Synthetic strategy with representation on mechanistic pathway for

European Journal of Medicinal Chemistry 123 (2016) 596e630
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Review article
Synthetic strategy with representation on mechanistic pathway for
the therapeutic applications of dihydroquinazolinones
K. Hemalatha, G. Madhumitha*
Chemistry of Heterocycles & Natural Product Research Laboratory, Department of Chemistry, School of Advanced Sciences, VIT University, Vellore, Tamil
Nadu 632014, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2016
Received in revised form
1 August 2016
Accepted 1 August 2016
Available online 3 August 2016
Dihydroquinazolinones is an important core structure reported with a wide variety of pharmacological
activities. They are capable of undergoing various transformations because of its reactivity towards
various reagents. The synthetic strategies for the functionalization and derivatization of the nucleus were
explained. The diversified pharmacological actions of this moiety were illustrated through various
biochemical pathways. The structural-activity relationship study of dihydroquinazolinones anticipated
the relationship between the various substituents and its role in the pharmacological action. The main
objective of this review is to summarize the importance of dihydroquinazolinones in the field of chemical
biology.
© 2016 Elsevier Masson SAS. All rights reserved.
Keywords:
Dihydroquinazolinones
Synthetic strategy
Functionalization
Pharmacological action
Biochemical pathway
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Synthesis and therapeutic applications of dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
2.1.
M1/M4 mAchR agonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
2.2.
MPO inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
2.3.
Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
2.4.
IRAP inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
2.5.
Antimalarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601
2.6.
Chorismate mutase inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602
2.7.
Cyclooxygenase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
2.8.
Antitumor agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 606
2.9.
5-HT2c receptor agonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
2.10.
Melanoma inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
2.11.
T-type calcium channel antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
2.12.
IMPDH inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
2.13.
Sodium/calcium exchange inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
2.14.
PDE7 inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
2.15.
p38 MAPK inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
2.16.
CDK5 inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617
2.17.
RyR agonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
2.18.
Non-nucleoside reverse transcriptase inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
2.19.
Aldosterone synthase inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Miscellaneous synthesis and applications of dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
* Corresponding author.
E-mail addresses: [email protected],
(G. Madhumitha).
[email protected]
http://dx.doi.org/10.1016/j.ejmech.2016.08.001
0223-5234/© 2016 Elsevier Masson SAS. All rights reserved.
K. Hemalatha, G. Madhumitha / European Journal of Medicinal Chemistry 123 (2016) 596e630
4.
597
3.1.
Synthesis of 2, 3-dihydroquinazolin-4(1H)-ones from N-heterocyclic carbenes of indazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
3.2.
Copper oxide nanoparticle mediated synthesis of dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
3.3.
Y(OTf)3 mediated synthesis of dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
3.4.
Boric acid mediated synthesis of dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
3.5.
Visible light mediated synthesis of dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623
3.6.
Importance of 7-fluoro-2, 2-dimethyl-2, 3-dihydroquinazolin-4(1H)one . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
3.7.
Bromination of 2, 3-dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
3.8.
Suzuki Miyaura coupling of 2, 3-dihydroquinazolinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
1. Introduction
Medicinal chemistry is an interdisciplinary area which links
both organic chemistry and biology [1]. The compounds isolated
from the natural resources [2,3] and by the synthesis [4e6] were
identified with numerous applications in various fields. In some
cases, the extracts from the natural resources were used as such
and the active components present in it either induce chemical
reaction [7e9] or biological response [10e16]. Nitrogen-rich heterocycles are present ubiquitously in natural products, pharmaceutical drugs and agrichemicals [17]. Among the various
heterocycles [18e22], quinazolinones [23e25] are of prime
importance because of its ease in synthetic feasibility from less
expensive chemicals [26]. Quinazolinones can be synthesized from
a wide variety of starting materials and also widely distributed in
natural sources [27,28]. The reviews concentrating on the synthetic
and isolated quinazolinones are maintained up to date [29,30]. The
quinazolinones can also exist in the form of 2, 3dihydroquinazolinones [31] and 3, 4-dihydroquinazolinones [32]
derivatives. The dihydroquinazolinones were found incorporated
in the marketed drugs and in the drugs undergoing clinical trial
(Fig. 1). Evodiamine [33] is an alkaloid isolated from the fruits of
Evodia rutaecarpa. It acts as a fat burner by increasing the number of
serotonin transporters in the brain and enhancing the serotonin
reuptake. Quinethazone [34], fenquizone and metolazone are
thiazide-like diuretics [35] and they are used to treat hypertension.
BIBN 4096 BS [36] is an antagonist of CGRP and it is used for
migraine headaches. DPC083, DPC961, and DPC963 are NNRTIs and
they act as a synergistic agent in the treatment of HIV-1 patient
[37]. Due to the tremendous increase in the number of research
outputs related to quinazolinone nucleus, the separate collections
of dihydroquinazolinones will be an efficient tool to assess the
properties of the nucleus. Recently enantioselective synthesis of
dihydroquinazolinone based anti-HIV agents were reviewed [38].
The main scope of this review is to elaborate the synthetic scheme
and the various reagents utilized in the functionalization pathway
of dihydroquinazolinones. The review also explains the diverse
pharmacological actions mechanistically portrayed through the
different biochemical pathways.
2. Synthesis and therapeutic applications of
dihydroquinazolinones
2.1. M1/M4 mAchR agonist
The mAchR subtypes M1 and M4 can regulate the cognitive
deficits and psychosis disorders and thereby its stimulation can
improve the symptoms of schizophrenia. The markedly available
Fig. 1. Drug moieties containing dihydroquinazolinones.
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M1 and M4 mAchR agonist, xanomeline produces unwanted
gastrointestinal stress because of its action through the M3 receptor
(Fig. 2) [39]. The importance of the M1 and M4 mAchR agonistic
activity was identified and the SAR study was performed for the
series of dihydroquinazolinone derivatives [40]. Based on the high
throughput screening, a hit compound 1 with weak M4 mAchR
agonist was selected as a potential compound. Through the earlier
reports, the pharmacophore N-carbethoxy-piperidine moiety was
thought to be essential for the M4 mAchR agonistic activity. The
change of the benzyl group of 1 by N-carbethoxy-piperidine moiety
2 activated the M2 agonist activity along with M1 and M4 mAchR
agonist activity. The removal of the methylene group 3 potentiated
the activity towards all the (M1, M2, M3, M4, M5) receptors. Therefore, the importance of the methylene group in increasing the
selectivity towards the receptor subtype was identified. The
replacement of piperidine as a linker to the various cyclic amine
linkers affected the M1 and M4 mAchR agonistic activity without
receptor subtype selectivity. The increase and decrease in the
agonist activity of the M1 and M4 mAchR were resulted for the Rsubstituted 4 pyrrolidine linker and the S-substituted 5 pyrrolidine
linker respectively. The presence of azetidine 6 lin ker also potentiated the activity. The M4-mAChR partial agonistic activity was
obtained through the replacement of N-carbethoxy piperidine by
N-carbethoxy tropane 9 moiety. This highly active compound was
tested for its pharmacokinetic profile. This compound is less
affected by liver enzymes, high cell permeability, effective brain/
blood penetration and good affinity for G-protein coupled receptors. The in vivo pharmacological profile resulted in the reversal
of METH-induced hyperlocomotion in rats and produced a potent
antipsychotic effect than the standard drug xanomeline. Finally, the
active compound was synthesized from sodium triacetoxyborohydride mediated reduction reaction between the readily available
starting material, (S)-3-(pyrrolidin-3-yl)-3, 4-dihydroquinazolin2(1H)-one 7 and ethyl 3-formyl-8-azabicyclo [3.2.1] octane-8carboxylate 8 (Scheme 1).
2.2. MPO inhibitor
MPO is an enzyme from heme peroxidase superfamily. MPO acts
a catalyst in the production of endogenous oxidant, hypochlorous
acid (Fig. 3) [41]. Hypochlorous acid also causes oxidative damage
to the host tissue. Endothelial-derived NO was utilized by MPO and
thereby reducing its bioavailability. Reduction in NO bioavailability
impairs its vasodilating and anti-inflammatory property [42]. Li
et al. [43] designed three series of compounds (12, 16 and 18) and
they were tested for their activity against MPO inhibition. The
synthesis of compound series 12 was carried out from the reaction
of isatoic anhydride 10 with various substituted alkyl amines and
carbon disulfide (Scheme 2). Another series of compounds 16 were
obtained from the reaction between benzamine 13 and thiophosgene 14 followed by reflux with alkyl hydrazine. The treatment
of thiocyanate 15 with hydrazine and chlorocarbonyl reagent
resulted in the formation of another series of compounds 18. The
SAR study concluded that halogen in 6th position and free amino
group in the 3rd position of quinazolinone were stringent for the
activity. Either change in the position of halogen/alteration of the
substituent in the place of halogen decreased the potency. Also, the
replacement of hydrogen in the amine group by other substituents
weakened the potency. An aromatic ring attached to NeN linkage of
compound 16, 18 was more active than the aliphatic chain containing compounds. The water solubility of the compound was
increased by introducing the methylene piperidinyl group 19. In
short, thioxo-dihydroquinazolinone derivatives were proved to be
effective inhibitors of MPO and can be utilized in the treatment of
inflammation-related neurodegenerative diseases and atherosclerosis. These compounds act reversibly and do not trap the enzyme
which showed its superiority over the existing inhibitors.
2.3. Antibacterial activity
Ma et al. [44] reported the synthesis of 2-substituted-3-(phenylamino)-dihydroquinazolin-4(1H)-ones through cascade reaction from isatoic anhydride 20 and phenyl hydrazine 21 (Scheme 3).
