Synthesis and biological evaluation of thiazole derivatives on basic defects underlying cystic fibrosis

Article abstract of DOI:10.1016/j.bmcl.2020.127473

Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of phenylalanine at position 508 (F508del), wh

Full text of DOI:10.1016/j.bmcl.2020.127473

Bioorganic & Medicinal Chemistry Letters 30 (2020) 127473
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of thiazole derivatives on basic defects
underlying cystic fibrosis
a
a
b
b
b,⁎
Emanuela Pesce , Nicoletta Pedemonte , Alberto Leoni , Alessandra Locatelli , Rita Morigi
b
a
U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy
Dipartimento di Farmacia e Biotecnologie, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
Cystic fibrosis is a genetic disease caused by loss-of-function mutations in the cystic fibrosis transmembrane
conductance regulator gene, encoding for CFTR protein. The most frequent mutation is the deletion of pheny-
lalanine at position 508 (F508del), which leads to distinct defects in channel gating and cellular processing. In
last years, several thiazole containing small molecules, endowed with dual F508del-CFTR modulator activity,
proved to be able to target these defects. In search of new chemical entities able to restore CFTR function, we
designed and synthesized a small series of sixteen thiazole derivatives. The designed compounds were studied as
correctors and potentiators of F508del-CFTR. Although none of the molecules showed significant corrector ac-
tivity, compounds 10 and 11 exhibited potentiator effects, thus allowing to determine some basic structural
features which enable to obtain F508del-CFTR potentiator activity. In silico ADME studies showed that these
derivatives obey Lipinski’s rule of five and are expected to be orally bioavailable. Therefore, these molecules may
represent a good starting point for the design of analogues endowed with improved CFTR potentiator activity
and a good pharmacokinetic profile.
Cystic fibrosis
F508del-CFTR
Ion channels
Thiazole derivatives
Structure-activity relationships
Introduction
to directly bind to CFTR to enhance its open probability, correctors may
5
act through different mechanisms of action. Depending on their target,
Cystic fibrosis (CF) is a life-threatening genetic disease caused by
loss-of-function mutations in the cystic fibrosis transmembrane con-
correctors can be divided into: i) pharmacological chaperones, that act
directly on mutant CFTR to stabilize its folding; and ii) proteostasis
regulators, able to modify the proteostasis environment, leading to
beneficial effects on CFTR maturation and trafficking to the plasma
1
ductance regulator (cftr) gene, encoding for CFTR protein. CFTR
functions is a cAMP-regulated chloride channel at the apical membrane
of epithelia and the disease affects the lungs, pancreas, liver, exocrine
glands and other organs. More than 2000 mutations have been de-
scribed in the cftr gene, however the most frequent is the deletion of
phenylalanine at position 508 (F508del). F508del-CFTR displays sev-
eral defects at the molecular level, including misfolding that results in
5
6
membrane. VX-809 or Lumacaftor™ (Vertex Pharmaceuticals Inc) was
the first corrector drug to be approved by the FDA and is combined with
7
the potentiator Ivacaftor™ (VX-770) (Fig. 1) in the drug Orkambi™
(Vertex Pharmaceuticals Inc) to treat CF patients homozygous for the
8
F508del mutation. High-throughput screening of large chemical li-
2
premature degradation by the proteasome, and if trafficked to the
braries and in silico approaches have led to the identification of several
chemical entities able to act as mutant CFTR correctors and/or po-
tentiators, among which thiazoles are particularly interesting
plasma membrane, reduced stability due to peripheral protein quality
3
4
control mechanisms and low open probability. Thus, this kind of
mutation leads to distinct defects in channel gating and cellular pro-
cessing. Drug-like small molecules, known as ‘CFTR modulators’, can
target these specific defects and restore, at least partially, CFTR func-
9
–12
(Fig. 1).
Thiazole is a well-known five-membered heterocyclic compound.
This scaffold is very versatile and widely used by the industry and
pharmaceutical academic researchers in the design of drugs with an-
algesic, anti-inflammatory, antimicrobial, antiviral, antioxidant,
5
tion. In particular, correctors are compounds able to improve mutant
CFTR folding and thus increasing protein maturation and trafficking to
5
13–15
the plasma membrane. Potentiators are instead compounds able to
diuretic, anticonvulsant, neuroprotective and antitumor activity.
stimulate activity of mutant CFTR channel with gating defect, but
In 2005, Verkman and colleagues disclosed the first F508del corrector
5
9
correctly expressed on the cell surface. While potentiators are thought
ever identified, corr-4a (Fig. 1). Further optimization led to improved
⁎
Corresponding author.
E-mail address: rita.morigi@unibo.it (R. Morigi).
https://doi.org/10.1016/j.bmcl.2020.127473
Received 30 June 2020; Received in revised form 24 July 2020; Accepted 4 August 2020
Available online 09 August 2020
0960-894X/ © 2020 Elsevier Ltd. All rights reserved.

