Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and aluminum chloride-induced (hetero) arylation reactions and biological evaluation as proteasome inhibitors

Article abstract of DOI:10.1016/j.tetlet.2020.151805

A new series of 3-(quinazol-2-yl)-quinolines was synthesized by S_NAr reaction from easily prepared 4-chloro-2-(2-chloroquinolin-3-yl)quinazolines and a range of phenols and thiophenol as nucleophiles. The AlCl₃-mediated C–C bond formation was also successfully exploited to introduce aryl and hereroaryl substituents on one or both heterocyclic units. These procedures afford efficient syntheses of polysubstituted 3-(quinazol-2-yl)-quinolines in few steps and high yields. Some of these polysubstituted 3-(quinazol-2-yl)-quinolines inhibit the human 20S proteasome.

Full text of DOI:10.1016/j.tetlet.2020.151805

Journal Pre-proofs
Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and aluminum
chloride-induced (hetero) arylation reactions and biological evaluation as pro‐
teasome inhibitors
Imen Boualia, Abdelmadjid Debache, Raouf Boulcina, Thierry Roisnel,
Fabienne Berrée, Joëlle Vidal, Bertrand Carboni
PII:
S0040-4039(20)30240-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151805
TETL 151805
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
5 January 2020
29 February 2020
4 March 2020
Please cite this article as: Boualia, I., Debache, A., Boulcina, R., Roisnel, T., Berrée, F., Vidal, J., Carboni, B.,
Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and aluminum chloride-induced (hetero) arylation
reactions and biological evaluation as proteasome inhibitors, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.151805
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. 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.
© 2020 Published by Elsevier Ltd.

1
Graphical Abstract
Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and
aluminum chloride-induced (hetero) arylation reactions and
biological evaluation as proteasome inhibitors
Leave this area blank for abstract info.
Imen Boualia, Abdelmadjid Debache, Raouf Boulcina,* Thierry Roisnel, Fabienne Berrée, Joelle Vidal,* and
Bertrand Carboni
O2N
R1
Cl
N
O
N
N
SNAr or
AlCl3-mediated reaction
N
R
R
N
N
R2
N
Cl
N
Cl
N
R1 = OAr, SPh, HetAr, morpholino
R2 = Cl, OAr, NHTol, HetAr, morpholino
20S constitutive proteasome inhibitor
ChT-L activity Ki = 19 µM
R = H, Me, OMe
PA activity Ki = 13 µM
26 examples

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and aluminum chloride-
induced (hetero) arylation reactions and biological evaluation as proteasome
inhibitors
Imen Boualia,a,b Abdelmadjid Debache,a Raouf Boulcina,a,c* Thierry Roisnel, b Fabienne Berrée,b Joëlle
Vidal,b* and Bertrand Carbonib
a Laboratoire de Synthèse des Molécules d’Intérêts Biologiques, Université des Frères Mentouri-Constantine, 25000 Constantine, Algérie.
b Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) - UMR 6226, F-35000 Rennes, France. E-mail: joelle.vidal@univ-rennes1.fr
c Département des Sciences et Techniques, Faculté de Technologie, Université Mostefa Benboulaïd-Batna 2, 05000 Batna, Algérie. E-mail: r.boulcina@univ-
batna2.dz
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new series of 3-(quinazol-2-yl)-quinolines was synthesized by SNAr reaction from easily
prepared 4-chloro-2-(2-chloroquinolin-3-yl)quinazolines and a range of phenols and thiophenol
as nucleophiles. The AlCl3-mediated C–C bond formation was also successfully exploited to
introduce aryl and hereroaryl substituents on one or both heterocyclic units. These procedures
afford efficient syntheses of polysubstituted 3-(quinazol-2-yl)-quinolines in few steps and high
yields. Some of these polysubstituted 3-(quinazol-2-yl)-quinolines inhibit the human 20S
proteasome.
Available online
Keywords:
Quinazoline
Quinoline
2009 Elsevier Ltd. All rights reserved.
SNAr
AlCl3-mediated reaction
Proteasome inhibitor
The quinoline core is found in many natural products and has
a privileged role in drug discovery.1 For example, camptothecin,
topotecan, belotecan or cabozatinib, that inhibit topoisomerase or
tyrosine kinases, are currently approved as anticancer treatment.
