Organocatalyzed Domino Synthesis of New Thiazole-Based Decahydroacridine-1,8-diones and Dihydropyrido[2,3-d : 6,5-d′]- dipyrimidines in Water as Antimicrobial Agents

Article abstract of DOI:10.1002/cbdv.201900577

Organopromoter, 2-aminoethanesulfonic acid was used to catalyze the synthesis of a series of structurally intriguing new hybrids thiazolyl acridine-1,8(2H,5H)-diones and dihydropyrido[2,3-d : 6,5-d′]dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones for the firs

Full text of DOI:10.1002/cbdv.201900577

Title: Organocatalysed Domino Synthesis of New Thiazole-Based
Decahydroacridine-1,8-diones and Dihydropyrido[2,3-d:6,5-
d']dipyrimidines in Water as Antimicrobial Agents
Authors: Manisha Rajaram Bhosle, Sayali A. Kharote, Giribala M
Bondle, Jaiprakash N. Sangshetti, Siddique A Ansari, and
Hamad M Alkahtani
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Biodiversity 10.1002/cbdv.201900577
Link to VoR: http://dx.doi.org/10.1002/cbdv.201900577

10.1002/cbdv.201900577
Chemistry & Biodiversity
Graphical Abstract
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10.1002/cbdv.201900577
Chemistry & Biodiversity
OrganocatalysedDomino Synthesis of New Thiazole-Based Decahydroacridine-1,8-
dionesand Dihydropyrido[2,3-d:6,5-d']dipyrimidines in Water as Antimicrobial Agents
Manisha R. Bhosle,a* Sayali A. Kharote,a Giribala M. Bondle,a Jaiprakash N. Sangshettib
Siddique A. Ansari,c Hamad M. Alkahtanic
aDepartment of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad
431004, Maharashtra, India
bDepartment of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy, Rafiq Zakaria
Campus, Aurangabad 431 001, India
cDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh,
Saudi Arabia. Po Box 2454, Riyadh 11451
E-mail: d.manisha11@gmail.com
Abstract
Organopromoter, 2-aminoethanesulfonic acid catalyzed synthesis of series of structurally
intriguing new hybrids thiazolyl acridine-1,8 (2H,5H)-diones and dihydropyrido[2,3-d:6,5-
d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones for the first time. 2-Aminoethanesulfonic acid
is a biobased organopromoter, used to generate four new bonds for the synthesis of new coupled
thiazole-Based decahydroacridine-1,8-diones.Superior green credentials, operational simplicity,
easy workup and recyclability of the catalyst are the key strengths of this method. Which
attributes to broad substrate scope, mild reaction conditions, short reaction time, cost
effectiveness, high atom economy and good to excellent yields make the present method a
distinct improvement over existing methods. Spectral (IR,1H NMR,13C NMR, Mass) data, and
elemental analyses confirmed the structures of the titled products. Series of thiazolyl acridine-1,8
(2H,5H)-diones and dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones
were screened for their antimicrobial activity against four bacterial and three fungal strains.
Keywords Antimicrobial; Thiazolyl decahydroacridine-1,8-diones; Dihydropyrido[2,3-d:6,5-
d']dipyrimidine; Multicomponent; Taurine
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Introduction
Organocatalysis has been one of the fastest growing areas in synthetic chemistry in the
last few years. It involved innate benefits in using small organic molecules of biological origin as
promoters, which are typically non-toxic, insensitive to moisture and air, cost-effective, easily
available, efficient and selective.[1-2] Organocatalyst corresponds to a low molecular weight
organic molecule which in stoichiometric amounts catalyzes a chemical reaction.[3-5] Bio-organic
catalysts are one of the organopromoter showing numerous excellent contributions in organic
synthesis.[6-9] Bio-organic catalyst produces a line of proprietary product compositions, based
upon its unique patented broad spectrum catalytic biochemistry, that establishes an entirely new
platform technology for the chemical industry.[10] Organopromoters when used in combination
with green solvents their real benefit are best realized.[11]
2-Aminoethanesulfonic acid (Taurine) is an organic compound that is widely distributed
in animal tissues. It is a sulfur-containing semi-essential amino acid that exists in the human
body and numerous other living creatures.[12-14] 2-Aminoethanesulfonic acid is in the zwitter
ionic shape in water and this leads to essential biological and medicinal properties. Very few
literature reports are available for 2-aminoethanesulfonic acid as catalyst. Recently Nader
Daneshvar et al used 2-aminoethanesulfonic acid as a green bio-organic catalyst for the
promotion of the Knoevenagel reaction and condensation reactions.[15,16] Silica gel supported 2-
aminoethanesulfonic acid was also reported in the oxidation reaction of sulfides to their
corresponding disulfides.[17]
The synthesis of acridine and analogues has attracted considerable attention from organic
and medicinal chemists for many years, as a number of natural sources have been reported to
have this heterocyclic nucleus. They are used in medicine and have enormous potential as
pharmaceutical agents due to their biological activities (Figure 1) such as antiviral,[18]
antibacterial,[19] anticancer,[20] anti-inflammatory activities[21] as well as efficiency in
photodynamic therapy.[22] The chemical modifications of acridines by introducing different
substitutions or heterocyclic rings were expanded the research on the structure activity
relationship to afford new insight into molecular interactions at the receptor level.[23] Thiazole
ring is a structural fragment of natural compounds such as thiamine (vitamin B1), thiamine
pyrophosphate, epothilones, carboxylase, and the large family of macrocyclic thiopeptide
antibiotics, thiostrepton and micrococcin P1.[24, 25] Thiazole derivatives are associated with a
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10.1002/cbdv.201900577
Chemistry & Biodiversity
broad spectrum of biological properties, including anticancer, antitumor, anticonvulsant,
antimicrobial, antituberculous and bacteriostatic activities (Figure 1).[26-29] Therefore we focused
on attention to club theses heterocycles in one molecular framework to synthesize new hybrids
thiazolyl acridinedione.
Figure 1: Biologically active molecules containing acridine and thiazole pharmacophore
There are many reported methods for the synthesis of acridinedione including multi-
component condensation (MCR) of various aromatic aldehydes, cyclic diketones, and various
aromatic amines in the presence of diverse catalysts Fe3O4@SiO2-MoO3H,[30] Pt NPs@rGO
nanoparticles,[31] proline,[32] benzyltriethyl ammoniumchloride,[33] Fluorotailed acidic
imidazolium salts,[34] 1-methylimidazolium trifluoroacetate [Hmim]TFA,[35] cericammonium
nitrate,[36] silica-bonded N-propyl sulfamic acid,[37] amberlyst-15,[38] carbon-based solid acid,[39]
4-dodecylbenzenesulfonic acid,[40] and Vitamin B1.[41] Acridinediones are also synthesized by
conventional heating in organic solvents and under MW irradiation.[42] However, all these
methods have not been entirely satisfactory, owing to various side-effects associated with them
viz., unsatisfactory yield, long reaction times, laborious work-up procedures, the requirement for
special apparatus and harsh reaction conditions.