The reaction was carried out using different acid catalyst and the
most efficient catalyst was found to be bentonite. Water was found
to be the best solvent and the reaction was carried out in the
presence of ultrasonic irradiation. Optimizing the amount of catalyst concluded that the change in the concentration (1e7 mol %)
displayed no significant change in the yield. However reduction in
the concentration of bentonite (0.5 mol %) decreased the
Fig. 2. Mechanism of action of M1/M4 muscarinic acetylcholine receptor agonist.
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599
Scheme 1. Synthesis of dihydroquinazolinones as an M1/M4 mAChRs agonist.
Fig. 3. Mechanism of action of myeloperoxidase inhibitor.
percentage yield. These optimized reaction conditions were utilized in the synthesis of various 2-substituted-3-(phenylamino)dihydroquinazolin-4(1H)-ones 22. The derivatives of dihydroquinazolin-4(1H)-ones with electron-donating substituents
resulted in good yields when compared to the electronwithdrawing substituents. The in vitro antibacterial activity
against the gram-negative bacteria Escherichia coli (E. coli) was
carried out for all the synthesized derivatives. The antibacterial
potency of the highly active compounds of dihydroquinazolin4(1H)-ones was supported through the docking studies with the
biotin carboxylase enzyme. Biotin carboxylase (E. coli) is an
important enzyme involved in the fatty acid biosynthesis [45]. This
pathway is utilized by the bacteria for the membrane biogenesis.
Enzymes involved in this pathway were proved to be a valuable
target for the antibacterial drug discovery [46]. This enzyme
requires three substrates: ATP, BCCP and CO2 and they are converted into ADP, phosphate and carboxybiotin-carboxyl-carrier
protein (Fig. 4). The active compounds displayed hydrogen
bonding interactions with the amino acid residues such as Leu204,
Lys159, and Gly166 of biotin carboxylase enzyme.
2.4. IRAP inhibitor
The spiro-oxindole containing dihydroquinazolinones were
synthesized from 5-bromo-1-methyl isatin 23, isatoic anhydride 20
and substituted aniline (Scheme 4) [47]. The time taken for the
conventional synthesis can be reduced from 2 h to 10 min by carrying out the reaction under MW irradiation. The reaction carried
out in the borosilicate glass reactor by MW batch synthesis end up
with the unreacted starting material along with unidentified
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Scheme 2. Synthesis of thioxo-dihydroquinazolinone derivatives.
Scheme 3. Synthesis of 2-substituted-3-(phenylamino)-dihydroquinazolin-4(1H)-ones.
byproducts. The flow rate of 1 mL/min and the temperature of
200 C were optimized to get an isolated yield of 40% for the reaction mixture collected after 5 min. The flow rate of 0.5 mL/min
and the temperature of 120 C were utilized in the SiC glass reactor
with the CF of MW irradiation to obtain an isolated yield of 55%. The
experimentation was carried out in borosilicate reactor using the
same reaction condition and the yield was only 8%. The SiC glass
reactor was advantageous over the borosilicate glass reactor in
terms of low temperature, less complex reaction mixture and
thereby it leads to the easy way of purification. Both in the batch
synthesis and CF, there is an existence of 5-bromo-1-methyl isatin
in the reaction mixture. The reaction proceeded to completion by
increasing the equivalence of p-toluidine. Increasing the equivalence of p-toluidine 24 lead to substantial increase in the yield of
spiro-oxindole dihydroquinazolinones 25. The reaction mixture
containing 1 equivalence of 5-bromo-1-methyl isatin, 1.5
equivalence of isatoic anhydride and p-toluidine with the flow rate
maintained at 0.5 mL/min at a temperature of 160 C resulted in the
completion of the reaction with the highest yield (82%). The other
derivatives of dihydroquinazolinones were synthesized using the
optimized conditions of MW-SiC-CF method. The aliphatic amines
were not utilized in the reaction because of the drawback of protonation. IRAP is a transmembrane protein and it belongs to the
family of aminopeptidases. It is also known as an AT4 receptor, a
binding site for the peptide angiotensin IV. Angiotensin IV is the
metabolite obtained from the biologically active peptide fragment,
angiotensin II. The role of angiotensin IV is to enhance the memory
and learning. Therefore, IRAP based inhibitors are useful for
improving cognition and develop an effective treatment for dementia (Fig. 5) [48,49]. The IRAP inhibitory activity of spirooxindole dihydroquinazolinones concluded that the 5th position
bromine atom is essential for the activity. The absence of bromine
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601
Fig. 4. The role of biotin carboxylase in E. coli fatty acid biosynthesis.
Scheme 4. Synthesis of spiro-oxindole containing dihydroquinazolinones.
atom decreased the activity whereas the changes in the position of
the bromine atom lead to the inactive compound. In order to carry
out the SAR study, spiro-oxindole dihydroquinazolinones were
subjected to Suzuki Miyaura coupling reaction. The MW batch
synthesis was carried out using this optimized reaction condition.
The result concluded that 1 equivalence of halide 25, 2 equivalence
of boronic acid 26, 1.5 equivalence of DBU, 2 mol% PdCl2(dppf),
acetonitrile with 2% water was appropriate to carry out the reaction. Using this optimized condition, the coupling reaction was
carried out in the borosilicate reactor using CF mode. The reactants
got consumed at the flow rate of 0.5 mL/min at 220 C with an
isolated yield of 71%. Because of the inactive nature of Suzuki
Miyaura product 27 towards the IRAP inhibition further optimization on the reaction methodology was not carried out.
2.5. Antimalarial activity
Malaria is one of the deadliest diseases and the treatment
mainly relies on the chemotherapy [50e52]. Even though there are
potential drugs for malaria, the treatments are no longer effective
due to the evolution of resistance. The present scenario is to focus
primarily on the complicated life cycle of the parasite [53] (Fig. 6)
and develop molecules that reduce the mortality rate effectively.
Derbyshire et al. reported the effectiveness of various compounds
that acts as an inhibitor against both the liver and blood stage of
malaria [54]. The malarial drugs act through different mechanism
because of the difference in the transcriptomic and proteomic data
of the liver and blood stage parasites. Preliminary high-throughput
phenotypic blood stage malarial screening identified compounds of
different chemotype which showed more than 80% inhibition
against the malarial parasites. The compounds on further screening
identified hit with inhibition against blood stage parasites. These
selected libraries of compounds were tested for its effectiveness
against liver stage parasites in infected human hepatoma HepG2
cells. The results explored that most of the compounds were not
effective against liver stage parasites. This difference in activity was
assumed to be either due to the process such as hemozoin formation or because of the metabolic instability of the compounds towards the liver cell. Among the hits, 32 compounds were active
against the liver stage parasites and 22 compounds displayed EC50
value less than 10 mM. The potential hit containing dihydroquinazolinone 28 (EC50 ¼ 1.4 mM) were further subjected to SAR
analysis (Fig. 7). The modification in the 2nd position of dihydroquinazolinone using bulky ring system revealed no change in
activity. This confirmed that the binding site residues are not sterically hindered. The alteration of substituents on the phenyl ring of
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Fig. 5. Mechanism of action of IRAP inhibitor as cognitive enhancers.
Fig. 6. The life cycle of the malarial parasite and the site of action of dihydroquinazolinones.
the compound 28 changed the activity. The elimination of liver
stage activity was reported in the ortho substituents whereas the
para and meta substituents were well tolerated. Variation in the 3rd
position of compound 28 indicated that 3-dialkyl aminoethyl group
was essential for activity, whereas the compounds with other group
were less potent. The presence of 3-dialkyl aminoethyl group was
found to be lethal for the blood stage parasite. Any factor which
increases the liver stage activity correspondingly increased the
blood stage activity. Through the SAR study, the compound 29 was
found to be an ideal candidate for both liver and blood stage malaria parasites.
2.6. Chorismate mutase inhibitor
Fig. 7. Quinazolinones for blood and liver-stage malarial parasites.
CM is an important enzyme that catalyzes the isomeric conversion of chorismate to prephenate (Fig. 8) [55]. This is the key
reaction involved in the biosynthesis of aromatic amino acids
essential for the survival of microorganisms and plants. CM is the
only naturally occurring enzyme catalyzing pericyclic reaction.
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603
Fig. 8. The role of chorismate mutase in amino acid synthesis.
Scheme 5. Synthesis of spiro 2, 3-dihydro-quinazolin-4(1H)-ones.
Since this pathway is not present in the mammals, it can be used a
selective pathway for the treatment of tuberculosis [56]. Rambabu
et al. synthesized the series of spiro 2, 3-dihydro-quinazolin-4(1H)ones 30 using Amberlyst-15 as a catalyst and ultrasound irradiation
in the presence of oxygen (Scheme 5). The standard CM inhibitor, 4(3, 5-dimethoxyphenethylamino)3-nitro-5-sulfamoylbenzoic acid
displayed IC50 value less than 10 mM. Among the synthesized series,
compound 31 and 32 were reported with 30e35% of CM inhibition
Fig. 9. Mechanism of action of anti-inflammatory agents.
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Scheme 6. Synthesis of 2, 3-diaryl 2, 3-dihydro-1H-quinazolin-4-ones.
Scheme 7. Synthesis of 3-aryl-2-substituted 1, 2- dihydroquinazolin-4(3H)-one metal complexes.
when compared to the other derivative. Because of very few reports
on CM inhibition and increasing resistance to antitubercular therapy, these derivatives are of pharmaceutically important [57].
2.7. Cyclooxygenase inhibitors
The reactions involving the conversion of arachidonic acid to
Fig. 10. The effect of an antitumor agent on the cell cycle.
