Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

Article abstract of DOI:10.3762/bjoc.14.224

The increasing emergence of multidrug-resistant pathogens is one of the biggest threats to human health and food security. The discovery of new antibacterials, and in particular the finding of new scaffolds, is an imperative goal to stay ahead of the evolution of antibiotic resistance. Herein we report the synthesis of a 3-decyltetramic acid analogue of the ureido dipeptide natural antibiotic leopolic acid A. The key step in the synthetic strategy is an intramolecular Lacey-Dieckmann cyclization reaction of a linear precursor to obtain the desired 3-alkyl-substituted tetramic acid core. The synthesized analogue is more effective than the parent leopolic acid A against Gram-positive (Staphylococcus pseudintermedius) and Gram-negative (E. coli) bacteria (MIC 8 μg/mL and 64 μg/mL, respectively). Interestingly, the compound shows a significant activity against Staphylococcus pseudintermedius strains expressing a multidrug-resistant phenotype (average MIC 32 μg/mL on 30 strains tested). These results suggest that this molecule can be considered a promising starting point for the development of a novel class of antibacterial agents active also against resistant strains.

Full text of DOI:10.3762/bjoc.14.224

Synthesis of a leopolic acid-inspired tetramic acid with
antimicrobial activity against multidrug-resistant bacteria
Luce Mattio1, Loana Musso1, Leonardo Scaglioni1, Andrea Pinto1, Piera Anna Martino2
and Sabrina Dallavalle*1,§
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2482–2487.
1Department of Food, Environmental and Nutritional Sciences,
Università degli Studi di Milano, via Celoria 2, I-20133 Milano, Italy
and 2Department of Veterinary Medicine - Microbiology and
Immunology, Università degli Studi di Milano, via Celoria 10, I-20133
Milano, Italy
doi:10.3762/bjoc.14.224
Received: 13 July 2018
Accepted: 04 September 2018
Published: 24 September 2018
Email:
This article is part of the thematic issue "Antibacterials, bacterial small
molecule interactions and quorum sensing".
Sabrina Dallavalle* - sabrina.dallavalle@unimi.it
* Corresponding author
Guest Editor: D. Spring
§ Tel. +39 0250316818; Fax +39 0250316801
© 2018 Mattio et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
antimicrobial activity; multidrug-resistant bacteria; natural products;
synthesis; tetramic acid
Abstract
The increasing emergence of multidrug-resistant pathogens is one of the biggest threats to human health and food security. The
discovery of new antibacterials, and in particular the finding of new scaffolds, is an imperative goal to stay ahead of the evolution
of antibiotic resistance. Herein we report the synthesis of a 3-decyltetramic acid analogue of the ureido dipeptide natural antibiotic
leopolic acid A. The key step in the synthetic strategy is an intramolecular Lacey–Dieckmann cyclization reaction of a linear pre-
cursor to obtain the desired 3-alkyl-substituted tetramic acid core. The synthesized analogue is more effective than the parent
leopolic acid A against Gram-positive (Staphylococcus pseudintermedius) and Gram-negative (E. coli) bacteria (MIC 8 µg/mL and
64 µg/mL, respectively). Interestingly, the compound shows a significant activity against Staphylococcus pseudintermedius strains
expressing a multidrug-resistant phenotype (average MIC 32 µg/mL on 30 strains tested). These results suggest that this molecule
can be considered a promising starting point for the development of a novel class of antibacterial agents active also against resis-
tant strains.
Introduction
The treatment of bacterial infections by antibiotics is widely bacteria, mainly due to the abuse of antimicrobial molecules
regarded as one of the major achievements of the 20th century. (e.g., for treatment of bacterial skin diseases [1]), emphasises
However, the continued emergence of multidrug-resistant the urgent need for novel antibiotic families. In this regard,
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natural products are privileged compounds, as they possess bio- In this paper we report the efforts made to develop a synthetic
logically validated structures, which could become suitable strategy to compound 1, which may, in principle, have a value
leads in drug discovery [2].
in the preparation of various analogues for structure–activity
relationship (SAR) studies. The antibacterial activity of com-
Recently, our research group reported the first total synthesis of pound 1 was tested on Staphylococcus pseudintermedius and
leopolic acid A (Figure 1), a fungal metabolite from a terres- Escherichia coli strains chosen as representative of Gram-posi-
trial-derived Streptomyces sp. isolated from the rhizosphere of tive and Gram-negative bacteria. In particular, we demon-
the plant Juniperus excelsa [3,4]. Leopolic acid A is endowed strated the ability of compound 1 to inhibit Staphylococcus
with antibacterial activity against Staphylococcus aureus and pseudintermedius strains expressing a multidrug-resistant
Staphylococcus pseudintermedius with a MIC of 16 μg/mL, and phenotype.
