Design and Synthesis of Metabolically Stable tRNA Synthetase Inhibitors Derived from Cladosporin

Article abstract of DOI:10.1002/cbic.201800587

Selective and specific inhibitors of Plasmodium falciparum lysyl-tRNA synthetase represent promising therapeutic antimalarial avenues. Cladosporin was identified as a potent P. falciparum lysyl-tRNA synthetase inhibitor, with an activity against parasite

Full text of DOI:10.1002/cbic.201800587

Accepted Article
Title: Design and Synthesis of Metabolically Stable t-RNA Synthetase
Inhibitors derived from Cladosporin.
Authors: Laure Christina Bouchez
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Design and Synthesis of Metabolically Stable t-RNA Synthetase
Inhibitors derived from Cladosporin.
Marion Rusch, Arnaud Thevenon, Dominic Hoepfner, Thomas Aust, Christian Studer, Maude Patoor,
Patrick Rollin, Madeleine Livendhal, Beatrice Ranieri, Esther Schmitt, Carsten Spanka, Karl
Gademann, and Laure C. Bouchez*
ER(mouse) 0.95 CLint(μL/min/mg = 425)).[6] In order to reveal potential
Abstract: Selective and specific inhibitors of Plasmodium falciparum
liabilities that could impair further its development as a drug-candidate,
lysyl-tRNA synthetase represent promising therapeutic antimalarial
cladosporin was also incubated, in vitro, with mouse liver microsomes.
avenues. Cladosporin was identified as a potent P. falciparum lysyl-
Each sample was analyzed by capillary-HPLC/MS(n) and the proposed
tRNA synthetase inhibitor, with an activity against parasite lysyl-tRNA
chemical structures were in accordance with accurate mass measurement
of the corresponding protonated molecular ions. To our surprise,
synthetase >100-fold more potent than the activity registered against
the human enzyme. Despite its compelling activity, cladosporin
exhibits poor oral bioavailability, a critical requirement for anti-malarial
drugs. We thus entered the quest to develop metabolically stable
cladosporin derived analogues, while retaining similar selectivity and
potency as the natural compound. Chemogenomic profiling of our
designed library allowed us to open the door to an entirely innovative
SAR studies, shedding the light on a structural evidence of a
privileged scaffold with a unique activity against tRNA synthetases.
cladosporin was hardly detectable. The only metabolic pathway that
could be detected was the glucuronidation of cladosporin. More in-depth
studies revealed three major fragmentations that helped identifying
structural Achilles’ heels responsible for the fast clearance in both
human and mouse. The weak points, including the
3 major
fragmentations that were observed, are highlighted in the Figure 1. They
will serve to the elaboration of our lead optimization approach.
Every year, malaria is responsible for over 500 million cases
requiring hospitalization. The rapid spread of anti-malarial drug-
resistance limits the available armamentarium to treat these patients.
Therefore, we are in an urgent need for finding the next generation drug
that will shift the path towards an increased sustainability of treatment
regimens and delaying the emergence and spread of drug resistance as
much as possible.[1,2,3]
Cladosporin, a fungal secondary metabolite, was identified during the
course of a screening campaign run against both Plasmodium falciparum
blood- and liver-stage proliferation.[4] Intrigued by its potent activity
several research groups embarked into its biosynthesis as well as its total
synthesis in order to provide a path to advance it in the anti-malarial drug
pipeline.[5] Unpredictably, despite its enticing nanomolar anti-parasitic
activity, cladosporin regressed very quickly to a tool compound class,
that could no longer be progressed due to its weak metabolic stability as
well as a high clearance in vivo.[6]
Figure 1. Metabolic liabilities and proposed modifications for
cladosporin core structure
The apparent structural simplicity of the cladosporin template motivated
us to propose and synthesize a series of inspired cladosporin analogues.