Consequently, in our continued pursuit towards the development of novel green synthetic
routes for the construction of biologically important clubbed heterocycles,[43-46] we became
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10.1002/cbdv.201900577
Chemistry & Biodiversity
interested in the design of a new eco-friendly, efficient and versatile one pot multicomponent
tandem synthesis of new hybrids thiazolyl decahydroacridine-1,8-dionesand dihydropyrido[2,3-
d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones by using 2-aminoethanesulfonic acid as
bio-organic promoter in water and evaluated for their antimicrobial activity.
Result and Discussion
Chemistry
The basic requirement for the synthesis of these hybrids was the availability of the 4-((2-
phenylthiazol-4-yl)methoxy)benzaldehyde (4). The synthesis of 4 (Scheme 1) was initiated by
condensation of thioacetamide (1) and 1,3-dichloro acetone (2) in ethanol at reflux temperature.
The resulting chloromethyl thazole (3) was then condensed with 4-hydroxy benzaldehyde in
DMF/K2CO3 at room temperature for 5-6 h and obtained 4-((2-phenylthiazol-4-
yl)methoxy)benzaldehyde (4) in 96 % yield.[47]
Scheme 1 Synthesis of4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde 4
To begin with, the one-pot synthesis of thiazolyl decahydroacridine-1,8-dione, was
performed, whereby, well stirred solution of 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde
(4a) (1 mmol), cyclohexadione (2) (2 mmol) and aniline (3a) (1 mmol) was considered as model
reaction.
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Scheme 2 Synthesis of3,3,6,6-tetramethyl-10-phenyl-9-(4-((2-phenylthiazol-4-
yl)methoxy)phenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione7a
To design more environmentally benign protocols, together with catalysts, there is need
of cautious selection of the medium. Use of water as the reaction medium represents the most
promising option in the search for cleaner, cheaper and more efficient technologies for organic
transformations.[48-50] However, the implementation of aqueous media in organic reactions is
often limited in scope due to the poor solubility of the organic precursors. To address this
solubility issue, we sought to utilize different catalysts like β-Cyclodextrin, CTAB,
tris(hydroxymethyl)aminomethane (THAM), p-TSA and 2-aminoethanesulfonic acid for the
model
reaction(Scheme
2).
The
reaction
mixture
of
4-((2-phenylthiazol-4-
yl)methoxy)benzaldehyde (4a), cyclohexadione (2) and aniline (5a) was stirred at room
temperature in water using above catalysts and obtained titled product thiazolyl
decahydroacridine-1,8-dione 7a, with 58, 62, 35, 59 and 73 % yield in 60 min. respectively
(Table 1, entries 1-5). Therefore, considering the effective catalytic activity of 2-
aminoethanesulfonic acid and for utilization of its applications in organic transformations, 2-
aminoethanesulfonic acid was preferred as a catalyst of choice for subsequent optimization
studies.
In order to improve the yield and rate of reaction, the effect of catalyst concentration and
temperature was also investigated. To determine the exact requirement of catalyst for the
reaction, we investigated the model reaction using different concentrations of 2-
aminoethanesulfonic acid such as 10, 20, 30, and 40 mol %. During this, formation of the
product was observed in 55, 73, 94 and 94% yield, respectively (Table 1, entry 6). This
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10.1002/cbdv.201900577
Chemistry & Biodiversity
indicated that 30 mol % of 2-aminoethanesulfonic acid was sufficient to carry out the reaction
smoothly.
Model reaction in 2-aminoethanesulfonic acid at reflux was found to proceed with
excellent yield (94%) to obtained thiazolyl decahydroacridine-1,8-dione 7a in 60 min (Table 1).
o
As temperature increased 40, 60, 80, 100 C the yield of the product was also increased (71, 74,
90, 94 %). As expected, when the temperature was low, the catalytic system showed very poor
activity, furnishing the desired product in low yields (Table 1, entry 1). However, on further
raising the temperature, the yield was increased.
To evaluate the effect of solvent, model reaction was further performed using 2-
aminoethanesulfonic acid in ethanol, water, ethanol:water (1:1), methanol, acetonitrile,
chloroform and dichloromethane as solvent. Chloroform and dichloromethane did not bring the
reaction to completion (Table 1, entry 7), but in contrast acetonitrile and methanol found to
furnish the product in a moderate yields (Table1, entry 6). Reaction in ethanol and aqueous
ethanol resulted in good yields 66% and 68%, respectively. Whereas, water brought the reaction
to completion efficiently to furnish the product in excellent 94% yield (Table 1, entry 5).During
the studies on the effect of the reaction medium, it was truly gratifying to notice an appreciable
increase in the yield of the desired product, 7a with the choice of water as the reaction medium.
The reason for this result could be referred to the solubility of taurine. Since taurine is only
soluble in water, use of ethanol removes this reagent from the homogeneous phase of the
reaction.
Efficient recovery and reusability of the catalyst are other important features of our
proposed protocol. Since 2-aminoethanesulfonic acid is soluble in water, it was easily separated
from the products by simple filtration. The filtered solution was evaporated and thus obtained 2-
aminoethanesulfonic acid reused for next two consecutive cycles for the synthesis of 7a. As
shown in there recyclability graph of catalytic efficiency of 2-aminoethanesulfonic acid, the
isolated yields were almost similar until the third recycling (Figure 2). Recycled 2-
aminoethanesulfonic acid was confirmed by FT-IR spectrum which determines structural
information about the molecule. No change was observed in the IR spectra of 2-
aminoethanesulfonic acid before the reaction and after third recycle (Figure 3).
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Chemistry & Biodiversity
Yield
Catalyst Recovery
94 94
93
92
91
90
90 90
Run III
Native
Run I
Run II
Figure 2 Recycle and recovery of 2-aminoethanesulfonic acid and its effect on yield.
3500
3000
2500
2000
1500
1000
3500
3000
2500
2000
1500
1000
Wavenumber cm-1
Figure 3 FT-IR spectra of 2-aminoethanesulfonic acid. Above Blue color: Fresh catalyst; Below
Red color: After III recycle recovered catalyst
With optimized conditions in hand, we attempted to widen the scope of the designed
protocol by reacting various substituted amines (aromatic and heterocyclic) with 4-((2-
phenylthiazol-4-yl)methoxy)benzaldehyde (4) and 5,5-dimethyl-1,3-cyclohexanedione under
aqueous medium in the presence of 2-aminoethanesulfonic acid. Pleasingly, in all cases, these
components reacted successfully to form the corresponding thiazolyl decahydroacridine-1,8-
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10.1002/cbdv.201900577
Chemistry & Biodiversity
diones (7a-n) in good yields (Scheme 3). The results are summarized in Table 2. The results
clearly revealed that the amines with electron-donating and electron-withdrawing functional
groups at different positions reacted with 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde (4)
and 5,5-dimethyl-1,3-cyclohexanedione smoothly and gave the corresponding product in good to
excellent yields. The products were obtained in pure form, which avoided complicated
purification operations, thus allowing the saving of both solvents and reagents.
