Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG)

Article abstract of DOI:10.1016/j.bmcl.2018.08.028

A series of trisubstituted thiazoles have been identified as potent inhibitors of Plasmodium falciparum (Pf) cGMP-dependent protein kinase (PfPKG) through template hopping from known Eimeria PKG (EtPKG) inhibitors. The thiazole series has yielded compounds with improved potency, kinase selectivity and good in vitro ADME properties. These compounds could be useful tools in the development of new anti-malarial drugs in the fight against drug resistant malaria.

Full text of DOI:10.1016/j.bmcl.2018.08.028

Accepted Manuscript
Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falci-
parum protein kinase G (PfPKG)
Denise J. Tsagris, Kristian Birchall, Nathalie Bouloc, Jonathan M. Large, Andy
Merritt, Ela Smiljanic-Hurley, Mary Wheldon, Keith H. Ansell, Catherine
Kettleborough, David Whalley, Lindsay B. Stewart, Paul W. Bowyer, David A.
Baker, Simon A. Osborne
PII:
S0960-894X(18)30704-2
https://doi.org/10.1016/j.bmcl.2018.08.028
BMCL 26008
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 June 2018
22 August 2018
24 August 2018
Please cite this article as: Tsagris, D.J., Birchall, K., Bouloc, N., Large, J.M., Merritt, A., Smiljanic-Hurley, E.,
Wheldon, M., Ansell, K.H., Kettleborough, C., Whalley, D., Stewart, L.B., Bowyer, P.W., Baker, D.A., Osborne,
S.A., Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG),
Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.08.028
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Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum
protein kinase G (PfPKG)
Denise J. Tsagris a,*, Kristian Birchall a, Nathalie Bouloc a, Jonathan M. Large a, Andy
Merritt a, Ela Smiljanic-Hurley a, Mary Wheldon a, Keith H. Ansell a, Catherine
Kettleborough a, David Whalley a, Lindsay B. Stewart b, Paul W. Bowyer b, David A.
Baker b, Simon A. Osborne a
a LifeArc, Accelerator Building, Open Innovation Campus, Stevenage, SG1 2FX, UK
b Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
Abstract
A series of trisubstituted thiazoles have been identified as potent inhibitors of Plasmodium
falciparum (Pf) cGMP-dependent protein kinase (PfPKG) through template hopping from
known Eimeria PKG (EtPKG) inhibitors. The thiazole series has yielded compounds with
improved potency, kinase selectivity and good in vitro ADME properties. These
compounds could be useful tools in the development of new anti-malarial drugs in the fight
against drug resistant malaria.
Keywords:
Plasmodium falciparum
Malaria
PfPKG
Thiazole
Malaria causes up to 450 000 deaths every year, most of which occur in sub-Saharan
Africa. 1 Most of the malaria mortality is caused by Plasmodium falciparum (Pf), one of the
four species known to infect humans. Transmitted through the bites of Anopheles
mosquitoes, the symptoms include fever, headache, chills and vomiting and if not treated
quickly, anaemia, respiratory distress and multi organ failure. The population groups who
are at highest risk are young children and pregnant women. Chloroquine was the first line
of treatment for malaria for many years; however due to the development of resistance,
its use has been substituted by drugs, the current standard of care being artemisinin-
based combination therapy (ACT). However, parasite resistance to ACTs in South East
1