The rationale for the design of our focused library was based on
structural weaknesses revealed by our metabolic evaluation and our in
silico docking study based on cladosporin-lysyl-tRNA synthetase
(KRS1) co-crystal structures published recently (Figure 1, Figure 2 and
supporting information).[4]
In particular for anti-malarial drugs, the oral bioavailability is critical as
affected countries often lack the infrastructure for complex therapies.
Cladosporin showed a very high clearance in both human as well as
mouse models (subtype ER(human) 0.64 CLint(μL/min/mg) = 46.926;
[a]
Dr. M. Rusch, A. Thevenon, T. Aust, C. Studer, Dr. D. Hoepfner, Dr.
B. Ranieri, M. Livendhal, M. Patoor, E. Schmitt, C. Spanka, Dr. L. C.
Bouchez: NIBR- Novartis Institute for Biomedical Research,
Fabrikstrasse 22-1.051.17, CH-4054 Basel, Switzerland,
corresponding author e-mail: laure.bouchez@novartis.com
Arnaud Thevenon: Imperial College, Department of Chemistry,
Oxford University, London, UK.
Pr. Patrick Rollin: Institut de Chimie Organique et Analytique
(ICOA), UMR7311, Université d’Orléans, 45100 Orléans, France.
Pr. Karl Gademann: University of Zurich, Department of Chemistry
Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
.
[b]
[c]
[d]
Figure 2. Pertinent part of the crystal structure of cladosporin/ KRS1:
cladosporin binds in the ATP-binding pocket of the lysyl-tRNA
synthetase acylation domain.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cbic.201800587
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steps (29, 43 and 26%).[7] After reaction with thiocarbonyl diimidazole
in refluxing toluene the corresponding thiocarbonates 5, 6 and 15 could
be isolated. Further treatment with a mixture of Bu3SnH and AIBN,[8]
allows for selective deoxygenation and the generation of the
corresponding mono-alcohols in a regioselective manner. Further
treatment with trimethyl orthoformate under acidic conditions, followed
by Jones oxidation afforded the three corresponding lactones 7, 8 and
16.[9] Final deprotection in the presence of BBr3 yielded the first
analogues 9 and 10 in 60% and 73% yield, respectively. Alternatively,
lactone 16 was treated with a solution of TFA and subsequently
hydrogenated to provide the aniline analogue 17 in 46% yield over two
steps. Satisfyingly, this first generation of analogues allowed for the
facile preparation of over 30 analogues, in a 9-step procedure with an
overall yield of roughly 8% (Scheme 1, see supporting information for
additional examples and respective data).
Indeed, the crystal structure can also be interrogated in stereochemical
and structural terms. Cladosporin binds in the ATP-binding pocket of
the lysyl-tRNA synthetase. The major interactions appear to be
hydrogen-bond with Glu332 and the π/cation ‘cage’ formed from
adjacent aromatic and charged residues. The lactone ring interacts with
Arg559 main-chain through structural water and must remain unchanged
in order to keep the principal electrostatic interactions. Under these
premises, we presumed that meaningful SAR-studies should focus on
the elucidation of the role of hydroxyl groups, the tetrahydropyran
frame, and the carbon C4 of the isochromenone core (Figure 3). Any
such structural editing, however, is difficult to achieve if one starts from
the natural products themselves; de novo synthesis seems to be much
more appropriated to garner relevant insights. Because our group had
been previously involved in the synthesis of Agrimonolide, [5] we felt in
a strong position to venture into such an endeavor. Indeed, the variety of
accumulated building blocks, starting from resorcinol and going to m-
methylaniline unit, allowed for the rapid generation of novel compounds
with altered properties and unprecedented biological activities.
a)
b)
Figure 3. a) Major interactions between cladosporin and KSR1, b)
Structural modifications relative to the parent natural product
cladosporin are colored; the C4 of the isochromenone core is specifically
annotated (4).