E. Pesce, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127473
Fig. 1. CFTR modulators: VX-809, VX-770 and some thiazole derivatives.
thiazole-containing correctors, including conformationally-locked bi- chloride, in presence of DMAP and Et
3
N, to obtain the corresponding
9
,16–18
thiazoles, pyrazolylthiazoles and triazolo-bithiazoles.
VX-809
benzamides (1–4), which in turn, treated with NaOH in EtOH, gave the
acetic acid derivatives 5–8. Compounds 9–12 were obtained by treating
benzamides 1–4 with EtBr in presence of NaH, and treated with NaOH
in EtOH to give the corresponding acids 13–16. The structure of the
also was obtained after a lead optimization process, starting from a
6
thiazole-containing lead compound, named VRT-768 (Fig. 1). In ad-
dition, some aminoarylthiazole (AATs) derivatives exhibit dual F508del
modulator ability, being correctors and/or potentiators of the channel
1
13
new derivatives (9–16) was confirmed by H NMR, C NMR spectro-
scopy and high resolution mass spectrometry (HRMS). Detailed syn-
thetic procedures and spectra of the new compounds are reported in the
Supplementary data section.
1
9–21
(
Fig. 1),
and thiazole based compounds proved also to act as
22,23
multitarget agents useful in CF.
Therefore, thiazole can be con-
sidered an interesting framework for the design of small molecules
addressed to overcome the underlying defects in the cellular processing
and chloride channel function of CF. Indeed, the thiazole ring possesses
a quite simple structure and electronic properties that allow to extend
A bibliographic survey performed using Reaxys database (http://
www.reaxys.com) showed that the synthesis of compounds 1–3 and
5–7 was already reported, although these compounds were studied as
1
3
25
the synthesis to new molecules.
VEGFR and PI3K kinases (1, 2, 5 and 6) or Xa factor (3, 7) in-
2
6
On this basis, we designed a small series of thiazole derivatives
Fig. 2), inspired to well known CFTR modulators (Fig. 1), but endowed
hibitors. Furthermore, the Reaxys database reports compounds 4 and
8 as commercially available, however we have described the synthesis
and the experimental data of these compounds, since they are not re-
ported in the literature.
(
with a simplified structure, which was progressively decorated in order
to get some basic SAR information. Specifically, the thiazole derivatives
bear at position 2 a benzamido group, which is contained in known
9
CFTR modulators and an acetic residue at position 4. The benzamido
Biological evaluation of thiazole derivatives as CFTR modulators
group can be unsubstituted, or bear a halogen or methoxy groups,
substituents present in various CFTR modulators previously described.
Both the ethylacetate (1–4) and the acetic acid derivatives (5–8) were
considered. Furthermore, the effect of the introduction of an ethyl
group at the benzamide nitrogen was investigated (8–16). Finally, since
pharmacokinetic properties have to be carefully evaluated in designing
compounds potentially used in therapy, we considered also this im-
portant aspect and proceeded to obtain molecules consistent with the
Lipinski’s rule of five. All the designed compounds (1–16) were studied
as correctors and potentiators of F508del-CFTR.
The ability of thiazole derivatives 1–16 to correct the basic defects
associated to F508del mutant was tested on immortalized CFBE41o-
bronchial epithelial cells stably expressing F508del-CFTR and the halide-
sensitive yellow fluorescent protein (HS-YFP). The compounds were first
tested as correctors, i.e. for their ability to correct the trafficking defect of
mutant CFTR. To this aim, cells were incubated for 24 h with vehicle alone
(
DMSO), or with test compounds at two concentrations (2 and 10 µM), or
with corrector VX-809 (1 µM) as positive control. At the time of the assay,
the activity of F508del-CFTR in the plasma membrane was stimulated with
forskolin (an adenyl cyclase activator, to increase intracellular cAMP
content; 20 µM) plus the potentiator VX-770 (1 µM), to overcome the
gating defect of mutant CFTR. Determination of F508del-CFTR activity
was then performed by measuring the rate of HS-YFP quenching caused by
iodide influx. Treatment with the thiazole derivatives did not cause any
significant increase of the ion transport activity as compared to the one
detected in cells treated with vehicle (Fig. 3).
Results
Chemistry
The synthetic route to the designed compounds is reported in
Scheme 1. The ethyl ester of the 2-(2-aminothiazol-4-yl)acetic acid (17)
2
4
was prepared according to literature in order to protect the carboxylic
Test compounds 1–16 were then evaluated for their ability to po-
tentiate F508del-CFTR activity upon acute stimulation. Thus, CFBE41o-
group. Then, compound 17 was treated with the appropriate benzoyl
2

