A new three-component reaction: Green synthesis of novel isoindolo[2,1-a]quinazoline derivatives as potent inhibitors of TNF-α

Article abstract of DOI:10.1039/c1cc10715a

Concurrent construction of five and six membered fused N-heretocyclic ring was achieved via a conceptually new three-component reaction affording 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones as novel inhibitors of TNF-α in vitro. This represents one of the few examples of direct TNF-α inhibition by small molecules.

Full text of DOI:10.1039/c1cc10715a

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COMMUNICATION
A new three-component reaction: green synthesis of novel
isoindolo[2,1-a]quinazoline derivatives as potent inhibitors of TNF-aw
K. Siva Kumar,ab P. Mahesh Kumar,a K. Anil Kumar,a M. Sreenivasulu,a Ahamed A. Jafar,b
D. Rambabu,c G. Rama Krishna,d C. Malla Reddy,d Ravikumar Kapavarapu,c
K. Shivakumar,c K. Krishna Priya,c Kishore V. L. Parsac and Manojit Pal*c
Received 6th February 2011, Accepted 9th March 2011
DOI: 10.1039/c1cc10715a
Concurrent construction of five and six membered fused
N-heretocyclic ring was achieved via a conceptually new
three-component reaction affording 6,6a-dihydroisoindolo-
[2,1-a]quinazoline-5,11-diones as novel inhibitors of TNF-a
in vitro. This represents one of the few examples of direct
TNF-a inhibition by small molecules.
TNF-a.4b However, inhibition of TNF-a by small molecules is
not common in the literature.4c In this communication we wish
to present our preliminary work on the design, and identification
of novel small molecules as inhibitors4c of TNF-a synthesis of
which was carried out using a conceptually new MCR.
During the last ten years the pharmaceutical industry has
focused on the development of novel anti-inflammatory agents
that inhibit phosphodiesterase 4 (PDE-4) as well as TNF-a to
treat chronic obstructive pulmonary disease (COPD) and
asthma.5 Because of its notable anti-inflammatory and analgesic
pharmacological profile the well known PDE-4 inhibitor
Nitraquazone (A, Fig. 1) or 3-ethyl-1-(3-nitrophenyl)-
2,4(1H,3H)-quinazolinedione6 (TVX-2706) has been used as
a starting template to develop potent inhibitors with improved
pharmacological properties.7 In our effort to develop novel
inhibitors of TNF-a we thought that A could be an interesting
starting point. Thus the possible areas of interaction as
hydrogen bond acceptors for A were analyzed. Subsequent
manipulation of the N-aryl amide moiety of A without
disturbing the possible areas of interactions afforded a
new heterocyclic structure i.e. 6,6a-dihydroisoindolo[2,1-a]-
quinazoline-5,11-dione (C via B, Fig. 1) that was explored as
a basic scaffold for the discovery of novel TNF-a inhibitors.
While as an individual class of heterocycles 2-aryl-2,3-
dihydroquinazolin-4(1H)-one8 and 2-arylisoindolin-1-one9
are well known in the literature their combined form i.e.
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones are rather
uncommon. One of the major challenges and aim of the
present work was therefore to develop a suitable methodology
leading to the heterocyclic structure C. We envisaged that the
Multi-component reactions (MCRs)1 allow simple and flexible
assembly of three or more building blocks in a user-friendly
one-pot operations to form a product containing substantial
elements of all the reactants. Through the generation of a
combinatorial library MCRs often provide convergent, atom-
economic, expedient and eco-friendly chemical methods for
the discovery of new chemical entities (NCEs) required by
pharmaceutical and agrochemical industries.2 While MCRs
like the Strecker, Passerini, Ugi, Pauson–Khand and Biginelli
reactions as well as the Mannich condensation have become
powerful tool in organic synthesis their usage for the
construction of heteroaryl-based structures is not common.3
Incidentally, most of the drugs currently in the market
or in the clinical trials contain heterocyclic structures. Thus
development of new MCR leading to novel heteroaryl
derivatives is of high interest both in academic and industrial
organizations.
