Δf508-CFTR correctors: Synthesis and evaluation of thiazole-tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles

Article abstract of DOI:10.1016/j.bmcl.2014.09.067

The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to correct the misfolding of defective ΔF508-CFTR have considerable promise for therapy. Reported here are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously identified bithiazole CF corrector 1. Interestingly, bisazole ΔF508-CFTR corrector activity was not increased by incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular geometry. The structure activity data, together with molecular modeling, suggested that active bisazole correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule's ability to access this molecular geometry.

Full text of DOI:10.1016/j.bmcl.2014.09.067

Bioorganic & Medicinal Chemistry Letters 24 (2014) 5840–5844
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
D
F508-CFTR correctors: Synthesis and evaluation of thiazole-
tethered imidazolones, oxazoles, oxadiazoles, and thiadiazoles
a
b
b
Long Ye a, , Bao Hu , Faris El-Badri , Brandi M. Hudson , Puay-Wah Phuan c,d, A. S. Verkman c,d
,
⇑
Dean J. Tantillo b, Mark J. Kurth b,
⇑
a Department of Chemistry, College of Chemical Engineering and Technology, Wuhan University of Science and Technology, Wuhan, Hubei 430081, PR China
b Department of Chemistry, University of California, One Shields Ave, Davis, CA 95616, United States
c Department of Medicine, University of California, San Francisco, CA 94143-0521, United States
d Department Physiology, University of California, San Francisco, CA 94143-0521, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 May 2014
Revised 14 September 2014
Accepted 24 September 2014
Available online 2 October 2014
The most common mutation causing cystic fibrosis (CF) is deletion of phenylalanine residue 508 in the
cystic fibrosis transmembrane regulator conductance (CFTR) protein. Small molecules that are able to
correct the misfolding of defective
are the design, preparation, and evaluation of five more hydrophilic bisazole analogs of previously iden-
tified bithiazole CF corrector 1. Interestingly, bisazole F508-CFTR corrector activity was not increased by
DF508-CFTR have considerable promise for therapy. Reported here
D
incorporation of more H-bond acceptors (O or N), but correlated best with the overall bisazole molecular
geometry. The structure activity data, together with molecular modeling, suggested that active bisazole
correctors adopt a U-shaped conformation, and that corrector activity depends on the molecule’s ability
to access this molecular geometry.
Keywords:
Cystic fibrosis
Correctors
Transmembrane regulator
C,C-linked bisazoles
Ó 2014 Elsevier Ltd. All rights reserved.
Cystic fibrosis (CF) is a genetic disorder caused by mutations in
the cystic fibrosis transmembrane conductance regulator protein
(CFTR). The most common CFTR mutation is deletion of a phenyl-
thiazole rings are constrained by an alkyl chain, is required for cor-
rector activity.6,7
However, bithiazoles are relatively hydrophobic (cLogP = 5.60
and 6.35 for 1 and 1a, respectively; Fig. 1) and so may not be suit-
able for development of an orally administered drug (cf., Lipinski’s
‘rule of five’).8 Considering that cLogP values for oxazole, oxadiaz-
ole, and thiadiazole are much lower (ꢀ0.18, ꢀ1.41, and ꢀ0.60,
respectively) than that of a thiazole ring (0.49), we set out to
replace one of the two thiazole rings in 1 with these more hydro-
philic five-membered aromatic heterocycles to explore different
chemotypes in the hope of identifying new CFTR correctors (e.g.,
2) with less hydrophobicity. Given the importance of the periphe-
ral pivalamide and 5-chloro-2-methoxyphenylamine moieties in
conveying corrector activity, these two structural motifs were
retained in the design of these new bisazole correctors. This ring
replacement strategy, in conjunction with considering the relative
accessibility of each target molecule, led to a series of bisazole ana-
logs—the cLogP for which is lowered into the range of 3.95 to 5.20
(Table 1). In addition to increased hydrophilicity, another possible
benefit associated with oxygen and nitrogen-rich bisazole rings
might be increased and stronger H-bonding interaction within
alanine residue at position 508,
DF508, which results in a mis-
folded CFTR that is retained at the endoplasmic reticulum and
rapidly degraded.1 Failure to provide functioning CFTR, an ATP-
gated chloride channel, in epithelial cells in the lungs, pancreas,
and other tissues leads to impaired chloride transport. Defective
chloride transport results in bacterial growth in the lung due to
the accumulation of viscous mucus, and pancreatic malfunction.2
Intensive efforts were taken to discover small molecules that are
able to correct the folding of the
DF508-CFTR and restore its nor-
mal processing and ion channel function3 with two investigational
correctors currently in clinical trial.4 The recent work of Yoo et al.