Asia has been detected and is predicted to grow; therefore development of other
treatments is highly desirable.2
One promising antimalarial drug target that is being investigated is Pf cGMP-dependent
protein kinase (PfPKG), an enzyme which is conserved to a high degree of homology in
other species of therapeutic relevance such as P. vivax and P. berghei. This protein kinase
is essential in all the key phases of the Pf parasite life cycle and in the blood stage,
inhibiting PfPKG stops replication by preventing merozoite egress3 and invasion.4 First
generation PfPKG inhibitors have also been shown to block gametogenesis5 and ookinete
motility6 - two key developmental events required for mosquito-borne transmission. It has
also been shown that PKG is essential for sporozoite motility and liver cell invasion7 as
well as late liver stage development,8 making PfPKG an attractive target for new classes
of anti-malarial drugs.
Herein, we will discuss PfPKG inhibitors derived from PKG inhibitors (compound 1 and 2)
developed to treat Eimeria infections in poultry9 (Figure 1). Both of these compounds
showed low nanomolar potencies in a biochemical assay against PfPKG10 and moderate
potency in an in vitro cell viability assay, the hypoxanthine incorporation assay (HXI).10
2
1
PfPKG IC50 = 3 nM
PfPKG IC50 = 6 nM
HXI EC50 = 400 nM
HXI EC50 = 450 nM
Figure 1. Structure and in vitro data of compounds of 1 (data unpublished) and 210.
This paper is focused on the monocyclic compound 1, containing a pyrrole and an
unflanked 4-pyridyl, both considered undesirable motifs for further SAR development.
Furthermore, poor kinase selectivity was seen with 1, as it also showed potent activity
against several other human kinases. Due to these unfavourable properties of 1, an
alternative core was sought for further analogue development with the aim of enhancing
anti-parasitical activity against PfPKG.
Literature searches on similar structures to compound 2 had showed examples where the
imidazopyridine core could be swapped for a thiazole core, while still maintaining the
interactions formed by the appended groups.11 In addition, homology modelling (data not
2

shown) indicated a good fit for our proposed compounds. With this knowledge, we
swapped the monocyclic pyrrole core to a thiazole core, and the pyridine for the 2-
aminopyrimidine from compound 2, to give thiazole 3 (Figure 2).
Compound 3, when tested, showed similar biochemical potency and a slight drop in
cellular potency when compared to compounds (1) and (2) (Figure 2), which was seen as
a positive result for the changed thiazole core.
3
PfPKG IC50 = 17 nM
HXI EC50 = 1810 nM
Figure 2. Structure and in vitro data of thiazole 3.
To optimize the potency, we first examined the pendent 2-aminopyrimidine (Scheme 1).
(a)
(b)
4
5
6
7
(c)
(d)
9a-d
8
Scheme 1. Reagents and conditions (a) LiHMDS (1M in THF), THF, 0 °C to r.t., 25%; (b)
(i) (Me)3SiCl, (nBu)4NBr, DMSO, THF, 0 °C to r.t., (ii) tert-butyl 4-carbamothioyl-
piperidine-1-carboxylate, EtOH, reflux, 79%; (c) (i) 4M HCl/dioxane (ii) HCHO,
3

Na(OAc)3BH, AcOH, CH2Cl2, 47%; (d) (i) H2O2, Na2WO4.2H2O, AcOH; (ii) NH4OAc, 130
°C or AlkNH2, THF, 70 °C or ArNH2, TFA, sBuOH, 130 °C, 10-45%.
Alkylation of 4 with benzoate 5 was achieved using LiHMDS to give ketone 6. This was
then reacted with (Me)3SiCl and (nBu)4NBr to yield the α-chloro ketone in situ, which was
cyclized with the Boc-protected thioamide in refluxing ethanol to give 7. Deprotection of
7, and subsequent reductive amination gave 8, and on oxidation, the resulting sulfone
could be displaced by the appropriate amine to yield 9a-d. Two alternatives to the N-
methylpiperidine ring were also made. 9e was synthesized following sulfone oxidation of
7, with Boc deprotection occurring in the displacement step by the amine. 9f was
synthesized from tert-butyl 3-carbamothioylpyrrolidine-1-carboxylate and 6 using similar
chemistry.
Table 1
Biochemical and cell potencies of thiazole analogues
Entry
R1
R2
PfPKG
HXI
IC50 (nM) EC50 (nM)
3
-
-
NH2
17
15
1810
1490
9a
NHMe
4

