Design, synthesis, and characterization of novel, nonquaternary reactivators of GF-inhibited human acetylcholinesterase

Article abstract of DOI:10.1016/j.bmcl.2014.02.049

The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.

Full text of DOI:10.1016/j.bmcl.2014.02.049

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1711–1714
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis, and characterization of novel, nonquaternary
reactivators of GF-inhibited human acetylcholinesterase
a
a
a
Stanton F. McHardy a, , Jonathan A. Bohmann , Michael R. Corbett , Bismarck Campos ,
Michael W. Tidwell a, Paul Marty Thompson a, Chris J. Bemben a, Tony A. Menchaca a, Tony E. Reeves a,
William R. Cantrell Jr. a, William E. Bauta a, Ambrosio Lopez a, Donald M. Maxwell b, Karen M. Brecht b,
Richard E. Sweeney b, John McDonough b
⇑
a Southwest Research Institute, Chemistry and Chemical Engineering Division, Department of Medicinal and Process Chemistry, 6220 Culebra Road, San Antonio, TX 78266, USA
b USAMRICD Research Division, Pharmacology Branch, 3100 Ricketts Point Road, APG, MD 21010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF
(cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited
human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-
inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited
hAChE were developed. Lead compounds from two different chemical series, represented by compounds
17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low
inhibition of native enzyme.
Received 10 December 2013
Revised 13 February 2014
Accepted 18 February 2014
Available online 28 February 2014
Keywords:
Acetylcholinesterase
Reactivation
Ó 2014 Elsevier Ltd. All rights reserved.
Cyclosarin (GF)
GF-inhibited hAChE
Structure–activity relationship
Heteroaryl keto-oximes
Exposure to highly toxic organophosphorus compounds in the
form of pesticides and their metabolites (e.g., paraoxon, malaoxon)
or nerve agents (VX, Sarin, Soman or Cyclosarin) pose substantial
threats to both military and civilian populations. Nerve agents of
this type have been studied extensively and there is significant evi-
dence showing their toxic effects are a result of phosphorylation of
the active site serine residue in acetylcholinesterase (AChE).1 Since
AChE is responsible for hydrolyzing acetylcholine to choline, this
irreversible inhibition of the AChE enzyme causes an accumulation
of acetylcholine in both peripheral and central synapses, ultimately
leading to deleterious effects, such as ocular pain, diminished vi-
sion, tightness of the chest, wheezing, bronchial constriction and
secretion, and ultimately respiratory failure and death. Of signifi-
cant relevance to our research efforts is the fact that nerve agents
also penetrate the blood–brain barrier, inhibiting central AChE,
thus causing a number of CNS related effects, such as confusion,
ataxia, convulsions, slurred speech, and coma. Furthermore, stud-
ies have suggested that exposure to sub-lethal doses of nerve agent
can dramatically impact CNS mediated behavioral attributes such
as decreased ability to perform tasks.2 Other studies have shown
that the detrimental effects of a single dose of agent can be pro-
longed3 and most of the human data, which is focused on organo-
phosphate pesticides, suggest long-term CNS effects such as
irritability, impaired memory, insomnia or anxiety.4
Pyridinium oxime compounds have been postulated to act as
reactivators by binding to nerve agent-inhibited AChE and hydro-
lyzing the phosphonate group from the serine residue via nucleo-
philic attack of the oxime moiety on the phosphorus atom. The
resulting reactivation of AChE allows the enzyme to continue con-
verting acetylcholine to choline, helping maintain functional levels
of acetylcholine.5 Quaternary pyridinium aldoxime compounds,
such as 2-PAM (Fig. 1) are limited to peripheral reactivation,6 how-
ever, results with uncharged dihydropyrine ‘pro-drugs’ of 2-PAM
have supported central protection.7 Historically,8 studies on non-
pyridinium based AChE oxime reactivators have received little
attention, with the exception of the simple acetyl oximes such as
MINA and DAM.9 During the course of our investigation reported
here, a small number of non-pyridium based AChE reactivators
were reported, represented by the dihydroisoquinoline 1,10
amidine 2,11 phenyl ketooxime 312 and the amide oxime RS41A13
(Fig. 1).
⇑
Corresponding author at present address: University of Texas San Antonio,
Department of Chemistry, Center for Innovative Drug Discovery, One UTSA Circle,
San Antonio, TX 78249, USA. Tel.: +1 210 458 8676; fax: +1 210 458 7428.