Scheme 3 Synthesis of 10-(4-substituted phenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4
yl)methoxy)phenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione 7a-n
In addition, this procedure was successfully extended to synthesis of new thiazolyl
dihydropyrido[2,3-d:6,5-d']dipyrimidines (9a-k) by the cyclocondensation of 4-((2-
phenylthiazol-4-yl)methoxy)benzaldehyde (4), barbituric acid (8) and aromatic amines (6a-k)
(Scheme 4) using 2-aminoethanesulfonic acid as bio organopromoter in water.2-
Aminoethanesulfonic acid catalyses the reaction efficiently and obtained desired thiazolyl
dihydropyrido[2,3-d:6,5-d']dipyrimidines (9a-k) in good to excellent yields with short reaction
time (Table 3).
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Scheme 4 Synthesis of10-(substituted phenyl)-5-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-
9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones 9a-k
Plausible Mechanism of reaction
A probable mechanistic pathway for the formation of 1,8-decahydroacridine-1,8-
dionesderivatives catalyzed by the 2-aminoethanesulfonic acid is outlined in Scheme 5. 2-
aminothanesulfonic acid is a natural, green and commercially available amino acid containing a
sulfonic acid group, in the acceleration of organic reactions.
The rate acceleration of this one pot four component cyclocondensation leading to N-
substituted 1,8-decahydroacridine-1,8-diones is attributed to unique role of 2-aminothanesulfonic
acid as a bifunctional donor-acceptor reagent and has binding capacity. Stronger hydrogen-
bonding capabilities of 2-aminothanesulfonic acid might be assisting to enhance electrophilic
character of carbonyl carbons of the reactants, viz; aldehydes and intermediate. It might also be
increasing the rate of in situ formation of carbanion from dimedone. They may be causing rate
acceleration resulting in high yields of the desired N-substituted 1,8-decahydroacridine-1,8-
diones.
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Scheme 5 Plausible reaction mechanism for the synthesis of thiazolyl decahydroacridine-1,8-
diones7a-n
Antimicrobial activity
Newly synthesized thiazolyl decahydroacridine-1,8-diones (7a-n) and dihydropyrido[2,3-d:6,5-
d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones (9a-k) were tested for the antimicrobial activity
against four pathogenic bacteria and three fungi including, Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus, Bacillus subtilis, Candida albicans, Aspergillus Niger and
Aspergillus Flavus in vitro using Ampicillin, Ciprofloxacin and Miconazole used as positive
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Chemistry & Biodiversity
controls. The results are summarized in Table 4 and 5. Among the series thiazolyl
decahydroacridine-1,8-diones, compounds 7a, 7b, 7d, 7f, 7g, 7h, 7j, 7l and 7nshowed significant
antibacterial activity against Staphylococcus aureus and Bacillus subtilis. Among the thiazolyl
dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones (9a-k) compounds 9d,
9f, 9i and 9k exhibited good inhibitory activity against selected all bacterial stains. Both the
series of compounds showed poor activity against fungal strains when compared with standards.
Table1 Optimization of the reaction conditions for the synthesis of thiazolyl decahydroacridine-
1,8-dione7a
Entry Catalyst
Solvent
Catalyst
Loading
(mol%)
Time
(h)
Yield (%)b
1
2
3
4
5
6
β-Cyclodextrin
CTAB
THAM
p-TSA
2-Aminoethanesulfonic acid
2-Aminoethanesulfonic acid
H2O
20
20
20
20
20
1
1
1
1
1
58
62
35
59
H2O
H2O
H2O
H2O
H2O
73
10, 20, 30, and 1
40
55, 73, 94 and 94
7
2-aminoethanesulfonic acid (40, H2O
60, 80, 100 oC)
30
1
71, 74, 90, 94
8
9
2-Aminoethanesulfonic acid
2-Aminoethanesulfonic acid
EtOH
EtOH:H2O
(1:1)
30
30
1
1
66
68
10
11
12
13
14
2-Aminoethanesulfonic acid
2-Aminoethanesulfonic acid
2-Aminoethanesulfonic acid
2-Aminoethanesulfonic acid
-
MeOH
CHCl3
CH3CN
DCM
30
30
30
30
-
1
1
1
1
42
No reaction
36
No reaction
No reaction
H2O
13
aReaction Conditions: 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (1) (4 mmol), Aniline (4 mmol), dimedone
(8 mmol), Water (15 mL), 80ºC bIsolated yield
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Table 2 Synthesis of 10-(4-substituted phenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4
yl)methoxy)phenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-diones 7a-n
O
O
O
O
N
R
N
O
N
S
Taurine
+
S
H2O, Reflux
NH2
O
2
O
R
Melting
Point
(ºC)
Sr.
Aniline
Compound
Yield (%)
No.
O
O
N
O
N
94
115-117
98-100
1
2
S
7a
O
O
N
S
O
N
89
92
CH3
7b
O
N
S
O
N
OCH3
112-114
3
4
O
7c
O
O
N
S
O
N
88
96-98
Cl
7d
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O
O
N
Br
O
N
76
79
104-106
120-122
5
6
S
7e
O
O
N
O
N
F
S
7f
O
N
O
N
75
89
87
168-170
146-148
118-120
7
8
9
NO2
SO2NH2
CH3
S
O
7g
O
O
N
O
N
S
7h
CH3
O
N
O
N
S
O
7i
OCH3
O
O
N
S
O
N
92
87
137-139
228-230
10
11
7j
OH
O
O
N
S
O
N
7k
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SH
O
O
N
S
O
N
84
146-148
12
7l
O
O
N
N
S
O
79
81
138-140
156-158
13
14
N
7m
O
O
O
N
O
N NH
S
7n
aReaction Conditions: 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde (4) (4 mmol), dimedone
(5) (8 mmol), substituted amines (6a-n) (4 mmol), 2-Aminoethanesulfonic acid (30 mol%),
Water (15 mL) Reflux
bIsolated yield
Table 3 Synthesis of10-(substituted phenyl)-5-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-9,10-
dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones 9a-k
Melting
Sr.
No.