against Escherichia coli with a MIC of 128 µg/mL [3,4]. In
terms of structural features, this compound contains a 4-decyl- Results and Discussion
2,3-pyrrolidinedione ring linked to the ureido dipeptide L-Phe- The instability of most of the N-unsubstituted 2,3-pyrrolidine-
L-Val. The 2,3-pyrrolidinedione ring is a quite unusual diones prepared for the construction of leopolic acid A [4]
skeleton. A limited number of compounds containing this forced us to develop a linear synthetic strategy consisting of
system have been synthesized so far [5-7] and, to the best of our 11 steps, not amenable for the preparation of analogues. Con-
knowledge, natural compounds with a 2,3-pyrrolidinedione versely, compound 1 appears well suited to a convergent syn-
nucleus are quite rare [8-11]. The lack of similar compounds thetic approach based around two fragments, the ureido dipep-
may be due to the instability of the 2,3 pyrrolidinedione moiety tide L-Phe-L-Val and the 3-decyltetramic acid core (Figure 1).
[12]. Indeed, while developing the total synthesis of leopolic
acid A, we encountered several difficulties in the construction Initially, we focused on the synthesis of the 2,4-pyrrolidine-
of the ring, most of the intermediates being unstable [4].
dione core. A review of the existing literature on tetramic acids
syntheses revealed a considerable amount of papers regarding
In light of these results, we intended to investigate the role of the preparation of 3-acyltetramic acids [14-18], whereas the
the 2,3 pyrrolidinedione ring by replacing it with a more stable synthesis of 3-alkyl-tetramic acids has been considerably less
isomeric 2,4-pyrrolidinedione moiety. Actually, 2,4 pyrrolidine- investigated [19-22]. We envisaged that the most straightfor-
diones (tetramic acids) have recently attracted considerable ward route to the 2,4-pyrrolidinedione system could be a
attention for their antibacterial, antiviral, antifungal and anti- Lacey–Dieckmann cyclization starting from a N-acetoacetyl-α-
cancer activities [13]. More than one hundred of them have amino ester. Interestingly, the biosynthetic pathways of the
been isolated from a variety of natural sources and numerous tetramic acid scaffold involves Lacey–Dieckmann cyclases [23]
analogues have been synthesized and studied for their multiple or a spontaneous intramolecular Claisen condensation, which
biological activities [13]. For this reason, we planned the syn- occurs in the cytosol. To protect the α-amino ester nitrogen we
thesis of a leopolic acid A analogue containing the tetramic acid chose the p-methoxybenzyl (PMB) group, easily removable by
moiety in place of the 2,3-pyrrolidinone ring (compound 1), ceric ammonium nitrate (CAN). N-(4-Methoxybenzyl)glycine
while maintaining unchanged all the other structural features of ethyl ester (5) was obtained in 87% yield by reacting
the natural compound. The advantage of this substitution should 4-methoxybenzylamine (3) with bromoacetic acid ethyl ester
be a higher stability of the heterocyclic ring, hopefully coupled (4) in THF (Scheme 1). The ester 5 was converted into com-
with an increased activity due to the presence of the tetramic pounds 6a and 6b by condensation with monoethyl malonate
acid core.
and monobenzyl malonate, in the presence of DCC and DMAP,
Figure 1: Structures of leopolic acid A and compound 1.
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Scheme 1: Synthesis of 3-decyltetramic intermediate 13. Reagent and conditions: a) TEA, THF, 0 °C to rt, 2.5 h, 87%; b) monoethyl malonate (for
6a), monobenzyl malonate (for 6b), DCC, DMAP, CH2Cl2, 0 °C to rt, 24 h (for 6a), 12 h (for 6b), 6a: 80%, 6b: 83%; c) TBAF, Et2O, THF, 1-iodode-
cane, rt, 24 h, 7a: 22%, 7b: 30%; d) CAN, CH3CN/H2O (3:1), 0 °C to rt, 1 h, 8a: 81%, 8b: 66%; e) dodecanoyl chloride, TEA, CHCl3, 0 °C to rt, 3 h,
90%; f) t-BuOK 1 M in THF, THF, reflux, 1.5 h, 65%; g) benzyl tosylate, KHMDS 0.5 M in toluene, crown ether 18-crown-6, THF, 0 °C to rt, 3 h, 35%;
h) TFA, 60 °C, 2h; i) CAN, CH3CN/H2O (3:1), 0 °C to rt, 1h; j) benzyl tosylate, KHMDS 0.5 M in toluene, crown ether 18-crown-6, THF, 0 °C to rt,
2.5 h, 30% over two steps.