TNF-a (Tumor Necrosis Factor-alpha), one of the key
cytokine mediators involved in the inflammatory response is
used as a marker for many inflammatory disorders.4a The
biological importance of TNF-a inhibition in the treatment of
inflammatory disorders such as rheumatoid arthritis, Crohn’s
disease, and ulcerative colitis became apparent with the discovery
and use of infliximab, a monoclonal antibody directed against
a Custom Pharmaceutical Services, Dr Reddy’s Laboratories Limited,
Bollaram Road Miyapur, Hyderabad, 500049, India
b PG and Research Department of Chemistry,
Jamal Mohamed College, Tiruchirappalli, 620020Tamil Nadu, India
c Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad, 500046, India
d Department of Chemical Sciences, Indian Institute of Science
Education and Research, KolkataWest Bengal, 741252, India
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, results of docking
study. CCDC 807140–807141. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c1cc10715a
Fig. 1 Design of novel inhibitors of TNF-a/PDE-4B.
c
5010 Chem. Commun., 2011, 47, 5010–5012
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Table
1
Effect of reaction conditions on MCR using isatoic
Table
2
Green synthesis of 6-substituted-6,6a-dihydroisoindolo-
anhydride (1) with aniline (2a) and 2-formylbenzoic acida (3)
[2,1-a]quinazoline-5,11-dionesa
Entry Amines (2)
Products (4)
Time (h) Yieldb (%)
1
15
12
15
72
93
85
Entry
Solvent
T/1C
Time (h)
% Yieldb
1
2
3
4
5
6
7
EtOH
80–85
80–85
60–65
25
100
40
15
15
24
24
8
72
70
i-PrOH
Methanol
Methanol
1,4-Dioxane
DCM
40
2
3
MeNH2 2b
EtNH2 2c
50c
60
24
15
—
75d (70)e
EtOH
80–85
a
All the reactions were carried out using isatoic anhydride
1
(6.13 mmol), aniline 2a (6.7 mmol) and 2-formylbenzoic acid 3
(6.74 mmol) and anhydrous CSA (0.31 mmol) in solvent
a
(10 mL). Isolated yield. Yield of 2-amino-N-phenylbenzamide.
b
c
d
Montmorillonite K10 (5% w/w) was used in place of CSA.
Recovered Montmorillonite K10 was used.
e
4
12
80
one-pot three-component synthesis of 2,3-dihydroquinazolin-
4(1H)-one from isatoic anhydride, ammonium acetate and an
aldehyde could be handy in the present case. Thus to maintain
the ‘‘R’’ group of C the ammonium acetate was replaced by
appropriate amines and 2-formylbenzoic acid was chosen as a
third component that would eventually allow the construction
of the fused isoindolin-1-one ring. To this end we have
observed that treatment of isatoic anhydride (1) with aniline
(2a) and 2-formylbenzoic acid (3) in the presence of commercially
available anhydrous (+)-camphor-10-sulfonic acid (CSA) in
ethanol at 80–85 1C produced 6-phenyl-6,6a-dihydroisoindolo-
[2,1-a]quinazoline-5,11-dione (4a) as the only product (entry 1,
Table 1). Among the other solvents examined i-PrOH was
found to be equally effective (entry 2, Table 1) whereas MeOH
provided 4a in low yield (entry 3, Table 1). Notably, 2-amino-
N-phenylbenzamide was obtained at 25 1C in MeOH indicating
