REVIEW ARTICLE

Chemistry, Structure Activity Relationship and an enormous increase in the interest among
biologists and chemists in their synthesis and
Biological Activity of Quinazolin -4 (3H)-One bioactivity of quinazoline derivatives.25

Derivatives Anticonvulsant Activity

Arun K Mahato 1*, Birendra Srivastava1, C Nithya Shanthi 2
Abstracts: Quinazolin-4-(3H)-one is a versatile lead molecule for the design of potential
bioactive agents. The molecular manipulation of a promising lead compound is still a major
line of approach for the discovery of new drugs. There has been considerable interest in the
development of novel compounds with antibacterial, antifungal, anti-HIV, CNS depressant,
antitubercular, anticancer, antioxidant, analgesic, anti-inflammatory, anticonvulsant and
antiviral activities. SAR studies have indicated that substitution at position 2 and 3 can
modulate activities of the molecule. Therefore many researchers have synthesized these
compounds as target structures and evaluated their biological activities. These observations
have been the guiding for the development for new quinazolinones that possesses varied
biological activities.
Key Words: Quinazolinone, SAR, biological activity.
INTRODUCTION and more complex variants of the
Quinazoline 1 is a compound made up of two quinazolinone structures are still being
fused six-membered aromatic rings, a discovered.6The first reported synthesis of a
benzene ring and a pyrimidine ring. quinazolinone occurred in 1869, which was
Quinazoline is a fused bicyclic compound prepared from anthranilic acid and cyanide
earlier known as benzo-1,3-diazine was first in ethanol creating 2-ethoxy-4(3H)-quina-
prepared in the laboratory by Gabriel1 in zolinone4. These findings were confirmed by
1903, although one of its derivative was the preparation of the derivatives of 2-
known much earlier.2 Quinazolinones are the amino-4(3H)-quinazolinone and 2,4(1H,3H)-
oxidized form of quinazoline and as such are quinazolinedione by reactions with ammonia
also part of the quinazoline alkaloids. Both and water respectively (Scheme 1).
naturally occurring and synthetic Investigations of quinazolinones show
quinazolines and quinazolinones have there is a strong lactam-lactim tautomeric
attracted widespread attention due to the interaction7 (Figure 2). The significance of
diverse range of pharmacological activities. this tautomeric interaction can also be seen
These structures are defined by the location when a 4(3H)-quinazolinone containing a
of the oxygen and the hydrogen on the methyl in the 3-position is subjected to
nitrogen (NH). Of the many derivatives of chlorination with POCl3, the methyl group is
quinazoline system known so far, keto- lost and chlorination proceeds8; and when
quinazolines also called as quinazolinones, the methyl group is present in the 2-position,
are the most important compounds.3 the tautomeric effect is extended generating
Depending upon the position of the keto or an exomethylene carbon, this compound can
oxo group, these compounds may be be condensed with aldehydes producing 2-
classified into three types4 (Figure 1): 2(1H) styryl-4(3H)-quinazolinones. The significance
quinazolinones 2, 4(3H)-quinazolinones 3 of these extended tautomeric effects is that
and 2,4(1H,3H)-quinazolinedione 4 . they enhance reactivity of the substituted
Of the three quinazolinone structures 4(3H)-quinazolinones.9
4(3H)-quinazolinones are most prevalent, The quinazolinone moiety is an
either as intermediates or as natural important pharmacophore showing many
products in many proposed biosynthetic types of pharmacological activities.10 The
pathways.3 This is partly due to the structure quinazolinones are considered to be a
being derived from the anthranilates “privileged structure” for drug development.11
(anthranilic acid or various esters, isatoic The chemistry of 4(3H)-quinazolinone has
anhydride, anthranilamide and received an increasing interest because of its
anthranilonitrile) while the 2(1H)- biological significance. Many derivatives of
quinazolinone is predominantly a product of this system showed antifungal12, anti-
anthranilonitrile or benzamides with bacterial13, anticancer14, anti-inflammatory15,
nitriles.5 anticonvulsant16, immunotropic17,
hypolipidemic18, antiulcer19, analgesic20 and
CHEMISTRY antiproliferative21 activities. Structure
Although quinazolinone chemistry is activity relationship studies of quinazolinone
considered to be an established area, newer ring system revealed in various literatures22-
24 suggest position 2, 6 and 8 are very much
1School of Pharmaceutical Sciences, Jaipur
important for structure activity studies and
National University, Jagatpura, Jaipur- 302025,
position 3 should be attached to different
Rajasthan, India. heterocyclic rings for better
E-mail: arunmahato@gmail.com chemotherapeutic activity.
*Correpsponing author
BIOLOGICAL ACTIVITIES
2LBS College of Pharmacy, Udai Marg, Tilak In light of the growing number of
Nagar, Jaipur- 302004, Rajasthan, India. applications in recent years there has been
Epilepsy is ubiquitous disease characterized
by recurrent seizures and inflicts more than
60 million people worldwide according to
epidemiological studies.26-28 Every year
approximately 250000 new cases are added
to this figure. It is roughly estimated that 28-
30% of patients are resistant to the available
medical therapies. Despite the development
of several new anticonvulsants29.30, the
treatment of epilepsy remains still
inadequate, and the patients suffer from a lot
of specific problems like neurotoxicity,
depression and other CNS related diseases.
Although several new anticonvulsants are
already in clinical use, some types of seizures
are still not adequately treated with current
therapy and have limitations, intolerable side
effects. In response to these limitations, the
development of new drugs to optimally
manage seizures has been strongly
advocated. Thus the search for new
anticonvulsant drugs continues to be an
active area of investigation in medicinal
chemistry.31
A literature survey revealed that the
presence of aromatic or aliphatic group at
position 2 and a substituted aromatic ring at
position 3 are an essential requirement for
CNS activities predominantly anticonvulsant
properties. Various hypotheses were
analyzed before the chemical synthesis of
proposed compounds. First hypotheses was
inspired from the 4 (3H)-quinazolinone
nucleus containing well known CNS active
Methaqualone (2-methyl-3-o-tolyl-4(3H)-
quinazolinone) 5. Modifications at the second
and third position of this agent have lead to
the generation of many CNS active agents.
Second hypotheses explained, methyl group
at the second position is not necessary for
the CNS activity and other groups can also
lead to potent CNS active agents.32-33 A
literature survey exposed that replacement
of the methyl group at the second position by
some other functionality such as alkyloxy
methyl or alkylthiomethyl groups reportedly
yielded structural analogues which retained
the anticonvulsant activity. The
anticonvulsant activity of quinazolinone
derivatives was attributed to its ability to
bind the noncompetitive site of α-amino-
hydroxy-methyl-4-isoxazolepropionic acid
(AMPA) receptors.34
Since the discovery of methaqualone 5
(Figure 3) as a sedative hypnotic, the search
for new anticonvulsant drugs with reduced
toxicity and fewer side effects has been
continuous. 35-36 Our literature survey
revealed that replacement of the methyl
group by some other functionality such as
alkylthiomethyl or alkyloxymethyl groups
reportedly yielded structural analogues
which retained the anticonvulsant activity.37
In a previous report, compounds 6a, b
(Figure 3) were synthesized and tested for