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Scheme 8. Synthesis of isoxazoline/oxazoline and dihydroquinazolinone derivatives. (i)Benzamide, p-toluene sulfonic acid monohydrate, DMA; (ii) Br(CH2)nBr, K2CO3, DMF.
prostaglandins were catalyzed by the COX enzyme. There are two
isoforms of COX referred to as COX-1 and COX-2. The COX-1 is a
constitutive enzyme and it is involved in the various physiological
processes for maintaining the homeostasis. The COX-2 is induced in
case of the inflammatory condition and it is the target for the selective NSAIDS (Fig. 9). The drugs selective for the COX-2 enzyme
can be designed on the basis of difference in the amino acid
sequence of both the enzymes [58]. Manivannan et al. designed the
molecule by applying the analog based pharmacophore design. The
quinazolinone nucleus was selected from the two well known
natural products, rutaecarpine, and tryptanthrin. The diaryl and the
methyl sulfonyl pharmacophore were chosen from the selective
COX-2 inhibitors, celecoxib, and rofecoxib. The designed compounds were categorized into methyl sulfanyl and methyl sulfonylcontaining series. The various substituted anilines 33 were
condensed with 4-thiomethyl benzaldehyde 34 to yield 4methylsulfanyl-benzylidene)-phenyl-amine 35. The oxidation of
4-methylsulfanyl-benzylidene)-phenyl-amine 35 into (4-methyl
sulfonyl-benzylidene)-phenyl-amine 37 was carried out in the
presence of oxone medium. The intermediate azomethines 35 & 37
were microwave irradiated with isatoic anhydride resulted in the
formation of 2, 3-diaryl 2, 3-dihydro-1H-quinazolin-4-ones 36 & 38
(Scheme 6). The compounds were screened for in vitro antiinflammatory activity using ovine cyclooxygenase enzyme. The
compound 40 was less active to inactive towards COX-1 enzyme
whereas highly active towards the COX-2 enzyme inhibition. The
in vivo anti-inflammatory activity of the compounds was evaluated
by carrageenan-induced rat paw edema method. The compounds
which showed positive results in the in vitro assay were correlated
with the in vivo methodology. Among the active series except 39, all
the other compounds belong to methyl sulfonyl series and they are
selective towards the COX-2 enzyme [59].
Hoonur et al. evaluated the analgesic and anti-inflammatory
activity of the 3-aryl-2-substituted 1, 2- dihydroquinazolin-4(3H)one derivatives and its various transition metal complexes. The
dihydroquinazolin-4(3H)-one ligand 43 was prepared by the
condensation of o-aminobenzoylhydrazine
41
with
2acetylpyridine 42 and followed by the treatment with benzaldehyde. The transition metal complexes 44 were obtained by
refluxing the ligand with the transition metal (II) chloride (Cu, Zn,
Mn, Ni, Co and Cd) in ethanol (Scheme 7). The analgesic activity was
evaluated by acetic acid induced writhing method. The induction of
acetic acid generated the visceral type of pain and produced
stretching of hind limbs and bending of trunks. The antiinflammatory activity was carried out by the carrageenaninduced rat paw edema method. The copper complex displayed
significant analgesic and anti-inflammatory activity than the ligand
and other metal complexes. The effectiveness of the metal complex
may be due to the metal chelation which increased the lipophilic
character [60].
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Scheme 9. Synthesis of dihydroquinazolinones containing anticancer activity.
2.8. Antitumor agents
Microtubules are the principle component of cytoskeleton and
function in the separation of chromosomes during mitosis. The two
closely related polypeptides a-tubulin and b-tubulin are polymerized to form the microtubules. Microtubules play a major role in
mitosis and the drugs which inhibit microtubule polymerization
(Fig. 10) are useful in the cancer chemotherapy [61]. The hybrid
molecules that inhibit microtubule polymerization were synthesized through the formation of ether linkage between the hydroxyl
group of 3, 5-diaryl isoxazoline/3, 5-diaryl oxazoline derivatives
and dihydroquinazolinones [62]. The synthesis of 2, 3dihydroquinazolinones 46 was carried out by the condensation of
aldehydes 45 and benzamide in the presence of p-toluene sulfonic
Fig. 11. Mechanism of action of antiobesity drugs.
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607
Scheme 10. Synthesis of 6, 6, 6- tricyclic dihydroquinazolinones. (i) (COCl)2/CH2Cl; (ii) NH3/MeOH-THF; (iii) H2/10% palladium on carbon/MeOH; (iv) N-boc-aminoacetaldehyde/
pTsOH/toluene; (v) Na2CO3 or K2CO3/allyl bromide/DMF or DMA/140 C; (vi) OsO4/NaIO4/THF-H2O; (vii) TFA/Et3SiH/CH2Cl2.
acid monohydrate. The hydroxyl group of phenyl ring in the 2nd
position of dihydroquinazolinones was reacted with dibromoalkanes for further condensation reaction to yield the product
47. The condensation reaction between 3, 5-diaryl isoxazoline/3,5diaryl oxazoline 48 and 2, 3-dihydroquinazolinones 49 using potassium carbonate afforded the hybrid compounds 50 (Scheme 8).
The compound was effective against nine types of cancer and 60
different cell lines. Based on the potency of the compound, the
other derivatives were also tested for their activity against the cell
lines. Most of the derivatives displayed significant activity against
MCF-7 (breast cancer) and PC3 (prostate cancer) cell lines. Through
the series of evaluation, the plausible mechanism of action for the
anticancer activity of the potent compound 51 was explored. The
inhibition of tubulin polymerization caused downregulation of
CDK1 and cyclin B1 protein which in turn arrested the cell cycle
progression in G2/M phase.
Roopan et al. [63] investigated the three-component reaction of
isatoic anhydride 20, heterocyclic aldehyde 52 and ammonium
acetate using different catalysts (Scheme 9). The montmorillonite
K10 was superior in terms of time and yield. Further, the cytotoxicity of the compounds was tested against the Ehrlich Ascites Carcinoma tumor cells. They displayed comparative cytotoxicity to that
of the standard drug 5-fluorouracil.
The Schiff bases [64] of 2, 3- dihydroquinazolinone derivatives
55 were obtained by refluxing one equivalent of aminobenzyhydrazide 53 with two equivalent of substituted aromatic
salicylaldehyde 54 in methanol for 2 h (Scheme 9). The compounds
were screened for their in vitro anticancer activity against MCF-10
breast cell line, normal WRL-68 hepatic cell line, and human
MCF-7 breast adenocarcinoma cell line by MTT assay. The compounds showed suppressive action against only MCF-7 breast
adenocarcinoma cell line.
Mahdavi et al. synthesized the trans-stilbene scaffold containing
N-substituted 2-arylquinazolinones with anticancer property. Isatoic anhydride 20 was used as a starting material and it was converted into anthranilamide 56 using primary amines. The
condensation of anthranilamide 56 with trans-stilbene 57 derivative using potassium carbonate resulted in the formation of 2, 3dihydroquinazolinone derivative 58. Dihydroquinazolinones 58
were converted into quinazolinones 59 using TBAB mediated reaction (Scheme 9). The synthesized series were tested for their
anticancer activity against three cancer cell lines (MCF-7, MDA-MB231, T-47D). Among the tested compounds, N-alkyl substituted
derivatives displayed higher anticancer activity than the corresponding N-aryl and N-benzyl derivatives. The bulkiest and
lengthiest N-alkyl substituents such as cyclopropyl, isopropyl and
sec-butyl showed favorable interaction in the binding pocket and
thereby it leads to the highest cytotoxic potency of the compounds
[65].
2.9. 5-HT2c receptor agonist
The drugs targeting central 5-HT system has been implicated in
the treatment of various ailments. The 5-HT2C receptor agonism is
the valid target for the treatment of obesity [66]. This was
confirmed through the 5-HT2C receptor knockout mice, which
displayed hyperphagia and developed obesity. There are three
members of the 5-HT2 receptor subclass (5-HT2A, 5-HT2B, 5-HT2C)
sharing close sequence homology. The wide distribution of 5-HT2B
subtype in the vascular and cardiac tissues causes valvulopathy. The
drugs acting through the 5-HT2A receptor subtype results in the
unwanted CNS related disorders [67,68]. To overcome these
adverse effects the molecules which are selective towards the 5HT2C receptor subtype have to be designed. The activation of hypothalamic 5-HT2C receptors results in the stimulation of POMC, a
precursor of a-MSH. The binding of a-MSH to the MC4R stimulates
the feeling of fullness (Fig. 11). Three compounds series were
designed on the basis of recently approved 5-HT2C receptor agonist,
Lorcaserin. The 2-nitrobenzoic acids 60 are converted into their
corresponding acid chlorides by the treatment with oxalyl chloride.
Further reaction with ammonia followed by reduction using
hydrogen and palladium on carbon afforded 2-aminobenzamides
61. The condensation of 2-aminobenzamides with N-boc-aminoacetaldehyde in the presence of p-toluenesulfonic acid resulted in
the cyclized product 62. The N1 of the cyclized product was subjected to allylation using allyl bromide to the yield N-allyl
substituted dihydroquinazolinones 63. In another reaction, 2fluorobenzoyl chlorides 65 are converted into their corresponding
2-fluorobenzamides and allylated 66 in the presence of ammonia
and allylamine. The cyclized product 67 was obtained using Nprotected-3-amino-1-propanal. All these resulting olefins 63 and
67 were converted into intermediate aldehydes in the presence of
sodium periodate and a catalytic amount of osmium tetroxide. The
cyclization of these intermediate aldehydes with TFA and triethylsilane resulted in the formation of 6, 6, 6-tricyclic dihydroquinazolinones 64 (Scheme 10) and 6, 6, 7-tricyclic
dihydroquinazolinones 68 (Scheme 11). The compounds containing
halogens 69 & 70 were subjected to Stille-type coupling reaction 71,
Suzuki Miyaura coupling 72 and Negishi coupling 73 with tetramethyltin, trimethylboroxine, and dimethyl zinc respectively. The
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Scheme 11. Synthesis of 6, 6, 7-tricyclic dihydroquinazolinones. (i) NH3/MeOH-THF; (ii) allylamine/K2CO3/DMA; (iii) N-cbz-3-amino-1-propanal/N-boc-3-amino-1-propanal/
pTsOH/dioxane; (iv) OsO4/NaIO4/THF-H2O; (v) Et3SiH/TFA/CH2Cl2; (vi) Boc anhydride/Et3N/THF; (vii) Me4Sn/Pd(Ph3P)4/LiCl/DMF; (viii) TFA/CH2Cl2; (ix)H2/10% Pd/C/MeOH; (x)
Pd(Ph3P)4/trimethylboroxine/K2CO3,H2O-Dioxane; (xi) PdCl2(dppf)2/Me2Zn/dioxane; (xii) BH3eMe2S/Et2O, H2O2/NaOH; (xiii) Dess-Martin periodinane/CH2Cl2.
deprotection was carried out by using TFA. The reduction in the
presence of hydrogen and palladium on carbon afforded unsubstituted dihydroquinazolinones 74 & 75 (Scheme 11). The another
isomeric 6, 6, 7-tricyclic dihydroquinazolinone 77 was obtained
from the alcohol containing dihydroquinazolinone 76 in which the
alcohol group was introduced by means of borane reagent followed
by hydrogen peroxide treatment. The alcohols are converted into
aldehydes using Dess-Martin periodinane as an oxidizing agent.