E-mail address: stanton.mchardy@utsa.edu (S.F. McHardy).
http://dx.doi.org/10.1016/j.bmcl.2014.02.049
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1712
S. F. McHardy et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1711–1714
H3CO
N
N
Cl
N
CH3
OH
Cl
H3CO
N
N
N
H
N
OH
1
2-PAM
2
N
OH
N
O
OH
R
HO
H3C
O
H
N
O
O
N
N
)
n
O
OH
N
H
(
N
OH
O
R = CH3, DAM
R = H, MINA
3 (n
= 1-
3)
RS41A
Figure 1. Structure of existing AchE reactivators.
Herein we report the design, synthesis and in vitro evaluation of
a novel class of small molecule reactivators of GF-inhibited
hAChE.14 In all design iterations, several factors were taken into
consideration. A balanced affinity for GF-inhibited AChE vs. unin-
hibited AChE is critical; however oxime pKa has also been postu-
lated to play a critical role for an efficient reactivation process.15
Physicochemical property values (LogD, tPSA, MW, # hydrogen
bond donors/acceptors) were determined and structures adjusted
to maintain the desired range of values for CNS drug-like proper-
ties.16 Based on these studies we chose to focus on two chemical
series highlighted by the amide oxime analogs 9–22 (Fig. 2) and
heteroaryl keto-oxime analogs 27–43 (Fig. 3). Both structural ser-
ies allow for introduction of lipophilic amine templates, as well
as various functional groups to modulate oxime properties.
The synthesis of the lipophilic amide oxime series is detailed
below in Scheme 1. Treatment of primary amines with ethyl 2-
(hydroxyimino)acetate provided the amide oxime analogs 4 in
moderate yield (50–70%). The primary amines could also be trea-
ted with the 1,3-dioxin-4-one in toluene at 150 °C to produce the
desired b-ketoamides 5, which underwent subsequent oxime for-
mation with sodium nitrite (NaNO2), under cold, aqueous acidic
conditions, which cleanly afforded the desired b-ketoamide oximes
6 in low (20–40%) yields. Finally, the cyanoamide analogs 8 were
easily prepared in two steps via condensation with methyl-2-cya-
noacetate, followed by oxime formation under tert-butyl nitrite/so-
dium propoxide conditions.
were prepared from the corresponding dihydroisoquinoline17 and
aminotacrine18 primary amines, respectively.
A representative synthetic route used to prepare the heteroaryl
keto-oxime analogs is shown below in Scheme 2. Cyclic amino
alcohol derivatives such as 23 were treated under reductive amina-
tion conditions with aldehydes and sodium triacetoxyborohydride
to provide the tertiary amines 24 in good yields.19 The acetyl pyr-
idyl ethers 25 were prepared via palladium catalyzed coupling
reaction of alcohol 24 and 2-bromo-acetyl pyridines in the pres-
ence of Pd2(dba)3/BINAP, which produced the desired pyridyl ke-
tones in moderate yields.20 Finally, oxime formation was
accomplished under t-BuONO/KOt-Bu21 conditions to provide the
keto-oxime analogs 26 in low yields. Unfortunately, attempts to
optimize the reaction conditions, as well as employ alternative
conditions (i.e. TMSCl, NOCl)22 were unsuccessful.
The synthetic route highlighted in Scheme 2 was used to pre-
pare a number of analogs varying substitution on the piperidine
and pyrrolidine rings, as well as the position of the keto-oxime
on the pyridine or pyrimdine rings (Fig. 3).
In vitro screening for reactivation of GF-inhibited hAChE was
assayed by a robotic spectrophotometric assay using acetylthioch-
oline as substrate at pH 7.4 and 25 °C.23 The time-course of reacti-
vation of GF-inhibited hAChE was determined by adding various
concentrations of oxime to GF-inhibited hAChE. Samples of the
oxime/inhibited AChE mixture were removed at sequential times
to measure the oxime-induced recovery of AChE activity.
The synthesis route highlighted in Scheme 1 was used to pre-
pare the analogs of various lipophilic amine templates as shown
in Figure 2. The N-benzyl piperidine analogs 9–15 were prepared
from the commercially available primary amines or the corre-
sponding N-BOC protected piperidines. Analogs 16–18 and 19–22
Table 1 summarizes two data points collected on each analog:
(1) Corrected cumulative reactivation by 20 uM oxime and (2)
Oxime/hAChE equilibrium constant for inhibition of hAChE. In
our initial studies, we were gratified to see low levels of reactiva-
tion of GF-inhibited hAChE as a proof of concept for our new chem-
ical matter in our piperidine amide oxime analogs 9 and 10.