E. Pesce, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127473
1
2
1
2
Comp.
1
R
R
R
Comp.
9
R
R
R
H
2
3
H
H
10
11
4
5
H
H
12
13
H
H
6
7
H
H
H
H
14
15
H
H
8
H
H
16
H
Fig. 2. Designed thiazole derivatives.
Scheme 1. Synthesis of the designed compounds (1–16). Reagents and Conditions: a) CH₂Cl₂, DMAP, Et N, room temperature; b) EtOH, NaOH 2 N, room tem-
3
perature; c) DMF, NaH, room temperature, then EtBr 90 °C.
3

E. Pesce, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127473
Fig. 3. Activity of novel thiazole derivatives as
F508del-CFTR correctors. The bar graphs report
F508del-CFTR activity in CFBE41o-cells after treat-
ment for 24 h with the indicated compounds (2 and
1
0 µM). Activity was elicited by acute (20 min)
treatment with forskolin (fsk, 20 µM) plus the po-
tentiator VX-770 (1 µM) and subsequently measured
with the HS-YFP assay. The dotted lines indicate the
level of activity in cells treated with vehicle alone
(
DMSO, negative control) and with the positive
control, corrector VX-809 (1 µM). Data are reported
as mean ± SD (n = 3).
Fig. 4. Activity of novel thiazole derivatives as
F508del-CFTR potentiators. The bar graphs report
F508del-CFTR activity in CFBE41o-cells, incubated
at 32 °C for 24 h to rescue defective mutant CFTR
maturation, after acute treatment with the indicated
compounds (2 and 20 µM). Activity was measured
with the HS-YFP assay. The dotted lines indicate the
level of activity in cells treated with forskolin alone
(
DMSO, negative control) and with the positive
control, potentiator VX-770 (1 µM). Data are re-
ported as mean ± SD (n = 3). **P < 0.01 versus
control (ANOVA with Dunnett’s post hoc test).
cells were incubated for 24 h at 32 °C to promote correction of the
trafficking defect of F508del-CFTR and its expression in the plasma
membrane, and then cells were assayed following acute treatment
In order to confirm specific activation of mutant CFTR by analogs
10 and 11, the compounds were tested as potentiators on CFBE41o-cells
kept for 24 h at 32 °C, in the presence of the specific CFTR inhibitor-172
(Fig. 6). The ion transport activity elicited by thiazoles 10, 11 and VX-
770 was completely abolished under these conditions, demonstrating
the specific effects of test compounds on F508del CFTR-mediated ion
transport (Fig. 6).
(
20 min) with test compounds (2 and 20 µM) in the presence of for-
skolin (20 µM) to increase intracellular cAMP content. The ion trans-
port activity detected under these conditions was compared to the one
measured in cells treated with forskolin alone (negative control) or with
forskolin plus the potentiator VX-770 (1 µM; as a positive control).
Significant increase of the halide influx was observed when cells were
acutely stimulated with thiazoles 10 and 11 (Fig. 4).
In silico ADME analysis
Next, the hits were submitted to an in depth analysis to evaluate
their potency and efficacy. To this aim, hits were tested as potentiators
at multiple concentrations in the range 80 nM–50 µM on CFBE41o-cells,
after rescue of the maturation defect at 32 °C for 24 h. Hits were found
to be active in the low micromolar range, although the efficacy was
lower than the positive control, potentiator VX-770 (Fig. 5).
The evaluation of the pharmacokinetic properties of molecules de-
signed to be eventually used in therapy is important in the early drug
discovery phases. The theoretical absorption, distribution, metabolism
and excretion (ADME) properties of compounds 1–16 were determined
by in silico analysis, using the free online software SwissADME
27
available at http://www.swissadme.ch/index.php.
The following
4