in 80% and 83% yield, respectively. Starting from intermedi- but they all were unsuccessful. Finally, we succeeded in prepar-
ates 6a and 6b, treatment with a tetrabutylammonium fluoride ing intermediate 10 by treatment of compound 9 with potas-
solution in diethyl ether at room temperature induced the cycli- sium tert-butoxide (1 M in THF) in THF [24]. The optimisation
sation and the formation of an enolate, which was subsequently of reaction conditions, work-up and purification, allowed us to
reacted with 1-iododecane and deprotected with ceric ammoni- obtain the desired compound in 65% yield.
um nitrate to afford derivatives 8a and 8b, respectively. Unfor-
tunately, at this stage all attempts to decarboxylate compounds Before removing the PMB group and installing the ureidodipep-
8a and 8b failed [22]. To overcome the problem of decarboxyl- tide fragment, we needed to protect the oxygen at C-4 [15]. We
ation, we planned to synthesize the alkyl-substituted tetramic selected a benzyl protecting group, as it could be cleaved by
core in one single step by Lacey–Dieckmann cyclisation of catalytic hydrogenation together with the benzyl ester of
ethyl 2-(N-(4-methoxybenzyl)dodecanoylamino)acetate (9), al- L-phenylalanine in the ureidodipeptide fragment (see synthesis
though this compound does not contain an active methylene of compound 20) by a one-pot reaction. To increase the reac-
group. Thus, compound 5 was acylated with dodecanoyl chlo- tion rate toward O-alkylation, we used an aprotic polar solvent
ride to obtain compound 9 in 90% yield. As expected, the cycli- like DMF, which weakly solvates the enolates. However, treat-
zation reaction was found to be quite troublesome. Several ment of compound 10 with benzyl bromide and K2CO3 in DMF
attempts were made using different conditions (TBAF, Et2O, rt; gave exclusively the C-3 alkylated derivative. Thus, we consid-
NaOEt, EtOH, reflux; NaH, THF, reflux; LDA, THF, −78 °C), ered that a hard leaving group such as a sulfonate should play a
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key role in favouring O-alkylation. Moreover, we selected a ester was easily cleaved by trifluoroacetic acid in DCM at room
base containing potassium as a metal cation, which provides a temperature to furnish the corresponding acid 19 (yield 95%),
greater electron density to the nucleophilic enolate, thus which was activated by pentafluorophenol, DCC in EtOAc to
favouring O-alkylation. Satisfyingly, O-selective alkylation of give the pentafluorophenylester ureido-dipeptide 20 (60%,
compound 10 was achieved by deprotonation with KHMDS fol- Scheme 2).
lowed by alkylation with benzyl tosylate in the presence of
18-crown-6 ether [15]. The synthesis of benzyl tosylate was With both key fragments 13 and 20 in hand, we finally accom-
accomplished using benzyl alcohol and freshly recrystallized plished the N-acylation reaction using n-BuLi in THF at −60 °C
p-toluenesulfonyl chloride in the presence of anhydrous tri- [15] in 60% yield. Removal of both protecting groups by cata-
methylamine and DMAP, in anhydrous dichloromethane [25]. lytic hydrogenation, gave the desired compound 1 in 72% yield
(Scheme 3).
At this stage, all attempts to obtain the key intermediate 13
removing the p-methoxybenzyl group [24,26-28] from 11 Compound 1 was subjected to a preliminary study to evaluate
failed. Finally, compound 13 was successfully obtained by the antimicrobial activity against 80 strains of Staphylococcus
modifying the sequence of reactions. Deprotection of com- pseudintermedius and 25 strains of Escherichia coli. Bacterial
pound 10 with TFA [24], followed by selective alkylation with isolates of S. pseudintermedius and E. coli, previously identi-
benzyl tosylate as previously described, afforded the desired fied using selective and differential cultural media (e.g.,
O-alkyltetramic acid 13 in 30% yield.