Furthermore, the analogs also possessed weak inhibition of native
enzyme. Incorporation of the b-ketoamide moiety (analog 12) not
only produced a significant increase in reactivation activity, but
also maintained weak inhibition of native hAChE. A similar result
was observed with the 3,4-dimethoxybenzyl analog 15. Addition
of the cyano group in compounds 13 and 14 resulted in a complete
loss of reactivation activity. Replacement of the N-benzyl piperi-
dine with the dihydroisoquinoline group delivered hAChE reactiva-
tors with very good reactivation levels and low inhibition of native
enzyme as long as the b-ketoamide moiety was present (17 and
18). Finally, incorporation of the tacrine group as represented by
compounds 19–22, provided compounds with substantial inhibi-
tion of native enzyme, yet only low levels of reactivation, regard-
less of amide oxime substitution or length of the amine tether.
Structure activity relationship (SAR) studies on the heteroaryl
keto-oxime series provided compounds with very good reactiva-
tion of GF-inhibited hAChE. Compounds 27–30 all possessed the
N-benzyl-4-piperidine moiety and only differed by the substitution
pattern of the ketooxime group on the pyridine ring, which had
9, n = 0, R1, R2 = H
R2
R2
10
,
n = 1, R1, R2 = H
11, n = 0, R1 = COCH3, R2 = H
12
N
R1
H
N
n
OH
(
)
,
n = 1, R1 = COCH3, R2 = H
13, n = 0, R1 = CN, R2 = H
14
N
O
,
n = 1, R1 = CN, R2 = H
15, n = 1, R1 = COCH3, R2 = OCH3
O
O
R1
16, X = Ph, R1 = H
H
N
N
OH
17
,
X = Ph, R1 = COCH3
N
18, X = H, R1 = COCH3
X
O
R1
19, n = 1, R1 = H
H
N
H
N
OH
20
,
n = 2, R1 = H
21, n = 1, R1 = CN
22
N
(
)
n
O
N
,
n = 4, R1 = H
Figure 2. Structure of prepared amide oxime analogs

S. F. McHardy et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1711–1714
1713
O
27, R = phenyl, Y = O, X = CH, 2,3-pyridine
N
X
OH
28
29
, R = phenyl, Y = O, X = CH, 2,4-pyridine
, R = phenyl, Y = O, X = CH, 2,5-pyridine
Y
N
30, R = phenyl, Y = O, X = CH, 2,6-pyridine
31
32
, R = 3,4-dimethoxyphenyl, Y = O, X = CH, 2,5-pyridine
, R = 3,4-difluorophenyl, Y = O, X = CH, 2,5-pyridine
N
33, R = 4-cyanophenyl, Y = O, X = CH, 2,5-pyridine
34
35
, R = 3-chlorophenyl, Y = O, X = CH, 2,5-pyridine
, R = phenyl, Y = O, X = N, 2,5-pyrimidine
R
36, R = phenyl, Y = NH, X = CH, 2,5-pyridine
O
O
( )n
37, n = 1, R = 3,4-dimethoxyphenyl, (+/-) 3-piperidine
N
N
38
39
, n = 1, R = 3,4-dimethoxyphenyl, (+/-) 2-piperidine
, n = 1, R = phenyl, (+/-) 2-piperidine
N
OH
R
40, n = 0, R = phenyl, (+/-) 3-pyrrolidine
41
, n = 0, R = 3,4-dimethoxyphenyl, (+/-) 3-pyrrolidine
X
O
N
OH
N
42, X = CH
43
, X = N
N
Figure 3. Structure of heteroaryl keto-oximes.
O
O
O
O
O
c
b
a
R
R
R
N
RNH2
N
H
CH3
OH
N
H
CH3
N
H
OH
5
N
4
6
O
O
e
d
R
CN
OH
R
CN
N
H
N
H
N
7
8
a) ethyl 2-(hydroxyimino)acetate, heat; b) 2,2,6-trimethyl-4H-1,3-dioxin-4-one, toluene, 150 oC;
c) NaNO2, THF, AcOH/H2O, 0oC to 20 oC; d) methyl 2-cyanoacetate, neat, 40 oC; e) t-butyl
nitrite, NaOPr
Scheme 1. Synthesis of amide oxime analogs.
O
O
N
CH3
OH
(
)
n
(
)
n
OH
OH
(
)
n
a
O
N
b
(
)
n
c
O
N
N
N
N
N
H
26
24
25
R
23
R
R
a) RCHO, NaHB(OAc)3, DCM, >95%; 5-acetyl-2-bromopyridine, Pd2(dba)3, BINAP, Cs2CO3, 60%; c) t-BuONO,
KOt-Bu, 30%.