E. Pesce, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127473
Fig. 5. Potentiator activity of novel thiazoles. The
bar graphs report F508del-CFTR activity in
CFBE41o-cells, incubated at 32 °C for 24 h to rescue
defective mutant CFTR maturation, after acute
treatment with hits, at the indicated concentrations.
Activity was measured with the HS-YFP assay. The
dotted lines indicate the level of activity in cells
treated with forskolin alone (DMSO, negative con-
trol) and with the positive control, potentiator VX-
7
70 (1 µM). Data are reported as mean
±
SD
(
(
n = 8). **P < 0.01, *P < 0.05 versus control
ANOVA with Dunnett’s post hoc test).
physicochemical parameters, which according to Lipinski’s rule of five
indicate crucial characteristics for oral bioavailability, were evaluated:
molecular weight (MW), calculated logarithm of the octanol-water
partition coefficient (LogP), number of H-bond donors (nHBD), number
of H-bond acceptors (nHBA) and number of rotatable bonds (nRB),
together with the topological polar surface area (TPSA). Lipinski’s rule
of five states that, to be orally active, a small molecule should have
MW ≤ 500 Daltons, LogP ≤ 5, nHBD ≤ 5, nHBA ≤ 10 and
nucleus of these compounds is not adequately decorated to obtain a
corrector activity. On the other hand, considering the potentiator ac-
tivity, two compounds emerged (10 and 11) that, although less effec-
tive than the positive control Ivacaftor™ (VX-770), significantly po-
tentiated F508del-CFTR function. Interestingly, comparing the results
obtained, it is possible to get some insights into the structural re-
quirements necessary to achieve potentiator activity. In particular, the
introduction of a halogen at para position of the phenyl group, led to an
improvement of the activity. Indeed compound 9, bearing an un-
substituted phenyl group, was not active, whereas compounds 10 and
11, having as substituent chlorine and iodine, respectively, gave the
best results as potentiators (Fig. 4). Furthermore, compounds 10 and 11
2
8,29
nRB ≤ 10.
Absorption and membrane permeability are also influ-
2
enced by TPSA, which should be lower than 140 Å to have intestinal
absorption. The results are reported in Table 1 together with the values
obtained for the reference compound VX-770. All the thiazole deriva-
2
tives obey the Lipinski’s rule and have a TPSA lower than 140 Å , thus
showed similar efficacy but slightly different potency (E
= 1.8,
max
suggesting good gastrointestinal absorption.
EC = 1.8 µM for compound 10; E
= 1.9, EC = 3.2 µM for
5
0
max
50
Finally, compounds 1–16 were not recognized by SwissADME
software as PAINS (Pan Assay INterference compoundS), i.e. molecules
containing substructures showing potent response in assays irrespective
of the target. This evidence allows to exclude that the studied thiazole
derivatives interact nonspecifically and yield false positive biological
output.
compound 11), suggesting that both the halogen substituents con-
tribute in enhancing the activity. Very important seems also the si-
multaneous presence of two ethyl groups, the one of the ester function
and the other one at the benzamide nitrogen. Indeed, neither the ethyl
esters 2 and 3, which do not have the benzamide nitrogen ethylated,
nor the acidic derivatives 6 and 7, bearing an ethyl group only at the
benzamide nitrogen, were active (Fig. 4).
Discussion
Conclusion
The results obtained allow to get some information about the effects
of the thiazole derivatives here described as correctors or potentiators
of F508del-CFTR. Although several thiazole-containing correctors have
In conclusion, although in the experimental model adopted the
designed derivatives showed only poor activity as correctors, this pre-
liminary study allowed to identify compounds 10 and 11, which proved
to have the structural requirements necessary to express some biolo-
gical effects as potentiators, thus suggesting that the studied scaffold,
9
,16–18,19–23
been described so far,
when tested as correctors and com-
pared with Lumacaftor™ (VX-809), none of the thiazole derivatives
–16 showed significant effects, thus suggesting that the thiazole
1
Fig. 6. Specific activation of mutant F508del-CFTR
by novel thiazoles. The bar graphs report F508del-
CFTR activity in CFBE41o-cells, incubated at 32 °C
for 24 h to rescue defective mutant CFTR matura-
tion, after acute treatment with forskolin (fsk,
2
0 µM) plus vehicle alone (DMSO) or VX-770 (1 µM)
or thiazoles (10 µM for both) in the absence or in the
presence of inh-172 (15 µM). Activity was measured
with the HS-YFP assay. The dotted lines indicate the
level of activity in cells treated with forskolin plus
vehicle. Data are reported as mean ± SD (n = 8).
*
**P
<
0.001 versus control (ANOVA with
Dunnett’s post hoc test).
5