9b
9c
1
155
92
0.7
9d
0.3
25
9e
9f
0.5
6
73
144
Introduction of a methyl group on the amino pyrimidine (9a) had little effect on potency but
extending to the phenylpiperazines (9b-c), gave a 10-fold improvement in both
biochemical and cellular potencies. The more basic phenylpiperidine (9d) gave a further
boost in potency with an IC50 of 300 pM in the biochemical assay and a cellular potency
of 25 nM. Not converting the piperidine N-Boc to methyl allowed access to 9e, while
swapping the piperidine group of the thiazole 2-position for the pyrrolidine (9f) gave an
equipotent compound to 9b. With the generation of an apo X-ray structure we were able
to model the compounds into the ATP binding site of PfPKG. This revealed the key
interactions made by compound 3 and the rationale for improved IC50 values of
compounds 9b-f. As shown in Figure 3, the 4-fluorophenyl is deeply buried in a
hydrophobic pocket between the catalytic lysine (K570) and the small gatekeeper residue
(T618).12 The piperidine attached to the thiazole core projects out towards solvent,
engaging in charge interactions with D682. The 2-aminopyrimidine forms a pair of H-bonds
with the backbone of V621 on the hinge and offers a vector for growth from that amine.
The pendent phenyl ring forms edge-face aromatic interactions with Y822 and positions
the terminal amine to form charge interactions with D628 at the entrance to the pocket.
5

Figure 3. Compounds 3 (left) and 9d (right) docked into an apo crystal structure of PfPKG
(PDB:5DYK)13 using Schrodinger GlideSP. The protein surface is coloured by electrostatic
potential (red negative, blue positive) and ligand H-bonding interactions are shown in
magenta (distance in angstroms), with aromatic interactions in cyan.
The kinase selectivity of 9c when measured against a panel of human kinases at a
concentration of 100 nM (Figure 5) showed extensive inhibition of several kinases across
the panel. It was thought that selectivity could be achieved via the gatekeeper or DGF
loop. Therefore, with the phenyl piperazine in place, variations were then explored around
the 4-fluorophenyl portion of the molecule. It was postulated that due to the proximity of
this group to the threonine gatekeeper residue,12 which is much smaller than the
corresponding residues in most human serine/threonine kinases,14 suitable changes here
might enhance the selectivity of the compounds (Table 3).
Methyl derivative (10) and cyclopropyl, (11) were synthesized using the same route as
shown in Scheme 1, from the appropriate ester starting material. The syntheses of 16a-e
are shown in Scheme 2, starting with the methyl m-(methylthio)benzoate 12, which was
elaborated via similar chemistry to intermediate 15. Compound 15 then underwent a
double SMe oxidation to the bis-sulfone with hydrogen peroxide and catalytic sodium
tungstate, followed by displacement of the (methylsulfonyl)pyrimidine by the requisite
amine.
6

(a)
(b)
4
12
13
14
(c)
(d)
16a-e
15
Scheme 2. Reagents and conditions (a) LiHMDS (1M in THF), THF, 0 °C to r.t., 80%; (b)
(i) (Me)3SiCl, (nBu)4NBr, DMSO, THF, 0 °C to r.t., (ii) tert-butyl 4-
carbamothioylpiperidine-1-carboxylate, EtOH, reflux, 25%; (c) (i) 4M HCl/dioxane (ii)
HCHO, Na(OAc)3BH, AcOH, CH2Cl2; (d) (i) H2O2, Na2WO4.2H2O, AcOH; (ii) NH4OAc,
130 °C or AlkNH2, THF, 70 °C or ArNH2, TFA, sBuOH, 130°C,12-35% from (14)
Table 2
Variations around the 4-fluorophenyl
Entry
R
PfPKG
HXI
IC50 (nM)
EC50 (nM)
9c
10
0.7
92
-
Me
149
NT
7

11
47
90
16a
0.9
105
NT – not tested
Replacement of the 4-fluoropenyl moiety with alkyl substituents gave rise to weakly active
analogues (10, 11) which both showed a significant drop in biochemical potency when
compared to 9c. The lower activity seen with the alkyl substituents could be attributed to
their inability to sufficiently fill the hydrophobic pocket between the catalytic lysine (K570)
and the small gatekeeper residue (T618) (Figure 3). Despite the binding potency of 11, it
showed similar cellular potency to 9c, possibly resulting from poor kinase selectivity as 11
is capable of binding to kinases in the cell with larger gatekeepers.14 Introduction of the
sulfone (16a) gave a compound with comparable IC50 values to 9c, but with a much
improved kinase selectivity profile (Figure 5).
To further enhance the kinase selectivity of the compounds, additional analogues were
made with groups of greater polarity in an attempt to capitalize on additional interactions
with the PfPKG enzyme. The new analogues were synthesized with smaller alkyl groups
on the pyrimidine ring instead of the large phenyl piperazine group (Table 3).
The synthesis of sulfonamide 23 is highlighted in Scheme 3.
8