Preparation of a focused library- Three main strategies have been
devised and executed in parallel to generate a focused library that was
subsequently assessed for its activity and metabolic stability. Although
not all the steps were optimized for each individual analogue prepared
during this campaign, the first route turned out to be efficient and
reproducible in most cases. Starting from the commercially available
3,5-methoxybromobenzene 1 as well as from the N-Boc-protected-3-
bromo-5-methyl aniline 11, both C-Br bonds are activated under Stille
coupling conditions in presence of tetrakis(triphenylphosphine)
palladium and LiCl to furnish the corresponding allyl derivatives 2 and
12 in 83% and 68%, respectively. Next, 2 and 12 are cross-reacted,
respectively with allylcyclopentane, allylcyclohexane and 13[5] in the
Scheme 1. First generation synthesis, preparation of 9, 10 and 17. Reagents and
conditions: a) vinyl-Bu3Sn, Pd(PPh3)4 (2 mol %), Cs2CO3, DMF, 100 °C, 16h, 2 83%,
12 68%; b) allylcyclopentane or allylcyclohexane, Grubbs II cat. (10 mol%), DCM,
reflux, 16-30h; c) -AD-mix, MeSO2NH2, t-BuOH/H2O (1:1), 0°C, 2-5 days, 3 29%, 4
43%, 14 26% (over two steps); d) thiocarbonyldiimidazole, DCE, reflux, 4-6h, 5
36%, 6 78%, 15 50%; e) Bu3SnH, AIBN, toluene, reflux, 4h; f) CH(OMe)3, p-TSA,
DCM, rt, 2h; g) Jones reagent, acetone, 0°C to rt, 1h, 7 42%, 8 64%, 16 27% (over 3
steps); h) BBr3, DCM, 0°C to rt, 5 days, 9 60%, 10 73%; i) TFA, DCM, rt, 16h; j) 10%
Pd/C, H2, EtOAc, rt, 16h, 17 46% (over two steps).
presence of Grubbs II catalyst, and subjected to
dihydroxylation with α-AD-mix to provide three new diol-intermediates
3, 4 and 14, as single enantiomers and in relatively good yield over two
a Sharpless
For our second approach, encouraged by the docking study and
the potential shape complementarity, we explored analogues bearing a
stereocontroled tetrahydropyran core (Scheme 2). The synthesis of the
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10.1002/cbic.201800587
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dihydroxyisocoumarins 25a and 25b commences with a similar strategy.
3,5-Dimethoxybromo benzene 1 is herein converted into 2-bromo-4,6-
dimethoxybenzaldehyde under standard Vilsmeier-Haack conditions.[10]
KMnO4 oxidation[11] and methyl iodide treatment in the presence of
K2CO3 furnishes the desired methyl ester 18. Palladium-catalyzed Stille
coupling reaction with allytributylstannane affords the allylic
intermediate 19 (92% yield) which is subjected to the Lemieux-Johnson
oxidative cleavage[12] to provide smoothly the aldehyde 20. Subsequent
enantioselective Brown allylation[13] delivers the chiral homoallylic
alcohol 21 which partially undergoes spontaneous intramolecular
esterification with the neighboring ester functionality. Final cyclization
of the remaining acyclic material is promoted by Amberlyst-15
catalyst,[14] leading to the allyl-modified isochromanone 22 in a 60%
yield over 2 steps. This compound is finally exposed to a catalytic
amount of Grubbs II complex (5%) in benzene at 45°C to perform a
cross-coupling metathesis reaction with the homoallylic alcohol (S)-(+)-
5-hexen-2-ol, leading to a remarkably clean formation of the E-olefin 23
in 64% yield. At this stage, despite the fact that we were seemingly only
two routine operations away from the final lactone 25, we could not
force the complete stereoselectivity of the ring closure step. Moreover,
given our interest in accessing both diastereoisomers, no particular effort
was further dedicated to guide specifically the stereoselectivity for the
ring closure. Hence, the strategy continues with an iodine-mediated
cyclization allowing the rapid generation of the C5-membered ring
system. The so-formed iodo-intermediate is engaged directly in a
halogen-hydride exchange reaction employing Bu3SnH/AIBN to yield
to a mixture of two diastereoisomers 24a and 24b, highly inseparable.