Quinoline scaffold has also been used in the search for inhibitors
of other important cancer targets, such as tubulin polymerization,
DNA repair and proteasome.1-2 In the field of proteasome,
quinolines are also widely represented as depicted in Figure 1.3
Such derivatives could overcome some problems encountered
with the pharmacodynamic and pharmacokinetic profiles of the
proteasome inhibitors currently approved in cancer therapy
(bortezomib, carfilzomib and ixazomib), usually attributed to
their peptide structure and the presence of an electrophilic
warhead.2b In the wide family of quinolines derivatives, hybrids
which combines this scaffold with a quinazoline moiety, another
important heterocycle possessing significant biological
activities,4 are poorly exemplified (Fig. 2).
NO2
A.
B.
H2N
O
NH2
NH
Cl
O2N
S
N
O
O
N
O
HN
S
H
N
N
N
I
N
Cl
N
N
N
OH
N
OH
S
O
N
clioquinol3c,3d
chloroquine3e
N
HN
VR-233g
S
N
5-AHQ3f
O
H
N
Ph
Cl
H
O
HO
H
O
N
SO2R1
PhSO2NH
N
O
NH
NMe2
2
NHtBu
NH
S
S
N
N
R2
N
capzimin3a
saquinavir3b
III3j
II3i
I3h
Fig.1 Structures of proteasome inhibitors bearing a quinoline scaffold (A. inhibitor of the proteasome 19S particle; B. inhibitors of the proteasome 20S core
particle).

2
They were mostly synthesized by palladium-catalyzed
carbonylation of 2-aminobenzylamine and 2-bromoquinoline,5
Suzuki coupling of the chloroquinazolinone with 2-quinolyl
boronic acid,6 or DMAP-catalyzed one-pot three-component
reaction from 2-formylquinolines, 2-aminobenzophenones and
ammonium acetate.7
yields of 7a-d (23 to 53%) were obtained by performing the
reactions in refluxing DMF within 16 h (Table 2).
Table 1
Synthesis of 2-chloro-3-(4-aryloxyquinazol-2-yl)-quinolines 6
Ar
Cl
X
ArXH, K2CO3
N
N
In continuation of our research program centered on the
R
R
MeCN, reflux
2h
N
N
8
design and synthesis of potentially bioactive molecules and, as
Cl
N
Cl
N
part of our studies on non-peptide and non-covalent 20S
proteasome inhibitors,3h,9 we here focus on the preparation of a
series of novel hybrid 3-(quinazol-2yl)-quinolines 6-15 via SNAr
and AlCl3 induced (hetero) arylation reactions of 5 and their 20S
proteasome inhibition evaluation (Fig. 2).
6a-i
5a c
-
X = O, S
6b
R1
Cl
N
N
R
R
N
N
R
X
Ar
Yield
84%
92%
88%
93%
71%
63%
89%
80%
83%
R2
6 15
Cl
N
N
6a
6b
6c
6d
6e
6f
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
O
S
C6H5
5
-
4-Me-C6H4
3-MeO-C6H4
1-naphthyl
4-NO2-C6H4
3-pyridyl
4-Me-C6H4
4-Me-C6H4
C6H5
Fig.2 Targeted 3-(quinazol-2yl)-quinolines 6-15 and their precursor 5.
To access to our common building blocks 5, intermediates 3a-
c were first prepared in high yields by using procedures
previously reported in our laboratory.8c Couplings of the 2-
aminobenzamide 1 with appropriate quinoline-3-carboxaldehydes
2 were carried out in the presence of K2CO3 in DMF at 80 °C
(Scheme 1). On treatment with iodine in DMF at 80 °C, 3a-c
exclusively gave the desired oxidized product 4a-c in 76-86%
yields. Chlorination was then readily achieved with phosphorus
oxychloride giving 5a-c in 70-78% yields.
6g
6h
6i
OMe
H
Me
To extend the range of available compounds, the reactions
between compounds 6 and p-toluidine, selected as model aniline,
were also examined. Aminoquinolines 8a-c were then prepared in
good yields after one hour in refluxed i-PrOH in the presence of
1N HCl (Table 3). NMR and mass spectra of 6a-i, 7a-c and 8a-c
are in full agreement with the proposed structures. It is worthy to
note the downfield shift of the NH signal in the 1H NMR spectra
of compounds 8 which would indicate that NH is located in an
aromatic deshielding area of the twisted structure.