(a)
(b)
17
18
4
19
(c)
(d) (e)
21
20
(f)
(g)
22
23
Scheme 3. Reagents and conditions (a) (i) H-cube, 10% Pd/C, 1 atm, r.t. (ii) methyl
chloroformate, pyridine, CH2Cl2, 0 °C to r.t., 94%; (b) LiHMDS (1M in THF), THF, 0 °C to
r.t., 67%; (c) (i) (Me)3SiCl, (nBu)4NBr, DMSO, THF, 0 °C to r.t., (ii) tert-butyl 4-
carbamothioylpiperidine-1-carboxylate, EtOH, reflux; (d) (i) 4M HCl/dioxane (ii) HCHO,
Na(OAc)3BH, AcOH, CH2Cl2; (e) MeSO2Cl, Et3N, CH2Cl2, 0 °C to r.t. 13% from (19); (f)
2M NaOH (aq), dioxane, 80 °C, 49%; (g) (i) H2O2, Na2WO4.2H2O, AcOH; (ii)
cyclopropylmethylamine, THF, 70 °C, 11% from (21)
The nitroester (17) was hydrogenated to the aniline, and protected as the methyl
carbamate to yield 18 which was subjected to subsequent ketone formation, then
chlorination and cyclization to give thiazole 20. Boc deprotection and reductive amination,
followed by hydrolysis with sodium hydroxide gave the unprotected aniline, 21.
Sulfonylation of 21 was carried out with two equivalents of methanesulfonyl chloride to
give firstly the bis sulfonamide, which on exposure to excess sodium hydroxide, yielded
the mono sulfonamide 22. Oxidation to the sulfone and displacement with
cyclopropylmethylamine yielded 23.
Table 3
Sulfone and sulfonamide analogues
9

Entry
R1
R2
PfPKG
HXI
IC50 (nM) EC50 (nM)
16b
16c
-
H
33
9
4570
1560
16d
16e
17
6
NT
1330
23
2
113
Replacement of the phenyl piperazine by a hydrogen to give the unsubstituted amino
pyrimidine (16b) showed a drop in potency, due to the loss of the aforementioned charge
interaction with D682. Small alkyl substituents on the amino pyrimidine with the methyl
sulphone (16c-e) all showed good potency in the biochemical assay but this did not
translate into good potency in the cell assay.
The fluorosulfonamide (23) was the most potent analogue in the biochemical assay and
docking of this compound (as shown in Figure 4) revealed the additional polar interactions
10

responsible. The cyclopropylmethyl efficiently fills the small hydrophobic pocket between
V621 and Y822, whilst the sulphonamide forms H-bonds with the DFG loop and a charge
interaction with K570.
Figure 4. Compounds 3 (left) and 23 (right) docked into an apo crystal structure of PfPKG
(PDB:5DYK)13 using Schrodinger GlideSP. The protein surface is coloured by electrostatic
potential (red negative, blue positive) and ligand H-bonding interactions are shown in
magenta (distance in angstroms).
Additionally 23 showed very good selectivity against human kinases, likely arising from
the small threonine gatekeeper residue as described earlier. Compound 23 and two
additional key examples were then profiled in a number of in vitro ADME assays (Table
4). Data for 9c showed a very good overall profile, good logD and stability along with good
PAMPA and kinetic solubility. Despite an otherwise excellent profile, the LogD of 16a was
low when measured, potentially contributing to the poor permeability seen. Compound 23
was found to be metabolically stable in human and mouse liver microsomes, and also
showed good permeability (Table 4). In transforming 9c (cLogP 3.76 pIC50 9.16 LLE15
5.40) to 23 (clogP 2.83 pIC50 8.70 LLE 5.87), we were able to reduce reliance on potency
gained from the large, lipophilic phenylpiperazine, and instead improve alternate polar
interactions.
11

