One pot synthesis of some new N-allyl and N-benzyl quinazolinones and their anti-inflammatory activity

Article abstract of DOI:10.1016/j.jics.2021.100033

The simple and more reliable one-pot synthesis of some novel compounds of allyl/Benzyl quinazolinone (4aa-4bd) with good yields from readily available derivatives of anthranilic acid and benzoyl chloride was also reported. Interestingly, as compared to Di

Full text of DOI:10.1016/j.jics.2021.100033

Journal of the Indian Chemical Society 98 (2021) 100033
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One pot synthesis of some new N-allyl and N-benzyl quinazolinones and
their anti-inflammatory activity
,
*
Sudharshan Reddy Sudula a, Ranjith Jala b, Kavitha Siddoju a, Jagadeesh Kumar Ega a
a Department of Chemistry Chaitanya Deemed to be University Warangal Urban, Telangana, India
b Organic &Biomolecular Chemistry Division CSIR-Indian Institute of Chemical Technology, Hyderabad, T.S, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Quinazolinones
One pot synthesis
Anti-inflammatory activity
The simple and more reliable one-pot synthesis of some novel compounds of allyl/Benzyl quinazolinone (4aa-4bd)
with good yields from readily available derivatives of anthranilic acid and benzoyl chloride was also reported.
Interestingly, as compared to Diclofenac sodium, compounds 4ac, 4ad, 4ba, 4bc and 4bd displayed remarkable
anti-inflammatory activity (Scheme 1 & Table 2).
Introduction
the targeted N-allyl and N-benzyl-quinazolinones 4aa-4bd (Scheme 1 &
Table 2).
A fair amount of analogue work has attended this area with the aim of
manufacturing effective chemotherapeutic agents. In general, this effort
has concerned the diamino heterocycle itself or the attached substituents.
On the other hand, we were interested in examining the amino groups
themselves to ascertain whether replacement of the amino group by more
or less basic groups might alter the binding of the enzyme sufficiently to
carry on profound changes in the compounds biological profile (see
Fig. 1).
Natural products enclosing quinazolinone Luotonin A (II), Rutae-
carpine (I), Chloroqualone (IV), Alloqualone (V), Tryptanthrin (III),
etc.).Represent a class of compounds of medicinal and pharmaceutical
relative importance [3,4]. Because of to their variety of biological
behavior, such as anti-cancer, diuretic, anti-inflammatory, anticonvul-
sant and anti-hypertensive activities” [5–8]. Numerous natural products
embedded for quinazolinone have been investigated in recent years
[9–17]. Medically approved as anti-cancer agents” [18–26] are the
cytotoxic alkaloid Luotonin A and its derivatives infused with quinazo-
linone moiety. Previous studies have clearly stated that Luo functions at
position with DNA topoisomerase-I [27]. Considering the effectiveness of
bioactivities of the compounds possessing Luo pharmacophore, we were
interested to synthesize novel Luo analogues and evaluated their
anti-cancer activities such as cytotoxicity, cell cycle regulation and
mechanistic aspects. Consequently, many groups were inspired to
develop new synthetic methods for the synthesis of quinazolinones by
using oxidative synthesis [1] and metal catalyst [2]. Herewith described
Chemistry
Initially, we treated 2-phenyl-4H-benzo [d] [1,3]oxazin-4-one3a (1.0
equiv) with allyl amine (1.0 equiv) and Cs2CO3 (2.0 equiv) in CH3CN at
82 ꢀC to afford the desired N-allyl quinazolinone (4aa) in good yield
(91%) after 3 h (Table 1, entry 1). Further optimization using other
organic solvents such as DMSO, toluene, 1,2- dichloroethane and THF
resulted in no improvement (Table 1, entries 2–5). The applicability of
other common bases such as K2CO3 and NaOAc were examined which
resulted in lower yields (Table 1, entries 6 and 7). Having identified the
effective conditions for synthesis of N-allyl quinazolinone4aa (Table 1,
entry 1), the versatility of the reaction was tested.
Earlier, the heterocyclic conversion of benzoxazin-4-ones to 2, 5-
disubstituted Oxazolines preceded through the in situ N-allyl-2-benza-
midobenzamide was established [27]. We then interested to expand this
methodology to synthesize some new N-allyl and N-benzyl-quinazoli-
nones directly in one-pot (Scheme 1). In this context, we started our
synthesis from the commercially available starting materials. At the
outset, the 2-amino benzoic acid derivatives 1 reacted with Benzoyl
chloride 2 in the presence of Triethylamine in MeCN at reflux tempera-
ture (82 ꢀC) for 2 h to give substituted Oxazolines [28]3. These Oxazo-
lines further treated with allyl and benzyl amine under the same reaction
conditions to yield in situ N-allyl and N-beznyl-2-benzamidobenzamide
(as monitored by TLC), which then subsequently underwent
* Corresponding author.
E-mail address: jkjagadeeshkumare@gmail.com (J.K. Ega).
https://doi.org/10.1016/j.jics.2021.100033
Received 28 January 2021; Received in revised form 16 March 2021; Accepted 19 March 2021
0019-4522/© 2021 Indian Chemical Society. Published by Elsevier B.V. All rights reserved.