Only after proceeding to their separation with a reversed-phase chiral
HPLC 24a and 24b were isolated with 99% d.e.[15] Ultimate deprotection
under Maier’s conditions (AlI3, TBAI, and phloroglucinol)[16] leads to
the lactones 25a and 25b, which could be unambiguously characterized
with a fully assigned configuration (See supporting information).
Sonogashira coupling reaction with prop-2-yn-1-ylcyclohexane 26 in
the presence of a catalytic amount of copper iodide and trimethylamine,
leading to the alkynylaryl ester 27 in 80% yield. FeCl3-mediated
cyclization of 27 selectively generated the expected six-membered ring
product which was subjected to BBr3 treatment, to afford the analogue
28 ready for biological evaluation (Scheme 3). [18]
Scheme 3. Third Route – A simplified approach to cladosporin analogue 28.
Reagents and conditions: a) Pd(PPh3)4, CuI, NEt3, DMF, 80%; b) FeCl3, DCM, rt, 18h,
40%; c) BBr3, DCM, rt, 8h, 55%.
Evaluation of biological potency and metabolic stability of the
compound library- With all these analogues in hand, we initiated a
profiling campaign to assess their respective biological
activity/selectivity for different t-RNA synthetases : lysyl, threonine and
phenylalanine as well as their metabolic stability. Follow up analysis,
using the haploinsufficiency profiling (HIP) method and genetic
mutational profiling, [19] confirmed that compounds 9, 10, and 28 were
still on target and the overall lysyl-tRNA binding mode was unchanged
(Supporting information). [20] This key assay allowed not only to assess
activity and selectivity in a cell-based fashion but also to verify that the
tested derivatives also have the potential to penetrate even thick
biological cell walls and membranes, an important requirement for
potential anti-infectives.
Critically, while presenting a relatively close structural similarity
with cladosporin, compounds 9 and 10 (IC50, p.f.LysRS = 0.3; 0.2 µM) were
found several-fold less potent and less selective than the parent
compound cladosporin (Table 1). Compound 25a and 25b did not
present any activity (IC50, p.f.LysRS >10 µM). HIP analysis of compounds
17 and 29 (obtained from commercial source) gave a most surprising
outcome as their respective activity revealed that the observed cell-based
activity was not elicited by inhibition of lysyl-tRNA synthetase, but
rather threonyl- and phenylalanyl-tRNA synthetase, respectively
(Supporting information).
Compound
IC50
IC50
HIP target
S.cerevisiae
with human
Lys.R.S.
(µM)
S.cerevisiae
with P.
falciparum
Lys.R.S.
hypothesis
Scheme 2. Second route proposed, yielding to the isolation of 25a and 25b.
Reagents and conditions: a) POCl3, DMF, 100°C, 4h, 91%, b) KMnO4, H2O, 75°C, 4h,
64%, c) MeI, K2CO3, DMF, rt, 3h, 95%. d) Pd(PPh3)4, LiCl, allyltributylstanane, DMF,
100 °C, 24h, 92%; e) OsO4, NaIO4, dioxan/water (3:1), rt, 5h, 62%; f) (+)-
Ipc2B(allyl)borane, Et2O, –78°C to rt, 2h; g) Amberlyst 15, DCM, rt, 2 days, 60%
(yield over two steps); h) (S)-(+)-5-hexen-2-ol, Grubbs II (5 mol %), benzene, 45 °C,
6h, 64%; i) I2, NaHCO3, toluene, –78 °C rt, 18h; then Bu3SnH, AIBN, benzene, 80 °C,
24a 21%, 24b 21% ( 57% yield over two steps and 42% after chiral separation);
j) Al, I2, TBAI, phloroglucinol, benzene, 30 min, 5 °C, 25a 58%, 25b 42%.
(µM)
cladosporin
100
0.05
Lysyl-tRNA synth.
