Synthesis, in vitro pharmacology, and molecular modeling of syn-huprines as acetylcholinesterase inhibitors

Article abstract of DOI:10.1021/jm010949b

Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioisomeric mixture of products, thus obtained. The new (±)-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us to explain the differences in inhibitory activity of these compounds on the basis of an inverse solvation effect.

Full text of DOI:10.1021/jm010949b

J . Med. Chem. 2001, 44, 4733-4736
4733
Brief Articles
Syn th esis, in Vitr o P h a r m a cology, a n d Molecu la r Mod elin g of syn -Hu p r in es a s
Acetylch olin ester a se In h ibitor s
Pelayo Camps,*,† Elena Go´mez,† Diego Mun˜oz-Torrero,† Albert Badia,‡ Nuria Mar´ıa Vivas,‡ Xavier Barril,§
Modesto Orozco,| and Francisco J avier Luque§
Laboratori de Quı´mica Farmace`utica, Facultat de Farma`cia, Universitat de Barcelona, Av. Diagonal 643,
E-08028, Barcelona, Spain, Departament de Farmacologia i de Terape`utica, Facultat de Medicina,
Universitat Auto`noma de Barcelona, 08193-Bellaterra, Barcelona, Spain, Departament de F´ısico-Quı´mica,
Facultat de Farma`cia, Universitat de Barcelona, Av. Diagonal 643, E-08028, Barcelona, Spain, and
Departament de Bioquı´mica, Facultat de Quı´mica, Universitat de Barcelona, Av. Mart´ı i Franque´s 1,
E-08028, Barcelona, Spain
Received J une 11, 2001
Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)]
(syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-
ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and
chromatographic separation of the regioisomeric mixture of products, thus obtained. The new
(()-syn-huprines were shown to be slightly less active bovine or human acetylcholinesterase
inhibitors than the corresponding anti-derivatives. Molecular modeling simulations allow us
to explain the differences in inhibitory activity of these compounds on the basis of an inverse
solvation effect.
In tr od u ction
Since the approval of tacrine, 1 (Figure 1), by the FDA
as the first drug for the cognitive enhancement in
Alzheimer’s disease (AD), several acetylcholinesterase
(AChE) inhibitors have been marketed and important
efforts are being made to develop new AChE inhibi-
tors.1-5 Huprines, 3, are a new class of very potent,
F igu r e 1. Structures of huprines and their starting models.
selective AChE inhibitors of potential interest for the
symptomatic treatment of AD.6-12 The most powerful
compound, named huprine X [(-)-3, R ) Et; R1 ) H; R3
subunit roughly occupies the same binding pocket as
(-)-huperzine A.
) Cl], exhibits one of the highest affinities reported for
a reversible inhibitor, being ca. 40-fold more potent than
More than 30 different huprines in racemic form have
donepezil, 180-fold more potent than (-)-huperzine A,
been synthesized by using Friedla¨nder condensation of
and 1200-fold more potent than tacrine hydrochloride.7
enones 4 with 2-aminobenzonitriles conveniently sub-
Huprines can be regarded as synthetic hybrids that
stituted at positions 4 and/or 6 in the presence of AlCl3
combine the 4-aminoquinoline substructure of tacrine,1
as a Lewis acid catalyst (Scheme 1). This procedure has
allowed us to explore the structure-activity relation-
1, with the carbobicyclic substructure of (-)-huperzine
A, (-)-2.5 Accordingly, they should be able to interact
ships (SAR) of substituents attached to the aminoquino-
simultaneously with several of the binding sites for
line subunit and to position 9 of huprines.6-10 However,
in all cases only huprines having the heterocyclic ring
and the endocyclic CdC double bond in an anti-ar-
tacrine and (-)-huperzine A, as they partially overlap
within AChE.13,14 Molecular modeling studies8-10 have
shown that the 4-aminoquinoline substructure occupies
rangement were obtained. Since the unsaturated three-
the same binding site as tacrine, i.e., stacked between
carbon bridge of huprines seems to be an essential
the rings of Trp84 and Phe330, while the carbobicyclic
feature for their AChE inhibitory activity,12 it would be
worthwhile to synthesize syn-huprines and to explore
* To whom correspondence should be addressed. Phone: int. code
their pharmacologic profile as AChE inhibitors. Herein
+ 34 + 93-402-4536. Fax: int. code + 34 + 93-403-5941. E-mail:
camps@farmacia.far.ub.es.