The TFA and triethylsilane mediated cyclization afforded the
isomeric 6, 6, 7-tricyclic dihydroquinazolinone 77 (Scheme 11) [67].
All the synthesized series for tested for their agonism against 5HT2C receptors and also its functional selectivity towards 5-HT2A
and 5-HT2B. The functional selectivity towards 5-HT2c receptors and
the absence of off-target effects was achieved using 6, 6, 6-tricyclic
dihydroquinazolinones. The 6, 6, 6-tricyclic dihydroquinazolinones
displayed suboptimal functional selectivity and reduced brain to
plasma concentration.
2.10. Melanoma inhibitor
Melanogenesis is a complex pathway and several proteins are
involved in this pathway [69,70]. The process is initiated by the
paracrine stimulator, POMC. It is the precursor of a-MSH, an
endogenous peptide hormone of melanocortin family. Due to the
induction of UV rays, the expression of POMC occurs in keratinocytes. The a-MSH cleaved from POMC acts through the MC1R. The
remaining processes of melanogenesis are carried out by the second messenger, cAMP. The transcriptional activity was regulated
through the phosphorylation of CREB and activation of the regulatory protein, MITF. Through the activation of the melanogenesisrelated protein, the melanogenetic enzyme tyrosinase was
expressed out. This enzyme is responsible for the formation of
melanin pigment through the series of reactions. If there is any
change in the melanogenetic pathway, it will affect the pigmentation process (Fig. 12). Thangamalai [71] et al. reported the synthesis
of quinazolinones and quinazoline-2-thiones with its activity profile against a-MSH induced melanin production. The amino compounds 78 on treatment with CDI in the presence of triethylamine
yielded dihydroquinazolinone derivatives 79. The quinazolinones
were converted into quinazoline-2-thione 80 by refluxing overnight with LR (Scheme 12). Quinazolinones displayed high IC50
value (>10 mM) when compared to the quinazoline-2-thione in aMSH induced melanin production in B16 melanoma cells. The
smaller substituent does not affect the activity whereas the substitution of chlorine in the quinazoline-2-thione ring system
resulted in slight variation. The presence of bulky ring system and
the addition of substituents in the side chain phenyl ring decreased
the activity. The number of methylene unit displayed marginal
variation in activity but one methylene unit was found to be optimum. While predicting the mechanism of action, quinazoline-2thione inhibited the a-MSH induced melanin production in B16
melanoma cells whereas the normal catalytic activity of the
tyrosinase enzyme was not affected.
2.11. T-type calcium channel antagonist
The role of calcium ions has been implicated in various physiopathological processes [72]. There are various types of calcium
channels in which T-type calcium channel plays a major role in the
regulation of sleep, nociception, epilepsy, hypertension and cell
cycle pathway. Because of the distribution of T-type calcium
channel in the thalamus and cortex region, they are identified as
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609
Fig. 12. Mechanism of action of melanoma inhibitor.
Scheme 12. Synthesis of quinazolinone and quinazoline-2-thione.
effective targets in the disorders of thalamocortical signaling
pathway [73]. As per the reports of FLIPR tetra high-throughput
cellular screening system, two piperidines 81, 82 and one quinazolinone analogs 83 were identified as T-type calcium channel
antagonists for the treatment of epilepsy with minimal cardiovascular side effects. Barrow et al. [74] designed the series of 4, 4disubstituted quinazolin-2-ones based on the earlier reports and
screened them for its antagonistic activity against the T-type calcium channel. The amino benzophenone 84 was cyclized in the
presence of CDI in DCM followed by subsequent treatment with
various primary amines. The cyclized product 85 was then heated
with toluene in Dean-Stark apparatus to obtain the dehydrated
product 86. The treatment of either the intermediates with
Grignard reagent in THF resulted in the formation of dihydroquinazolinones 87 (Scheme 13). The compounds were tested for
their potency against two types of FLIPR assays to identify their
state dependent inhibition. Type 1 is based on measuring the potency in the inactivated state of the channel (depolarized assay) and
type 2 is based on the resting state of the channel (hyperpolarized
assay). All the compounds are selective towards the T-type calcium
channel and the reading in the EEG displayed a reduction in the
seizure time. The compound with the trifluoroethyl group in the
3rd position and fluorine in the 4th position of the phenyl ring
displayed weak time dependent inhibition in the metabolic assay.
Also, the compound acts as a weak substrate for the PXR which is
responsible for the induction of metabolic enzyme (CYP3A4). In
short, the compounds 88 and 89 are effective against harmaline
induced tremor, active wake suppression, and epileptic seizures
through the T-type calcium channel blockade.
Schlegel et al. [75] extended the work on 4, 4-disubstituted
quinazolin-2-ones as T-type calcium channel antagonists and
increased the number of derivatives by varying the substituents on
the quinazolinone ring system 90. The presence of trifluoro ethyl
group in the 3rd position of quinazolinone is maintained constant
because of its potency and metabolic stability. The halogen
replacement in the 4th position phenyl ring 91 was carried by using
either Suzuki Miyaura coupling reaction or by using cuprous iodide
mediated coupling with morpholine. The Suzuki coupling involves
the reaction of bromo derivative with boronic acid in the catalyst
medium containing PCy3 and Pd2dba3 using potassium phosphate
as a base. The amino benzophenone 92 containing fluorine in the
5th and 6th position follows the alternative way to form the quinazolinone nucleus. The quinazolinone obtained from the grignard
reaction 93 and allyl magnesium bromide 94 was subjected to
ozonolysis yields the aldehyde 95. The dimethyl sulfide acts as a
reducing agent in the ozonolysis reaction. The aldehydes are
directly converted into geminal difluorides 96 with DAST. The alkyl
fluorides 97 are obtained after the reduction of the aldehyde into
alcohols and then treated with DAST. The selection of various amino
ketones as the starting material leads to the different substituents
in the aromatic ring of the quinazolinone (Scheme 14). The racemic
mixtures obtained through the synthetic routes were resolved into
enantiomers using chiral HPLC. All these trifluoroethyl containing
derivatives were subjected to preliminary evaluation of calcium
channel antagonistic activity in the depolarized FLIPR assay. The
compounds ability to activate the PXR was also evaluated. The
metabolic stability of the compounds was found out by incubating
the compounds with human liver microsomes. The potent compounds were studied for their pharmacokinetic profiling in the rat,
dog, and monkey. The compound which is potent in the FLIPR assay,
metabolically stable and has reduced PXR activation was subjected
to further studies. The compound resulted in 70% inhibition against
seizure, decreased the active wake and REM sleep. Based on these
findings, the compound with T-type calcium channel antagonist
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Scheme 13. Synthesis of 4, 4-disubstituted quinazolin-2-ones-I.
activity could be a valuable agent for the treatment of CNS
disorders.
2.12. IMPDH inhibitor
IMPDH is an enzyme which catalyzes the conversion of IMP to
XMP. It is an example of oxidation reaction using NADþ as a cofactor
in the biosynthesis of guanine nucleotides (GMP, GDP, and GTP).
There are two isoforms, IMPDH I and IMPDH II. The upregulation of
IMPDH II is expressed in highly proliferating cells. This acts as a key
mechanism for the IMPDH inhibitors (Fig. 13). Therefore, the inhibition of IMPDH has been exploited in the therapeutic intervention
of anticancer, antiviral, antiparasitic and immunosuppressive
therapy [76,77]. From the earlier reports [78], 7-methoxy-6-oxazol5-yl]-1H-quinazoline-2, 4-diones 100 were identified as IMPDH II
inhibitors with poor physical properties. A slight modification of
the structure resulted in a series of 7-methoxy-6-oxazol-5-yl-2, 3dihydro-1H-quinazolin-4-ones 99 with potent IMPDH II inhibition.
The compounds were prepared by EDC coupling of amino-acid 98
with appropriate amines (Scheme 15). These derivatives were
designed with the objective of improving its potency along with the
favorable DMPK properties. The replacement of 2-oxo moiety by
gem-dimethyl group 101 resulted in a moderate decrease in activity
with improved solubility. The substitution of one of the methyl
group of the gem-dimethyl series by styrene moiety 102 improved
the potency along with solubility. A range of spiro analogues was
synthesized which showed comparable activity to that of dione and
improved the potency in the PBMC proliferation assay. Many of the
spiro-centered compounds generated chiral centre and the activity
was reported in one of the enantiomers. The SAR of spiropyrrolidine containing compounds were studied by replacing the
t-butyloxy group 103 with different electrophiles. The oxy-urea
substituted spiro-pyrrolidine 104 displayed reduction in the hepatic clearance (CLint) with promising enzyme and cellular activities. Another set of experimentation was performed to rectify the
increase in hepatic clearance rate. From the in vivo pharmacokinetic
study, the major site of metabolism was identified in the pyrrolidine core. The pyrrolidine moiety was replaced by proline core 105
to create a metabolically stable structure. A pair of diastereomers
was produced and they were purified by HPLC. The compound 105
having S stereochemistry at the spiro-centre reported less CLint
value (18 mL/min/mg) with significant results aganist IMPDH II inhibition and PBMC proliferation assay.