the intermediacy of this compound in the present MCR. The
use of 1,4-dioxane and CH2Cl2 was found to be either less or
not effective (entry 5 & 6, Table 1). The MCR did not proceed
in the absence of CSA, indicating the vital role played by the
catalyst. The MCR was sluggish when p-TSA was used in
place of CSA. To develop an environmentally friendly process
we examined the use of montmorillonite K10 as a catalyst and
observed that MCR proceeds well (entry 7, Table 1). To test
the recyclability of the catalyst, montmorillonite K10 recovered
by simple filtration was reused and the MCR afforded 4a
without affecting the yield significantly (entry 7, Table 1). The
compound 4a was characterized by the appearance of two
CQO signals at 1723 & 1686 cmÀ1 in IR and 164.7 &
163.4 ppm in 13C NMR spectra. A signal at 6.60 d in the
1H NMR and 71.5 ppm in the 13C NMR spectra confirmed the
presence of C–H group at 6a-position of 4a.10a
5
6
7
8
15
12
95
92
75
n-PrNH2 2f
8
7
7
85
84
82
92
9
10
11
8
We were pleased to find that the present green MCR
provided 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones
with a variety of substitution patterns (Table 2). The reaction
proceeded well with a variety of aliphatic and aromatic amines
to give a range of 6-substituted derivatives (Table 2). All the
(NH4)2CO3 2k
10
c
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Table 2 (continued )
Entry Amines (2)
In conclusion, a green and general synthesis of novel
6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-diones has been
accomplished via a new three component reaction involving
concurrent construction of a five and six membered fused
N-heterocyclic ring.13 This research has led to the identification
of a small molecule-based potent inhibitor of TNF-a.
KSK thanks Dr Vilas Dahanukar and the analytical group
of DRL.
Products (4)
Time (h) Yieldb (%)
12
12
78
Notes and references
a
All the reactions were carried out using isatoic anhydride
(6.7 mmol) and 2-formylbenzoic acid
1
3
1 For recent reviews, see: (a) B. B. Toure and D. G. Hall, Chem.
Rev., 2009, 109, 4439; (b) B. Ganem, Acc. Chem. Res., 2009, 42,
463.
2 For a review on the use of MCRs in drug discovery, see: C. Hulme
and V. Gore, Curr. Med. Chem., 2003, 10, 51.
(6.13 mmol), amine
2
(6.74 mmol) and Montmorillonite K10 (5% w/w) in EtOH (10 mL)
b
at 80–85 1C. Isolated yield.
3 For reviews, see: (a) J. Sapi and J.-Y. Laronze, Arkivoc, 2004, (vii),
208; (b) N. Isambert and R. Lavilla, Chem.–Eur. J., 2008, 14, 8444;
(c) J. D. Sunderhaus and S.-F. Martin, Chem.–Eur. J., 2009, 15,
´ ´
1300; (d) V. Estevez, M. Villacampa and J. C. Menendez, Chem.
Soc. Rev., 2010, 39, 4402.
4 (a) K. Pfeffer, Cytokine Growth Factor Rev., 2003, 14, 185;
(b) N. Scheinfeld, J. Dermatol. Treat., 2004, 15, 280; (c) D.
Shiu-Hin Chan, H.-M. Lee, F. Yang, C.-M. Che, C. C.
L. Wong, R. Abagyan, C.-H. Leung and D.-L. Ma, Angew. Chem.
Int. Ed., 2010, 49, 2860.
5 A. Kodimuthali, S. S. L. Jabaris and M. Pal, J. Med. Chem., 2008,
51, 5471.