indicates that bithiazole 1, a 4-(thiazol-5-yl)thiazole derivative,
has significant corrector action on the mutant
D A
F508-CFTR.5
bithiazole-focused structure–activity-relationship study by Yu
et al. showed that an s-cis coplanar conformation of the bithiazole,
a peripheral pivaloyl group, and a substituted aniline moiety are
crucial structural features in eliciting
DF508-CFTR corrector activ-
ity with the bithiazole chemotype.6 Indeed, the s-cis coplanar con-
formation, as exemplified by bithiazole 1a wherein the two
the
thiazole-tethered imidazolone, oxazole, oxadiazole and thiadiazole
bisazole analogs, their F508-CFTR corrector activity, and struc-
ture–activity-relationships in this series of bisazoles.
DF508-CFTR binding site. Herein, we report the synthesis of
D
⇑
Corresponding authors. Tel.: +1 530 554 2145.
E-mail addresses: yelong@wust.edu.cn (L. Ye), mjkurth@ucdavis.edu (M.J. Kurth).
http://dx.doi.org/10.1016/j.bmcl.2014.09.067
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

L. Ye et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5840–5844
5841
MeO
O
O
H
N
H
N
C
S
N
N
3
HN
NH2
MeO
MeO
H2N
O
N
S
O
S
a
N
Cl
Br
MeO
Cl
Cl
S
SAR study
9
H
N
H
N
1a; cLogP = 6.35
4
S
N
MeO
MeO
atom
replacement
H
H
H
N
O
N
S
N
N
H2N
S
N
N
study
Cl
1; cLogP = 5.60
O
N
O
N
O
MeO
H
N
H
Cl
Cl
N
2a
5
Z
X
Z'
X'
O
Y
Y'
Scheme 1. Reagents & conditions: (a) NH3, THF, room temperature; 81%.
2 (reduced CLogP)
Cl
X = CH/CCH3/N X' = CH/CCH3/N
Y = N/S
Z = N/O/S
Y' = N/O/S
Z' = N/O/S
expected as azole formation is problematic in the presence of inter-
fering amino functionalities. With this backdrop, our first target,
oxazolyl analog 2a, was initially expected to be available as
depicted in Scheme 1 where isocyanate 3 is converted to urea 4
which would then be condensed with 1-(2-amino-4-methylthia-
zol-5-yl)-2-bromoethanone to deliver thiazole-oxazole 5. Chemo-
selective N-acylation with pivaloyl chloride would then give 2a.
An advantage of this planned route would be the opportunity to
incorporate different acid chlorides in this final step. Unfortu-
nately, all attempts at formation of oxazole 5 from urea 4 and thi-
azole 9 by reference methods were unsuccessful.12
Figure 1. cLogP and CFTR corrector lead development.