2.13. Sodium/calcium exchange inhibitor
NCX is a membrane protein responsible for the maintenance of
calcium ions (Ca2þ) in the cardiac myocytes [79]. The role of Ca2þ is
to control the contraction in myocytes. Any impairment in the exchange of Naþ and Ca2þ can affect the function of cardiac myocytes.
The increase in Ca2þ overload causes an increase in the force of
contraction of the heart thereby it leads to myofibril hyper
contracture. The NCX inhibitor regulates the improper functioning
of NCX and provides a valuable treatment in the case of reperfusion
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611
Scheme 14. Synthesis of 4, 4-disubstituted quinazolin-2-ones-II. (i) AreB(OH)2, R ¼ Ar/P(Cy)3/Pd2dba3/K3PO4/Dioxane; (ii) Morpholine, R ¼ Morpholine/CuI, proline/K2CO3/DMSO;
(iii) Triphosgene/Et3N/CF3CH2NH2/ether/0 C; (iv) Et3N/THF; (v) SOCl2/THF; (vi) RMgBr/THF; (vii) DAST/0 C/CH2Cl2; (viii) NaBH4/MeOH/0 C.
Fig. 13. Mechanism of action of IMPDH inhibitor.
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Scheme 15. Synthesis of 7-methoxy-6-oxazol-5-yl-2, 3-dihydro-1H-quinazolin-4-ones. (i) EDC/CH2Cl2/R1-NH2; (ii)PTSA/ClCH2CH2Cl/ketone.
injury [80]. Hasegawa et al. found that the derivatives of 3, 4dihydro-2(1H)-quinazolinone exhibited significant activity against
the NCX inhibition (Fig. 14).
The SAR study was carried out to evaluate the effect of substituents on the various positions of 3, 4-dihydro-2(1H)-quinazolinone nucleus. The reaction of 2-amino benzophenones 106 with
trichloroacetyl chloride resulted in the formation of trichloroacetamide 107 which on subsequent reaction with primary
amines gave cyclized products 108. Further treatment with NaBH4
resulted in the loss of trichloromethyl group and formed 3, 4dihydro-2(1H)-quinazolinone 109. Debenzylation 111 of the compound 110 can be achieved by the reaction with ammonium
formate in the presence of Pd/C in methanol. The free NH group of
quinazolinone 112 can be methylated 113 with iodomethane in the
presence of NaH. NaH is a strong base and it acts as a deprotonating
agent for the NeH bond. The carbonyl group of quinazolinone 112
can be converted into thiocarbonyl group 114 by treating with
phosphorous pentasulfide in xylene. The introduction of piperidine
ring is essential for the further derivatization of the dihydroquinazolinones. The cyclized product 116 was obtained by
refluxing the aniline derivative 115 with CDI. Removal of benzyl
group 117 was effected through the treatment with ammonium
formate in the presence of palladium on carbon. The reductive
amination 118 was favored when the aldehyde and sodium cyanoborohydride reacted with an amine. Alternatively, the amine can
be N-alkylated 118 using alkyl halide and potassium carbonate
Fig. 14. Mechanism of action of sodium/calcium exchange inhibitor.
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613
Scheme 16. Synthesis of dihydroquinazolinone as sodium/calcium exchange inhibitor. (i) CDI, THF; (ii) HCO2NH4, Pd/C, MeOH; (iii) NaBH3CN, HCl, MeOH/R-X, K2CO3, DMF.
(Scheme 16). The compounds were evaluated for their fura 2
fluorescence ratio, an index for measuring the calcium ion concentration in an isolated left atria from guinea pigs. The inhibition
against Naþ and Kþ free contracture was calculated as IC30 value.
The removal of chlorine atom from the 6th position does not
change the activity. The introduction of a methyl group and the
conversion of carbonyl to thiocarbonyl diminished the activity. The
presence of phenyl ring 119 in the 4th position was found to be
optimum for retaining the activity. The side chain attached to the
3rd position should have tertiary nitrogen atom. The optimum of
three carbon atoms between the ring and side chain nitrogen
should be preferred. The inclusion of piperidine ring with benzyl
group in the 3rd position and 3-methoxy substituent 120 in the
phenyl ring was found to be essential for the inhibition [81,82]. The
same author extended the work by synthesizing the citrate form of
compound 112 and 116 using citric acid in methanol medium [83].
2.14. PDE7 inhibitor
Phosphodiesterases are a class of enzymes that plays the catalytic
role in the degradation of cAMP/cGMP to AMP/GMP. PDE7 is one
among the family and it selectively catalyzes the conversion of cAMP
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Fig. 15. Mechanism of action of PDE7 inhibitor.
Scheme 17. Synthesis of dihydroquinazolinones as PDE7 inhibitor-I. (i) NIS, TFA, H2SO4; (ii) Pd(PPh3)4/2-pyridylZnBr/THF/RB(OH)2/K2CO3/DMF; (iii) SOCl2/toluene; (iv) R3R4NH/
toluene.
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Scheme 18. Synthesis of dihydroquinazolinones as PDE7 inhibitor-II.
to AMP [84]. Therefore, inhibition of PDE7 leads to increase in the level
of cAMP which affects various signal transduction pathways. The
expression of PDE7 is highly upregulated in T-cells and B-lymphocytes. The inhibitors of PDE7 have been considered as a valuable
therapeutics in the treatment of T-cell related diseases, autoimmune
diseases, CNS disorders and airway disease (Fig. 15) [85].
The synthesis of dihydroquinazolinones was initiated by the
reaction between ureas and different ketones in the presence of
PPA. The mono substituted (2/4- substitution) ureas 124 resulted in
the formation of single type cyclized product 125. The mixture of
isomers 122, 123 (5, 6 and 6, 7-dichloro substituted quinazolinones)
was obtained from 3-chloro substituted or 3, 4-dichloro substituted
phenyl ureas 121. The chlorination reaction using NCS converted 6substituted derivatives 125 into 6, 8-disubstituted derivatives 126.
The 8-chloro intermediates 127 were subjected to iodination reaction to afford 6-chloro-8-iodo intermediates 128. The iodide
atom present in the intermediate was replaced with phenyl ring
using Negishi/Suzuki coupling 129 reactions. The iodide atom
reacted with 2-pyridyl zinc bromide and phenyl boronic acid in the
negishi and Suzuki coupling reaction respectively. The carboxylic
group present in the intermediate was transformed into acid
chloride using thionyl chloride. The amide derivatives 130 were
obtained by the reaction between an acid chloride and respective
amines (Scheme 17). The compounds were screened for their
effectiveness against PDE7A subtype inhibitory activity. The
unsubstituted 4th position spirocyclohexyl ring, 6th position
phenyl ring, and dihalogen substitution were the features essential
for the potent action. The presence of carboxyl group increased the
activity but the lack of selectivity towards the enzyme subtypes.
Whereas the introduction of amide group with the linker containing 2e3 carbon atom displayed effective inhibition score and
good selectivity against PDE7A enzyme. The amide containing
piperazine derivatives displayed similar potency but decreased
solubility [86].
Bernardelli et al. [87] extended the work on spiroquinazolinones
by screening the potency and selectivity of various 5, 8disubstituted derivatives towards the PDE enzyme. The
substituted anilines 131 reacted with potassium cyanate and
transformed the amine derivatives into urea derivatives 132. The
urea derivatives were cyclized into spiroquinazolinones 133 by
reacting with cyclohexanone using PPA. The phenol containing
quinazolinone 135 was obtained from the methoxy derivative 134
by using boron tribromide as a demethylating agent. The O-alkylation 136 of phenol intermediate was carried out in the presence of
various alkyl halides (Scheme 18). The functionalization of 5hydroxy-8-chloro-spirocyclohexane-quinazolinone 137 was summarized in Scheme 19. The carboxylic acid 138 was introduced
through the treatment of phenol 137 with ethyl bromoacetate
followed by the hydrolysis of the ester with KOH. The nitrile 141
was synthesized using bromoacetonitrile and it reacted with azidotrimethyltin (IV) to form tetrazole 139. The nitrile 141 was also
used in the synthesis of hydroxy-oxadiazole 140 through oximes
142 as an intermediate. The introduction of alcohol in the side chain
143 was obtained through the reaction with 2-(2-bromoethoxy)
tetrahydro-2H-pyran followed by hydrolysis with HCl. The mesylate group 144 can be replaced either with morpholine 145 or ethyl
glycinate 146 to form their corresponding derivatives.
2.15. p38 MAPK inhibitor
The p38 MAPK pathway involves the sequential activation of
three protein kinases: MAPK, MAPKK, and MAPKKK. p38 MAPK is
responsible for regulating the biosynthesis of pro-inflammatory
cytokines, namely IL-1 and TNFa [88]. The interruption of this
pathway through p38 inhibitors was responsible for the treatment
of rheumatoid arthritis (Fig. 16) [89]. Stelmach et al. [90] reported
p38a MAP kinase inhibitory activity and pharmacokinetic profile of
dihydroquinazolinones and they were designed on the basis of the
reported structures. VX-745, 147 was reported as the phase II
clinical trial undergoing drug for rheumatoid arthritis and they are
selective for p38a MAP kinase. The compound 148 is the reduced
isomeric analog of VX-745 with polar amine substituents in the C-7
position for increasing the potency and physicochemical properties.