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 REVIEW ARTICLE

O O O
O O
NH N NH

N N N
N NH N NH major tautomer H H

N N N O N O
H H OH OH

1 2 3 4 N N

N N
H
Figure 1: Core structures of quinazoline and quinazolinone alkaloids Figure 2: Diagram of the tautomeric states of 2-methyl-4(3H)-
quinazolinone

H3C R
O O

N N NHR O
N CH3 N N
N
5 O
N
Cl Cl 7
6
Figure 3: Known anticonvulsant compounds. 6a: R = 4-(2- Figure 4: 3-(arylideneamino)-2-phenylquinazoline-4(3H)-ones. R =
chlorophenyl)-piperazin-1-ylmethylaminocarbonyl, 6b: R = H substituted aldehydes

R R
O O
R
O O N N
N
R
N N
N S
N N N N N N
N NH N N N N CH3
N
R
S 11
8 R 9 10
Figure 5: Fused quinazolinones Figure 6: 2-methyl-3-(1’3’4’thiadiazoyl)-4-(3H) quinazolinones

O O S
R' H 13a, R = N CH3
H H2 N N C R
N N C N Me
R'' N C6H5 13b, R = N
Me
N CH3 13
Et
13c, R = N
12 Et
Figure 7: 2-methyl-3-(substituitedmethylamino)-(3H)-quinazolin-4- Figure 8: 2-phenyl-3-substituted quinazolin-4(3H)-ones
ones, NR’R” = substituted amines

their anticonvulsant activity, which was
comparable to that of diazepam.38 As a result,
these compounds are potential leads for
further design of more active compounds.
Antimicrobial Activity (Antibacterial,
Antifungal, Anti-HIV)
4(3H)-Quinazolinones with 3-substitution
has been reported to be associated with
antimicrobial properties.39-41 The 3-
substitution which were reported are various
substituted phenyl ring moieties42, bridged
phenyl rings43, heterocyclic rings44,45 and
aliphatic systems.46 2,3-Substituted- 4(3H)-
quinazolinones were reported to possess
antimicrobial properties.47 Hydrazine
derived Schiff bases have potential
antibacterial activity.48 Expecting an
enhancement of biological activity recently
Nanda et al.. have placed two potential bio-
active sites (Figure 4), a quinazolone moiety
as well as a Schiff base in the system 7.49
1,2,4,5-Tetrazines are an important class
of heterocycles that find many practical and
synthetic applications.50 Similarly,
derivatives of 1,2,4-triazole and 1,2,4-
triazine have been found to possess wide
spectrum of pharmacological, medicinal and
biological activities.51-54 The indole nucleus
plays an important role as a common deno -
minator for various biocidal activities.55-57
In light of the above observations and
keeping in mind that most of the biologically

