Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors

Article abstract of DOI:10.1016/j.bmcl.2017.09.058

A novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides has been synthesized and assayed for β-Secretase (BACE1) inhibitory activity. BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's Disease (AD). The introduction of benzyl substituents on the nitrogen atom of the arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC₅₀ values ranging from 1.6 to 1.9 μM. Therefore, a significant improvement over the previously reported series of N-carboxamides (displaying IC₅₀'s ≥ 2.5 μM) has been achieved, thus suggesting an active role of the sulfonamido-portion in the inhibition process. Preliminary molecular modeling studies have been carried out to rationalize the observed structure-activity relationships.

Full text of DOI:10.1016/j.bmcl.2017.09.058

Accepted Manuscript
Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors
Simone Bertini, Elisa Ghilardi, Valentina Asso, Filippo Minutolo, Simona
Rapposelli, Maria Digiacomo, Giuseppe Saccomanni, Veronica Salmaso,
Mattia Sturlese, Stefano Moro, Marco Macchia, Clementina Manera
PII:
S0960-894X(17)30967-8
https://doi.org/10.1016/j.bmcl.2017.09.058
BMCL 25322
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 July 2017
25 September 2017
27 September 2017
Please cite this article as: Bertini, S., Ghilardi, E., Asso, V., Minutolo, F., Rapposelli, S., Digiacomo, M.,
Saccomanni, G., Salmaso, V., Sturlese, M., Moro, S., Macchia, M., Manera, C., Sulfonamido-derivatives of
unsubstituted carbazoles as BACE1 inhibitors, Bioorganic & Medicinal Chemistry Letters (2017), doi: https://
doi.org/10.1016/j.bmcl.2017.09.058
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Sulfonamido-derivatives of unsubstituted
carbazole as BACE1 Inhibitors
Leave this area blank for abstract info.
Simone Bertini, Elisa Ghilardi, Valentina Asso, Filippo Minutolo, Simona Rapposelli, Maria Digiacomo,
Giuseppe Saccomanni, Veronica Salmaso, Mattia Sturlese, Stefano Moro, Marco Macchia, Clementina Manera

Bioorganic & Medicinal Chemistry Letters
jo u r n a l h o m e p a g e : w w w . e ls e v ie r . c o m
Sulfonamido-derivatives of unsubstituted carbazoles as BACE1 inhibitors
Simone Bertini,a  Elisa Ghilardi,a Valentina Asso, a Filippo Minutolo,a Simona Rapposelli,a
Maria Digiacomo,a Giuseppe Saccomanni,a Veronica Salmaso,b Mattia Sturlese,b
Stefano Moro,b Marco Macchia,a Clementina Maneraa
a
Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126, Pisa, Italy.
b Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, I-35131 Padova, Italy.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A
novel series of variously substituted N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-
arylsulfonamides has been synthesized and assayed for -Secretase (BACE1) inhibitory activity.
BACE1 is a widely recognized drug target for the prevention and treatment of Alzheimer's
Disease (AD). The introduction of benzyl substituents on the nitrogen atom of the
arylsulfonamide moiety has so far led to the best results, with three derivatives showing IC50
values ranging from 1.6 to 1.9 M. Therefore, a significant improvement over the previously
reported series of N-carboxamides (displaying IC50’s ≥ 2.5 M) has been achieved, thus
suggesting an active role of the sulfonamido-portion in the inhibition process. Preliminary
molecular modeling studies have been carried out to rationalize the observed structure-activity
relationships.