The thioether group in C-6 position can be replaced with C-5
phenyl ring for occupying the p38a hydrophobic pocket. The derivatives of dihydroquinazolinones containing C-5 phenyl ring 149
were prepared as per Scheme 25. The Ullmann type coupling reaction of 150 afforded cyclized product 151. The deprotection of
PMB group was effected with TFA. The C-5 bromine was subjected
to Suzuki coupling 152 with aryl boronic acids in the presence of
Pd(PPh3)4. As a demethylating agent, boron tribromide converted
C-7 methoxy group 153 into phenolic hydroxyl group 154. The
conversion of phenolic OH into its triflates 155 was carried out by
phenyl triflimide. The triflates reacted with vinyl trimethyltin in the
presence of Pd(PPh3)4 and lithium chloride resulted in Stille type
coupling product 156. The presence of lithium salt is to increase the
polarity of the solvent for the easy removal of triflates. The platinum dioxide also known as Adam's catalyst was used for the
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Scheme 19. Synthesis of dihydroquinazolinones as PDE7 inhibitor-III. (i) Ethyl bromoacetate/K2CO3/DMF; (ii) KOH/THF; (iii) Bromoacetonitrile/K2CO3/DMF; (iv) NH2OH$HCl/NaOH,
EtOH; (v)ClCO2Et/CHCl3/Et3N; (vi)DBU/ACN; (vii) Me3SnN3/Toluene; (viii)2-(2-bromoethoxy)tetrahydro-2H-pyran/K2CO3/DMF; (ix) HCl/THF/H2O; (x) Methanesulfonyl chloride/
Et3N/CH2Cl2/0 C; (xi) Morpholine/EtOH; (xii) Ethyl glycinate/CH3CN; (xiii) 6 N HCl/1, 4-dioxane.
hydrogenation of vinyl group and N-boc can be deprotected using
TFA (Scheme 20). The triflates 157 were also subjected to
Buchwald-Hartwig coupling reaction 158 in the presence of
amines. The Mitsunobu reaction was carried out to convert the
phenolic OH 159 into ether 160 using DEAD and triphenylphosphine. The dihydroquinazolinones containing methylene linker 162
and carbonyl linker 163 at C-7 were obtained either by reductive
amination and CDI coupling of ester 161 respectively (Scheme 21).
The compounds containing piperazine/piperidine at C-7 position
exhibited significant inhibition against p38a enzyme assay. They
also inhibited the TNFa production. The rat pharmacokinetic profile
displayed that these compounds resulted in low oral bioavailability
and rapid clearance. The compound containing t-butyl group in the
C-7 piperidine ring increased the oral bioavailability and decreased
the clearance rate.
Hunt et al. [91] investigated the p38 inhibitory activity of
dihydroquinazolinones in addition to naphthyridinones 164 and
quinolinones 165. The reaction scheme was initiated with 1, 3-
dibromo-2-methyl-5-nitrobenzene 166. The reaction up to the
synthesis of the intermediate 152 was followed as per the report of
the previous author except deprotection of PMB group 167. The
amine group 168 was introduced by means of reduction with
hydrogen in the presence of palladium on carbon. The reductive
alkylation of the amine with ketone was carried out by using the
mild reducing agent, sodium triacetoxyborohydride. Finally, the
PMB group was deprotected by TFA to yield the dihydroquinazolinones 169 (Scheme 22). The three series of C7piperidine and 4-aminopiperidine substituted naphthyridinones
164, quinolinones 165 and dihydroquinazolinones 169 were
screened for their inhibition against p38a enzyme assay and TNFa
production. The naphthyridinone and quinolinone derivatives were
more potent and exhibited improved pharmacokinetic profile in
the rat. The comparatively less potency of the dihydroquinazolinone derivatives was due to the difference in the C-4
position. The C-4 position was stabilized because of the sp2 hybridized centre, the clearance rate was lowered and oral
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617
Fig. 16. Mechanism of action of p38 inhibitor.
bioavailability was increased. This is the reason for the enhanced
pharmacokinetic profile of the naphthyridinone derivatives.
Schlapbach et al. [92] synthesized the dihydroquinazolinone
derivatives from diclofenac and tested its inhibition score against
the p38a enzyme. The a-arylamino phenylacetic acid 170 was
subjected to curtius rearrangement in the presence of DPPA. The
intramolecular ring closure of the isocyanate intermediate led to
the formation of 1-(2, 6-dichlorophenyl)-3, 4-dihydroquinazolin2(1H)-one 171. The dihydroquinazolinone are subjected to C-6
functionalization by various reactions. The bromination and further
coupling at the C-6 position were preceded via Buchwald-Hartwig
reaction 172. The 2, 4-difluoro-thiophenol reacted with the
bromine intermediate in the presence of tetrakis palladium and
sodium tert-butoxide. The C-6 position was nitrated using potassium nitrate and reduced in the presence of hydrogen and palladium on carbon for introducing the amine group 173. The 6-amino1-(2, 6-dichlorophenyl)-3,4-dihydroquinazolin-2(1H)-one was utilized in the synthesis of arylamines, benzylamines, carboxamides
or sulfonamides. The Buchwald-Hartwig coupling of the amine
with 2, 4-difluoro-bromobenzene was carried out using Pd2dba3
and DPEphos afforded arylamine 174. The formation of benzylamines 175 through the reductive amination of amine and benzaldehyde was carried out with the aid of sodium cyanoborohydride.
The reaction of amine with benzoyl chloride and the
benzenesulfonyl-chloride resulted in the formation of carboxamide
176 and sulfonamide 177 respectively (Scheme 23). The phenyl ring
at the N-1 position of dihydroquinazolinones replaced with various
substituents as a p38a inhibitor was synthesized. The urea derivatives 178 were cyclized using palladium complex Pd2dba3 to
afford N-1 substituted dihydroquinazolinones 179. The O-alkylated
180 and N-alkylated 181 derivatives of 1-(4-hydroxy-2, 6dimethylphenyl)-6-nitro-3, 4-dihydroquinazolin-2(1H)-one were
obtained from chloropropyl-morpholine and 3-chloro-4-fluoro
benzenesulfonylchloride respectively (Scheme 24). Because of the
selectivity towards the p38 MAP kinase, significant inhibition of
TNFa release and non-interference with liver enzymes, the compound was identified as a valuable candidate for drug discovery.
2.16. CDK5 inhibitor
CDK5 is a proline-directed serine/threonine kinase and its activation requires various cyclin (cyclin I, E, and G1) and non-cyclin
activators (p35, p39, and p67). This protein plays a vital role in the
normal development of CNS and they have been involved in controlling several neuronal processes. The role of CDK5 has also been
implicated in several non-neuronal functions (Fig. 17) [93]. The
deregulation of CDK5 has been corroborated in several neurodegenerative diseases such as Alzheimer's disease, Huntington's
chorea, stroke, Parkinson's disease and Lou Gehrig's disease [94].
Rzasa et al. [95] designed a series of 3, 4-dihydroquinazolin-2(1H)ones as CDK5 inhibitors. The molecule 183 was designed on the basis
of intramolecular hydrogen bond formation between the two nitrogen atoms in the pyridyl urea 182. It was assumed that the
intramolecular hydrogen bond between N1 and hydrogen atom
from N3 occupies the active site of CDK5 enzyme. This assumption
was confirmed from the cocrystallographic data of pyridyl urea 182
and CDK2, an analog of CDK5. Various modifications have been
made in the A, B, C and D ring systems of the structure 183. From the
SAR study, it was found that the compounds containing dihydroquinazolinones ring system (B ring: U]CH2) were more potent
than the quinazolinedione and benzimidazolone ring. It is because
of the van der waals contact with the amino acid residues found
within the active site of the enzyme. The derivatives with the range
of substituents were tolerated in the ring A, thiazolo moiety in the
place of C ring and 4- pyridyl moiety in the ring D showed significant
activity against HTRF human CDK5/p25 assay. The importance of 4pyridyl ring was supported by the formation of hydrogen bonding to
the Asp145-Lys33 salt bridge.
The anilines 184, 186, 189, 191 and 194 obtained through the
various methodologies were cyclized using p-nitrophenyl chloroformate or CDI mediated reaction to give dihydroquinazolinones
185, 187, 190, 192 and 195. The ester containing dihydroquinazolinones 187 was hydrolysed and decarboxylated in the
presence of alkaline and acidic medium to give the final product
188 (Scheme 25).
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Scheme 20. Synthesis of dihydroquinazolinones as p38 inhibitor-I.
2.17. RyR agonist
Ryanodine is a natural insecticide and the receptor through
which it acts is called RyR. RyR is an example of non-voltage-gated
calcium channel and it causes the regulation of calcium release
from intracellular storage [96]. Ryanodine type agonist causes the
continuous release of calcium from the sarcoplasmic reticulum.
Thereby the concentration of calcium in the myoplasm of insect
increases and the muscles remain in the state of continuous
contraction. The massive muscular contraction causes paralysis of
muscles leading to the death of the insects (Fig. 18) [97]. Zhou et al.
[98] carried out the synthesis of 2, 3-dihydroquinazolinones and
tested their insecticidal activity against oriental armyworm
(Mythimna separata). The 2-aminobenzoic acid 196 was used as a
starting material for the synthesis of various amides. The amides
197 & 198 were obtained by the reaction of the 2-aminobenzoic
acid with thionyl chloride/triphosgene/CDI followed by the treatment with corresponding amines. The ethyl 3-bromo-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxylate 199 was reduced
into alcohol 200 in the presence of one equivalent of LiAlH4.
Dechlorination of pyridine ring 201 was obtained from the treatment of more than two equivalent of reducing agent. The primary
alcohol 200 & 201 was oxidized using PCC into aldehyde 202. The
amide and the aldehyde were refluxed in the presence of PTSA and
toluene medium to afford the dihydroquinazolinones 203. When
the same reaction was carried out in the presence of ethanol, quinazolinones 204 were obtained (Scheme 26). The compound 205
exhibited 100% mortality against the larvae of Spodoptera exigua.