While some directly-linked bisazoles have been reported,9–11
the thiazole-tethered bisazoles (2) targeted here have not been
reported in the literature. Indeed, the preparation of directly-
linked bisazoles with amide substituents are more difficult than
These failed oxazole-forming reactions (4 + 9 ? 5) prompted us
to investigate the alternative route to 4-(thiazol-5-yl)oxazole 2a
detailed in Scheme 2. In this approach, the amino group of thiazole
6 was N-acylated first to give pivalamide 7 in a CDI-mediated cou-
pling reaction (83% yield). We reasoned that making the amide first
would decrease electron-donation into the thiazole ring (e.g., 6 vs
7), thereby increasing the reactivity of the corresponding a-bromo-
ketone 8 with urea 4. Unfortunately, while bromination of 7 with
pyridinium tribromide gave 8 in 90% yield, subsequent reaction
Table 1
Corrector activity, Vmax, and cLogP data for bisazoles
M)a = 0.87
Vmax (l
M/s)b = 97.97
MeO
EC50 (l
H
N
H
N
S
S
N
cLogP = 5.60
O
N
N
S
1
Cl
M)a = not active
Vmax (l
M/s)b = not active
O
EC50 (l
H
N
HN
OMe
of this
a-bromo ketone with urea 4 delivered 4-(thiazol-5-yl)-
cLogP = 3.95
N
1H-imidazol-2(3H)-one 2a00 in 18% yield, instead of the targeted
4-(thiazol-5-yl)oxazole 2a.13 The Crank/Khan protocol for oxazole
formation (replacing the –Br of 8 with an –OH and subsequent
reaction with cyanoamide)14 also did not yield the desired oxazole.
We next set out to prepare oxazole 2b—the C5 analog of 2a. This
thiazole-tethered oxazole analog was prepared via the three trans-
formations depicted in Scheme 3. Treatment of bromide 9 with
sodium azide gave 10 in 78% yield. Subsequent Staudinger reduc-
O
Cl
2a"
M)a = 0.74
Vmax (l
M/s)b = 84.46
MeO
EC50 (l
H
N
H
N
S
N
N
O
cLogP = 5.20
O
N
S
S
N
N
N
N
S
2b
Cl
Cl
Cl
Cl
Cl
tion of this azide delivered the corresponding
a-amino ketone as
M)a = 0.66
Vmax (l
M/s)b = 65.00
MeO
MeO
MeO
MeO
EC50 (l
an unisolated intermediate; addition of thioisocyanate gave a urea
intermediate which underwent in situ heterocyclization to give 5-
(thiazol-5-yl)oxazole 11 in 44% overall yield. Acylation of 11 with
pivaloyl chloride gave 2b (40% yield).
H
N
H
N
O
N
cLogP = 4.39
O
O
O
O
2c
EC50
(l
M)a = not active
Vmax (l
M/s)b = not active
H
N
H
N
S
N
cLogP = 5.04
H
H2N
N
O
O
S
S
2d
a
b
N
O
N
EC50
(l
M)a = 0.59
Vmax (l
M/s)b = 35.46
H
N
H
N
6
7
Cl
H
N
N
O
N
cLogP = 4.39
O
S
C4
c
OMe
O
N
O
Br
2e
H
N
8
N
S
EC50
(l
M)a = not active
Vmax (l
M/s)b = not active
H
N
H
N
NH
C5
O
N
N
S
2a
cLogP = 5.60
S
N
2a' (C4 attachment; not observed)
23
2a" (C5 attachment; observed product)
a
Concentration where the increased Iꢀ influx is 50% of Vmax
.
Scheme 2. Reagents
Pyridinium tribromide, 33% HBr in HOAc; 90%. (c) 4, CaCO3, 120 °C; 18%.
& conditions: (a) pivalic acid, CDI, DMF, 80 °C; 83%. (b)
b
Vmax is the maximum increase in Iꢀ influx due to compound dosing.

