which are
typically synthesized in over 15
linear steps. Compound 20, our
most potent analog, was ob-
tained from starting material 3
in an overall yield of 62%. Our
analogues and platensimycin/
platencin contain the benzoic
acid core structure. As all syn-
theses of platensinmycin or an-
alogues require one or two
steps to append the benzoic
acid core to the polycyclic frag-
ment, comparisons of the total
steps required to make the re-
spective polycyclic fragment
give a good indication of how
facile it is to make a particular
analogue. Whereas it takes be-
Figure 5. a) Compound 20 docked (using Autodock Vina) into the platensimycin-binding site in FabF (PDB
2GFX); b) interactions between compound 20 and FabF amino acid residues; c) superpoised structures of pla-
tensimycin and (À)-myrtamycin (20) in their FabF binding modes (green: platensimycin, purple: compound
20).
tween seven to ten steps to
make the core structure of pla-
tencin/platensimycin, the core
Chem. Eur. J. 2011, 17, 3352 – 3357
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www.chemeurj.org
3355

H. O. Sintim and J. Wang
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Keywords: antibiotics
products · platencin · platensimycin
· fatty acid synthase · natural
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