Keywords:
Alzheimer
BACE1
Carbazole
Sulfonamides
Molecular Docking
2009 Elsevier Ltd. All rights reserved.
Alzheimer's disease (AD) is the most common form of
dementia, which occurs predominantly in older people (over 65
brain levels of amyloid beta and, consequently, for the treatment
or prevention of AD.
years of age). It is
a
progressive and irreversible
Many BACE1-inhibitors studied to date are peptidomimetics
and incorporate the hydroxyethylamine (HEA) moiety,6 which is
known to well mimic the transition state of aspartyl proteases
(like BACE1) substrates.7 These compounds have in general high
molecular weights and suffer from poor blood brain barrier
permeability.8 So, in recent years, more efforts have been
dedicated to the development of non-peptidomimetic BACE1-
inhibitors, with the aim of obtaining smaller active molecules
and, therefore, more drug-like agents for the treatment of AD.9-11
Among those, only a few compounds have entered in advanced
clinical phases.11, 12
neurodegenerative disorder, which compromises cognitive
functions (memory, thinking, reasoning) and behavioral skills in
such a way as to interfere with daily life and with the fulfillment
of the simplest tasks. The main neuropathological features of AD
are extracellular senile plaques, essentially made of amyloid 
peptide (A),1 and intracellular neurofibrillary tangles, caused by
the aggregation of phosphorylated tau proteins.2
The A peptide is generated through proteolytic processing of
the amyloid precursor protein (APP) first by -secretase
(BACE1) followed by -secretase. In particular, the cleavage
operated by BACE1 produces the secreted amino-terminal
part of APP (sAPPβ) and the membrane-bound carboxy-
terminal fragment, which is 99 amino acids in length (C99).
γ-Secretase subsequently cleaves the C99 fragment,
releasing the A peptide, which aggregates to form toxic
amyloid plaques in the brain.3 It has been demonstrated that
BACE1 knockout (BACE1 -/-) mice are unable to generate C99
and Aβ, are viable,4 and drastically ameliorate the pathology
when crossed with APP transgenic mice (a mouse model of
We previously reported a series of -naphthylaminoalcohol
derivatives of unsubstituted carbazole showing a BACE1
inhibitory activity in the low M range.13 Furthermore, we
recently reported that N-carboxamido-derivatives are still active
against this enzyme (Figure 1).14
In this work, we describe the synthesis and the evaluation of
BACE1 inhibitory activity of a further series of derivatives, in
which the unsubstituted carbazole-methyl carbinol portion was
kept constant and the N-atom was sulfonylated with different
AD).5 Therefore, BACE1 is an attractive drug target for lowering
———
 Corresponding author. Tel.: +39 050 2219579; e-mail: simone.bertini@unipi.it

groups (1-24, Figure 1). A focused screening in the literature of
this type of compounds was primarily carried out, and six
derivatives were found commercially available (1-3, 5, 11 and
22, see Table 1).
on the sulfonamide nitrogen, regardless the presence of
substituents in position 4 of the aryl sulfonamide moiety
(compounds 17-20), the activity is preserved or slightly
decreased respect to the most active compounds of the previous
series of N-carboxamides (IC50 = 2.5 M).14 The activity
generally decreases when R1 is a completely aliphatic group,
such as a cyclohexyl (compounds 21-24). Regarding to the
substituent on the sulfonamide aromatic ring, when R2 = H and
R1 = phenyl, 4-substituted phenyl, 4-substitutedbenzyl, phenethyl
or cyclohexyl, the BACE1 inhibitory activity worsens slightly
(compounds 1, 7-8, 15-17 and 21) or is lost (compounds 6, 9 and
14). When R2 = Me, the activity is preserved (compounds 2, 11
and 18) or slightly worsened (compounds 22). When the phenyl
ring of the sulfonamide is substituted with an alogen atom (Cl in
this case) or a methoxy group, the activity is almost preserved
(compounds 3 and 4), improved (compounds 12 and 13) or
worsened (compounds 19, 23, 20 and 24). In general, the BACE1
inhibitory activity of this kind of molecules is mostly influenced
by the substituent on the sulfonamide nitrogen (R1) and the N-
benzyl-substituted compounds are the most active (except 11)
regardless the substitution on the 4-position of the sulfonamide
phenyl ring (R2).