O
O
OHC
Cl
R
NH
NH2
a
R
+
N
H
Cl
NH2
N
2
3
1
N
a
b
c
R = H
R = Me
R=OMe
b
Cl
N
O
N
NH
c
R
R
Table 2
N
Synthesis of 2-aryloxy-3-(4-aryloxyquinazol-2-yl)-quinolines 7
N
Cl
N
Cl
Ar
O
Cl
5
4
N
N
Scheme 1 Reagents and conditions: (a) K2CO3, DMF, 80° C, 3h, 3a (94%),
3b (91%) 3c (90%); (b) I2, DMF, 80° C, 6h, 4a (76%), 4b (84%), 4c (86%);
(c) POCl3, reflux, 18h, 5a (76%), 5b (78%), 5c (70%).
R
R
N
2 ArOH
N
O
Ar
N
K2CO3, DMF,
reflux, 16h
Cl
N
Based on our previous study related to the synthesis of 4-
anilinoquinolino-quinazoline hybrids using SNAr reactions with
various aromatic amines,8c we then decided to use phenols as
nucleophiles. With 1 equiv. under refluxed acetonitrile in the
presence of K2CO3, the corresponding adducts 6a-h were isolated
in high yields (Table 1). A complete conversion occurred within
a short time (2 h) with no substitution at the C-2 position of the
quinoline. This high regioselectivity at the C-4 position was
confirmed by X-ray diffraction of 6b that reveals a dihedral angle
of 50° between the quinazoline and the quinoline subunits.10
Similarly, the 4-phenylthio derivative 6i was synthesized from
thiophenol and 5a in 83% isolated yield.
5a c
-
7a-d
Yield
Compound
R
Ar
7a
7b
7c
7d
Me
Me
H
phenyl
23%
52%
53%
43%
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
OMe
We then turned our attention to the formation of a new
carbon-carbon bond. Introduction of an aryl or heteroaryl moiety
at C-2 of quinoline ring or C-4 of quinazoline was frequently
carried out via Ni-catalyzed reaction of quinolone with arylzinc,11
On the other hand, when the reaction of 5a was performed with
two equivalents of phenol under the same conditions, the
formation of disubstituted quinazoline derivatives did not occur
at all even after 16 h in CH3CN under reflux. However, modest

3
11b
Suzuki coupling with arylboronic acids
or reaction of
of two equivalents of morpholine, the conversion of 5b to 11
quinoline N-oxide with indole.12
was completed in methylene chloride at 45°C within 2h. With
morpholine as solvent, at 80 °C for 1h, 12b and 12c were
obtained in 88 and 84% yields, respectively (Scheme 3). Under
the same conditions, were synthesized 13-15 with 2,4,6-
trimethoxyphenyl, indolyl and pyrrolyl moieties at the 4-position
of quinazolines.
Table 3
Synthesis of 2-arylamino-3-(4-aryloxyquinazol-2-yl)-quinolines 8
Ar
O
Ar
O
N
p-toluidine
N
O
N
i-PrOH,
HCl 1N,
reflux, 1h
O
N
N
N
HN
N
Cl
N
N
8a-c
6
R
N
N
N
N
N
O
Cl
N
Compound
Ar
Yield
12b:
12c:
R = methyl
R = methoxy
11
8a
8b
8c
C6H5
88%
62%
72%
a
b
5b-c
4-Me-C6H4
1-naphthyl
c
(Het)Ar
Despite the merit of these protocols, they are not free from
limitations in terms of longer reaction time, use of costly
catalysts, requirement of stringent conditions or multistep
synthesis of starting materials. Over the last few years, the C–C
bond forming reactions between heteroaryl chlorides containing a
C(Cl)=N moiety and various electron rich arenes or heteroarenes
in the presence of AlCl3 have been reported on several
occasions.13 2-Chloro-3-(4-(het)arylquinazol-2-yl)-quinolines 9a-
c were effectively obtained under this catalytic conditions in
excellent yields from 2,4,6-trimethoxybenzene, indole and
pyrrole (Scheme 2). Notably, as previously observed for SNAr
reactions, no 2-substituted quinoline adducts were detected. In
view of the mechanism generally proposed for this reaction,13g
this regioselectivity could be explained by the favored
complexation of AlCl3 to the quinazoline nitrogen. However, the
use of an excess of 2,4,6-trimethoxybenzene with 5b as substrate,
for 15h instead of 3h, afforded the desired bi-substituted
derivative 10.