we describe (i) the first synthesis of two syn-huprines
in racemic form, (ii) the AChE inhibitory activity of syn-
huprines, and (iii) a discussion of the relative AChE
inhibitory potency of a syn-huprine and its anti-regio-
isomer in light of the results provided by molecular
modeling studies.
† Laboratori de Qu´ımica Farmace`utica, Facultat de Farma`cia,
Universitat de Barcelona.
‡ Universitat Auto`noma de Barcelona.
§ Departament de F´ısico-Qu´ımica, Facultat de Farma`cia, Universitat
de Barcelona.
| Departament de Bioqu´ımica, Facultat de Qu´ımica, Universitat de
Barcelona.
10.1021/jm010949b CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/28/2001

4734 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Brief Articles
Sch em e 1. A Possible Explanation of the
Regioselectivity Observed in the Friedla¨nder Reaction
Leading to (()-Huprines, (()-6, Based on the
Equilibration of Regioisomeric Derivatives (()-6 and
(()-7, through Acid-Promoted Carbon-Carbon Double
Bond Migration
THF from -78 °C to room temperature for 4.25 h
afforded a crude product consisting mainly of a mixture
of starting imine and the regioisomeric aminoquinolines
(()-6a /(()-7a , in the approximate ratio of 70:30, from
which the less polar syn-regioisomer (()-7a could be
isolated in pure form by silica gel column chromatog-
raphy. The use of 4 equiv of NaHMDS led to lower yields
of (()-6a plus (()-7a , while longer reaction times (15
h) led to higher yields of aminoquinolines [up to 61%
total yield of (()-6a and (()-7a ] with a lower ratio of
the syn-regioisomer (()-7a .
Similarly, from imine (()-9b, after reaction with 8
equiv of NaHMDS for 6 h and silica gel column chro-
matography of the resulting crude product, pure (()-
7b was obtained. The new syn-huprines (()-7a and (()-
7b were fully characterized as hydrochlorides through
their spectroscopic data and elemental analyses (C, H,
N, Cl). Structural assignment of (()-7a and (()-7b and
differentiation from the corresponding anti-regioiso-
mers, (()-6a and (()-6b, was straightforward on the
1
1
basis of H/1H and H/13C COSY experiments (HMQC
Sch em e 2. Synthesis of (()-syn-Huprines
sequence).
P h a r m a cology
To evaluate the potential interest of syn-huprines for
the treatment of AD, the AChE inhibitory activity of
(()-7a ‚HCl and (()-7b‚HCl was determined by the
method of Ellman et al.16 on AChE from bovine and
human erythrocytes. To establish their selectivity, the
butyrylcholinesterase (BChE) inhibitory activity was
also assayed by the same method on human serum
BChE.
Table 1 summarizes the data for the syn-huprines (()-
7a ‚HCl and (()-7b‚HCl, as well as for tacrine‚HCl, (-)-
huperzine A, and huprines (()-6a ‚HCl and (()-6b‚HCl
as reference compounds. syn-Huprines (()-7a ‚HCl and
(()-7b‚HCl are less potent than (()-6a ‚HCl and (()-
6b‚HCl, respectively, as bovine (7.9 and 4.3-fold, re-
spectively) and human (8.4 and 2.0-fold, respectively)
AChE inhibitors. However, in contrast to tacrine‚HCl
and (-)-huperzine A, which are less active toward
human than bovine AChE, syn-huprines (()-7a ‚HCl and
(()-7b ‚HCl, as well as huprines (()-6a ‚HCl and (()-
6b‚HCl, are slightly more potent toward human AChE.