Scheme 2. Synthesis of heteroaryl keto-oxime 26.
substantial effects on activity. The initial analog in this series, com-
pound 29, which possessed the 2,5-subsitution pattern on the pyr-
idine, provided 23% reactivation and a Ki of 31 uM. Compound 30,
the 2,6-substituted pyridine, as compared to 29 showed a decrease
dine ring 35, produced compounds with very similar activity to
the corresponding pyridine 29. The ether linkage in 29 can also
be replaced by an amine, resulting in a compound 36 with equiv-
alent reactivation activity and a 9-fold decrease in affinity for na-
tive enzyme.
in the affinity for native hAChE (199 lM vs 31 lM) as well as the
corrected reactivation (7% vs 23%). Moving the keto-oxime group
to the 2,4-position 28 decreased both reactivation (17%) and inhi-
bition (144 uM) relative to 29. However, the 2,3-substitution
pattern in 27 displayed a marked improvement in reactivation
(45%), while possessing low inhibition (180 uM). Based on these
SAR findings the order of reactivation activity for substitution on
the pyridine ring is 2,3- > 2,5- > 2,4- > 2,6. Changing the piperidine
sidechain from benzyl 29 to 3,4-dimethoxybenzyl 31 produced
equivalent reactivation activity, but showed a >60-fold decrease
in affinity for native enzyme. Additional modifications to the
N-benzyl side chain, as represented by compounds 32–34, led to
moderate improvements in reactivation activity with the
3,4-difluoro analog 32. Installment of the 2,5-substituted pyrimi-
Finally, we attempted to translate SAR trends from the
4-substituted piperidines to the 2- and 3-substituted piperidines,
as well as pyrrolidines, an effort which produced lead compounds
with good activity. Compound 38 produced a significant increase
in reactivation activity (65%) as compared to the corresponding
3-subsituted pipieridine 37 (38%) or the 4-substituted analog 29.
The 3-subsituted pyrrolidines 40 and 41 showed similar reactiva-
tion activity, however, as observed before, the 3,4-dimethoxyben-
zyl side chain displayed a decrease in affinity for native enzyme.
Analogs 42 and 43, which possess the oxime directly attached
to the pyridine or pyrimidine ring, produced a significant decrease
in reactivation relative to the corresponding keto-oximes 29 and
35.25

1714
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In vitro GF-Inhibited hAChE reactivation dataa
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MINA
9
7.7
7.5
7.7
11.8
23.7
0.1
4.8
22.7
2.7
36.5
28.9
7.2
2.4
6.9
0
28
29
30
31
32
33
17.2
23.0
7.3
144
31.2
199
1930
159
1608
298
55.2
285
345
233
551
2430
3178
234
2300
732
10
11
12
13
14
15
16
17
18
19
20
21
22
27
25.3
30.8
21.4
18.9
23.8
22.9
38.2
64.9
33.9
25.1
24.7
0.4
29938 34
1625
595
1926
2671
6.2
1.5
3.1
0.59
180
35
36
37
38
39
40
41
42
43
137
2517
270000
198
0.8
45.3
2.0
a
Mean and STD data available in Supplementary information.
b
% Corrected cumulative reactivation of GF-inhibited hAChE by 20 uM oxime at
4 h.24
c
Ki inhibition constant for native AChE (uM).
In conclusion, two new chemical series of non-pyridinium
based reactivators of hAChE have been discovered, both of which
possess a range of reactivation activities for GF-inhibited hAChE
and a varying degrees of selectivity over affinity for native enzyme.
Lead compounds from these studies, such as 15, 17, 27, 29 and 38,
which possess substantial reactivation activity, low affinity for na-
tive enzyme, and favorable physiochemical properties, have been
advanced to blood brain barrier permeability, multiple in vivo
reactivation, and agent-challenge studies. The results of these
studies will be reported in due course.
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Acknowledgments
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Support for this work by Defense Threat Reduction Agency
(HDTRA1-10-C-0041) is gratefully acknowledged.
21. Yonishi, S.; Aoki, S.; Matsushima, Y.; Akahane, A., US Patent 20050113387,
2005.
Supplementary data
22. Mohammed, A. H. A.; Nagendrappa, G. Tetrahedron Lett. 2003, 44, 2753.
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24. Reactivation at the 4 h time point was initially assessed due to slow
reactivation rates observed with early analogs. Future work will involve
testing the more advanced analogs at therapeutically relevant time points.
25. pKa’s of various analogs were assessed via a capillary electrophoresis method
(Analiza, Inc.) across a 24-point titration curve. pKa’s for oximes 42 and 43
were higher (11.2 and 10.7, respectively) than the corresponding keto-oxime
derivatives 29 and 35 (7.8 and 7.6, respectively).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.02.
049.
References and notes
1. Marrs, T. C.; Maynard, R. L.; Sidell, F. R. In Chemical Warfare Agents, Toxicology
and Treatment, 2nd ed.; Wiley & Sons: Ltd, 2007.