98 93 85 91 92 22 72 88 95 ## 89 ## ## 59 67 88 98 ## 10 97 92 94 ## 83 87 ## 91
82 83 74 ## ## 69 71 88 91 20
7
## 94 99 ## ## ## ## 83 82 97 95 13
9
88 93 68 21 ## 91
1
95 13 59 74 ## ## 78
83 56 10 70 94
3
9
99 78 52 83 ## 96 46 93 44
9c
16a
23
97 92 94 77 87 69 ## 92 94 85 93 93 99 90 ## 94 ## 95 32 ## 86 ## ## 98 91 97 ## 78 97 ## 94 97 ## ## 82 91 ## ## 92 99 91 93 94 85 ## 82 95 92 87 ## 80 ## 94 ## 83 77 ## ## 74 44 35 81 ## 99 93 97 96 78 90 82 85 99
## 99 27 95 96 ## 79
93 ## 82 86 71 75 99 85 86 95 ## 94 66 84 88 81 96 ## 93 88 ## 90 79 92 91 97 92 81 ## 96 82 79 98 92
81 91 95 83 ## 80 98 80 75 80 92 79 92 88 85 73 83 81 ## 94 ## ## ## 79 87 70 95 ## 91 ## 88 88 72 57 ## 57 93 ## 96 ## ## 89 95 53 86
Figure 5. Selectivity of compounds 9c, 16a and 23 against a panel of human kinases at
a concentration of 100 nM.16 Red is >90% inhibition; yellow between 90% and 70%
inhibition, green <70% inhibition, white—not tested
Table 4
In vitro ADME data for compounds 9c, 16a and 23
MLMa
HLMa
mLogD
PAMPA Kinetic
Entry
(% rem) (% rem) (@ pH 7.4) (nm/s)
Solubility
(µM)
9c
16a
23
97
89
89
91
84
95
1.8
0.3
1.9
75
0
209
208
190
57
a % remaining at 40 mins
In summary, several PfPKG inhibitors have been developed and synthesized around the
new thiazole core with several possessing low nanomolar biochemical potencies and
cellular potencies around 100 nM. Excellent selectivity was achieved over human kinases
through modification of the 4-fluorophenyl group to more polar substituents such as 23,
removing previous inhibition seen against p38a MAPK and PKA kinases. Furthermore, the
anti-parasitical activity of the compounds has been enhanced greatly, as 23 shows a 4-
fold improvement in cellular potency over compound 1. Presently, the thiazole series is
being further developed to improve anti-parasite activity.
Acknowledgements
This work was funded by MRC DPFS grant no G1000779. We thank David Tickle, Sadhia
Khan and Katie Barnes (LifeArc) for compound purification and in vitro ADME data, Win
12