The results of calcium imaging techniques demonstrated that RyR
may be the possible site of action for the compounds containing
dihydroquinazolinones.
2.18. Non-nucleoside reverse transcriptase inhibitor
HIV is a member of retroviridae family and it specifically attacks
the T-helper cells. The T-helper cells are the important component
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619
Scheme 21. Synthesis of dihydroquinazolinones as p38 inhibitor-II. (i) NBS/Benzoyl peroxide/p-methoxy benzyl amine; (ii) 2, 6-di-Cl-PhNCO; (iii) CuI/K2CO3/DMF; (iv)TFA/(v)
ArB(OH)2/Pd(PPh3)4; (vi) N-boc-4-trimethylstannyl-5, 6-dihydropyridine/Pd(PPh3)4/LiCl, (vii) H2, PtO2; (viii) TFA.
Scheme 22. Synthesis of dihydroquinazolinones as p38 inhibitor-III.
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Scheme 23. Synthesis of dihydroquinazolinones as p38 inhibitor-IV. (i)Diphenylphosphoryl azide/NEt3/dimethoxyethane; (ii) Br2/CH2Cl2; (iii) 2, 4-difluoro-thio-phenol/Pd(PPh3)4/
NaOtBu/toluene; (iv) KNO3/H2SO4/0 C; (v) H2, Pd/C, ethanol; (vi) 2, 4-di-F-bromobenzene/Pd2dba3/DPEphos/NaOtBu/toluene; (vii) benzaldehyde/NaBH3CN/3% AcOH in DMF; (viii)
Benzoyl chloride/NEt3/THF; (ix) Benzenesulfonyl chloride/DMAP/pyridine.
Scheme 24. Synthesis of dihydroquinazolinones as p38 inhibitor-V. (i) Boc2O/DMAP/CH2Cl2; (ii) Pd2dba3/2-(dicyclohexyl-phosphino)biphenyl/K3PO4; (iii) Chloropropylmorpholine/CsI/DMF; (iv) H2/Pd/C/MeOH; (v) 3-chloro-4-fluoro benzenesulfonylchloride/pyridine/DMAP/CH2Cl2.
of WBC helps to coordinate the immune response. HIV enters the
host cell through binding with host cell CD4 receptors found on the
surface of the cell. After entering into the host cell, HIV utilizes the
host cell machinery for the replication process and leaves them as a
mature virion. Several proteins are involved in the replication
process and they can act as a valuable target for the treatment of
HIV (Fig. 19) [99]. RT is an attractive target for HIV and they are
categorized into NRTIs and NNRTIs. The development of NNRTI
based drug candidate is advantageous because of its potency and
low cytotoxicity [100]. Corbett et al. [101] synthesized dihydroquinazolinones from amino ketones 206 as starting materials.
The aminols 207 were obtained by the reaction of amino ketones
206 with TMSNCO and TBAF. The trifluoromethyl ketimines 208 are
the dehydrated product of aminols treated in the presence of
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621
Fig. 17. The role of CDK5 inhibitors in neurodegenerative diseases.
toluene or xylene and the moisture is absorbed by 4 Å molecular
sieves. Then the ketimines were alkylated with lithiated alkynes
using the catalytic amount of lewis acid like boron trifluoride
etherate to afford quinazolinones 209 (Scheme 27). The analogs
were screened for their in vitro inhibition of HIV-1 RT assay. The 5,
6-dihalogen compounds and the presence of trifluoromethyl group
improved the overall resistance of the molecule. The compounds
DPC 961 210, DPC 963 211, DPC 082 212, and DPC 083 213 exhibited
pharmacokinetic property similar to that of efavirenz. These compounds also provided superior antiviral potency and safety profile
against the mutant HIV variants (see Scheme 28).
and they are synthesized from the wide variety of starting materials. Guan et al. [105] developed an efficient protocol for the synthesis of dihydroquinazolinones from anthranilamide obtained via
indazoles. Indazoles 221 are either prepared by Buchwald-Hartwig
reaction (i) or by copper-catalyzed aryl coupling reaction (ii). The
indazole is converted into indazolium salts 222 by methylating
with dimethylsulphate. The indazolium salts are reacted with potassium tert-butoxide in the presence of toluene and water gives
the corresponding anthranilamides 223. The anthranilamides on
treatment with 50% sulphuric acid and formaldehyde yielded 2, 3dihydro-4(1H)-quinazolinones 224 (Scheme 29).
2.19. Aldosterone synthase inhibitor
3.2. Copper oxide nanoparticle mediated synthesis of
dihydroquinazolinones
Aldosterone synthase is an important enzyme involved in the
biosynthesis of aldosterone. Aldosterone is a mineralocorticoid
hormone essential for the homeostasis of blood volume and electrolyte balance. The excessive secretion of aldosterone is responsible for the pathological conditions such as hypertension, cardiac
fibrosis and congestive heart failure (Fig. 20) [102,103]. Grombien
et al. [104] carried out the synthesis of moieties designed on the
basis of 3, 4-dihydroquinolinone nucleus in which the methylene
unit of 3, 4-dihydropyridinone were bioisosterically exchanged
with various heteroatoms 214.2-(aminomethyl)aniline 216 was
cyclized into 3, 4-dihydroquinazolinone 217 in the presence of
triphosgene. The bromine atom was introduced in to 3, 4dihydroquinazolinone using NBS 218 and it was subjected to
Suzuki Miyaura coupling 219 using heteroarylboronic acid. The
compound 220 showed minor selectivity towards the human
CYP11B1 gene responsible for encoding of the aldosterone synthase
enzyme. The replacement of lactame 214 by sultame 215 moiety
displayed significant reduction in the biological activity.
3. Miscellaneous synthesis and applications of
dihydroquinazolinones
3.1. Synthesis of 2, 3-dihydroquinazolin-4(1H)-ones from Nheterocyclic carbenes of indazole
Indazoles are medicinally and pharmaceutically important motif
Zhang et al. [106] carried out the one pot condensation of isatoic
anhydride 20, anilines 225 and aldehydes in the presence of various
catalysts to afford dihydroquinazolinones 226 & 227 (Scheme 30).
CuO nanoparticles were found to be superior among the catalyst.
The experimentation on the effect of ethanol:water ratio on the
yield of the product was tested. The increase in the amount of water
substantially increased the yield. The yield was optimised at 1:1
ratio of ethanol: water and a further increase in the water
decreased the yield. The 10 mol% of CuO nanoparticles was
necessary to increase the yield. When the reaction was stirred at
reflux temperature, it required 3 h for completion. In the presence
of ultrasound irradiation (40 KHz and 250 W), the reaction was
completed in 10e30 min. The condensation reaction between isatoic anhydride, ammonium chloride 228 and various aldehydes in
the presence of CuO nanoparticles, quinazolinones 229 were obtained as a product. When the ethanol: water system was maintained at 3:1 ratio, there is a maximum conversion of
quinazolinone. The reason for the unexpected formation of quinazolinones may be due to the intramolecular electron transfer and
rearrangement in the presence of inorganic salts.
3.3. Y(OTf)3 mediated synthesis of dihydroquinazolinones
The synthesis of dihydroquinazolinones was carried out by the
condensation reaction between anthranilamide 230 and various
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Scheme 25. Synthesis of dihydroquinazolinones as CDK5 inhibitor. (i) p-nitophenyl chloroformate/Et3N/toluene/THF; (ii) CDI/NaH/DMF; (iii) NaOH/MeOH/H2SO4; (iv) iron dust/
NH4Cl/aq. EtOH.
aldehydes 231. In the absence of a catalyst, traces of product were
obtained even after long time treatment. The comparison of acidic
catalyst resulted in improved yields. The uniqueness of the rare
earth metal chloride as catalyst displayed effectiveness in yield.
However, Y(OTf)3 was found to be superior among the rare earth
metals. Ethanol was optimized as the suitable solvent for the reaction. These optimized reaction conditions yielded traces of
quinazolinones 233 along with dihydroquinazolinones 232
(Scheme 31). The role of oxidants identified dimethyl sulfoxide in
providing a satisfactory yield of quinazolinones [107].
3.4. Boric acid mediated synthesis of dihydroquinazolinones
Anthranilamide
234
was
converted
into
3,
5-
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623
Fig. 18. The role of the ryanodine receptor in insecticidal activity.
Scheme 26. Synthesis of dihydroquinazolinones as an insecticidal agent. (i) a) SOCl2, b) R2NH2/THF; (ii) a) triphosgene, b) CH3NH2/H2O; (iii) CDI/THF; (iv) NH3/H2O; (v) LiAlH4/THF;
(vi)PCC/CH2Cl2; (vii) PTSA/toluene/reflux; (viii) CH3CH2OH/reflux.
dibromoanthranilamide 235 using N-bromosuccinimide in
chloroform-carbon tetrachloride mixture. It was then cyclized with
benzaldehyde derivatives using boric acid as a catalyst in the
presence of solvent-free condition to obtain 2-aryl-6,8-dibromo2,3-dihydroquinazolin-4(1H)-ones 236. Further derivativatization
of dihydroquinazolin-4(1H)-ones was carried out by subjecting the
bromine to Suzuki Miyaura coupling reaction. The coupling reaction between 2-aryl-6,8-dibromo-2,3-dihydroquinazolin-4(1H)ones and phenylboronic acid in the presence of PdCl2(PPh3)2-Xphos
catalyst complex yields biarylated 2, 3-dihydroquinazolin-4(1H)one derivatives 237. The 2, 3-dihydroquinazolin-4(1H)-one derivatives were oxidized into quinazolin-4(3H)-one 238 derivatives
in the presence of molecular iodine as an oxidant. The formation of
lactam form of quinazolin-4(3H)-one derivative 239 was confirmed
through the NMR spectra (Scheme 32) [108].