2
R
O
N
O
N
O
1
OH
OH
N
N
S
R2
1
R
R
active carboxamides
IC50 = 2.5 - 4.8
sulfonamides 1-24
M

Figure 1. General structure of already reported N-[3-(9H-carbazol-9-yl)-
2-hydroxypropyl]-arylcarboxamides and novel variously substituted N-[3-
(9H-carbazol-9-yl)-2-hydroxypropyl]-arylsulfonamides (1-24, see also Table
1).
These sulfonamido-derivatives were synthesized as shown in
Scheme 1. Commercially available carbazole 25 was alkylated
with epichlorohydrin (2.5 eq., added dropwise at 0 °C) in the
presence of KOH (1.2 eq.) in DMF, affording epoxide 26.
Reaction of this intermediate with the appropriate amine (2.0 eq.)
in EtOH afforded aminoalcohols 27-38. These derivatives were
then treated with variously substituted aryl-sulfonyl-chlorides
(1.1 eq.) in the presence of PS-DIEA (1.2 eq.) and DMAP
(catalytic amount) in CH2Cl2, obtaining final compounds 1-24.
A molecular docking study of the sulfonamide derivatives in
BACE1 active site was conducted to give an interpretation of the
structure-activity relationship at a molecular level. First, BACE1
holo crystal structures were retrieved from the Protein Data
Bank, resulting in 302 ligand-BACE1 complexes. The
preliminary operations of our work were devoted to the
identification of the best protein structure and docking protocol
to use in the subsequent docking calculations.
a
b
OH
O
N
N
N
H
NH
1
R
25
26
27-38
O
N
O
1
OH
R2
c
N
S
R
1-24
Scheme 1. Reagents and conditions: a) epichlorohydr in, KOH, DMF, 0
°C, 5 h, 50%; b) R1-NH2, EtOH, 65 °C, overnight, 40-79%; c) ArSO2Cl, PS-
DIEA, DMAP, CH2Cl2, r. t., overnight, 13-86%.
The inhibitory activity of the newly synthesized compounds
towards BACE1 was determined by a previously reported
fluorescence-based assay15 and the results are shown in Table 1.
The introduction of a simple phenyl substituent on the
sulfonamide nitrogen (R1), together with the presence of an
unsubstituted or substituted aryl sulfonamide (compounds 1-4,
IC50 ranging from 2.4 to 3.0 M), leads to a BACE1-inhibitory
activity comparable to that of some of the most active
compounds included in the previous series of N-carboxamides
(IC50 = 2.5 M).14 When the sulfonamide aromatic ring is
unsubstituted (R2 = H) and the phenyl on the sulfonamide
nitrogen is substituted in position 4, the activity worsens slightly
(compounds 7 and 8), significantly (compound 5) or is
completely lost (compounds 6 and 9). The presence of a benzyl
substituent on the sulfonamide nitrogen causes an appreciable
increase in the inhibitory activity, except in one case (compound
11); compounds 10, 12 and 13 proved to be the most potent
inhibitors of this series, with IC50 values ranging from 1.6 to 1.9
M. The para-substitution of the benzyl group (leaving the aryl
sulfonamide unsubstituted) generally causes a decrement in the
activity (compounds 14-16). If a phenethyl group is introduced
Figure 2. Schematic representation of the principal interactions resulting
from the docking study of compound 13.
According to a previously validated protocol,16 crystal
structures were filtered according to chemical similarity of their
co-crystallized ligand to compound 13, chosen as representative
of the series of inhibitors herein described because of its highest
potency (IC50 = 1.6 µM). MACCS Tanimoto similarity was
computed exploiting RDKit17 functionalities, and the 6 structures
characterized by highest similarity values were selected (PDB
ID: 2WF2,18 2WF3,18 2WF4,19 2VNN,20 2VKM,21 4FCO, with
the addition of structure 1W5122 used in a previous study14). The
selected structures were subjected to a docking benchmark study

to evaluate the performance of different docking protocols and
scoring functions in the self-docking exercise. The co-
crystallized ligands were prepared by adding hydrogens using the
Protonate3D tool of MOE,23 while the proteins were prepared by
exploiting the Protein-preparation tool and the Protonate3D of
the same software suite.
centered on the center of mass of the co-crystallized ligand in the
corresponding complex.