N
N
N
N
O
13
14
15
: Ar = 2,4,6-trimethoxyphenyl
: Het = indol-3-yl
: Het = pyrrol-3-yl
Scheme 3 Reagents and conditions: (a) morpholine (2 equiv), CH2Cl2, 45° C,
2h, 11 (91%); (b) morpholine (solvent), 80°C, 1h, 12b (R = Me, 88%), 12c (R
= OMe, 84%); (c) (Het)ArH, AlCl3, 80°C, (CH2Cl)2, 3h, then morpholine (2
equiv), CH2Cl2, 45° C, 2h, 13 (Ar = 2,4,6-trimethoxyphenyl, 92%), 14 (Het =
indol-3-yl 78%), 15 (Het = pyrrol-3-yl, 79%).
Having in hands a small library of 3-(quinazol-2-yl)-
quinolines 6-15, we evaluated their biological activities as
inhibitors of the purified human constitutive 20S proteasome.
The ability to inhibit the three proteolytic activities, ChT-L, T-L
and PA, was measured by fluorescence. Owing to their weak (7c,
9a, 9b, 9c, 13) or moderate fluorescence (7d) at the working
wavelengths, these compounds were excluded from the
screening.
(Het)Ar
N
N
a
5b
Cl
N
9a :
Ar = 2,4,6-trimethoxyphenyl
: Het = indol-3-yl
OMe
9b
9c
Ten compounds over 18 inhibited fairly (20%) to strongly
(90%) the ChT-L or the PA activities at 50 µM (Fig.3 A.). The T-
L activity was fairly inhibited by 4 products. Compounds that
gave more than 70% inhibition were further characterized by
their effect-dose response (Fig. S1 in supplementary material) to
determine concentrations giving 50% inhibition (IC50, table 4).
As for the quinoline 20S proteasome inhibitors saquinavir,3b 5-
AHQ3f and III3j (Fig. 1), the best compound 6e inhibits both
ChT-L and PA activities, with a similar potency for PA and a
lower one for ChT-L.
: Het = pyrrol-3-yl
MeO
OMe
N
N
b
MeO
N
OMe
MeO
10
Scheme 2 Reagents and conditions: (a) (Het)ArH, AlCl3, DCE, 80 °C, 3h, 9a
(83%), 9b (71%), 9c (91%); (b) 1,3,5-trimethoxybenzene, AlCl3, DCE, 80 °C,
15h, 10 (61%)
Table 4
IC50 (µM) values for inhibition of human constitutive CP (pH 8, 37 °C)
6e
6f
11
12b
chloroquine
6.3 ± 0.4
Finally, because morpholines are privileged substitiuents
abundantly used as in drugs and medicinal chemistry,14 we
applied the above-described methodologies to the synthesis of
new derivatives presenting a morpholino substituent on the
quinazoline or (and) quinoline parts. For example, in the presence
ChT-L activity
PA activity
35.4 ± 0.6 19 ± 1
66%a
44 ± 1
55% a
41 ± 1
13.2 ± 0.6
34.2 ± 0.8 22.5 ± 0.6
a % inhibition at 50 µM

4
We also investigated the mechanism of inhibition by
compound 6e (Fig. S2 and Fig. S3 in supplementary material).15
A competitive inhibition of the ChT-L activity was observed.15
This indicates that inhibitor 6e binds exclusively to the free
enzyme with an inhibition constant Ki = 19 ± 1 µM. Such a
competitive inhibition mechanism has been reported mainly for
the ChT-L activity of non-covalent peptide derivatives16 and also
for the PA activity of tamoxifen derivatives.17 The PA activity
was inhibited non-competitively.15 Inhibitor 6e binds with an
equal affinity to the enzyme alone or the enzyme in complex with
the substrate (Ki = K’i = 13.2 ± 0.6 µM). Non-competitive
inhibition of 20S proteasome has been observed for the PA
activity of quinoline 5-AHQ (Fig.1),3f and for the ChT-L activity
of oxadiazoles,9a tamoxifen derivatives17 or peptide
derivatives.16a,18
References and notes
[1] (a) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18,
1488-1508;
(b) Musiol, R. Expert Opin. Drug Discov. 2017, 12, 583-
597.