9
30
15
0.3
0.2
40
Lysyl-tRNA synth.
Lysyl-tRNA synth.
10
17
180
Phenylalanyl-tRNA
synth.
Our third strategy resembles a small pilot synthesis, on a
simplified set of analogues. A representative case is outlined in Scheme
3. In fact, the presence of the isocoumarin ring was known to be vital
but some structural modifications were allowed by the “π- cage” formed
with the aromatic residues. Inspired by previous findings from a set of
compounds generated by biotransformation, we proposed to introduce
a strategic unsaturation within the isocoumarin core as illustrated by
compound 28.[17a]
25a
25b
28
>100
>100
10
>100
>100
0.02
n.d.
n.d.
Lysyl-tRNA synth.
As shown in Scheme 3, our pivotal starting material, methyl 2-
bromo-4,6-dimethoxybenzoate 18 is subsequently engaged in
a
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10.1002/cbic.201800587
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COMMUNICATION
Experimental Section
40
40
Threonyl-tRNA synth.
All experiments and associated data are described in detail in the
Supporting information.
29
Acknowledgements ((optional))
Table 1. IC50 values for the inhibitory activity of the more potent cladosporin
analogues in the two yeast species P. falciparum versus human. Values
compared to the parent compound cladosporin (n.d.= not determined).
This work was supported by Global Discovery Chemistry (GDC)
department and Presidential Postdoctoral Program at the Novartis
Institute for BioMedical Research (NIBR). We would like to thank Dr.
Owen Wallace for guidance as for the design of the analogues of
cladosporin and docking studies.
Finally, the metabolic stability was assessed for selected
compounds with interesting biological activities. The results are
reported in Table 2 as a measure of intrinsic clearance (CL int), half-life
(T1/2)and ER in human. As aligned with their low potency and selectivity,
structural modifications conferred to compounds 9 and 10 did not
address the metabolic stability aspect and were as weak as cladosporin.
Astonishingly, the seemingly minor modifications proposed earlier
payed off as compound 28 turned out to be significantly more potent
than cladosporin itself, while conserving its selectivity and presenting a
reasonable metabolic stability (Table 2). Notably, as the glucuronidated
product of 28 could not be observed, we did not engage any further
campaign to modify any of the hydroxyl group carried by the aromatic
moiety of the molecule.
Keywords: tRNA synthetase inhibitors • Cladosporin analogues •
Malaria • Plasmodium falciparum • metabolically stable
[1] a) Poonam, Y. Gupta, N. Gupta, S. Singh, L. Wu, B. S. Chhikara, M.
Rawat, B. Rathi. Med. Res. Rev. 2018, doi: 10.1002/med.21486; b) V.
Baraka, H. M. Mavoko, C. Nabasumba, F. Francis, P. Lutumba, M.
Alifrangis, J. P. Van Geertruyden, PLoS One. 2018, 13, e0191922; c) G.
W. Rangel, M A. Clark, U. Kanjee, C. Lim, K. Shaw-Saliba, M. J.
Menezes, A. Mascarenhas, L. Chery, E. Gomes, P. K. Rathod, M. U.
Ferreira, M. T. Duraisingh. Antimicrob. Agents Chemother. 2018, doi:
10.1128/AAC.02519-17.
Compound
Subtype
T
Hepatic
Extraction
(%)
CL int
(µL/min/mg)
½
(min)
[2] P. M. Graves, L. Choi, H. Gelband, P. Garner. Cochrane Database
Syst. Rev. 2 2018, CD008152.
cladosporin
Human
Human
Human
Human
Human
269
370
405
13
12
12
6.9
[3] S. Bhattacharjee, I. Coppens, A. Mbengue, N. Suresh, M. Ghorbal,
Z. Slouka, I. Safeukui, H. Y. Tang, D. V. Speicher, R. V. Stahelin, N.
Mohandas, K. Haldar. Blood 2018, doi: 10.1182/blood-2017-11-
814665.
