Facile synthesis of 1,4-benzodiazepine-2,5-diones and quinazolinones from amino acids as anti-tubercular agents

Article abstract of DOI:10.1039/c8nj04936j

A family of 1,4-benzodiazepine-2,5-diones and quinazolinones with diverse substituents at the C-3 position were synthesized via a novel, simple and convenient methodology using H₂PtCl₆ as the catalyst. The substitution at the C-3 pos

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Facile synthesis of 1,4-benzodiazepine-2,5-diones
and quinazolinones from amino acids as
anti-tubercular agents†
Cite this: New J. Chem., 2019,
43, 182
Seegehalli M. Anil,ab Rangappa Shobith,c Kuppalli. R. Kiran,a
Toreshettahally R. Swaroop,d Ningegowda Malleshab and
a
Maralinganadoddi P. Sadashiva
*
A family of 1,4-benzodiazepine-2,5-diones and quinazolinones with diverse substituents at the C-3
position were synthesized via a novel, simple and convenient methodology using H2PtCl6 as the catalyst.
The substitution at the C-3 position was varied using pre-defined amino acids as precursors. The
synthesized benzodiazepines were screened for anti-mycobacterial tuberculosis (anti-TB) activity. The
results revealed that the 1,4-benzodiazepine-2,5-diones displayed promising activity in comparison with
their open chain precursors, which indicates that the diazepine frame is vital for their activity. The
compounds 4h and 4f were found to be the lead nominees in the series with MIC values of 1.55 and
2.87 mg mLÀ1, respectively. A docking study was carried out on the enoyl acyl carrier protein to provide
a better understanding of the mechanism of action of these compounds. Based on this study, the
1,4-benzodiazepine-2,5-dione framework is a good starting point for the development of new lead drug
candidates in the treatment of multi-drug resistant tuberculosis.
Received 28th September 2018,
Accepted 12th November 2018
DOI: 10.1039/c8nj04936j
rsc.li/njc
glycoprotein IIb–IIIa antagonism agents,8 endothelin receptor
antagonists,9 HDM2-p53 interaction antagonists,10 anxiolytic
Introduction
The 1,4-benzodiazepine-2,5-dione scaffold, a subset of benzo- agents,11 antileishmanial agents12 and herbicidal agents.13
diazepinone, and its derivatives possess diverse therapeutic
On the other hand, quinazolinones are fused heterocycles,
properties and are ubiquitous in medicinal chemistry. Function- which are present in many naturally occurring alkaloids.14 They
alized benzodiazepinone structures exhibit a diverse array of are extensively explored in both the synthetic and biological
biological activities and have stimulated substantial interest in fields due to their diverse range of biological properties such as
the scientific community.1 Moreover, due to its physicochemical antimicrobial,15 antimalarial,16 anticancer,17 anti-inflammatory,18
properties, this scaffold is considered a novel non-peptide peptido- anticonvulsants,19 antitubercular,20 antidepressant21 and anti-
mimetic and exists as active core structure in many therapeutics.2 diabetic.22 Some important biologically active 1,4-benzodiazepine-
As an illustration of its significance, it is involved in the develop- 2,5-diones and quinazolinones are given in Fig. 1. Besides, amino
ment of drugs against some of the most deadly diseases in the acid/peptide conjugated heterocyclic compounds are reported to
word, such as HIV, diabetes and obesity, by inhibiting meta- have diverse biological activities.23 This prompted us to develop a
bolic pathways such as capsid assembly3 and monoacylglycerol new method involving amino acids for the construction of
acyltransferase-2.4 Also, it is present in several natural pro- heterocycles.