6 M. I. Crespo, L. Pages, A. Vega, V. Segarra, M. Lopez,
T. Domenech, M. Miralpeix, J. Beleta, H. Ryder and
J. M. Palacios, J. Med. Chem., 1998, 41, 4021.
compounds synthesized were characterized by spectral and
analytical data and this was supported by the molecular
structure of 4j being confirmed by X-ray analysis (Fig. 2).10b
Some of the compounds synthesized were tested for their
TNF-a inhibitory potential in vitro.11 Compounds 4h–4k
showed significant inhibition of TNF-a at 10 mM whereas
the compound 4k showed dose-depended inhibition with an
IC50 value 9.33 mM (Fig. 3). This was supported by the
docking results of 4k with TNF-a protein (see ESIw) which
showed strong interactions with the hydrophobic binding
site (binding energy À8.57 Kcal/mol) consisting primarily of
glycine, leucine and tyrosine residues. The binding interaction
therefore not unexpectedly contributed mainly by hydro-
phobic and van der Waals type interactions. Since the low
potency, poor selectivity and adverse side effects are associated
with some of the small molecules based inhibitors12 the
development of new inhibitors remained a highly desirable
goal. Thus, compounds 4h–k may have medicinal value with
potential therapeutic applications.
7 J. A. Lowe, III, R. L. Archer, D. S. Chapin, J. B. Cheng,
D. Helweg, J. L. Johnson, B. K. Koe, L. A. Lebel, P. F. Moore,
J. A. Nielsen, L. L. Russo and J. T. Shirley, J. Med. Chem., 1991,
34, 624.
8 J. Chen, W. Su, H. Wu, M. Liu and C. Jin, Green Chem., 2007, 9,
972 and reference cited therein.
9 Y. Zhang, G. Yu, J. Wu and W.-M. Dai, Synlett, 2010, 1075 and
references cited therein.
10 (a) Since our attempt to prepare a single crystal of 4a for X-ray
analysis was failed hence 6-(3-chlorophenyl)-6,6a-dihydroisoindolo-
[2,1-a]quinazoline-5,11-dione was prepared (by using 1, 3 and
3-chloroaniline) the structure of which was confirmed by X-ray
analysis (see ESIw); (b) Crystal data of 4j: Molecular formula =
C22H15ClN2O2, Formula weight = 374.1, Crystal system =
Monoclinic, space group
= P21/c, a = 11.6223(6) A,
b = 7.8255(4) A, c = 19.9457(10) A, V = 1772.91(16) A3,
T = 296 K, Z = 4, Dc = 1.404 Mg mÀ3, m(Mo-Ka) =
0.71073 mmÀ1, 27 323 reflections measured, 3833 independent
reflections, 3311 observed reflections [I > 2.0s(I)], R1_obs =
0.047, Goodness of fit = 1.030. Crystallographic data (excluding
structure factors) for 4j have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 807140.
11 K. V. Parsa, L. P. Ganesan, M. V. Rajaram, M. A. Gavrilin,
A. Balagopal, N. P. Mohapatra, M. D. Wewers, L. S.
Schlesinger, J. S. Gunn and S. Tridandapani, PLoS Pathog.,
2006, 2, e71.
Fig. 2 X-ray crystal structure of 4j (ORTEP diagram). Thermal
ellipsoids are drawn at 50% probability level.
12 (a) R. P. McGeary, A. J. Bennett, Q. B. Tran, K. L. Cosgrove and
B. P. Ross, Mini-Rev. Med. Chem., 2008, 8, 1384; (b) H. Sun and
G. S. Yost, Chem. Res. Toxicol., 2008, 21, 374; (c) The TNF-a
inhibitors based on synthetic antibodies e.g. etanercept, infliximab,
and adalimumab have been approved for the treatment of
inflammatory diseases. But their uses cause serious side effects
such as eliciting an autoimmune anti-antibody response or the
weakening of the body’s immune defenses.
13 Mechanistically, the reactionseemsto proceed via 2-amino-N-
arylbenzamide intermediate generated in situ from the reaction of
1 with amine 2. The reaction of this intermediate with 2-formyl-
benzoic acid 3 provides the second intermediate the azomethine
moiety of which subsequently participates in an intramolecular
concurrent cyclization involving the carboxylic acid and amide
group to give the desired product 4.
Fig. 3 In vitro TNF-a inhibition of compounds 4 and IC50 of 4k.
5012 Chem. Commun., 2011, 47, 5010–5012
c
This journal is The Royal Society of Chemistry 2011