3.5. Visible light mediated synthesis of dihydroquinazolinones
Hemalatha et al. reported the visible light mediated synthesis of
2, 3- dihydroquinazolinones from isatoic anhydride and ketones in
the presence and absence of acetic acid. The reaction was efficient
in the presence of acetic acid. The solvatochromic effect of the
synthesized series was carried out using various solvents of
increasing polarity. All the compounds exhibited significant quantum yield and they yielded maximum fluorescence in dimethyl
sulfoxide. Further the antioxidant activity and in vitro antiinflammatory activity of dihydroquinazolinones concluded those
isatin containing derivatives 240 are most effective among the
synthesized series (Fig. 21) [109]. The biological activity of the
compounds was correlated with the docking studies carried out
using PARP [110] enzyme.
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Fig. 19. Mechanism of action of anti-HIV drugs.
Scheme 27. Synthesis of trifluoromethyl-containing dihydroquinazolinones.
Scheme 28. Synthesis of 3, 4-dihydroquinazolinones as aldosterone synthase inhibitor. (i) Triphosgene/THF; (ii) NBS/DMF/0 C; (iii) Heteroarylboronic acid/Pd(PPh3)4/aq. Na2CO3/
DME/reflux.
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625
Fig. 20. Mechanism of action of aldosterone synthase inhibitor.
Scheme 29. Synthesis of dihydroquinazolinones from indazoles.
3.6. Importance of 7-fluoro-2, 2-dimethyl-2, 3-dihydroquinazolin4(1H)one
Due to the importance of fluorinated compounds in the field of
drug discovery and development, the fluorine containing 2, 2dimethyl-2, 3-dihydroquinazolin-4(1H)one was synthesized. The
amide 243 for the synthesis of the fluorinated derivative was prepared from the condensation reaction between 2-amino-4fluorobenzoic acid 241 and methylamine 242 in the presence of
EDC and hydroxybenzotriazole. The amide 243 undergoes
cyclization with acetone in the presence of concentrated HCl to
afford the fluorinated derivative of 2, 3-dihydroquinazolinone 244
(Scheme 33). The interaction between the fluorinated derivative
and lysozyme was predicted using NMR study in addition to the
various spectrophotometric studies. The difference in the chemical
shift value of the ligand after interaction with the protein
confirmed the interaction between them. In silico prediction of the
metabolic pathway of the fluorinated derivative confirmed that the
presence of fluorine atom prevents the oxidation of aromatic ring
and makes the molecule metabolically stable. From the MTT assay,
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Scheme 30. CuO nanoparticle-mediated synthesis of dihydroquinazolinones.
Scheme 31. Y(OTf)3 mediated synthesis of dihydroquinazolinones.
Scheme 32. Boric acid mediated synthesis of dihydroquinazolinones.
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627
3.8. Suzuki Miyaura coupling of 2, 3-dihydroquinazolinones
Fig. 21. Isatin containing dihydroquinazolinone derivative.
Hemalatha et al. extended the work by subjecting the brominated derivatives of 2, 3-dihydroquinazolinones 248 to Suzuki
Miyaura coupling (Scheme 35). The Suzuki coupled products 249
were screened for antifungal activity against the Aspergillus species.
The interaction of dihydroquinazolinones containing CeO bond
with the amino acid residues of the protein N-myristoyl transferase
Scheme 33. Synthesis of 7-fluoro-2, 2-dimethyl-2, 3-dihydroquinazolin-4(1H)one. (i) EDC. HCl/HOBt/Et3N/DCM; (ii) Acetone/HCl.
Scheme 34. Bromination of 2, 3-dihydroquinazolinones.
was identified to be the reason for the superior antifungal activity
of the compounds. The active compound among the synthesized
series was subjected to lysozyme interaction studies. The interaction between the compound and the lysozyme was justified
through various spectroscopic studies [113].
In another work, optimization of the same reaction using
palladium nanoparticles was carried out. The coupling reaction
carried out in the presence of both microwave and ultraviolet
irradiation was resulted in maximum yield. The toxicity of the
palladium nanoparticles was tested using Artemia salina bioassay
and it was found to be non toxic. Environmental impact of the reaction conditions was assessed from the E-factor and eco scale
value. The analysis confirmed the ecofriendliness of the reaction
condition [114].
Scheme 35. Synthesis of 6-substituted 2, 3-dihydroquinazolinones via Suzuki Miyaura
coupling.
the concentration greater than 80 mM was identified as the cytotoxic concentration [111].
3.7. Bromination of 2, 3-dihydroquinazolinones
Hemalatha and co-worker carried out the bromination of 2, 3dihydroquinazolinones 245 using NBS as the brominating agent.
In the presence of 1 equivalent of NBS, bromine was substituted in
the 6th position of 2, 3-dihydroquinazolinones 246. However in the
presence of 1.1 equivalent of NBS, there may be a chance for the
substitution of bromine atom in the 5th position of 2, 3dihydroquinazolinones 247 I n addition to 6th position bromine
atom (Scheme 34). The introduction of hydrophobic bromine atom
was justified for the significant anthelmintic activity of the compounds. The interaction study with bovine serum albumin was
determined from the spectroscopic studies [112].
4. Conclusion
The summation of the synthetic methodology will drive the
interest of the chemist towards the dihydroquinazolinone nucleus.
The compounds with the same reactivity can also be experimented
using the same reaction condition. The schematic representation of
the biochemical pathway will be clear cut for even the nonbiologist to understand the mechanism easily. The designing of
the compounds based on the effects of the substituents will result
in the development of an effective molecule for the future scenario.
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Abbreviations
5-HT: 5-hydroxytryptamine
ADP: adenosine diphosphate
AMP: 50 -adenosine monophosphate
AT4: angiotensin IV
ATP: adenosine triphosphate
BCCP: biotin-carboxyl-carrier protein
Boc2O: di-tert-butyl-dicarbonate
cAMP: 30 ,50 -cyclic adenosine monophosphate
CDI: 1, 1-carbonyl diimidazole
CDK1: cyclin-dependent kinase 1
CDK5: cyclin-dependent kinase 5
CF: continuous flow
cGMP: 30 ,50 -cyclic guanosine monophosphate
CGRP: calcitonin gene-related peptide
CM: chorismate mutase
CNS: central nervous system
COX: cyclooxygenase
CREB: cAMP-responsive element-binding protein
CuO: copper (II) oxide
CYP: cytochromes P450
DAST: diethylaminosulfur trifluoride
DBU: 1, 8-diazabicycloundec-7-ene
DCM: dichloromethane
DEAD: diethyl azodicarboxylate
DMAP: dimethylaminopyridine
DME: dimethoxyethane
DMPK: drug metabolism and pharmacokinetics
DPEPhos: (Oxydi-2, 1-phenylene)bis(diphenylphosphine)
DPPA: diphenylphosphoryl azide
EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
EEG: electroencephalogram
FLIPR: fluorometric imaging plate reader
GDP: guanosine diphosphate
GMP: guanosine monophosphate
GTP: guanosine triphosphate
HCl: hydrochloric acid
HIV-1: human immunodeficiency virus type 1
HOBt: hydroxybenzotriazole
HPLC: high performance liquid chromatography
HTRF: homogenous time resolved fluorescence
IL-1: interleukin 1
IMP: inosine 50 -monophosphate
IMPDH: inosine-50 -monophosphate dehydrogenase
IRAP: insulin-regulated aminopeptidase
KOH: potassium hydroxide
LiAlH4: lithium aluminium hydride
LR: lawesson's reagent
mAchR: muscarinic acetylcholine receptors
MAPK: mitogen-activated protein kinase
MAPKK: MAPK kinase
MAPKKK: MAPKK kinase
MC1R: melanocortin receptor 1
MC4R: melanocortin receptor 4
METH: methamphetamine
MITF: microphthalmia-associated transcription factor
MPO: myeloperoxidase
MTT: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide
MW: microwave
NaBH4: sodium borohydride
NAD: nicotinamide adenine dinucleotide
NaH: sodium hydride
N-boc: tert-butyloxycarbonyl
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
NCX: sodium calcium exchanger
NMR: nuclear magnetic resonance
NNRTIs: nonnucleoside reverse transcriptase inhibitors
NO: nitric oxide
NRTIs: nucleoside reverse transcriptase inhibitors
NSAIDs: non-steroidal anti-inflammatory drugs
PARP: poly(adenosine diphosphate-ribose)polymerase
PBMC: peripheral blood mononuclear cell
PCC: pyridinium chlorochromate
PCy3: tricyclohexylphosphine
Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0)
Pd2dba3: tris(dibenzylideneacetone)dipalladium(0)
PdCl2(dppf): bis(diphenylphosphino)ferrocene]palladium(II) dichloride
PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloride
PDE7: phosphodiesterase 7
PMB: p-methoxy benzyl
POMC: proopiomelanocortin
PPA: polyphosphoric acid
Psi: per square inch
PTSA: p-toluenesulphonic acid
PXR: pregnane X receptor
REM: rapid eye movement
RT: reverse transcriptase
RyR: ryanodine receptor
SAR: structural-activity relationship
SiC: silicon carbide
TBAF: tetra-n-butylammonium fluoride
TFA: trifluoroacetic acid
THF: tetrahydrofuran
TMSNCO: trimethylsilylisocyanate
TNFa: tumor necrosis factor alpha
UV: ultraviolet
WBC: white blood cells
XMP: xanthosine 50 - monophosphate
Xphos: 2-dicyclohexylphosphino-20 , 40 , 60 -triisopropylbiphenyl
Y(OTf)3: ytterbium(III) triflate
a-MSH: alpha-melanocyte stimulating hormone