5842
H2N
L. Ye et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5840–5844
H2N
obtained in 66% yield by the reaction of 18 with tosyl chloride in
O
O
S
S
a
pyridine, while 2-(thiazol-4-yl)-1,3,4-thiadiazole 2d was accessed
via a phosphoryl trichloride-mediated cyclization process in 75%
yield.
b
N
O
N
Br
N3
H2N
MeO
9
10
H
N
MeO
S
O
H
N
H
N
Finally, 2-(thiazol-4-yl)-1,3,4-oxadiazole analog 2e was pre-
pared via the four-step process shown in Scheme 6. Treatment of
N-substituted thiourea 19 with ethyl 3-bromo-2-oxopropanoate
produced ethyl thiazolo-4-carboxylate 20 in 92% yield. Reacting
ester 20 with hydrazine hydrate produced 21 and treatment of this
hydrazide with CNBr delivered 1,3,4-oxadiazole 22 in 60% yield.
Microwave irradiation of this 1,3,4-oxadiazol-2-amine with piva-
loyl chloride in 1,4-dioxane (+TEA) gave 2e in 45% yield.
c
S
O
N
N
N
N
Cl
11
Cl
2b
Scheme 3. Reagents and conditions: (a) NaN3, MeOH, 78%. (b) PPh3, DCM; 4-chloro-
2-isothiocyanato-1-methoxybenzene, DCM, 44%. (c) Pivaloyl chloride, Et3N, DCM,
40%.
Bisazole analogs 2a00/2b–e were assayed for
DF508-CFTR cor-
rect- or activity using our well-established cell-based corrector
MeO
MeO
assay. Briefly, the influx of Iꢀ as surrogate for Clꢀ was measured
H
N
H
N
N
D
F508-CFTR employing the Iꢀ-
HN NH
N
a
in FRT cells co-expressing human
HO2C
H2N
S
S
sensitive fluorescent sensor YFP-H148Q/I152L.16,17 Following 24 h
incubation with each test compound, Iꢀ influx was determined
from the kinetics of YFP-H148Q/I152L quenching in response to
Iꢀ addition in cells treated with a cAMP agonist and the potentiator
genistein. The corrector activity of each analog was calculated from
influx versus concentration data.18 The corrector activity of bisaz-
ole analogs 2a00/2b–e, as well as lead compound 1 and reference
bithiazole compound 23,2 are listed in Table 1.
X
O
Cl
Cl
12
13 (X = S; = O)
MeO
H
N
N
X
N
N
S
H2N
Cl
14
Scheme 4. Reagents & conditions: (a) NH2NHC(X)NH2 (X = O or S), EtN(iPr)2, DCC,
Three of the five new bisazole analogs, thiazole-tethered oxa-
zole 2b and oxadiazoles 2c and 2e, are effective at recovering the
CH2Cl2.
ion efflux function of
DF508-CFTR. Among these three active bisaz-
Our initial approach to oxadiazole and thiadiazole analogs is
shown in Scheme 4, but two problems were encountered with this
route. Firstly, thiazole-4-carboxylic 12 reacted effectively with
hydrazinecarbothioamide (? 13, X = S), but not hydrazinecarboxa-
mide (? 13, X = O). Secondly, carbothioamide 13 (X = S) could not
be cyclized to thiadiazole 14 (X = S) in a practical yield under any of
the protocols reported in literature.15
In light of these issues, we decided to focus on replacing the
right-hand thiazole ring of lead compound 1 (see Fig. 1) with oxa-
diazole and thiadiazole heterocycles. Both targeted analogs, 2c and
2d, were delivered via the unified route depicted in Scheme 5. In
this approach, 2-aminothiazole 15 was converted to amide 16,
which was then reacted with hydrazine hydrate to give thiazole-
4-carbohydrazide 17 in 60% overall yield from 15. Hydrazide 17
was next reacted with 4-chloro-2-isothiocyanato-1-methoxyben-
zene to give 2-carbonylhydrazinecarbothioamide 18. From this
common intermediate, 2-(thiazol-4-yl)-1,3,4-oxadiazole 2c was
oles, 5-(oxazol-50-yl)oxazole analog 2b is more potent than the
oxadiazolyl analogs (2c and 2e) and its corrector activity is compa-
rable with lead compound 1. Interestingly, thiadiazole analog 2d
and heteroatom invertomer 23 are not active. Thiazole-tethered
oxazole 2b is active in the corrector assay, while, not surprisingly,
thiazole-tethered imidazol-2-one 2a00 is not. It is intriguing to note
that the active oxazole analog 2b is an isostere of inactive bithiaz-
ole 23. Collectively, the results within this series suggest that cor-
rector activity is tied to overall molecular geometry.