Particularly, syn-huprine (()-7b‚HCl is 2.7- and 3.4-fold
more potent than tacrine‚HCl and (-)-huperzine A
against human AChE. Regarding the BChE inhibitory
activity, syn-huprines (()-7a ‚HCl and (()-7b‚HCl are
comparable to huprines (()-6a ‚HCl and (()-6b‚HCl.
The results in Table 1 allow us to conclude that syn-
huprines, though less active than their anti-regioiso-
meric huprines, have significant AChE inhibitory ac-
tivity. On the basis of our previous SAR studies,6-10
attachment of a chlorine atom at position 3 of syn-
huprines could further enhance the binding affinity for
human AChE relative to both tacrine and (-)-huperzine
A.
Ch em istr y
The observed anti-regioselectivity of the Friedla¨nder
condensation leading to huprines could result from the
equilibration under the acidic conditions of this reaction
of a mixture of the hitherto not observed syn-huprines
and the reasonably more stable and always isolated
anti-regioisomeric huprines (Scheme 1). Therefore, an
alternative procedure operating under nonequilibrating
conditions would be required to synthesize syn-huprines.
Recently, aza-analogues of tacrine were prepared by
cyclization of 2-[2-(trifluoromethyl)phenylimino]pyr-
rolidine and related compounds on reaction with sodium
hexamethyldisilazide (NaHMDS) in THF.15 These reac-
tions may be considered as a modification of the Fried-
la¨nder reaction in which the 2-aminobenzonitrile is
replaced by 2-(trifluoromethyl)aniline, the condensation
step taking place under strongly basic conditions,
through the chemistry of the anionically activated
trifluoromethyl group.
Reaction of enones (()-4a and (()-4b with 2-(trifluo-
romethyl)aniline, 8 (1.4 equiv), in toluene under reflux
for 2 days, followed by column chromatography of the
resulting crude product, afforded in good yields imines
(()-9a and (()-9b as mixtures of the (E)- and (Z)-
stereoisomers, one of them being slightly more abundant
(approximate ratio of 3:2) (Scheme 2), which were used
in the cyclization step without further purification.
Treatment of imine (()-9a with NaHMDS (6 equiv) in
Molecu la r Mod elin g Stu d ies
The unexpected difference in AChE inhibitory activity
between the syn-huprines and their anti-regioisomers
led us to study the relationship between the anti f syn
migration of the CdC double bond and the change in
inhibitory potency. This information can be valuable to

Brief Articles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4735
Ta ble 1. Pharmacological Data of Tacrine‚HCl, (-)-Huperzine A, and the Hydrochlorides of the Huprines (()-6a ,b and Their
Regioisomeric (()-syn-Huprines (()-7a ,ba
IC50 (nM)
IC50 bovine AChE/IC50
human AChE
IC50 human BChE/IC50
compound
bovine AChE
human AChE
human BChE
human AChE
(-)-tacrine‚HCl
(-)-huperzine A
(()-6a ‚HCl
130 ( 10
74.0 ( 5.5
65 ( 15
38.5 ( 4.0
511 ( 40
165 ( 21
205 ( 18
260 ( 18
51.6 ( 5.4
37.8 ( 3.7
436 ( 68
76.9 ( 6.4
44 ( 17
0.63
0.28
1.26
1.02
1.17
2.14
0.21
>38
>10000
126 ( 21
79.3 ( 9.7
148 ( 15.3
63.0 ( 17.1
2.44
(()-6b‚HCl
2.10
0.34
0.82
(()-7a ‚HCl
(()-7b‚HCl
a
Values are expressed as mean ( standard error of the mean of at least four experiments. IC50 inhibitory concentration (nM) of AChE
(from bovine or human erithrocytes) or BChE (from human serum) activity.
the 4-aminoquinoline subunit to interact with a water
molecule in syn-huprine compared to its anti-regioiso-
mer. Such a difference in the affinity for a water
molecule can be related to the closer proximity of the
CdC double bond to the amino group in the syn-huprine.