Both R and S stereoisomers find a good accommodation
within the active site of BACE1, with the (2-
hydroxypropyl)sulfonamide portion protected behind the flap
region and the benzylic and carbazolic moieties pointing toward
two hydrophobic clefts positioned on left and right. The
interaction established by compound 13 are depicted in Figure 2
using the ligand interaction diagram as implemented in the
Schrodinger suite.27 In detail, the predicted binding mode of
compound 13 is reported in Figure 3, panel A. The benzylic
moiety attached to the sulfonamide nitrogen is inserted into a
hydrophobic pocket defined by Leu91, Ile179, Trp176, Ile171,
and Phe169. Also, the carbazole portion leans on a hydrophobic
portion of the protein, characterized by Tyr259, Ile287, and
Val393. The sulfonamide function acts as a hydrogen bond
acceptor with Gln134 positioned in the flap region. The hydroxyl
groups of both R and S stereoisomers are involved in a hydrogen
bond with one of the two catalytic aspartates: in particular, the R-
enantiomer interacts with Asp93, while the S enantiomer with
Asp289. Moreover, both enantiomers are stabilized by a further
hydrogen bond between the methoxy group in R2 and Thr293.
The pose of compound 13 (Figure 3, panel B) is similar to that
displayed by the crystallographic binding mode of the co-
crystallized ligand (PDB ID: 2WF4; ligand ID: ZY4) within the
protein conformation used in our docking calculations. The (2-
hydroxypropyl)sulfonamide of compound 13 resembles the gem-
diol group of the (2,2-dihydroxypropyl)amide moiety of the
crystallographic compound: here the amide carbonyl group
makes a hydrogen bond with Gln134 and the two hydroxyls are
engaged as donors in two hydrogen bonds with Asp93.
Table 1. Structures and BACE1 inhibitory activities of novel
variously sustituted arylsulfonamides 1-24.
O
N
O
1
OH
N
R2
S
R
b
Compd
R1
R2
H
IC50a (M)
logBBpred
1
Ph
3.0
2.6
2.9
2.4
7.1
> 10
3.6
3.8
> 10
1.9
2.7
1.7
1.6
> 10
2.7
5.7
2.8
2.5
3.8
3.0
4.1
3.9
6.5
3.2
-0.58
-0.57
-0.61
-0.64
-0.57
-0.61
-0.60
-0.79
-0.63
-0.61
-0.61
-0.65
-0.67
-0.61
-0.65
-0.68
-0.60
-0.59
-0.63
-0.66
-0.61
-0.60
-0.65
-0.67
2
Ph
CH3
Cl
3
Ph
4
Ph
OCH3
H
5
4-CH3-Ph
4-Cl-Ph
4-CF3-Ph
4-NO2-Ph
4-F-Ph
Bn
6
H
7
H
8
H
9
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
H
Bn
CH3
Cl
Bn
Bn
OCH3
H
4-CH3-Bn
4-Cl-Bn
H
4-OCH3-Bn
Phenethyl
Phenethyl
Phenethyl
Phenethyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
H
H
CH3
Cl
OCH3
H
CH3
Cl
OCH3
a IC50 measurements were performed as reported in Ref. 15. Data represent
mean values for at least three separate experiments. Standard errors are not
shown for the sake of clarity and were never higher than 15% of the means.
b Predicted blood-brain barrier permeation (logBBpred = log[Brain]/[Blood]).28
DockBench tool24 was employed to automatically perform the
docking benchmark, and, after the analysis of the benchmark
results, the protein 2WF4 with the Gold-goldscore25 protocol
were chosen because of the high performance in DockBench
Protocol Score.
The structures of the sulfonamide derivatives (stereoisomer R
and S of each compound) were constructed by using the MOE
builder function, the starting conformation was initially generated
exploiting Corina26 and then minimized using PM3 theory. The
docking calculations were performed for each compound,
limiting the conformational search within a 20 Å radius sphere
Figure 3. (A) Docking results of compound 13 in BACE1. Both (R) and (S)-
stereoisomer are respectively shown in cyan and pink. (B) The obtained
docking result is compared to the crystallographic binding mode of ligand
ZY4 within the BACE1 conformation selected for docking studies (PDB ID:
2WF4).