E. Pesce, et al.
Bioorganic & Medicinal Chemistry Letters 30 (2020) 127473
Table 1
ADME in silico analysis (data obtained by using SwissADME software).
Comp
MW
LogP
nHBD
nHBA
nRB
TPSA (Å2)
GI absorption
PAINS alert
1
2
3
4
5
6
7
8
9
290.34
324.78
416.23
380.42
262.28
296.73
388.18
352.36
318.39
352.84
444.29
408.47
290.34
324.78
416.23
380.42
392.49
2.36
2.88
3.02
2.38
1.61
2.16
2.29
1.53
2.86
3.45
3.59
2.87
2.19
2.71
2.81
2.18
4.47
1
1
1
1
2
2
2
2
0
0
0
0
1
1
1
1
3
4
4
4
7
4
4
4
7
4
4
4
7
4
4
4
7
3
7
96.53
96.53
96.53
124.22
107.53
107.53
107.53
135.22
87.74
87.74
87.74
115.43
98.74
98.74
98.74
126.43
82.19
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
7
7
10
5
5
5
8
8
1
1
1
1
1
1
1
0
1
2
3
4
5
6
8
8
11
6
6
6
11
5
VX-770
MW: molecular weight; LogP: values correspond to Consensus LogPo/w; nHBD: number of H-bond donors; nHBA: number of H-bond acceptors; nRB: number of
rotatable bonds; TPSA: topological polar surface area; GI: gastrointestinal; PAINS: Pan Assay INterference compoundS.
adequately substituted, enables to obtain F508del-CFTR potentiator
activity. Interestingly, in silico ADME analysis showed that these thia-
zole derivatives do not violate the Lipinski’s rule of five, therefore they
are expected to have good oral bioavailability. Moreover, SwissADME
software did not recognize them as PAINS, thus excluding nonspecific
effects. On this basis, compounds 10 and 11 could represent a valuable
starting point for the design of analogues characterized by improved
CFTR potentiator activity and endowed with promising pharmacoki-
netic properties.
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