Aniline
Compound
Yield (%)
Point
(ºC)
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O
HN
HN
O
O
NH
N
N
O
95
261-263
1
S
NH
O
9a
O
HN
HN
O
O
NH
N
N
O
CH3
95
92
91
280-282
278-280
284-286
2
3
4
S
NH
O
9b
O
HN
O
NH
N
N
O
OCH3
S
O
NH
O
9c
HN
O
HN
O
NH
N
N
O
Cl
S
O
NH
O
9d
HN
HN
O
O
O
NH
N
N
O
Br
89
86
248-250
239-241
5
6
S
NH
O
9e
HN
O
HN
HN
O
NH
N
N
O
NO2
S
O
NH
O
9f
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10.1002/cbdv.201900577
Chemistry & Biodiversity
O
HN
HN
O
O
NH
N
N
S
O
SO2NH2
87
89
250-252
7
NH
O
9g
O
HN
OCH3
O
NH
N
N
O
275-277
8
9
S
O
NH
O
9h
HN
HN
O
OH
O
NH
N
N
O
O
90
281-282
S
O
NH
O
9i
HN
HN
O
O
O
NH
N
N
N
S
79
86
264-266
267-269
10
11
NH
O
9j
HN
O
HN
HN
O
NH
O
N
S
O
N NH
NH
O
9k
N
O
aReaction Conditions: 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (4) (4 mmol), barbituric
acid (5) (8 mmol), substituted amines (6a-k) (4 mmol), 2-Aminoethanesulfonic acid (30 mol%),
Water (15 mL) Reflux
bIsolated yield
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10.1002/cbdv.201900577
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Table 4 MIC values of 10-(4-substituted phenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4
yl)methoxy)phenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-diones 7a-n after antimicrobial
screening
Compound
MIC Values in µg/mL[a]
MIC Values in µg/mL[b]
Antifungal Activity
Antibacterial Activity
Escherichia coli Pseudomonas Staphylococcus Bacillus
Candida
albicans
48.5±0.36
Aspergillus Aspergillus
aeruginosa
98.0± 0.31
188.4± 0.60
178.4± 0.24
ND
225.7± 0.38
178.1± 0.23
ND
aureus
subtilis
67.5± 0.85
Niger
Flavus
165.8± 0.26
107.1± 0.38
165.9± 0.04
207.3± 0.34
219.4± 0.64
199.0± 0.52
ND
107.1±0.20
181.2± 0.25
97.5± 0.41
129.7± 0.34
198.2± 0.74
146.3± 0.08
109.0± 0.51
100± 1.24
25± 1.00
79.0± 0.14
98.5± 0.08
186.3± 0.34
233.0± 0.64
ND
194.2.± 0.27
217.4± 0.09
172.6± 0.24
ND
185.4± 0.36
ND
105.6± 0.50
ND
77.3±0.22
91.5±0.37
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
108.0± 0.61 125.1±0.22 182.0±0.36 198.2±0.34
175.1± 0.38 102.1±0.33 142.1±0.66 138.3±0.88
204.1± 0.93 165.5±0.74 157.5±0.65 118.6±0.07
ND
216.4± 0.75 212.0±0.76 195.4±067
241.3±0.70
91.22± 0.40 ND
144.7± 0.16 ND
168.7± 0.55 225.1±0.03 192.2±0.40 160.5±0.98
ND 192.3±0.56 ND 238.1±0..58
272.5± 0.14 231.0±0.38 251.7±0.64 183.4±0.43
201.1± 0.30 196.1±0.17 187.4±0.62 175.3±0.58
161.1± 0.94 245.3±0.58 243.7±0.32 205.1±0.67
250± 0.88
50± 0.96
-
240.1±0.24 198.3±22
205.1±0.38
229.3±0.87
208.7±0.81 265.7±0.24 193.1±0.30
118.3±0.45
ND
239.1±0.21 243.3±0.71
ND 193.7±0.54
108.0± 0.97
182.7± 0.54
97.6± 0.22
165.3± 0.34
140.6± .37
100± 2.14
25± 1.15
-
131.0± 0.22
250± 2.99
50± 1.44
-
7n
-
-
-
-
Ampicillin
Ciprofloxacin
Miconazole
-
-
-
25±1.17
25±1.11
12.5±0.98
[a]No activity reported up to 400 µg/mLfor antibacterial
[b]No activity reported up to 250 µg/mLfor antifungal, ND: No activity detected
Data are presented as mean±SD, n=3
Table 5 MIC values of 10-(substituted phenyl)-5-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-
9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones 9a-k after
antimicrobial screening
MIC Values in µg/mLa
Antibacterial Activity
MIC Values in µg/mLb
Antifungal Activity
Compound
Escherichia
coli
Pseudomona Staphylococ
Bacillus
subtilis
Candida
albicans
Aspergillus Aspergillus
saeruginosa
cus aureus
Niger
Flavus
ND
101± 0.45
93± 0.08
85± 0.24
48±0.34
38±0.47
90±0.31
84±0.22
55±0.26
107±0.22
131±0.24
46±0.34
103±0.38
9a
9b
9c
9d
9e
9f
130± 0.24
ND
187.3± 0.64
98± 0.30
75± 0.36
191± 0.34
57± 0.11
ND
115.7± 0.27
67± 0.41
168.1± 0.47
ND
64±0.53
78±0.39
ND
49±0.08
23±0.72
ND
97± 0.57
179± 0.38
76± 0.09
ND
82± 0.33
130± 0.63
164± 0.31
135± 0.60
1981± 0.38
72.1± 0.51
101± 0.17
216± 0.34
31±2.20
39±0.11
106±0.22
44.1±0.54
41±0.90
155±0.76
9g
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190± 0.06
174± 0.13
178.1± 0.57
91± 0.22
ND
ND
68±0.21
243±0.38
32±0.47
43.1±0.55
-
37±0.10
105±0.71
91±0.40
62.9±0.36
-
28±0.72
136.7±0.37
37±0.71
29±0.88
-
9h
ND
129.6± 0.17
68± 0.34
ND
9i
76± 0.85
68± 0.17
100± 1.24
111± 0.62
66.0± 0.74
250± 0.88
9j
9k
44± 0.92
98.1± 0.64
250± 2.99
100± 2.14
Ampicillin
Ciprofloxac
in
Miconazole
25± 1.00
25± 1.15
50± 1.44
-
50± 0.96
-
-
-
-
-
-
25±1.17
25±1.11
12.5±0.98
[a]No activity reported up to 400 µg/mL
[b]No activity reported up to 250 µg/mL, ND: No activity detected
Data are presented as mean±SD, n=3
Experimental
Reagents and instrumentation
All the chemicals used were of laboratory grade. Melting points of all the synthesized
1
compounds were determined in open capillary tubes and are uncorrected. H NMR spectra were
recorded with Bruker Avance 400 and Bruker Topspin spectrometer operating at 400 and
700MHz using CDCl3 and DMSO solvent and tetramethylsilane (TMS) as the internal standard
and chemical shift in δ ppm Mass spectra were recorded on a Sciex, Model; API 3000
LCMS/MS Instrument. CHNS Analysis was performed on Thermofisher Flash EA112 series
Analyser. The purity of each compound was checked by TLC using silica-gel, 60F254 aluminum
sheets as adsorbent and visualization was accomplished by iodine/ultraviolet light.
Synthesis of 2-phenyl-4-chloromethylthiazole 3
In the first step, 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde (4) was prepared according to
the method already reported in our previous publication.35Thiobenzamide (1)(10 mmol) and 1,3-
dichloro acetone (2) (10 mmol) were dissolved in ethanol. The reaction mixure was refluxed.
The progress of the reaction was monitored by TLC. After 4h of the reflux, reaction mixture was
cooled and solvent was removed under vacuum. The reaction residue was then poured on
crushed ice. Thus obtained solid was filtered, washed with water, and crystallized from ethanol.
Yield: 98%, M.P. 61-63oC.[47]
Synthesis of 4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde 4
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A mixture of chloromethylthiazole (3) (10mmol), powdered potassium carbonate (20 mmol), and
4-hydroxybenzaldehyde (10 mmol) was added to N,N-dimethylformamide (20-30 mL). The
reaction mixture was then stirred for 5-6 hr at r.t. After completion of the reaction, the reaction
mixture was poured on crushed ice. Thus obtained solid was filtered, washed with water, and
crystallized from ethanol. Yield: 97%, M.P. 100-102oC.