[2] (a) Manasanch, E. E.; Orlowski, R. Z. Nat. Rev. Clin. Oncol.
2017, 14, 417;
(b) Park, J. E.; Miller, Z.; Jun, Y.; Lee, W.; Kim, K. B.
Translational Research 2018, 198, 1-16.
[3] (a) Perez, C.; Li, J.; Parlati, F.; Rouffet, M.; Ma, Y.;
Mackinnon, A. L.; Chou, T.-F.; Deshaies, R. J.; Cohen, S.
M. J. Med. Chem. 2017, 60, 1343-1361;
(b) Pajonk, F.; Himmelsbach, J.; Riess, K.; Sommer, A.;
McBride, W. H. Cancer Res. 2002, 62, 5230-5235;
(c) Mao, X.; Li, X.; Sprangers, R.; Wang, X.; Venugopal,
A.; Wood, T.; Zhang, Y.; Kuntz, D. A.; Coe, E.; Trudel, S.;
Rose, D.; Batey, R. A.; Kay, L. E.; Schimmer, A. D.
Leukemia 2009, 23, 585-590;
(d) Zhai, S.; Yang, L.; Cui, Q. C.; Sun, Y.; Dou, Q. P.; Yan,
B. JBIC, J. Biol. Inorg. Chem. 2010, 15, 259-269;
(e) Ruschak, A. M.; Kay, L. E. Proc. Natl. Acad. Sci. U. S.
A. 2012, 109, E3454-E3462, SE3454/1-SE3454/31;
(f) Li, X.; Wood, T. E.; Sprangers, R.; Jansen, G.; Franke,
N. E.; Mao, X.; Wang, X.; Zhang, Y.; Verbrugge, S. E.;
Adomat, H.; Li, Z. H.; Trudel, S.; Chen, C.; Religa, T. L.;
Jamal, N.; Messner, H.; Cloos, J.; Rose, D. R.; Navon, A.;
Guns, E.; Batey, R. A.; Kay, L. E.; Schimmer, A. D. J. Natl.
Cancer Inst. 2010, 102, 1069-1082;
(g) Pundir, S.; Vu, H.-Y.; Solomon, V. R.; McClure, R.;
Lee, H. Cancer Research 2015, 75, 4164-4175;
(h) Basse, N.; Montes, M.; Marechal, X.; Qin, L.; Bouvier-
Durand, M.; Genin, E.; Vidal, J.; Villoutreix, B. O.;
Reboud-Ravaux, M. J. Med. Chem. 2010, 53, 509-513;
(i) Di Giovanni, C.; Ettari, R.; Sarno, S.; Rotondo, A.; Bitto,
A.; Squadrito, F.; Altavilla, D.; Schirmeister, T.; Novellino,
E.; Grasso, S.; Zappala, M.; Lavecchia, A. Eur. J. Med.
Chem. 2016, 121, 578-591;
Fig.3 Effect of 3-(quinazol-2-yl)-quinolines 6-15 on human constitutive CP
(pH 8, 37 °C). Compared inhibitions of the ChT-L, PA and T-L activities by
compounds 6-15 at 50 µM.
The many crystallographic structures of inhibitors in complex
with 20S proteasome have provided a deep understanding of the
binding channel and specificity pockets that can be targeted by
competitive inhibitors.19 However a non-competitive modulation
of 20S proteasome suggests that binding to other sites could
occur while blocking 20S proteasome activities. As yet, the only
direct evidences (NMR3e or X-ray20) for such a mechanism
involving non-peptide derivatives have been brought using
quinoline derivatives (respectively chloroquine or I).
(j) McDaniel, T. J.; Lansdell, T. A.; Dissanayake, A. A.;
Azevedo, L. M.; Claes, J.; Odom, A. L.; Tepe, J. J. Bioorg.
Med. Chem. 2016, 24, 2441-2450.
[4] Alagarsamy, V.; Chitra, K.; Saravanan, G.; Solomon, V. R.;
Sulthana, M. T.; Narendhar, B. Eur. J. Med. Chem. 2018,
151, 628-685.
[5] Chen, J.; Natte, K.; Neumann, H.; Wu, X.-F. RSC Adv.