Conformational searches on 1, 2a–e and 23 were carried out
using the Merck molecular force field in Spartan.19,20 The lowest
energy conformers were then optimized using GAUSSIAN0921 with
the M06-2X/6-31+G(d,p)22 density functional method. Relative
energies were calculated both in the gas phase (as an extreme
model of nonpolar environments) and water (using the SMD con-
tinuum solvation method).23 Structural drawings in Table 2 were
produced using CYLView.24
H
N
H
N
O
O
N
N
b
MeO
MeO
O
S
O
S
H
N
H
N
NHNH2
OEt
EtO
O
H2NHN
O
N
N
16
17
b
a
S
S
c
H2N
20
21
Cl
Cl
O
N
a
MeO
S
MeO
H
N
S
H
N
OEt
c
O
N
Cl
H2N
15
MeO
N
H
H
N
O
S
S
HN NH
18
H2N
O
N
N
19
Cl
N
S
22
MeO
d
H
N
H
N
Cl
or
N
X
N
MeO
e
H
H
N
O
S
N
N
d
O
N
Cl
2c (X=O)
O
N
S
N
2d (X=S)
Cl
2e
Scheme 5. Reagents & conditions: (a) pivaloyl chloride, DCM, TEA, 50 °C, 1 h; 85%.
(b) NH2NH2ꢁH2O, EtOH, 90 °C, 5 h; 71%. (c) 4-Chloro-2-isothiocyanato-1-methoxy-
benzene, THF, rt, 18 h; 88%. (d) (? 2c) TsCl, THF, pyridine, 75 °C, 3 h; 66%. (e) (? 2d)
POCl3, 110 °C, 4 h; 75%.
Scheme 6. Reagents & conditions: (a) ethyl 3-bromo-2-oxopropanoate, ethanol,
90 °C, 3 h; 92%; (b) NH2NH2ꢁH2O, EtOH, 90 °C, 12 h; 77%; (c) CNBr, MeOH, rt, 18 h;
60%; (d) pivaloyl chloride, 1,4-dioxane, TEA, microwave, 40 min; 45%.

L. Ye et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5840–5844
5843
Table 2
Results of conformational analyses
Compd
Active or inactive
Lowest energy conformer in water
Lowest energy U-shaped conformer in water
1
Active
+7.1 kcal/mola
ꢀ0.2 kcal/mol in gas phaseb
2a
2b
Unknown (see 2a00)
Active
+0.2 kcal/mola
ꢀ1.3 kcal/mol in gas phaseb
2c
Active
+1.7 kcal/mola
+0.6 kcal/mol in gas phaseb
2d
Inactive
+7.3 kcal/mola
+12.2 kcal/mol in gas phaseb
2e
Active
+1.0 kcal/mola
ꢀ0.9 kcal/mol in gas phaseb
23
Inactive
+8.4 kcal/mola
+5.9 kcal/mol in gas phaseb
a
Free energies are relative to the lowest energy conformer in water.