K.; Gemma, S.; Tang, J. Neurotherapeutics 2008, 5, 399. (d)
Hills, I. D.; Vacca, J. P. Curr. Opin. Drug Discov. Devel. 2007,
10, 383.
This makes plausible the binding of both the stereoisomers of
compound 13 to the BACE1 binding site. A binding mode
similar to that of compound 13 was obtained by docking
simulations for almost all the other sulfonamide derivatives, as
reported in Video-S1 (Supplementary Material).
7. (a) Konvalinka, J.; Brynda, J.; Sedlacek, J.; Fabry, M. J. Med.
Chem. 2002, 45, 1432. (b) Ghosh, A. K.; Fidanze, S. J. Org.
Chem. 1998, 63, 6146. (c) Tucker, T. J.; Lumma, W. C.; Payne, L.
S.; Wai, J. M.; Desolms, S. J.; Giuliani, E. A.; Darke, P. L.;
Heimbach, J. C.; Zugay, J. A.; Schleif, W. A.; Quintero, J. C.;
Emini, E. A.; Huff, J. R.; Anderson, P. S. J. Med. Chem. 1992, 35,
2525.
8. Yuan, J.; Venkatraman, S.; Y. Zheng, Y.; B.M. McKeever, B. M.;
L.W. Dillard, L. W.; S.B. Singh, S. B. J. Med. Chem. 2013, 56,
4156-4180.
9. Chiriano, G.; De Simone, A.; Mancini, F.; Perez, D. I.; Cavalli,
A.; Bolognesi, M. L.; Legname, G.; Martinez, A.; Andrisano, V.;
Carloni, P.; Roberti, M. Eur. J. Med. Chem. 2012, 48, 206-213.
10. Butler, C. R.; Ogilvie, K.; Martinez-Alsina, L.; G. Barreiro, G.;
Beck, E. M.; Nolan, C. E.; Atchison, K.; Benvenuti, E.; Buzon, L.;
Doran, S.; Gonzales, C.; Helal, C. J.; Hou, X.; Hsu, M.- H.;
Johnson, E. F.; Lapham, K.; Lanyon, L.; Parris, K.; O'Neill, B. T.;
Riddell, D.; Robshaw, A.; Vajdos, F.; Brodney, M. A. J. Med.
Chem. 2017, 60, 386-402.
All the BACE1 inhibitors are meant to have central nervous
system (CNS) activity, so they are expected to cross the blood-
brain barrier (BBB). Thus, the logBB was computed with the
Stardrop software23 for all compounds, to estimate their
capability to distribute from blood to the CNS. The logBB
predicted values, being higher than -0.8 in all cases, fall under the
-1 limit for passing the blood-brain barrier, so they seem to
satisfy the CNS permeability expectation. Compound 8, which is
characterized by the presence of a nitrophenyl substituent, shows
the highest value of this series (logBB = -0.79), due to the
relatively high polarity of the NO2 group, thus making its
putative BBB permeation less promising than those of the other
analogues.
11. Scott, J. D.; Li, S. W.; Brunskill, A. P. J.; Chen, X.; Cox, K.;
Cumming, J. N.; Forman, M.; Gilbert, E. J.; Hodgson, R. A.;
Hyde, L. A.; Jiang, Q.; Iserloh, U.; Kazakevich, I.; Kuvelkar, R.;
Mei, H.; Meredith, J.; Misiaszek, J.; Orth, P.; Rossiter, L. M.;
Slater, M.; Stone, J.; Strickland, C. O.; Voigt, J. H.; Wang, G.;
Wang, H.; Wu, Y.; Greenlee, W. J.; Parker, E. M.; Kennedy, M.
E.; Stamford, A. W. J. Med. Chem. 2016, 59, 10435-10450.