General Procedure for the synthesis of 10-(4-substituted phenyl)-3,3,6,6-tetramethyl-9-(4-
((2-phenylthiazol-4 yl)methoxy)phenyl)-3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-diones
7a-n
A mixture of 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde (4) (1 mmol) and5,5-
dimethylcyclohexane-1,3-dione (2) in water (20 mL) containing 2-aminothanesulfonic acid (30
mol%) was refluxed for 15 min. After that substituted anilines (3a-n) (1 mmole) was added and
refluxed at 100 ̊C. Progress of the reaction was monitored by thin layer chromatography using
ethyl acetate:hexane (3:7) as solvent. After 60 min reaction mixture was cooled. Thus obtained
solidwas filtered, dried and purified by crystallization.
General procedure for the synthesis of 10-(substituted phenyl)-5-(4-((2-phenylthiazol-4-
yl)methoxy)phenyl)-9,10-dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-
tetraones 9a-k
A mixture of 4-((2-phenylthiazol-4-yl)methoxy)benzaldehyde (4)(1 mmol) and barbituric acid(2)
in water (20 mL) containing 2-aminothanesulfonic acid (30 mol%) was refluxed for 15 min.
After that substituted anilines (3a-k) (1 mmole) was added and refluxed at 100 ̊C. Progress of the
reaction was monitored by thin layer chromatography using ethyl acetate:hexane (3:7) as solvent
system. After 60 min reaction mixture was cooled. Thus obtained solid was filtered, dried and
purified by crystallization.
4-((2-Phenylthiazol-4-yl)methoxy)benzaldehyde 4[47]
IR (ATR, υ cm-1) Characteristic absorptions: 3117 (Ar-H stretch), 2830 (-C-H stretch), 1745
(C=O) and 1266 (C-O-C stretch). 1H-NMR (400 MHz, DMSO, δ ppm):5.33 (s, 2H, CH2), 7.14-
7.50 (m, 6H, Ar-H and thiazolyl-H), 7.82-8.00 (m, 4H, Ar-H) and 9.89 (s, 1H, -CHO). MS
(Scanning mode, ESI+): m/z (% intensity): 295.9 (M+, 100)
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9-(4-((2-Phenylthiazol-4-yl)methoxy)phenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-10-
phenylacridine-1,8(2H,5H,9H,10H)-dione 7a
IR (ATR, υ cm-1) Characteristic absorptions: 3048, 2948, 2870, 1663, 1578, 1381, 1221, 882,
820, 783, 615.1H-NMR (400 MHz, DMSO, δ ppm): 0.82 (s, 3H, CH3), 0.86 (s, 3H, CH3), 0.95-
0.96 (m, 6H, CH3), 2.15-2.45 (m, 8H, CH2), 5.21 (s, 2H, CH2), 5.34 (s, 1H, CH), 6.89-7.96 (m,
13
15H, Ar-H); C NMR (176 MHz, CDCl3) δ 169.65, 168.74, 142.53, 141.80, 134.43, 132.90
(2C), 131.21 (2C), 130.53, 130.71 (2C), 129.87 (2C), 128.70 (2C), 127.69 (2C), 127.63, 125.82
(2C), 126.43 (2C), 124.74 (2C), 115.89, 114.31, 77.65, 66.76, 50.24, 49.65 , 44.21, 29.72; MS
(Scanning mode, ESI+): m/z 615.5 (M+); Anal. calcd. For C39H38N2O3S: N, 4.56; C, 76.19; H,
6.23; S, 5.22 Found: N, 4.60; C, 76.13; H, 6.28; S, 5.21%.
10-(4-Methylphenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione 7b
IR (ATR, υ cm-1)Characteristic absorptions: 3053, 2959, 2868, 1670, 1582, 1367, 1245, 891,
834, 786, 617;1H NMR (700 MHz, CDCl3δ ppm):0.83-0.85 (m, 6H, CH3), 1.19-1.27 (m, 9H,
CH3), 2.07-2.21 (m, 4H, CH2), 2.27-2.51 (m, 4H, CH2), 5.25 (s, 2H, CH2), 5.38 (s, 1H, CH),
6.93-7.05 (m, 5H, Ar-H),7.06-.47 (m, 8H, Ar-H), 7.98 (d, 2H, J=8 Hz, Ar-H);13C NMR (176
MHz, CDCl3) δ 169.78, 168.51, 142.32, 141.78, 134.56, 132.23 (2C), 131.56 (2C), 130.87,
130.08 (2C), 129.93 (2C), 128.97 (2C), 127.89 (2C), 127.34, 125.76 (2C), 126.60 (2C), 124.86
(2C), 115.77, 114.39, 77.24, 66.47, 50.26, 49.92 , 44.61, 29.32, 27.43; MS (Scanning mode,
ESI+): m/z 629.3 (M+); Anal. calcd. For C40H40N2O3S: N, 4.45; C, 76.40; H, 6.41; S, 5.10 Found:
N, 4.48; C, 76.38; H, 6.50; S, 5.06%.
10-(4-Bromophenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione 7e
IR (ATR, υ cm-1) Characteristic absorptions: 3048, 2948, 2870, 1663, 1578, 1381, 1221, 882,
820, 783, 615; 1H NMR (700 MHz, CDCl3 δ ppm): 1.08-1.25 (m, 12H, CH3), 2.27-2.52 (m, 8H,
CH2), 5.24 (s, 2H, CH2), 5.35 (s, 1H, CH), 6.59-6.97 (m, 5H, Ar-H),6.89-7.13 (m, 2H, Ar-H),
7.21-7.95 (m, 7H, Ar-H); 13C NMR (176 MHz, CDCl3) δ 169.57, 168.67, 142.32, 141.65,
141.02, 133.79, 132.78, 131.67, 130.92, 130.54 (2C), 128.29 (2C), 127.74 (2C), 126.28 (2C),
125.93 (2C), 124.10 (2C), 121.60, 120.58 (2C), 120.36, 119.61, 114.78, 77.45, 76.58, 66.45,
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Chemistry & Biodiversity
47.24, 40.87, 32.59, 29.62; MS (Scanning mode, ESI+): m/z 693.5 (M+); Anal. calcd. For
C39H37BrN2O3S: N, 4.04; C, 67.53; H, 5.38; S, 4.62 Found: N, 4.11; C, 67.54; H, 5.42; S, 4.65%.
10-(4-Nitrophenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione 7g
IR (ATR, υ cm-1) Characteristic absorptions: 3074, 2992, 2875, 1670, 1565, 1388, 1254, 879,
1
825, 791, 630; H NMR (700 MHz, CDCl3 δ ppm):0.85-0.98 (m, 6H, CH3), 1.14 (s, 3H, CH3),
1.26 (s, 3H, CH3), 2.18-2.50 (m, 8H, CH2), 5.27 (s, 2H, CH2), 5.38 (s, 1H, CH), 6.95-7.41 (m,
13
11H, Ar-H), 7.90-7.99 (m, 3H, Ar-H); C NMR (176 MHz, CDCl3) δ 169.96, 168.64, 142.69,
141.34, 140.23, 133.85, 132.91, 131.43, 130.35, 130.09 (2C), 128.94 (2C), 127.89 (2C), 126.61
(2C), 125.12 (2C), 124.75 (2C), 121.78, 120.95 (2C), 120.34, 119.63, 114.42, 77.24, 76.88,
66.46, 47.09, 40.90, 32.65, 29.75; MS (Scanning mode, ESI+): m/z 660.5 (M+); Anal. calcd. For
C39H37N3O5S: N, 6.37; C, 70.99; H, 5.65; S, 4.86 Found: N, 6.41; C, 70.93; H, 5.61; S, 4.90%.