ducts and their derivatives are active anticholinesterase
The development of efficient and environmentally benign
agents,5 histone deacetylase inhibitors,6 melanocortin agonists,7 synthetic methodologies for biologically important heterocycles
from the same intermediate is one of the major challenges in
modern organic synthesis. A literature survey revealed that three
major strategies are used for the synthesis of 1,4-benzodiazepine-
2,5-dione. The first is the condensation of an anthranilic acid or
its derivative with a-amino acid followed by seven-membered ring
closure mediated by either acid or base.24 The second is a versatile
Ugi four-component condensation employing a substituted N-Boc
protected anthranilic acid, aldehyde, isonitrile and amine.25
a Department of Studies in Chemistry, University of Mysore, Manasagangothri,
Mysuru, Karnataka, 570 006, India. E-mail: mpsadashiva@gmail.com
b Sri Ram Chem, Plot No.: 31, JCK industrial park, Mysuru, Karnataka, 570 016, India
c Adichunchanagiri Institute for Molecular Medicine, Nagamangala,
Karnataka, 571448, India
d Department of Studies in Organic chemistry, University of Mysore,
Manasagangothri, Mysuru, Karnataka, 570 006, India
† Electronic supplementary information (ESI) available: The detailed experimental
procedures and characterization data for all compounds. See DOI: 10.1039/c8nj04936j The third approach is the base-induced rearrangement of
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Fig. 1 Selected structures of some biologically active compounds con-
taining 1,4-benzodiazepine-2,5-dione and quinazolinone motifs.
3-aminoquinoline-2,4-diones to yield 1,4-benzodiazepine-2,5-
dione.26 The first is less advantageous than the other two
methods, which generally uses harsh reaction conditions, long
reaction time and results in a low yield of products.
Scheme 1 Reagents and reaction conditions: (i) Na2CO3, ACN:H2O, 4 h,
and rt; (ii) 15 mol% H2PtCl6, THF, reflux, and 30 min; and (iii) (a) hydrated or
anhydrous H2PtCl6, DMF, reflux, and 30 min and (b) 1 N NaOH, rt, and 30 min.
Similarly, there are several methodologies available for the
synthesis of quinazolinone. Among them, the most common
approach involves amidation followed by base-mediated oxida-
tive cyclization of 2-aminobenzonitrile, 2-aminobenzoic acid or
2-aminobenzamide.27 Several related approaches are employed
through the condensation of 2-aminobenzoic acid derivatives
with imidate,28 polymer-bound isothioureas,29 guanidine,30 alkyl
or aromatic diamines31 or aldehydes32 followed by oxidative ring
closure under basic conditions or intramolecular cyclodehydra-
tion under acidic conditions. Other methods involve microwave-
promoted cyclocondensation33 or the use of catalysts/reagents
such as ionic liquids,34 T3Ps,35 PEG-4000,36 H3PW12O40Á13H2O,37
silica-supported Preyssler nanoparticles38 I2/KI,39 InCl3,40 iron,41
Pd2(dba)3/Xantphos42 and Pd(OAc)2/PPh3.43
reaction conditions for the synthesis of 3-methyl-3,4-dihydro-1H-
benzo[e][1,4]diazepine-2,5-dione (4b), initially we conducted several
screening experiments using different solvents with compound 3b
as a model substrate with 10 mol% H2PtCl6 as the catalyst. Amongst
the solvents used, THF was found to be the best solvent at its reflux
temperature with respect to reaction time and yield (30 min, 71%,
Table 1a, entry 6). However, other solvents including methanol,
Table 1 Optimization of solvent, catalyst loading and catalyst screening
(a) Solvent optimization with 10 mol% of H2PtCl6 catalyst and 3b as the
model substrate
S. no.
Solvent
Temperature
Yield in %
1
2
3
4
5
6
7
Methanol
Acetonitrile
Acetone
Toluene
Diethyl ether
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
62
34
48
53
29
71
18
Due to the considerable synthetic and biological importance
of 1,4-benzodiazepine-2,5-dione and quinazolinone derivatives,
it is necessary to discover new strategies for their synthesis. As a
part of our interest in exploring the applicability of chloroplatinic
acid as a catalyst in organic synthesis,44 herein, we report a novel
approach for the synthesis of C-3 substituted 1,4-benzodiazepine-
THF
2,5-diones and quinazolinones from isatoic anhydride and amino (b) Optimization of catalyst loading with 3b as the model substrate in
THF at reflux temperature
acid methyl esters as starting materials in a simple two-step
S. no.
Catalyst load in mol%
Yield in %
protocol. The anti-TB activity of the synthesized compounds with
a docking study correlation is also presented.