Free energies are relative to the lowest energy conformer in the gas phase.
b
Our previous work,5–7 especially that with tethered bithiazoles
(see 1 and 2b,c,e) when a U-shaped conformer can be readily
accessed (i.e., gas phase U-shaped conformer within ꢂ1 kcal/mol
of the lowest energy conformer; that activity appears to track with
gas phase energies suggests that the target binding site is not par-
ticularly polar). Of course, having an accessible U-shaped con-
former does not guarantee activity, since a compound could be
inactive due to subtle differences in non-covalent interactions with
its binding site, off-target effects or other issues with this whole
cell assay. Point (2) above suggests that the putative bioactive
conformation shown in Figure 2 likely needs to be accessible for
such as 1a, provides circumstantial evidence in support of a
‘U-shaped’ bioactive conformation (Fig. 2), rigidified in part by
Sꢁ ꢁ ꢁlone pair interactions.6,25 The overall lowest energy conformer
found for each compound, along with the lowest energy U-shaped
conformer (both in water) are shown in Table 2 (see Supporting
information for additional details, including interatomic dis-
tances). These results indicate that: (1) the preferred conformer
varies from bisazole to bisazole and (2) not having a U-shaped con-
former as the preferred conformation does not preclude activity

5844
L. Ye et al. / Bioorg. Med. Chem. Lett. 24 (2014) 5840–5844
2. Widdicombe, J. H. In Cystic Fibrosis Transmembrane Conductance Regulator; Kirk,
planar amide
"internal"
hydrogen
with O & S cis
K. L., Dawson, D. C., Eds., 2003; pp 137–159.
3. Becq, F. Curr. Pharm. Des. 2006, 12, 471.
Cl
4. (a) Deeks, E. D. Drugs 2013, 73, 1595; (b) Kopeikin, Z.; Yuksek, Z.; Yang, H.-Y.;
Bompadre, S. G. J. Cyst. Fibros. 2014. Ahead of Print.
5. Yoo, C. L.; Yu, G. J.; Yang, B.; Robins, L. I.; Verkman, A. S.; Kurth, M. J. Bioorg. Med.
Chem. Lett. 2008, 18, 2610.
6. Yu, G. J.; Yoo, C. L.; Yang, B.; Lodewyk, M. W.; Meng, L.; El-Idreesy, T. T.;
Fettinger, J. C.; Tantillo, D. J.; Verkman, A. S.; Kurth, M. J. J. Med. Chem. 2008, 51,
6044.
7. Coffman, K. D.; Nguyen, H. H.; Phuan, P.-W.; Hudson, B. M.; Yu, G. J.;
Bagdasarian, A. L.; Montgomery, D.; Lodewyk, M. W.; Yang, B.; Yoo, C. L.;
Verkman, A. S.; Tantillo, D. J.; Kurth, M. J. J. Med. Chem. 2014, 57, 6729.
8. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Adv. Drug. Deliv. Rev.
1997, 23, 3.
O
H
OCH3
N
N
S
N
H
H
~coplanar rings
N
S
with S & Ar trans
CH3
~coplanar rings
with S & N cis
Figure 2. Putative bioactive U-shaped conformation (illustrated for bithiazole 1).
9. Kim, J. Y.; Seo, H. J.; Lee, S.-H.; Jung, M. E.; Ahn, K.; Kim, J.; Lee, J. Bioorg. Med.
Chem. Lett. 2009, 19, 142.
10. Quan, C.; Kurth, M. J. Org. Chem. 2004, 69, 1470.
activity; note that gas phase U-shaped conformers for inactive 2d
and 23 are 12.2 and 5.9 kcal/mol, respectively, higher in energy
than their preferred conformations. Our previous work indicates
that the conformation about the inter-ring bond (see ꢂcoplanar
bisazole rings in Fig. 2) correlates with activity as constrained 1a
is more active than unconstrained 1.5–7 It therefore appears that
access to the conformational control elements highlighted in Fig-
ure 2 are required for activity.
11. Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.; Thomas,
M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.; Fleming, I.; Green, S.;
McNae, I.; Wu, S. Y.; McInnes, C.; Zheleva, D.; Walkinshaw, M. D.; Fischer, P. J.
Med. Chem. 2004, 47, 1662.
12. For protocols, see: (a) Pathak, V. N.; Goyal, M. K.; Jain, M.; Joshi, K. C. J. Indian
Chem. Soc. 1993, 70, 539; (b) Kidwai, M.; Dave, B.; Bhushan, K. R. Chem. Pap.