Thus, whereas the MIP minimum located around the
>NH group of the 4-aminoquinoline unit in syn-huprine
is nearly identical to that in the anti-regioisomer (-66.5
and -66.3 kcal mol-1, respectively), the minima around
the NH2 group are slightly lower (in absolute values)
in the syn-huprine compared to its anti-regioisomer,
especially in the region closer to the carbobicyclic ring
(-60.5 and -62.0 kcal mol-1, respectively).
Very often, a reduction in the desolvation penalty of
a drug leads to an increase in the binding free energy.
For the syn-huprine and its anti-regioisomer, the situ-
ation is just the opposite, since the compound with the
strongest binding affinity (i.e., anti-regioisomer) has also
the better hydration. (i.e., the largest desolvation pen-
alty). Therefore, the better binding affinity of huprine
(-)-(7S,11S)-6a must stem from stronger drug-enzyme
interactions than for the syn-huprine (7R,11S)-7a . This
is shown by combination of the free energy change for
F igu r e 2. Thermodynamic cycle used in free energy calcula-
tions in water and in the AChE enzyme to determine relative
binding affinities between (7R,11S)-7a and (-)-(7S,11S)-6a .
The results for the forward and reverse mutations are given
in parentheses. Values are in kcal mol-1
.
design chemical modifications that improve the phar-
macological profile of syn-huprines relative to their anti-
regioisomers. To this end, thermodynamic integration
(TI) calculations coupled with molecular dynamics (MD)
were performed to rationalize the difference in binding
affinity between syn-huprines and their anti-regioiso-
mers (see Supporting Information). The change in
binding free energy between the more active enantiomer
(eutomer) of huprine 6a , (-)-(7S,11S)-6a , and the cor-
responding product of CdC double bond isomerization,
the syn-huprine (7R,11S)-7a , both in protonated form,
was determined from the thermodynamic cycle shown
in Figure 2. The results predict that the conversion of
huprine (-)-(7S,11S)-6a to the syn-huprine (7R,11S)-
7a decreases the binding affinity for the enzyme by 0.5
kcal mol-1, which is in agreement with the experimental
data (see above and Table 1).
the anti f syn mutation in the protein (+0.7 kcal mol-1
;
see Figure 2) and in the gas phase (-0.1 kcal mol-1),
which indicates that the protein stabilizes preferentially
the binding of the anti-regiosomer, (-)-(7S,11S)-6a , by
around 0.8 kcal mol-1
.
Inspection of the snapshots collected during the last
500 ps of the 2 ns MD simulations for the complexes
TcAChE-(-)-(7S,11S)-6a and TcAChE-(7R,11S)-7a in-
dicate that the only remarkable structural alteration
in the interaction pattern between syn-huprine (7R,-
11S)-7a and its anti-regioisomer (-)-(7S,11S)-6a with
the AChE binding site is the disruption of the highly
hydrated environment of the NH2 group of huprine.
Thus, whereas the two N-H bonds of the amino group
in (-)-(7S,11S)-6a form hydrogen-bonds to water mol-
ecules in around 90% and 99% of the structures exam-
ined, they are hydrogen-bonded to water molecules only
in around 80% and 85% in the syn-regioisomer (7R,-
11S)-7a . Since the binding of huprine is mediated by
water bridges that link the amino group to several
residues of the binding site, such as Asp72, Tyr121, and
Ser122, the disruption of the network of water-mediated
bridges leads to the reduced binding affinity of the syn-
huprine.
Combination of the free energy change for the anti f
syn mutation in water (+0.2 kcal mol-1; Figure 2) with
the free energy difference for the anti f syn mutation
in the gas phase (-0.1 kcal mol-1) indicate that the anti-
regioisomer hydrates better than the syn-huprine by 0.3
kcal mol-1. This result is confirmed by self-consistent
reaction field calculations17 (see Supporting Informa-
tion), which indicate that the anti-regioisomer is better
hydrated than the syn-huprine by around 0.6 kcal mol-1
.