9
3.2
3.4
10
17
28
12
80
104
101
[4] a) E. Bilsland, L. van Vliet, K. Williams, J. Feltham, M. P. Carrasco,
W. L. Fotoran, E. F. G. Cubillos, G. Wunderlich, M. Grøtli, F. Hollfelder,
V. Jackson, R. D. King, S. G. Oliver. Sci. Rep., 2018, doi:
10.1038/s41598-018-19549-x; b) P. Fang, H. Han, J. Wang, K. Chen, X.
Chen, M. Guo Chem. Biol. 2015, 22, 734-744.
14
79.5
Table 2. Metabolic stability assessment of the key synthetic analogues
compared to their parent compound cladosporin.
In conclusion, we have successfully identified a simplified
cladosporin analogue presenting not only improved potency and
metabolic stability compared to its natural parent, but retained selectivity
towards the human enzyme. Gratifyingly, our screening campaign has
led to the identification of two additional fungal active drugs, selective
inhibitors of threonyl- and phenylalanyl-tRNA synthetase and thus
allowing expanding the biological space modulated by this isocoumarin-
derived scaffold. Additionally, as reported in the precedent publication,
an additional biotransformation-based approach, [17a] resulted into the
discovery of a set of active hydroxylated-cladosporin analogues,
targeting specifically the lysyl-tRNA synthetase. This discovery
represents a real breakthrough as it suggests that such a natural product
derived structure could provide a privileged scaffold to inhibit
synthetases beyond lysyl-tRNA synthetase.
[5] a) R. Felten, E. Dervovic, F. Chasset, J.E. Gottenberg, J. Sibilia, F.
Scher, L. Arnaud Autoimmun Rev. 2018, 18, 30133-2; b) M.J. Chaparro,
F. Calderón, P. Castañeda, E. Fernández-Alvaro, R. Gabarró, F.J. Gamo,
M.G. Gómez-Lorenzo, J. Martín J, Fernández ACS Infect. Dis. 2018, 4,
568-576; c) D. K. Mohapatra, S. Maity, S. Banoth, R. G. Gonnade, J. S.
Yadav. Tetrahedron Lett. 2016, 57, 53-55; d) R.V.K. Cochrane,
R.Sanichar, G.R. Lambkin, B. Reiz, W. Xu, Y. Tang, J.C. Vederas Ang.
Chem. Int. Ed. 2016, 55, 664-668; e) B.J. Rawlings, P.B. Reese, S.E.
Ramer, J.C. Vederas J. Am. Chem. Soc. 1989, 111, 3382-3390; f)
L.C.Bouchez et al. “Asymmetric Total Synthesis of Agrimonolide, a
Potent Cytotoxic Agent” is under revision.
[6] For metabolic stability see: a) W. Sun, X. Huang, H. Li, G. Tawa, E.
Fisher, T. Q. Tanaka, P. Shinn, W. Huang, K. C. Williamson, W. Zheng.
Malar. J. 2017, 16, 147; b) R. Wampfler, N. E. Hofmann, S. Karl, I.
This article is protected by copyright. All rights reserved.

10.1002/cbic.201800587
ChemBioChem
COMMUNICATION
Betuela, B. Kinboro, L. Lorry, M. Silkey, L J. Robinson, I. Mueller, I.
Riedl, T. Aust, S. L. McCormack, D. M. Plouffe, S. Meister, S. Schuierer,
U. Plikat, N. Hartmann, F. Staedtler, S. Cotesta, E. K. Schmitt, F.
Petersen, F. Supek, R. J. Glynne, J. A. Tallarico, J. A. Porter, M. C.
Fishman, C. Bodenreider, T. T. Diagana, N. R. Movva, E. A. Winzeler.
Cell Host Microbe 2012, 11, 654-663.
Felger. PLoS Negl. Trop. Dis. 2017, 11, e0005753.
[7] K. B. Sharpless. J. Org. Chem. 1992, 57, 2768-2771.