10-(4-Hydroxyphenyl)-3,3,6,6-tetramethyl-9-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-
3,4,6,7,9,10-hexahydroacridine-1,8(2H,5H)-dione 7k
IR (ATR, υ cm-1) Characteristic absorptions: 3029, 2952, 2874, 1683, 1580, 1373, 1242, 879,
1
849, 776, 623; H NMR (700 MHz, CDCl3 δ ppm):1.13 (s, 6H, CH3), 1.26 (s, 6H, CH3), 2.33-
13
2.44 (m, 8H, CH2), 5.24 (s, 2H, CH2), 5.37 (s, 1H, CH), 6.62-7.52 (m, 14H, Ar-H); C NMR
(176 MHz, CDCl3) δ 169.48 (2C), 143.56, 141.76, 140.72, 133.02, 132.05 (2C), 131.39, 130.36,
130.16, 129.03 (2C), 127.92 (2C), 126.57, 125.65 (2C), 124.21 (2C), 123.87, 122.35, 122.21,
121.70, 117.11, 115.76, 114.57, 77.25, 66.48, 47.08, 46.46, 31.43, 29.72; MS (Scanning mode,
ESI+): m/z 631.7 (M+); Anal. calcd. For C39H38N2O4S: N, 4.44; C, 74.26; H, 6.07; S, 5.08 Found:
N, 4.43; C, 74.27; H, 6.11; S, 5.01%.
10-(4-nitrophenyl)-5-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-9,10-dihydropyrido[2,3-
d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraone 9f
IR (ATR, υ cm-1) Characteristic absorptions: 3421, 3139, 2950, 2875, 1671, 1554, 1478, 1390,
1
1223, 886, 876, 721, 667. H NMR (700 MHz, CDCl3 δ ppm): 5.38 (s, 2H, CH2).6.61 (s, 1H,
CH), 7.22 (d, 2H, J=8 Hz, Ar-H), 7.46-7.59 (m, 4H, Ar-H), 7.87-8.39 (m, 8H, Ar-H), 11.21 (s,
2H, NH), 11.33 (s, 2H, NH); 13C NMR (176 MHz, DMSO) δ 165.65 (2C), 164.39 (2C), 155.27,
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Chemistry & Biodiversity
150.76, 137.89, 133.32, 131.32, 131.42, 130.97, 129.94, 128.94 (2C), 127.21 (2C), 126.74,
124.09 (2C), 123.21 (2C), 122.01, 121.90 (2C), 120.54 (2C),119.65 (2C), 115.76, 89.41, 48.56;
MS (Scanning mode, ESI+): m/z 636.3 (M+); Anal. calcd. For C31H21N7O7S: N, 15.43; C, 58.58;
H, 3.33; S, 5.04 Found: N, 15.41; C, 58.62; H, 3.35; S, 5.02%.
N-(2,4,6,8-tetraoxo-5-(4-((2-phenylthiazol-4-yl)methoxy)phenyl)-1,2,3,4,6,7,8,9-
octahydropyrido[2,3-d:6,5-d']dipyrimidin-10(5H)-yl)isonicotinamide 9k
IR (ATR, υ cm-1) Characteristic absorptions: 3459, 3139, 2950, 2863, 1668, 1565, 1435, 1389,
1
1243, 849, 765, 690. H NMR (700 MHz, CDCl3 δ ppm): 5.30 (s, 2H, CH2), 5.37 (s, 1H, CH),
7.18-7.52 (m, 5H, Ar-H), 7.72-7.95 (m, 6H,Ar-H), 8.42-8.79 (m, 3H, Ar-H), 11.20 (s, 2H, NH),
11.29 (s, 2H, NH), 11.98 (s, 1H, NH); 13C NMR (176 MHz, DMSO) δ 164.59 (2C), 163.92 (2C),
155.67, 151.07, 136.43, 133.76, 131.76, 131.21, 130.87, 129.93, 127.96 (2C), 127.41 (2C),
126.40, 124.64 (2C), 123.12 (2C), 122.87, 121.94 (2C), 120.34 (2C), 119.75 (2C), 115.67, 89.73,
48.21; MS (Scanning mode, ESI+): m/z 635.7 (M+); Anal. calcd. For C31H22N8O6S: N, 17.66; C,
58.67; H, 3.49; S, 5.05 Found: N, 17.65; C, 58.69; H, 3.42; S, 5.09%.
Conclusion
In this work, a highly efficient and environmentally green methodology has been developed for
the synthesis of new hybrids thiazolyl acridine-1,8 (2H,5H)-dione and dihydropyrido[2,3-d:6,5-
d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones using an inexpensive and recoverable bio-
organopromoter, 2-aminothanesulfonic acid under aqueous conditions, which to the best of our
knowledge has no precedents. The reaction system was significantly affected by catalyst loading,
temperature and solvent. Therefore, the significant advantages of this procedure are low catalyst
loading, short reaction times, high to excellent yields, elimination of toxic transition metals or
organic solvents, simple workup, reusability of the catalyst and simple purification of the
products. The developed catalytic system has ample scope to be utilized further towards the
development of green methodologies. New thiazolyl acridine-1,8 (2H,5H)-dione and
dihydropyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8(1H,3H,5H,7H)-tetraones showing moderate to
good antimicrobial activity.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgement
The authors are thankful to Professor Ramrao A. Mane for his invaluable discussions and
guidance. The authors are also thankful to Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad and Central Drug Research Institute (CDRI), Lucknow for
providing necessary facilities and spectral analysis respectively. The authors SAA and HMA
acknowledges to the Deanship of Scientific Research (DSR) at King Saud University, for
funding through the Research Group Project No. RG-1439-010.
Author Contribution Statement
M. R. Bhosle conceived and designed the work. S. A. Kharote performed the experiments. G. M.
Bondle contributed samples, reagents, analysis tools and analyzed the data. J. N. Sangshetti and
S. A. Ansari carried out the antimicrobial assays. H. M. Alkahtani interpreted the spectral data.
References
[1]
I. R. Shaikh, ‘Organocatalysis: Key Trends in Green Synthetic Chemistry, Challenges,
Scope towards Heterogenization, and Importance from Research and Industrial Point of
View’, J of Catalysts 2014, 402860, 1-35.
[2]
[3]
M. Raj, V. K. Singh, ‘Organocatalytic reactions in water’, Chem. Commun. 2009, 6687-
6703.
F. Alexander, de la Torre, A. Ali,· F. Z. Galetto, A. L. Braga, J. A. C. Delgado, M. W.
Paixao, ‘One-pot organocatalytic/multicomponent approach for the preparation of novel
enantioenriched non-natural selenium-based peptoids and peptide-peptoid conjugates’,
Molec Diversity https://doi.org/10.1007/s11030-019-09923-w.