S.R. Sudula et al.
Journal of the Indian Chemical Society 98 (2021) 100033
Fig. 1. Some known biologically potent quinazolinones (I–V) and designed strategy (VI).
Scheme 1. Synthesis of N-ally l and N-benzyl quinazolinones.
Table 1
Optimization of the quinazolinones reaction conditions.
.
Entry
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
CH3CN
DMSO
Toluene
DCE
THF
CH3CN
CH3CN
91
83
15
0
0
36
23
Na(OAc)2
a
Reaction conditions: 3a (0.35 mmol, 1 equiv), allyl amine (0.35 mmol, 1 equiv), Cs2CO3 (0.68 mmol, 2 equiv), solvent (2 mL) at 82 ꢀC for 3 h.
2

S.R. Sudula et al.
Journal of the Indian Chemical Society 98 (2021) 100033
Table 2
In vivo Anti-inflammatory activity of newly synthesized compounds 4aa-4bd 100 mg/kg b.wt as mean ꢁ SD (Carrageenan-induced paw edema test in rats).
Entry
Rat paw edema in mLb
(Treatment in hours)
1h
2h
3h
4h
4aa
2.42 ꢁ 0.295
11.67
2.08 ꢁ 0.310**
27.52
1.42 ꢁ 0.254**
54.48
1.02 ꢁ 0.265**
67.61
4 ab
4ac
2.24 ꢁ 0.278
1.82 ꢁ 0.297**
1.12 ꢁ 0.309**
0.98 ꢁ 0.284**
18.24
36.58
64.10
68.88
2.26 ꢁ .0267
17.51
1.91 ꢁ 0.281***
33.44
1.21 ꢁ 0.302***
61.21
0.85 ꢁ 0.262***
73.01
4ad
2.21 ꢁ 0.285
1.88 ꢁ 0.292***
1.18 ꢁ 0.275***
0.82 ꢁ 0.270***
19.34
34.49
62.17
73.96
4ba
2.11 ꢁ 0.264
22.99
1.68 ꢁ 0.289***
41.46
1.06 ꢁ 0.284***
66.02
0.72 ꢁ 0.308***
77.14
4bb
2.14 ꢁ 0.289
1.96 ꢁ 0.276***
1.09 ꢁ 0.266***
0.81 ꢁ 0.254***
21.89
31.70
65.06
74.28
4bc
2.18 ꢁ 0.308
20.40
1.72 ꢁ 0.295***
40.06
1.11 ꢁ 0.278***
64.42
0.75 ꢁ 0.249***
76.19
4bd
Control
2.16 ꢁ 0.310
1.69 ꢁ 0.306***
1.10 ꢁ 0.256***
0.78 ꢁ 0.251***
21.16
41.11
64.74
75.23
2.74 ꢁ 0.242
NA
2.87 ꢁ 0.254
NA
3.12 ꢁ 0.289
NA
3.15 ꢁ 0.291
NA
Diclofenac
Sodium
1.84 ꢁ 0.251***
1.32 ꢁ 0.254***
0.91 ꢁ 0.257***
0.52 ꢁ 0.309***
32.84
54.01
70.83
83.49
Statistically significant compared to respective control values, ***P < 0.001, **P < 0.01, *P < 0.05 (Dunnet’s test).
aDose level: test compounds (100 mg/kg b.wt), Diclofenac sodium(10 mg/kg b.wt).
bValues are expressed as mean ꢁ SD (number of animals N ¼ 6 rats).
Scheme 2. Plausible Mechanism.
intramolecular cyclization by means of cesium carbonate under the
standard conditions and afforded our targeted N-allyl and N-benzyl--
quinazolinones 4aa-4bd in good yields after 1 h.
inflammatory activity. Besides, rest of the compounds showed moder-
ate anti-inflammatory activity.
On the basis of these results, a plausible mechanism is proposed
(Scheme 2). Firstly, the regioselective addition of amine nucleophile on
benzoxazinone 3 affords a ring opened intermediate A. Further, A by
Cs2CO3 gives corresponding diimine intermediate B. which after cycli-
zation generates dihydroquinazolinone C. Intermediate C on aromatiza-
tion affords 4 with generation of H2o.
Declaration of competing interest
The authors declare no conflict of interest regarding the publication
of the article.
Acknowledgement
Anti-inflammatory activity: The anti-inflammatory activity of the
synthesized compounds were tested by injecting means of carrageen an
induced rat paw edema method [28], using Diclofenac sodium as refer-
ence drug for comparison. The results are presented in Table 2.
In conclusion, we have synthesized some novel substituted quinazo-
linones (4aa-4bd) in good yields via simple and more effective one-pot
tandem approach. The anti-inflammatory screening data of all the syn-
thesized compounds indicated that all the compounds exhibited inter-
esting activity, however with a degree of variation. Among all, the
compounds 4ac, 4ad, 4ba, 4bc and 4bd exhibited significant anti-
The authors are thankful to the Director, IICT, Hyderabad for
providing 1H NMR and 13C NMR spectra and department of Biotech-
nology as well as Microbiology, Kakatiya University, TS for providing
necessary facilities for anti-inflammatory activity studies.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://do
i.org/10.1016/j.jics.2021.100033.
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S.R. Sudula et al.
Journal of the Indian Chemical Society 98 (2021) 100033
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