2000, 54, 231; (c) Gonzalez, M. I.; Stock, H. T.; Pinnock, R. D.; Pritchard, M. C.;
Wayman, C. P.; Van der Graaf, P. H.; Naylor, A. M.; Higginbottom, M. 2002
WO2002040008A2.; (d) Dabholkar, V. V.; Mishra, S. K. J. Ind. J. Chem., Sec. B: Org.
Chem. Incl. Med. Chem. 2006, 45B, 2112; (e) Jorgensen, W. L.; Ruiz-Caro, J.;
Hamilton, A. D. 2007 WO2007038387A2.; (f) Moriconi, A.; Aramini, A. 2009
WO2009050258A1.; (g) Allegretti, M.; Aramini, A.; Bianchini, G.; Cesta, M. C.
2010 WO2010031835A2.
13. (a) The authors thank BMCL Reviewer #1 for thoughtful comments regarding
Scheme 1 and 2a versus 2a0/2a00. Using NMR chemical shift calculations {done
using the GIAO13b–f method at the SCRF-mPW1PW91/6-311+G(2d,p)//M06-2X/
6-31+G(d,p) level13g and empirically scaled [SCRF refers to the inclusion of
solvent effects (chloroform) using the SMD continuum model]13h,13i},
structures 2a and 2a0 are ruled out as the product of the reaction of 8 + 4
and 2a00 is assigned as the product (see SI for details). Mean absolute deviations
were 0.4, 0.4, and 0.1 for 1H NMR and 4.6, 3.0, and 3.1 for 13C NMR (2a, 2a0, and
2a00, respectively). Furthermore, DP4 analysis13j showed 0.4% and 98.7% match
for 1H NMR and 33.6% and 66.4% match for 13C NMR to experimental chemical
shifts (2a0 and 2a00, respectively); 2a00 is therefore assigned as the 8 + 4
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Thiazole-tethered bisazoles [thiazole-oxazole (2b), thiazole-
oxadiazole (2c and 2e), and thiazole-thiadiazole (2d)], which are
structurally related to the bithiazole
DF508-CFTR corrector 1, were
prepared from carbonyl-substituted thiazoles and a series of new
bisazole CF correctors have been identified. While the newly iden-
tified bisazole correctors contain more oxygen and/or nitrogen
atoms and have lower cLogP values than bithiazole 1, their
D
F508-CFTR corrector activity does not correlate with the number
of the H-bonding acceptors. SAR analysis suggested that incorpora-
tion of more H-bond acceptors can fundamentally change the
molecular geometry in these bisazole systems (see 1 vs 2b–e vs
23). Finally, bithiazole-to-bisazole atom substitution can modulate
the accessibility of the U-shaped conformation required for correc-
tor activity.
Acknowledgments
The authors thank the Tara K. Telford Fund for Cystic Fibrosis
Research at the University of California, Davis, the National Insti-
tutes of Health (Grants DK072517, GM089153, and HL073856),
the Petroleum Research Fund of the American Chemical Society
(Grant 52801-ND4), the National Science Foundation (Grants
CHE-0910870, CHE-0443516, CHE-0449845, and CHE-9808183
supporting NMR spectrometers), and the Faculty Research Starting
Fund at Wuhan University of Science and Technology (04020301).
This work used the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by the National Science
Foundation [ACI-1053575].
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Supplementary data
21. Frisch, M. J. et al Gaussian 09, Revision B.01; Gaussian: Wallingford CT, 2009.
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24. CYLview, 1.0b; Legault, C. Y., Université de Sherbrooke, 2009 (http://
www.cylview.org).
Supplementary data (experimental details) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2014.09.067.
25. Sadchikova, E. V.; Bakulev, V. A.; Subbotina, J. O.; Privalova, D. L.; Dehaen, W.;
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References and notes
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