[4]
[5]
C. M. Marson, ‘Multicomponent and sequential organocatalytic reactions: diversity with
atom-economy and enantiocontrol’, Chem. Soc. Rev. 2012, 41, 7712-7722.
R. Ramesh, J. Jayamathi, C. Karthika, J. G. Malecki, A. Lalitha, ‘Innovative Green
Synthesis of 4-Aryl-Pyrazolo[5,6]Pyrano[2,3-d]Pyrimidines under Catalyst-Free
Conditions’, Poly. Arom. Comp. https://doi.org/10.1080/10406638.2018.1454968.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900577
Chemistry & Biodiversity
[6]
[7]
[8]
[9]
P. Dalko, L. Moisan, ‘Enantioselective Organocatalysis’, Angew Chemie. Int. Ed. 2001,
40(20), 3726-3748.
D. Enders, O. Niemeier, A. Henseler, ‘Organocatalysis by N-Heterocyclic Carbenes’,
Chem. Rev. 2007, 107, 5606-5655.
A. Dondoni, A. Massi, ‘Asymmetric Organocatalysis: From Infancy to Adolescence’,
Angewandte Chemie. 2008, 47, 4638-4660.
C. M. Volla, I. Atodiresei, M. Rueping, ‘Catalytic C-C Bond-Forming Multi-Component
Cascade or Domino Reactions: Pushing the Boundaries of Complexity in Asymmetric
Organocatalysis’, Chem. Rev. 2014, 114, 2390-2431.
[10] F. Nafiseh, A. R. Sardarian,‘Citric Acid: A Green Bioorganic Catalyst for One-Pot
Three-Component Synthesis of 2,3-dihydroquinazoline-4 (1H)-ones’, Curr Organocat.
2016, 3(1), 39-44(6).
[11] S. Caputo, L. Banfi, A. Basso, A. Galatini, L. Moni, R. Riva, C. Lambruschini,
‘Diversity‐Oriented Synthesis of Various Enantiopure Heterocycles by Coupling
Organocatalysis with Multicomponent Reactions’, Eur. J. Org. Chem. 2017, 6619-6628.
[12] H. Kataoka, N. Ohnishi, ‘Occurrence of Taurine in Plants’, Agric. Biol. Chem. 1986, 50,
1887-1888.
[13] G. P. Salz, D. A. Davis, ‘Taurine: a critical nutrient for future fish feeds’, Aquaculture
2015, 437, 215-229.
[14] J. M. Menzie, C. Pan, H. Prentice, J. Y. Wu, ‘Taurine and central nervous system
disorders’, Amino Acids 2014, 46, 31-46.
[15] F. Shirini, N. Daneshvar, ‘Introduction of taurine (2-aminoethanesulfonic acid) as a green
bio-organic catalyst for the promotion of organic reactions under green conditions’, RSC
Adv. 2016, 6, 110190-110205.
[16] N. Daneshvar, F. Shirini, M. Safarpoor, N. Langarudi,R. Karimi-Chayjani, ‘Taurine as a
green bio-organic catalyst for the preparation of bio-active barbituric and thiobarbituric
acid derivatives in water media’, Bioorg. Chem. 2018, 77, 68-73.
[17] H. M. Shen, H. B. Ji, H. X. Shi, Y. B. She, W. J. Zhou, H. K. Wu, W. B. Yu, N. Ai,
‘Metal-free chemoselective oxidation of sulfides to sulfoxides catalyzed by immobilized
taurine and homotaurine in aqueous phase at room temperature’, Tetrahedron Lett. 2015,
56, 4494.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900577
Chemistry & Biodiversity
[18] O. Tabarrini, G. Manfroni, A. Fravolini, V. Cecchetti, S. Sabatini, E. De Clercq, J.
Rozenski, B. Canard, H. Dutartre, J. Paeshuyse, J. Neyts, ‘Synthesis and Anti-BVDV
Activity of Acridones As New Potential Antiviral Agents’, J. Med. Chem. 2006, 49,
2621-2627.
[19] M. M. Amini, Y. Fazaeli, Z. Yassaee, S. Feizi, A. Bazgir, ‘Polytungstozincate acid: a
new and efficient catalyst for the synthesis of xanthenes under solvent-free conditions’,
Open J. Catal. 2009, 2, 40-44.
[20] M. G. Kowalewska, G. Cholewi´nski, K. Dzierzbicka, ‘Recent developments in the
synthesis and biological activity of acridine/acridone analogues’, RSC Adv. 2017, 7,
15776-15804.
[21] J. P. Poupelin, G. Saint-Rut, O. Foussard-Blanpin, G. Narcisse, G. Uchida-Ernouf, R.
Lacroix, ‘Synthesis and Antiinflammatory Properties of Bis(2-Hydroxy, 1-Naphthyl)
Methane Derivatives’, Eur. J. Med. Chem. 1978, 13, 67-71.
[22] R. M. Ion, D. Frackowiak, A. Planner, K. Wiktorowicz, ‘The incorporation of various
porphyrins into blood cells measured via flow cytometry, absorption and emission
spectroscopy’, Acta Biochim. Pol. 1998, 45, 833-845.
[23] R. J. Harrison, J. Cuesta, G. Chessari, M. A. Read, S. K. Basra, A. P. Reszka, J. Morrell,
S. M. Gowan, C. M. Incles, F. A. Tanious, W. D. Wilson, L. R. Kelland, S. Neidle,
‘Trisubstituted acridine derivatives as potent and selective telomerase inhibitors’, J Med.
Chem. 2003, 46(21), 4463-4476.
[24] T. E. Glotova, M. Y. Dvorko, A. I. Albanov, O. N. Kazheva, G. V. Shilov, O. A.
D’yachenko, ‘1,3-Dipolar cycloaddition of 3-phenylamino-5-phenylimino-1,2,4-
dithiazole to 1-acyl-2-phenylacetylenes-A new route to functionalized 1,3-thiazole
derivatives’, Russian J Org Chem. 2008, 44, 1532-1537.
[25] R. K. Yadlapalli, O. P. Chourasia, M. P. Jogi, A. R. Podile, R. S. Perali, ‘Design,
synthesis and in vitro antimicrobial activity of novel phenylbenzamido-aminothiazole-
based azasterol mimics’, Med. Chem. Res. 2013, 22, 2975-2983.
[26] T. I. de Santana, M. de O. Barbosa, P. Andr, T. de M. Gomes, A. C. N. da Cruz, T. G. da
Silva, A. C. L. Leite, ‘Synthesis, anticancer activity and mechanism of action of new
thiazole derivatives’, Eur. J Med Chem. 2018, 144, 874-886.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900577
Chemistry & Biodiversity
[27] W. Xie, Y. Wu, J. Zhang, Q. Mei, Y. Zhang, N. Zhu, R. Liu, H. Zhang, ‘Design,
synthesis and biological evaluations of novel pyridone-thiazole hybrid molecules as
antitumor agents’, Eur. J Med Chem. 2018, 145, 35-40.
[28] A. Rouf, C. Tanyeli, ‘Bioactive thiazole and benzothiazole derivatives’, Eur. J Med
Chem. 2015, 97, 911-927.