12. Ghosh, A. K.; Brindisi, M.; Tang, J. J. Neurochem. 2012, 120, 71-
83.
13. Asso, V.; Ghilardi, E.; Bertini, S.; Digiacomo, M.; Granchi, C.;
Minutolo, F.; Rapposelli, S.; Bortolato, A.; Moro, S.; Macchia, M.
ChemMedChem 2008, 3,1530.
14. Bertini, S.; Asso, V.; Ghilardi, E.; Granchi, C.; Manera, C.;
Minutolo, F.; Saccomanni, G.; Bortolato, A.; Mason, J.; Moro, S.;
Macchia, M. Bioorg. Med. Chem. Lett. 2011, 21, 6657.
15. Porcari, V.; Magnoni, L.; Terstappen, G. C.; Fecke, W.; Assay
Drug Dev. Technol. 2005, 3, 287.
In conclusion, we have synthesized a series of BACE1
inhibitors
possessing
a
N-[3-(9H-carbazol-9-yl)-2-
hydroxypropyl]-arylsulfonamido structure. Among the 24
derivatives, 21 active analogues were found, with three highly
active compounds (IC50 values ranging from 1.6 to 1.9 M). The
docking study showed that both enantiomers of the most active
compound of this series (13) find a good accommodation within
the active site of BACE1; a similar binding mode was obtained
by docking simulations of almost all the other sulfonamide
derivatives, as reported in Video-S1 (Supplementary Material).
Moreover, the predicted logBB values of all compounds (ranging
from -0.57 to -0.79) indicate satisfactory BBB permeabilities.
16. Salmaso, V.; Sturlese, M.; Cuzzolin, A.; Moro, S. J Comput Aided
Mol Des 2016, 30, 773–789.
17. RDKit: Open-source cheminformatics.
Acknowledgments
18. Charrier, N.; Clarke, B.; Demont, E.; Dingwall, C.; Dunsdon, R.;
Hawkins, J.; Hubbard, J.; Hussain, I.; Maile, G.; Matico, R.;
Mosley, J.; Naylor, A.; O’Brien, A.; Redshaw, S.; Rowland, P.;
Soleil, V.; Smith, K. J.; Sweitzer, S.; Theobald, P.; Vesey, D.;
Walter, D. S.; Wayne, G. Bioorg Med Chem Lett 2009, 19, 3669–
3673.
19. Charrier, N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.;
Dunsdon, R.; Hawkins, J.; Howes, C.; Hubbard, J.; Hussain, I.;
Maile, G.; Matico, R.; Mosley, J.; Naylor, A.; O’Brien, A.;
Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer, S.;
Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. Bioorg Med
Chem Lett 2009, 19, 3674–3678.
The authors are grateful to the University of Pisa (Progetti di
Ricerca di Ateneo, PRA_2016_59) for funding and to Siena
Biotech SpA – Italy, for scientific and financial support. The
computational work coordinated by S.M. has been supported
with financial support from the University of Padova, Italy.
MMS lab is also very grateful to Chemical Computing Group and
OpenEye for the scientific and technical partnership.
20. Charrier, N.; Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.;
Dunsdon, R.; East, P.; Hawkins, J.; Howes, C.; Hussain, I.;
Jeffrey, P.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.; O’Brien,
A.; Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer,
S.; Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. J Med
Chem 2008, 51, 3313–3317.
21. Ghosh, A. K.; Kumaragurubaran, N.; Hong, L.; Kulkarni, S.; Xu,
X.; Miller, H. B.; Reddy, D. S.; Weerasena, V.; Turner, R.; Chang,
W.; Koelsch, G.; Tang, J. Bioorg Med Chem Lett 2008, 18, 1031–
1036.
22. Patel, S.; Vuillard, L.; Cleasby, A.; Murray, C. W.; Yon, J. J Mol
Biol 2004, 343, 407–416.
23. Chemical Computing Group (CCG) Inc. Molecular Operating
Environment (MOE); Chemical Computing Group: 1010
Sherbooke St. West, Suite #910, Montreal, QC, Canada, H3A
2R7, 2016.