Gutteridge and Simon Croft for many helpful discussions, and Jeremy Burrows and Sir
Simon Campbell (Medicines for Malaria Venture) for their support of this work
References and Notes
1. World Health Organisation. World Malaria Report 2017.
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Fairhurst R.M., Slutsker L., MacArthur J.R., Breman J.G., Guerin P.J., Wellems T.E.,
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A.A., Baker D.A. Euk. Cell. 2010;9:37.
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Viskaduraki M., Lee K., Chitnis C.E., Doerig C., Moon R.W., Green J.L., Hopp C.S.,
Holder A.A., Baker D.A., Tobin A.B. Nat. Commun. 2015;6:7285.
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Billker O., Baker D.A. PLoS Biol. 2008;6:e139.
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Baker D.A., Billker O. PLoS Path. 2009;5:e1000599.
7. Govindasamy K., Jebiwott S., Jaijyan D.K., Davidow A., Ojo K.K., Van Voorhis W.C.,
Brochet M., Billker O., Bhanot P. Mol Microbiol. 2016;102:349.
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2010;285:3282.
9. Biftu T., Feng D., Fisher M., Liang G.,Qian X., Scribner A., Dennis R., Lee S.,
Liberator P.A., Brown C., Gurnett A., Leavitt P.S., Thompson D., Mathew J., Misura
A., Samaras S., Tamas T., Sina J.F., McNulty K.A., McKnight C.G., Schmatz D.M.,
Wyvratt M. Bioorg. Med. Chem. Lett. 2006;16:2479.
10. Full experimental details can be found in Baker D.A., Stewart L.B., Large J.M.,
Bowyer P.W., Ansell K.H., Jiménez-Díaz M.B., El Bakkouri M., Birchall K, Dechering
K.J., Bouloc N.S., Coombs P.J., Whalley D., Harding D.J., Smiljanic-Hurley E.,
Wheldon M.C., Walker E.M., Dessens J.T., Lafuente M.J., Sanz L.M., Gamo F.J.,
Ferrer S.B., Hui R., Bousema T., Angulo-Barturén I., Merritt A.T., Croft S.L.,
Gutteridge W.E., Kettleborough C.A., Osborne S.A. Nat. Commun. 2017;8:430.
11. Stellwagen J.C., Adjabeng G.M., Arnone M.R., Dickerson S.H., Han C., Hornberger
K.R., King A.J., Mook R.A., Petrov K.G., Rheault T.R., Rominger C.M., Rossanese
13

O.W., Smitheman K.N., Waterson A.G., Uehling D.E., Bioorg. Med. Chem. Lett.
2011;15:4436.
12. (a) Donald R.G., Zhong T., Wiersma H., Nare B., Yao D., Lee A., Allocco J., Liberator
P.A. Mol. Biochem. Parasitol. 2006;149:86. (b) Gurnett A.M., Liberator P.A., Dulski
P.M., Salowe S.P., Donald R.G., Anderson J.W., Wiltsie J., Diaz C.A., Harris G.,
Chang B., Darkin-Rattray S.J., Nare B., Crumley T., Blum P.S., Misura A.S., Tamas
T., Sardana M.K., Yuan J., Biftu T., Schmatz D.M., J. Biol. Chem. 2002;277:15913.
13. Wernimont A.K., Tempel W., He H., Seitova A., Hills T., Neculai A.M., Baker D.A.,
Flueck C., Kettleborough C.A., Arrowsmith C.H., Edwards A.M., Bountra C., Hui R.,
Hutchinson A., El Bakkouri M. Crystal structure of PF3D7_1436600; Structural
Genomics Consortium; to be published.
14. Huang D., Zhou T., Lafleur K., Nevado C., Caflisch A. Bioinformatics. 2010;26:198.
15. LLE = pIC50 - cLogP
16. Kinase selectivity profiling was carried out at the MRC Protein Phosphorylation Unit at
the University of Dundee.
Kinase list (reading left to right): MKK1, ERK1, ERK2, JNK1, JNK2, p38a, MAPK,
RSK1, RSK2, PDK1, PKBa, PKBb, SGK1, S6K1, PKA, ROCK 2, PRK2, PKCa,
PKCz, PKD1, MSK1, MNK1, MNK2, PRAK, CAMKKb, CAMK1, SmMLCK, PHK,
CHK1, CHK2, GSK3b, CDK2-Cyclin A, PLK1, Aurora A, Aurora B, AMPK,
MARK3, BRSK2, MELK, CK1, CK2, DYRK1A, NEK2a, NEK6, IKKb, PIM1,
SRPK1, MST2, EF2K, HIPK2PAK4, Src, Lck, CSK, FGF-R1, IRR, EPHA2,
MST4, SYK, YES1, IGF-1R, VEG-FR, BTK, EPH-B3, TBK1, IKKe, GCK, IRAK4,
NUAK1, MLK1, MINK1, MLK3, LKB1, HER4, TTK, IR, RIPK2, TAK1
MEKK1, TrkA, JAK2, DAPK1, IRAK1.
14

Highlights




A series of thiazole compounds inhibit the malarial kinase PfPKG
SAR development of this series led to compound 23
23 has a biochemical potency of 2 nM and an in vitro cellular potency of 113 nM
23 also possesses good in vitro ADME and excellent kinase selectivity
15