[29] C. Chen, J. Song, J. Wanga, C. Xu, C. Chen, W. Gu, H. Sun,X. Wena, ‘Synthesis and
biological evaluation of thiazole derivatives as novel USP7 inhibitors’, Bioorg Med Chem
Lett. 2017, 27, 845-849.
[30] M. Kiani, M. Mohammadipour, ‘Fe3O4@SiO2–MoO3H nanoparticles: a magnetically
recyclable nanocatalyst system for the synthesis of 1,8-dioxo-decahydroacridine
derivatives’, RSC Adv. 2017, 7, 997-1007.
[31] B. Aday, Y. Yıldız, R. Ulus, S. Eris, F. Sen, M. Kaya, ‘One-pot, efficient and green
synthesis of acridinedione derivatives using highly monodisperse platinum nanoparticles
supported with reduced graphene oxide’, New J. Chem. 2016, 40, 748-754.
[32] K. Venkatesan, S. S. Pujari, K. V. Srinivasan, ‘Proline-catalyzed simple and efficient
synthesis of 1,8-dioxo- decahydroacridines in aqueous ethanol medium’, Synth.Commun.
2009, 39, 228-241.
[33] X. S. Wang, D. Q. Shi, D. Q. Zhang, Y. F. Wang, S. J. Tu, ‘Synthesis of 9-
arylpolyhydroacridine in water catalyzed by trieth-ylbenzylammonium chloride (TEBA)’,
Chin. J. Org. Chem. 2004, 24, 430-432.
[34] W. Shen, L. M. Wang, H. Tian, J. Tang, J. J. Yu, ‘Brønsted acidic imidazolium salts
containing perfluoroalkyl tails catalyzed one-pot synthesis of 1,8-dioxo-
decahydroacridines in water’, J. Fluorine Chem. 2009, 130, 522-527.
[35] M. Dabiri, M. Baghbanzadeh, E. Arzroomchilar, ‘1-Methylimidazolium triflouroacetate
([Hmim]TFA): An efficient reusable acidic ionic liquid for the synthesis of 1,8-dioxo-
octahydroxanthenes and 1,8-dioxo-decahydroacridines’, Catal. Commun. 2008, 9, 939-
942.
[36] M. Kidwai, D. Bhatnagar, ‘Ceric ammonium nitrate (CAN) catalyzed synthesis of N-
substituted decahydroacridine-1,8-diones in PEG’, Tetrahedron Lett. 2010, 51, 2700-
2703.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900577
Chemistry & Biodiversity
[37] F. Rashedian, D. Saberib, K. Niknam, ‘Silica‐Bonded N‐Propyl Sulfamic Acid: A
Recyclable Catalyst for the Synthesis of 1,8‐Dioxo‐decahydroacridines,
1,8‐Dioxo‐octahydroxanthenes and Quinoxalines’, J. Chin. Chem. Soc. 2010, 57, 998-
1006.
[38] B. Das, P. Thirupathi, I. Mahender, V. S. Reddy and Y. K. Rao, ‘Amberlyst-15: An
Efficient Reusable Heterogeneous Catalyst for the Synthesis of 1,8-Dioxo-
Octahydroxanthenes and 1,8-Dioxo-Decahydroacridinesao’, J. Mol. Catal. A: Chem.
2006, 247, 233-239.
[39] A. Davoodnia, A. Khojastehnezhad, N. Tavakoli-Hoseini, ‘Carbon-based solid acid as an
efficient and reusable catalyst for the synthesis of 1, 8-dioxodecahydroacridines under
solvent-free conditions’, Bull. Korean Chem. Soc. 2011, 32, 2243-2248.
[40] T. S. Jin, J. S. Zhang, T. T. Guo, A. Q. Wang, T. S. Li, ‘One-pot clean synthesis of 1, 8-
dioxo-decahydroacridines catalyzed by p-dodecylbenezenesulfonic acid in aqueous
media’, Synthesis 2004, 12, 2001-2005.
[41] A. Işık, B. Aday, R. Ulus, M. Kaya, ‘One-Pot, Facile, Highly Efficient, and Green
Synthesis of Acridinedione Derivatives Using Vitamin B1’, Synth Commun. 2015, 1(45),
2823-2831.
[42] N. Hazeri, A. Masoumnia, M. Taher, M. S. Salahi, M. Kangani, S, Kianpour, S. Kiaee, J.
Abonajmi, ‘Acetic acid as an efficient catalyst for synthesis of 1, 8-dioxo-
octahydroxanthenes and 1, 8-dioxo-decahydroacridines’, Res Chem Intermed. 2015, 41,
4123-4131.
[43] M. R. Bhosle, P. Andil, D. Wahul, G. M. Bondle, A. Sarkate, S. V. Tiwari,
‘Straightforward multicomponent synthesis of pyrano [2, 3-d] pyrimidine-2, 4, 7-triones
in β-cyclodextrin cavity and evaluation of their anticancer activity’, J Iran Chem Soc.
2019, 16, 1553-1561.
[44] M. R. Bhosle, D. Nipte, J. Gaikwad, M. A. Shaikh, G. M. Bondle, J. N. Sangshetti, ‘A
rapid and green method for expedient multicomponent synthesis of N-substituted
decahydroacridine-1, 8-diones as potential antimicrobial agents’, Res. Chem. Interm.
2018, 44, 7047-7064.
This article is protected by copyright. All rights reserved.

10.1002/cbdv.201900577
Chemistry & Biodiversity
[45] C. Jadhav, L. D. Khillare, Manisha R. Bhosle, ‘Efficient sonochemical protocol for the
facile synthesis of dipyrimido-dihydropyridine and pyrimido[4,5-d]pyrimidines in
aqueous β-cyclodextrin’, Synth. Commun. 2018, 48, 233-246.
[46] M. R. Bhosle, L. D. Khillare, J. R. Mali, A. P. Sarkate, D. K. Lokwani, S. V. Tiwarie,
‘DIPEAc promoted one-pot synthesis of dihydropyrido [2, 3-d: 6, 5-d′]
dipyrimidinetetraone and pyrimido [4, 5-d] pyrimidine derivatives as potent tyrosinase
inhibitors’, New J. Chem. 2018, 42, 18621.
[47] M. R. Bhosle, J. R. Mali, U. R. Pratap, R. A. Mane, ‘An Efficient Synthesis of New
Pyrazolines and Isoxazolines Bearing Thiazolyl and Etheral Pharmacophores’, Bull.
Korean Chem. Soc. 2012, 33(6), 2012-2016.
[48] Y. Gu, ‘Multicomponent reactions in unconventional solvents: state of the art’, Green
Chem 2012, 14, 2091-2128.
[49] S. K. Rout, S. Guin, J. Nath, B. K. Patel, ‘An “on-water” exploration of CuO nanoparticle
catalysed synthesis of 2-aminobenzothiazoles,’Green Chem 2012, 14, 2491-2498.
[50] C.-J. Li, L. Chen, ‘Organic chemistry in water’, Chem. Soc. Rev.2006, 35, 68-82.
This article is protected by copyright. All rights reserved.