[8] B. G. Song, B. Suk Son, M. J. Seo, J. K. Kim, G. Lee, Z. No, H. R.
Kim. Bull. Korean Chem. Soc. 2005, 26, 375-376.
[9] H. Zheng, C. Zhao, B. Fang, P. Jing, J. Yang, X. Xie, and X. She. J.
Org. Chem. 2012, 77, 5656-5663.
[10] K. Koch, J. Podlech, E. Pfeiffer, M. Metzler. J. Org. Chem. 2005,
70, 3275-3276.
[11] V. Rys, A. Couture, E. Deniau, P. Grandclaudon. Eur. J. Org. Chem.
2003, 1231-1237.
[12] R. Pappo, D. S. Jr. Allen, R. U. Lemieux, W. S. J. Johnson. J. Org.
Chem. 1956, 21, 478-479.
[13] P. K. Jadhav, K. S. Bhat, P. T. Perumal, H. C. Brown. J. Org. Chem.
1986, 51, 432-439.
[14] X. Huang, N. Shao, A. Palani, R. Aslanian, A. Buevich. Org. Lett.
2007, 9, 2597-2600.
[15] D. D. Martín, I. S. Marcos, P. Basabe, R. E. Romero, R. F. Moro,
W. Lumeras, L. Rodríguez, J. G. Urone. Synthesis 2001, 7, 1013-1022.
[16] S. J. Gharpure, S. K. Porwal. Tetrahedron 2011, 67, 1216-1230.
[17] Findings from both publications led the synthesis of the
intermediate 28 : a) A. Fredenhagen, K. Schroer, H. Schröder, D.
Hoepfner, M. Ligibel, L. Porchet Zemp, C. Radoch, E. Freund, A.
Meishammer, Angew. Chem. 2018; b) C. Rink, F. Sasse, A. Zubrienė,
D. Matulis, M. E. Maier. Chem. Eur: J. 2010, 16, 14469-14478;
[18] A. Sperança, B. Godoi, S. Pinton, D. F. Back, P. H. Menezes, G.
Zeni. J. Org. Chem. 2011, 76, 6789–6797.
[19] A.M. Deutschbauer, D.F. Jaramillo, M. Proctor, J. Kumm, M. E.
Hillenmeyer, R. W. Davis, C. Nislow, G. Giaever Genetics 2005 , 169
(4), 1915-1925
[20] a) R.V.K. Cochrane, A.K. Norquay, J.C. Vederas MedChemComm
2016, 7, 1535-1545; b) D. Hoepfner, S. B. Helliwell, H. Sadlish, S.
Schuierer, I. Filipuzzi, S. Brachat, B. Bhullar, U. Plikat, Y. Abraham, M.
Altorfer, T. Aust, L. Baeriswyl, R. Cerino, L. Chang, D. Estoppey, J.
Eichenberger, M. Frederiksen, N. Hartmann, A. Hohendahl, B. Knapp,
P. Krastel, N. Melin, F. Nigsch, E. J. Oakeley, V. Petitjean, F. Petersen,
R. Riedl, E. K. Schmitt, F. Staedtler, C. Studer, J. A. Tallarico, S. Wetzel,
M. C. Fishman, J. A. Porter, N. R. Movva. Microbiol. Res. 2014, 169,
107-120; c) D. Hoepfner, C. W. McNamara, C. S. Lim, C. Studer, R.
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SAR approach and best cladosporin analogue:
Selective and specific inhibitors of Plasmodium falciparum tRNA
synthetases represent promising therapeutic antimalarial avenues.
Chemogenomic profiling of a focused library allowed us to open the door
to entirely innovative SAR studies, shedding the light on a structural
evidence of a privileged scaffold with a unique activity against a panel
of tRNA synthetases: lysyl-, threonyl- and phenylalanyl-tRNA
synthetases.
We successfully identified a simplified cladosporin analogue
comprising an improved potency, a superior metabolic stability
compared to its natural parent, and retaining its selectivity towards
the human enzyme.
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