Mannitol Salt Agar; MacConkey Agar, Oxoid, Italy), were iso-
lated on blood agar plates (Tryptic Soy Agar plus 5% defibri-
The synthesis of the activated ureido fragment was achieved in nated sheep blood, Microbiol, Italy) to obtain pure cultures [29].
four steps from suitably protected L-valine and L-phenylala- The isolated colonies were used to assess the phenotypic profile
nine. The benzyl protection of L-phenylalanine (14) was carried of antimicrobial resistance. For this purpose, the Kirby Bauer
out with PTSA and benzyl alcohol in toluene and the ester 15 disk diffusion method was used in accordance to Clinical Labo-
was isolated as its p-toluensulfonic acid salt by recrystallization ratory Standards Institute guidelines [30]. All the strains were
with Et2O in 70% yield (Scheme 2). L-valine (16) was pro- treated with a panel of antimicrobial molecules belonging to
tected as tert-butyl ester 17 by using perchloric acid in t-BuOAc five pharmacological categories: amoxicillin + clavulanic acid,
in 75% yield. The unsymmetrical urea 18 was synthesized using cephalexin, cefovecin, clindamycin, doxycycline, enrofloxacin
triphosgene at room temperature in 50% yield. The tert-butyl and marbofloxacin. Only for S. pseudintermedius strains,
Scheme 2: Synthesis of dipeptide L-Phe-L-Val intermediate 20. Reagents and conditions: a) PTSA·H2O, benzyl alcohol, toluene, reflux, 10 h, 70%;
b) HClO4, tert-butyl acetate, 0 °C, 1 h, then rt, 20 h, 75%; c) triphosgene, DIEA, DCM, rt, 3 h, 50%; d) trifluoroacetic acid, DCM, rt, 3 h, 95%;
e) pentafluorophenol, DCC, EtOAc, 0 °C, 1h, then rt, 3 h, 60%.
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Scheme 3: Synthesis of compound 1. Reagents and conditions: a) n-BuLi, THF, −60 °C, 220 min, 60%; b) H2, Pd/C 10%, AcOEt, rt, 100 min, 72%.
oxacillin was also tested to assess methicillin-resistance (see thetic strategy. Compound 1 is more effective than the parent
Table S1, Supporting Information File 1, for details). After leopolic acid A against Staphylococcus pseudintermedius and
incubation, 30 strains of S. pseudintermedius revealed E. coli strains (MIC 8 µg/mL and 64 µg/mL, respectively) and
resistance phenoptype to three or more pharmacological cate- Staphylococcus pseudintermedius strains expressing a
gories and were considered multidrug resistant (MDR) [31]. multidrug-resistant phenotype (average MIC 32 µg/mL on
MICs (minimum inhibitory concentrations) of compound 1 30 strains tested). The results confirm that the replacement of
were evaluated on each bacterial strain (E. coli and S. pseudin- the 2,3-pyrrolidinedione core with the tetramic acid nucleus
termedius MDR or not) as reported by CLSI guidelines [30,32]. leads to an increase of antimicrobial activity even on MDR
strains, thus suggesting that the new scaffold can be considered
The average MIC values of 1 against 50 Staphylococcus pseud- as a promising candidate for further investigation. Efforts to
intermedius isolates were 8 μg/mL and versus Escherichia coli synthesize analogues of compound 1 to deepen the structure–ac-
64 μg/mL, lower than the MICs shown by the parent leopolic tivity relationship (SAR) study of this novel class of antibacteri-
acid A (Staphylococcus pseudintermedius average MIC al agents are underway.
16 μg/mL; Escherichia coli average MIC 128 μg/mL) [4]. Inter-
estingly, compound 1 showed a significant activity also against
Supporting Information
Staphylococcus pseudintermedius strains expressing a
multidrug-resistant phenotype (average MIC 32 µg/mL on
Supporting Information File 1
30 strains tested).
General experimental methods, synthetic procedures and
analytical data for the reported compounds, antimicrobial
activity evaluation procedures.
Conclusion
The development of novel strategies to fight bacterial infec-
tions is an imperative goal, mainly due to the increasing num-
ber of bacterial strains resistant to a wide spectrum of antibiot-
ics. Aim of this work was the development of a synthetic
strategy for obtaining new natural compound-derived scaffolds
endowed with increased antimicrobial activity. Attention was
focused on 2,4-pyrrolidinedione derivatives, so-called tetramic
acids. As part of our search for new tetramic acid containing
scaffolds, we have synthesized the 2,4-pyrrolidinone analogue
of the natural compound leopolic acid A, by a convergent syn-
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-224-S1.pdf]
Supporting Information File 2
1H NMR and 13C NMR spectra of the new compounds;
COSY spectra of compounds 1, 10; HDMS spectra of
compound 1.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-224-S2.pdf]
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ORCID® iDs
Luce Mattio - https://orcid.org/0000-0003-0955-3982
Loana Musso - https://orcid.org/0000-0002-6838-7753
Andrea Pinto - https://orcid.org/0000-0002-2501-3348
Piera Anna Martino - https://orcid.org/0000-0003-0108-638X
Sabrina Dallavalle - https://orcid.org/0000-0002-8813-8922
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