2014, 4, 56502-56505.
[6] Sutherland, H. S.; Hwang, I. Y.; Marshall, E. S.; Lindsay, B.
S.; Denny, W. A.; Gilchrist, C.; Joseph, W. R.; Greenhalgh,
D.; Richardson, E.; Kestell, P.; Ding, A.; Baguley, B. C.
Invest New Drugs 2012, 30, 2035-45.
[7] Derabli, C.; Boulcina, R.; Kirsch, G.; Carboni, B.; Debache,
A. Tetrahedron Lett. 2014, 55, 200-204.
We described in this paper an efficient synthesis of poly-
substituted 3-(quinazol-2-yl)-quinoline derivatives 6-15 in few
steps and high yields. Chemical diversity was introduced by
selective mono or double SNAr of a range of phenols, thiophenol,
amines or anilines with the easily prepared di-chloro derivatives
5. Aryl or heteroaryl carbon nucleophiles allowed the AlCl3
mediated and controlled creation of one or two C-C bonds.
Several 3-(quinazol-2-yl)-quinoline derivatives inhibited the
ChT-L and PA activities of the human constitutive 20S
proteasome. The best compound 6e inhibited these activities by
different mechanisms, with moderate affinities (Ki = 13-19 µM).
[8] (a) Mahdjoub, S.; Boulcina, R.; Yildirim, M.; Lakehal, S.;
Boulebd, H.; Debache, A. Synth. Commun. 2018, 48, 2366-
2381;
Acknowledgments
(b) Derabli, C.; Boualia, I.; Abdelwahab, A. B.; Boulcina,
R.; Bensouici, C.; Kirsch, G.; Debache, A. Bioorg. Med.
Chem. Lett. 2018, 28, 2481-2484;
(c) Derabli, C.; Boulcina, R.; Kirsch, G.; Debache, A.
Tetrahedron 2017, 73, 351-358.
This work was supported by the University of Rennes 1 and
the Centre National de la Recherche Scientifique (CNRS). IB
gratefully acknowledges le Ministère de l’Enseignement
Supérieur et de la Recherche Scientifique (Algeria) and The
Algerian-French scholarship program PROFAS B+.
[9] (a) Maréchal, X.; Genin, E.; Qin, L.; Sperandio, O.; Montes,
M.; Basse, N.; Richy, N.; Miteva, M. A.; Reboud-Ravaux,
M.; Vidal, J.; Villoutreix, B. O. Curr. Med. Chem. 2013, 20,
2351-2362;
(b) Villoutreix, B. O.; Khatib, A. M.; Cheng, Y.; Miteva, M.
A.; Marechal, X.; Vidal, J.; Reboud-Ravaux, M. Oncotarget
2017, 8, 10437-10449.
Supplementary Material
[10] CCDC 1871916 contains the crystallographic data for
compounds 6b.These data can be obtained free of charge
Supplementary data to this article can be found online at

5
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac. uk/data_request/cif.
[20] Beck, P.; Reboud-Ravaux, M.; Groll, M. Angew. Chem.
Int. Ed. 2015, 54, 11275-11278.
[11] (a) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc.
2009, 131, 12070-12071;
Graphical Abstract
Highlights:
(b) Fleckenstein, C. A.; Plenio, H. Chem. Eur. J. 2008, 14,
4267-4279.
[12] Hoemann, M. Z.; Kumaravel, G.; Xie, R. L.; Rossi, R. F.;
Meyer, S.; Sidhu, A.; Cuny, G. D.; Hauske, J. R. Bioorg;
Med. Chem. Lett. 2000, 10, 2675-2678.
 A new series of polysubstituted 3-(quinazol-
2-yl)-quinolines have been synthesized by
SNAr reaction.
[13] (a) Pal, M.; Batchu, V. R.; Parasuraman, K.; Yeleswarapu,
K. R. J. Org. Chem. 2003, 68, 6806-6809;
(b) Pal, M.; Batchu, V. R.; Dager, I.; Swamy, N. K.;
Padakanti, S. J. Org. Chem. 2005, 70, 2376-2379;
(c) Kodimuthali, A.; T. C, N.; Prasunamba, P. L.; Pal, M.