1
2
3
4
5
10
15
20
68
71
86
83
Results and discussion
Chemistry
(c) Catalyst screening with 3b as the model substrate in THF at reflux
temperature
Various functionalized precursors, 2-aminobenzamido methyl ester
(3a–m), required for this study were synthesized from commercially
available isatoic anhydride 1 and L-amino acid methyl ester
hydrochlorides (2a–m) in 61–68% yield (Scheme 1). To optimize the
S. no.
Catalyst
Catalyst load in mol%
Yield in %
1
2
Pt metal powder (Pt)
PtO2
15
15
13
39
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acetonitrile, acetone, toluene and diethyl ether failed to give the yields (59–86%). The N-unsubstituted substrates (R1 = H),
product in satisfactory yields (Table 1a, entries 1–5). It is reason- required 15 mol% of catalyst for efficient cyclization; whereas,
able to assume that the chloroplatinic acid catalyst assisted the the substituted precursor 4i (R1 = Me) required only 5 mol% for
ring closure. Further, reaction in THF at rt gave 4b in a lower yield efficient cyclization. The intermediates 3k–m failed to give the
(Table 1a, entry 7). Thus, we selected THF as the reaction medium respective products, which may be due to suppression of the
to explore the effect of catalyst concentration on the product yield catalytic activity of chloroplatinic acid by the –OH group of
and reaction time. It was found that an increase in catalyst the substrates. In contrast, the reactions with moist H2PtCl6
concentration from 5 mol% to 20 mol% resulted in an increase were too slow and/or resulted in unacceptable low conversions
in product yield and decrease in reaction time (Table 1b). Thus, for practical application for preparative purposes.
yield (86%) and reaction time (30 min, Table 1) were saturated at
15 mol% of H2PtCl6 (Table 1b, entry 3). A further increase in the high boiling point solvent would enhance the product yield.
amount of catalyst had no effect on the reaction yield and time. Consequently, when DMF was used as the solvent, unexpectedly,
We thought an increase in reaction temperature using a
Later, we screened the above reaction using 15 mol% of PtO2 quinazolinones 5c and 5e were obtained as products in 72%
and platinum metal powder (Pt) with compound 3b as a model and 78% yield, respectively (Scheme 1). The chemical compo-
substrate in refluxing THF, which gave the product in 56% and sitions of all the compounds under investigation were well-
36% yield, respectively (Table 1c). It appeared that the efficiency characterized and confirmed using standard spectroscopic and
of this cyclization depends on the acidic character of the catalyst; analytical methods. The detailed experimental procedures and
thus, H2PtCl6 was the best.
spectroscopic data of the synthesized compounds are provided
The optimized reaction conditions (15 mol% H2PtCl6 in in the supplementary material, which is in accordance with the
refluxing THF) were used for the synthesis of 4a–j in varying assigned structures of the compounds.