24. Cuzzolin, A.; Sturlese, M.; Malvacio, I.; Ciancetta, A.; Moro, S.
Molecules 2015, 20, 9977–9993.
25. Verdonk, M. L.; Cole, J. C.; Hartshorn, M. J.; Murray, C. W.;
Taylor, R. D. Proteins 2003, 52, 609–623.
26. Molecular Networks GmbH CORINA; Germany.
27. Schrödinger, LLC Schrödinger Release 2017-1: Maestro; New
York, NY, 2017.
28. StarDrop. Optibrium Ltd, 7221 Cambridge Research Park, Beach
Drive, Cambridge, CB25 9TL, UK. http://www.optibrium.com/.
References and notes
1. Hardy, J.; Selkoe, D. J. Science 2002, 297, 353.
2. Gendron T. F. and Petrucelli L. Mol. Neurodegener. 2009, 4, 13.
3. Kandalepas, P. C. and Vassar, R. J. Neurochem. 2012, 120, 55.
4. (a) Luo, Y.; Bolon, B.; Kahn, S.; Bennett, B. D.; Babu-Khan, S.;
Denis, P.; Fan, W.; Kha, H.; Zhang, J.; Gong, Y.; Martin, L.;
Louis, J.-C.; Yan, Q.; Richards, W. G.; Citron, M.; Vassar, R. Nat.
Neurosci. 2001, 4, 231−232. (b) Roberds, S. L.; Anderson, J.;
Basi, G.; Bienkowski, M. J.; Branstetter, D. G.; Chen, K. S.;
Freedman, S. B.; Frigon, N. L.; Games, D.; Hu, K.; Johnson-
Wood, K.; Kappenman, K. E.; Kawabe, T. T.; Kola, I.; Kuehn, R.;
Lee, M.; Liu, W.; Motter, R.; Nichols, N. F.; Power, M.;
Robertson, D. W.; Schenk, D.; Schoor, M.; Shopp, G. M.; Shuck,
M. E.; Sinha, S.; Svensson, K. A.; Tatsuno, G.; Tintrup, H.;
Wijsman, J.; Wright, S.; McConlogue, L. Hum. Mol. Genet. 2001,
10, 1317.
5. McConlogue, L.; Buttini, M.; Anderson, J. P.; Brigham, E. F.;
Chen, K. S.; Freedman, S. B.; Games, D.; Johnson-Wood, K.; Lee,
M.; Zeller, M.; Liu, W.; Motter, R.; Sinha, S. J. Biol. Chem. 2007,
282, 26326.
6. (a) Kumar, A. B.; Anderson, J. M.; Melendez, A. L.; Manetsch, R.
Bioorg. Med. Chem. Lett. 2012, 22, 4740. (b) De Strooper, B.;
Vassar, R.; Golde, T. Nat. Rev. Neurol. 2010, 6, 99. (c) Ghosh, A.

interaction energy (kcal/mol) and
a
scoring estimating
hydrophobic interactions (Arbitrary Unit, AU) were computed
with MOE suite and their values are coded into colorimetric
metrics from blue (negative value) to green palette (positive
values).
Supplementary Material
All experimental procedures and Video S1 are available as
supplementary material.
Video-S1 Caption. The file contains an Animation of the
energetically most favorable pose of all the compounds. The
ligands are colored in cyan while the protein more relevant
residues are colored in gold. The background of the poses shows
a heat map corresponding to the contribution of the most relevant
residues belonging to the binding site. The electrostatic
Click here to remove instruction text...
Graphical Abstract
Sulfonamido-derivatives of unsubstituted
carbazole as BACE1 Inhibitors
Leave this area blank for abstract info.
Simone Bertini, Elisa Ghilardi, Valentina Asso, Filippo Minutolo, Simona Rapposelli, Maria Digiacomo,
Giuseppe Saccomanni, Veronica Salmaso, Mattia Sturlese, Stefano Moro, Marco Macchia, Clementina Manera