Tetrahedron Lett. 2009, 50, 354-358;
(d) Kodimuthali, A.; Chary, B. C.; Prasunamba, P. L.; Pal,
M. Tetrahedron Lett. 2009, 50, 1618-1621;
(e) Kumar, K. S.; Chamakuri, S.; Vishweshwar, P.; Iqbal, J.;
Pal, M. Tetrahedron Lett. 2010, 51, 3269-3273;
(f) Rajasekhar, M.; Rao, K. U. M.; Sundar, C. S.; Reddy, N.
B.; Kumar Nayak, S. K.; Reddy, C. S. Chem. Pharm. Bull
2012, 60, 854;
 Various amines, phenols and thiophenol
have been used as reactants.
 AlCl3 has mediated C–C bond forming
reactions.
(g) Sunke, R.; Nallapati, S. B.; Kumar, J. S.; Shiva Kumar,
K.; Pal, M. Org. Biomol. Chem. 2017, 15, 4042-4057.
[14] (a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med.
Chem. 2014, 57, 5845-5859;
(b) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem.
2014, 57, 10257-10274;
(c) Ritchie, T. J.; Macdonald, S. J. F.; Peace, S.; Pickett, S.
D.; Luscombe, C. N. MedChemComm 2012, 3, 1062-1069.
[15] Bisswanger, H.; Wiley‐VCH Verlag GmbH & Co:
Weinheim, 2008.
 The methodology can be viewed as a useful
alternative to the Suzuki reactions.
 Some of the synthesized 3-(quinazol-2-yl)-
quinolines inhibit the human 20S
proteasome.
[16] (a) Desvergne, A.; Genin, E.; Maréchal, X.; Gallastegui,
N.; Dufau, L.; Richy, N.; Groll, M.; Vidal, J.; Reboud-
Ravaux, M. J. Med. Chem. 2013, 56, 3367-3378;
(b) Maréchal, X.; Pujol, A.; Richy, N.; Genin, E.; Basse, N.;
Reboud-Ravaux, M.; Vidal, J. Eur. J. Med. Chem. 2012, 52,
322-7;
Declaration of interests
(c) Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi, K.;
Okuda, T.; Ohnuki, T.; Komatsubara, S. J. Antibiot. 2000,
53, 105-9.
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
[17] Hasegawa, M.; Yasuda, Y.; Tanaka, M.; Nakata, K.;
Umeda, E.; Wang, Y.; Watanabe, C.; Uetake, S.; Kunoh, T.;
Shionyu, M.; Sasaki, R.; Shiina, I.; Mizukami, T. Eur. J.
Med. Chem. 2014, 71, 290-305.
[18] (a) Myung, J.; Kim, K. B.; Lindsten, K.; Dantuma, N. P.;
Crews, C. M. Mol. Cell 2001, 7, 411-420;
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
(b) Santos, R. d. L. A.; Bai, L.; Singh, P. K.; Murakami, N.;
Fan, H.; Zhan, W.; Zhu, Y.; Jiang, X.; Zhang, K.; Assker, J.
P.; Nathan, C. F.; Li, H.; Azzi, J.; Lin, G. Nat. Commun.
2017, 8, 1692;
(c) Karpowicz, P.; Osmulski, P. A.; Witkowska, J.;
Sikorska, E.; Gizynska, M.; Belczyk-Ciesielska, A.;
Gaczynska, M. E.; Jankowska, E. PLoS One 2015, 10,
e0143038.
[19] Borissenko, L.; Groll, M. Chem. Rev. 2007, 107, 687-717.
Synthesis of novel 3-(quinazol-2-yl)-quinolines via SNAr and
aluminum chloride-induced (hetero) arylation reactions and
biological evaluation as proteasome inhibitors
Leave this area blank for abstract info.
Imen Boualia, Abdelmadjid Debache, Raouf Boulcina,* Thierry Roisnel, Fabienne Berrée, Joelle Vidal,* and
Bertrand Carboni
O2N
R1
Cl
N
O
N
N
SNAr or
AlCl3-mediated reaction
N
R
R
N
N
R2
N
Cl
N
Cl
N
R1 = OAr, SPh, HetAr, morpholino
R2 = Cl, OAr, NHTol, HetAr, morpholino
20S constitutive proteasome inhibitor
ChT-L activity Ki = 19 µM
R = H, Me, OMe
PA activity Ki = 13 µM
26 examples

6