Table 2 In vitro anti-TB and docking studies of the compounds 3, 4 and 5
Anti-Mtb activity
MICa
Docking score
H-Bond interactions
with AAb residue
p–p stacking
interaction
Compound
R
R1
(mg mLÀ1
)
(kcal molÀ1
)
3a
3b
3c
3d
–H
–CH3
–H
–H
–H
–H
–H
50
100
25
25
25
À6.508
À6.696
–7.631
–8.279
À8.437
À8.53
Tyr-158
Tyr-158
Tyr-158
Tyr-158
Tyr-158
Tyr-158
Tyr-158
Tyr-158
Tyr-158
NF
Tyr-158
Tyr-158
Tyr-158
NF
NF
NF
NF
NF
NF
NF
–CH(CH3)2
–CH2–CH(CH3)2
–CH(CH3)–CH2–CH3
Proline derived
–CH2–Ph
–CH2–Indole
–H
3e
3f
12.5
3gc
–H
–H
–CH3
–H
–H
–H
–H
–H
–H
–H
–H
–H
6.08 Æ 0.81
À10.51
À11.1
Phe-149
Phe-149
Tyr-158
NF
Phe-149
NF
Phe-149
Tyr-158
Tyr-158
NF
Tyr-158
NF
Tyr-158
NF
Tyr-158
NF
NF
3hc
5.75 Æ 0.43
3i
3j
3k
3l
3m
4a
50
À7.636
À9.0206
À8.16
–Ph
25
25
25
25
100
25
–CH2–OH
–CH(OH)–CH3
–CH2–Ph–OH
–H
À8.105
À10.08
À6.003
À6.522
À7.972
À8.706
À8.667
À7.908
À8.855
À9.221
À7.248
À8.26
4b
–CH3
NF
4cc
–CH(CH3)2
–CH2–CH(CH3)2
–CH(CH3)–CH2–CH3
Proline derived
–CH2–Ph
–CH2–Indole
–H
5.75 Æ 0.43
Tyr-158
Tyr-158
Tyr-158
NF
NF
NF
Tyr-158
Tyr-158
Tyr-158
Tyr-158
Tyr-158
NF
4d
12.5
4e
12.5
4fc
2.87 Æ 0.21
6.08 Æ 0.81
1.55 Æ 0.05
50
50
12.5
12.5
3.12
3.12
6.25
4gc
–H
–H
–CH3
–H
–H
–H
—
4hc
4i
4j
5c
5e
–Ph
–CH(CH3)2
–CH(CH3)–CH2–CH3
—
—
—
À9.317
À8.863
À4.233
À7.279
À9.63
NF
NF
NF
Phe-149
NF
Pyrazinamide
Ciprofloxacin
Streptomycin
—
—
Tyr-158
a
b
c
MIC is defined as the minimum concentration of compound required to inhibit bacterial growth completely (0% growth). Amino acid. The
values are the means of three determinations; and NF: not formed.
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enzyme involving the type II fatty acid biosynthesis pathway of
Mtb and has been identified as a high-confidence drug target.46
Thus, we focused and docked the target compounds using the
GLIDE module of Schrodinger. The docking scores of all the
targeted compounds are listed in Table 2. The docking studies
showed that docking scores over the range of À6.003 to À11.1,
which are comparable to the standard drug pyrazinamide and
ciprofloxacin with docking scores of À4.233 and À7.279,
respectively. The higher negative docking value of the targeted
candidates is marked as efficient binding for the ligand. The
result showed that the compounds 3g, 3h, 4c, 4f, 4g and 4h
exhibited better receptor interaction with superior docking-score
values of À10.51, À11.1, À7.972, À7.908, À8.855 and À9.221,
respectively, which is in agreement with our observed in vitro
anti-TB result. The lead compounds (4c, 4f, 4g and 4h) repre-
senting the 2D and 3D dock pictures are shown in Fig. 2. Among
them, compound 4h had the highest docking score due to
having one p–p staking interaction with the amino acid resi-
dues of the protein.
The preliminary anti-TB screening of all compounds (3, 4 and 5)
was performed against Mycobacterium tuberculosis (Vaccine strain,
MtbH37Rv (ATCC-27294)) using the microplate alamarBlue assay
(MABA), as reported by Maria et al.45 The minimum inhibitory
concentration (MIC) of the compounds against the MtbH37Rv
strain and its correlation with the docking studies are presented
in Table 2. The in vitro studies indicated that six compounds
(3g, 3h, 4c, 4f, 4g and 4h) have moderate to good activity, while the
rest showed lower inhibition against Mycobacterium tuberculosis
(Mtb) in comparison with the standards. The MIC values of the
non-peptide peptidomimetics 1,4-benzodiazepine-2,5-diones
(4) were found to be better than their acyclic precursors (3),
signifying that the diazepine ring is vital for the Mtb inhibition.
The molecules 3g and 3h with phenyl and indole side chains were
the most active among the acyclic intermediates (3), showing
inhibitory concentrations of 6.08 and 5.75 mg mLÀ1 respectively.