Con clu sion
The preferential hydration of the anti-regioisomer can
be understood from comparison of molecular interaction
potential (MIP) maps18 (see Supporting Information),
which point out the lower affinity of the NH2 group of
For the first time, the regioisomeric (()-syn-huprines
(()-7a ,b have been obtained through a protocol that
implies: (i) condensation of ketones (()-4a ,b with

4736 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26
Brief Articles
(4) Prous, J .; Rabasseda, X.; Castan˜er, J . SDZ-ENA-713 Cognition
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mediate stereoisomeric mixture of (E)- and (Z)-imines
with excess sodium hexamethyldisilazide, and (iii)
separation of the thus formed regioisomeric mixture of
syn- and anti-derivatives, (()-7a ,b/(()-6a ,b. The AChE
inhibitory activity of (()-7a ,b‚HCl toward AChE from
bovine and human erythrocytes was shown to be slightly
lower than that of the corresponding anti-regioisomers,
huprines (()-6a ,b‚HCl, although (()-7b‚HCl showed
higher activity toward human AChE than tacrine‚HCl
and (-)-huperzine A. The reduction in the binding
affinity related to the anti f syn isomerization in
huprines stems from an inverse solvation mechanism,
which reveals the structural features of the interaction
of huprines with the binding site of AChE and particu-
larly the important role of water molecules in mediating
the binding of these AChE inhibitors. The new proce-
dure of obtaining (()-syn-huprines, (()-7a ,b, opens the
way to a new kind of AChE inhibitors, whose develop-
ment can take advantage of the known structure-
activity relationships in the anti-regioisomeric series
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(Huprines):
A New Class of Highly Potent and Selective
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Alzheimer’s Disease. Mini-Rev. Med. Chem. 2001, 1, 163-174.
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J .; Mun˜oz-Torrero, D.; Rosenberry, T. L. Huprine X is a Novel
High-Affinity Inhibitor of Acetylcholinesterase That is of Interest
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(8) Camps, P.; El Achab, R.; Morral, J .; Mun˜oz-Torrero, D.; Badia,
A.; Ban˜os, J . E.; Vivas, N. M.; Barril, X.; Orozco, M.; Luque, F.
J . New Tacrine-Huperzine A Hybrids (Huprines): Highly Potent
Tight-Binding Acetylcholinesterase Inhibitors of Interest for the
Treatment of Alzheimer’s Disease. J . Med. Chem. 2000, 43,
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(9) Camps, P.; El Achab, R.; Go¨rbig, D. M.; Morral, J .; Mun˜oz-
Torrero, D.; Badia, A.; Ban˜os, J . E.; Vivas, N. M.; Barril, X.;
Orozco, M.; Luque, F. J . Synthesis, in Vitro Pharmacology, and
Molecular Modeling of Very Potent Tacrine-Huperzine A Hybrids
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Ack n ow led gm en t. Fellowships from Fundacio´ La
Marato´ de TV3 to E.G., from Ministerio de Educacio´n y
Cultura to X. Barril, and financial support from Fun-
dacio´ “La Marato´ de TV3” (project 3004/97) and Direc-
cio´n General de Investigacio´n Cient´ıfica y Te´cnica
(projects PB98-1222 and PB99-0046) are gratefully
acknowledged. We also thank the Centre de Supercom-
putacio´ de Catalunya (CESCA) for computational facili-
ties, the Serveis Cient´ıfico-Te`cnics of the University of
Barcelona for NMR facilities, and Ms. P. Dome`nech from
the Centro de Investigacio´n y Desarrollo (C.I.D.) of
Barcelona for carrying out the elemental analyses. We
are indebted to Prof. Dr. A. Kozikowski (GICCS, George-
town University, Washington, D.C.) for a generous gift
of a sample of natural (-)-huperzine A.
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Su p p or tin g In for m a tion Ava ila ble: Experimental part
(chemistry, pharmacology, and molecular modeling with ad-
ditional references and a figure of MIP maps for the interaction
of (-)-(7S,11S)-6a and (7R,11S)-7a with the TIP3P water
oxygen atom). This material is available free of charge via the
Internet at http://pubs.acs.org.
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J M010949B