It was observed from structural activity relationship studies that
substitution at the C-3 position enhances activity due to the
increase in hydrophobicity in the molecule. The 1,4-benzo-
diazepine-2,5-dione 4c with an isopropyl group at the C-3
position had a high docking score of À7.631 kcal molÀ1 with
an MIC value of 5.75 mg mLÀ1, which is comparable with that of
the standards. The 1,4-benzodiazepine-2,5-dione 4f derived from
proline having three fused rings, structurally resembles the
naturally occurring aszonalenin. This compound showed a high
docking score of À7.908 kcal molÀ1 and in vitro activity at
2.87 mg mLÀ1 against Mtb, which is comparable with that of
the standards. The molecule 4g with phenyl substitution at C-3,
with much more hydrophobicity, showed equal activity against
Mtb (6.08 mg mLÀ1) as its acyclic precursor 3g, leaving no
explanation for this deviation. The molecule of 4h tethered
with an indole side chain derived from tryptophan was found to
be the most active among the series examined, exhibiting a
superior docking score of À9.221 kcal molÀ1 and lowest MIC
value of 1.55 mg mLÀ1, which is much lower than that of the
standards. Notably, the 4-N-methylated benzo[1,4]diazepine-
2,5-dione 4i derived from the amino acid sarcosine showed
decreased biological activity, which may be due the presence
of N-substitution, indicating the need for an unconstrained
–CO–NH- bond in the 1,4-benzodiazepine-2,5-dione ring for
better receptor interaction. The 1,4-benzodiazepine-2,5-diones
derived from tryptophan (4h) and proline (4f) were found to be
the most efficient in the series. Thus, the presence of active
indole or fused pyrrolidine moieties on the 1,4-benzodiazepine-
2,5-dione may have added a key-boost for their activity. These
molecules can open a new door for the development of active
anti-TB drug candidates in the future.
This p–p staking interaction occurred from the aromatic ring
of the diazepine-2,5-dione (4h) to the Tyr-158 of the bacterial
Docking study
A molecular docking study was performed to support the mode
of action, interaction and preferred binding sites of the targeted
compounds with the active sites of the bacterial protein. The
enoyl acyl carrier reductase (InhA, PDB ID-2NSD) of Mtb was
Fig. 2 2D and 3D representations of the 4c, 4f, 4g and 4h molecular
chosen as the bacterial protein-bearing active site. InhA is a key docking studies with the InhA protein.
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¨
4 J. G. Barlind, L. K. Buckett, S. G. Crosby, O. Davidsson,
protein (InhA). Similarly, the benzodiazepinediones derived from
valine (4c), proline (4f) and phenylalanine (4g) also exhibited
hydrogen bonding interaction/p–p staking interaction with the
amino acid residues of the protein, which are depicted in Fig. 2.
¨
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Conclusions
In conclusion, a novel approach to 1,4-benzodiazepine-2,5-dione
and quinazolinone scaffolds from the same precursor, 2-amino-
benzamido methyl ester (3), using chloroplatinic acid under mild
reaction conditions was reported. The structure of 1,4-diazepine-
2,5-dione was varied using various L-amino acid methyl ester
hydrochlorides. Furthermore, we studied the anti-mycobacterial
activity and docking correlations of the synthesized compounds.
All the compounds were found to be active against Mtb, and
among them 4f and 4h derived from proline and tryptophan,
respectively, showed better activity compared to traditional anti-
TB drugs. The 1,4-diazepine-2,5-dione derived from the trypto-
phan 4h was found to be the most active in terms of in vitro
screening, which had an MIC value of 1.55 mg mLÀ1 with a
docking score of À10.58 kcal molÀ1. These amino acid-derived,
biocompatible, non-peptide peptidomimetics open a new door
in anti-TB drug design perspective by providing an entire range
of highly specific and non-toxic boost candidates.
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Acknowledgements
MPS thank UGC-SAP DRS III (Grant No. UGC F-540/10/DRS-III
(SAP-I) Dated 14–09-2016). Authors are grateful to Institution of
Excellence, University of Mysore, Mysuru for spectral analysis
and HPC Lab, University potential for Excellence, University of
Mysore, Mysuru for providing docking software facility. N. Rajeev
thanks UGC, New-Delhi for providing RGNF Fellowship.
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