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 REVIEW ARTICLE

O S H
H 14a, R = N CH3 N SCH3
N N C R
Me O S
N CH3 14b, R = N S
Me S CH3
14 N H3C N S
Et H H
14c, R = N
Et 15 16
Figure 9: 2-methyl-3-substituted quinazolin-4(3H)-ones Figure 10: Structures of Brassinin 15 and Sulforamate 16

O S 18 R1 = R2 =R3 = H
R3
R1 17a, NR1R2 = N N F R1 O
19 R1 =R3 = H; R2 = Cl
HN S N
R2 NH
N 20 R2 =R3 = H; R1 = Cl
H3C N N
17 R2 21 R1 = H; R2 = CH3; R3 = F
Figure 11: 4(3H)-quinazolinone derivatives with dithiocarbamate Figure 12: Quinazolinone derivatives as PARP inhibitors
side chain

O O O
N N CH3 CH3 C2H5
N N N

N C N S C N N N N N H3CO N N
Cl N Cl N N
HS
ClH2C
22a 22b 23 24 25
Figure 13: Structural unit expressing potent leishmanicidal activity Figure 14: Potent compounds with leishmanicidal activity

O
I R2
N R1 R1 = allyl; R2 = Br
H H
OO N NH2 O O N NH2 N S
O
6
Cl CO2CH3.HCl 28
N N
O
I 29, R1 = R2 = allyl
N N N R1

N SR2 30, R1 = benzyl; R2 = allyl

26 27 29-30
Figure 15: Non-peptidic human GH secretagogues Figure 16: 2-alkylthio-6-iodo-3-substituted-quinazolin-4-one derivatives

active quinazolinones are either C-2 or N-3
mono- and/or disubstituted derivatives,
Pandey et al. fused indole, 1,2,4-triazole,
1,2,4-triazine and 1,2,4,5-tetrazine nuclei in
between N-1 and C-2 positions of
quinazolinone ring (Figure 5) to get novel
fused systems, triazolo[4,3-a]-quinazolin-7-
ones, tetrazino[4,3-a]-quinazolin-8-ones and
indolo[2,3-c][1,2,4]- triazino[4,3-a]-
quinazolin-8-ones. Preliminary experiments
were carried out to determine the
antibacterial activities of titled compounds in
vitro against (i) Gram-positive bacteria:
Streptococcus pneumoniae, Bacillus subtilis
and (ii) Gram-negative bacteria: Escherichia
coli, Pseudomonas aeruginosa by disc
diffusion method. From the antimicrobial
screening it was found that triazolo[4,3-a]-
quinazolin-7-ones 8 seemed to be more The biological activities of 1, 3, 4-
potent than tetrazino [4,3-a]-quinazolin-8- thiadiazoles, including antimicrobial
ones 9 and indolo[2,3-c][1,2,4]-triazino[ 4,3- activities were reported.59,60 With a view to
a]-quinazoline-8-ones 10. The data also explore the versatile lead molecule 4(3H)-
revealed that presence of triazole moiety at N- quinazolinones, a series of novel 2-methyl-3-
1 and C-2 exerted more influence on the (1’3’4’thiadiazoyl)-4-(3H) quinazolinones
antimicrobial profile than triazine and (Figure 6) have been synthesised by reacting
tetrazine moieties. Therefore, it can be 2-amino-5-aryl/alkyl-1’3’4’-thiadiazoyl with
inferred that presence of triazole nucleus at N- 2-substituted benzoxazin-2-one. The
1 and C-2 of quinazolinone ring works better designed compounds 11 were screened in
for antimicrobial activity of this series of vitro for antibacterial activity on
compounds than others.60 Titled compounds Staphylococcus aureus, Bacillus subtilis, and
were also screened for their antifungal activity Escherichia coli. Antifungal activity was
against Candida albicans, Aspergillus screened against Candida albicans,
fumigatus, Aspergillus flavus and Aspergillus Aspergillus niger, and Curvularia lunata.
niger. The screening data of antifungal activity Synthesised compounds exhibited both
of these series of compounds shows moderate antibacterial and antifungal activity.61
to good antifungal activity.58 Alagarsamy et al. synthesized 2- methyl -3-

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 REVIEW ARTICLE
O O O chemo-preventive agent Sulforamate67 16
OH i NH ii NH
NH2 N OEt N NH2
iii
O quinazolinone
NH
N O
H myelogenous leukemia K562 cells by MTT
Scheme 1. Griess synthesis of 4(3H)-quinazolinone and 2,4(1H,3H)-quinazolinedione.
Reagents and conditions: i) HCN, EtOH; ii) NH4OH, reflux; iii) H2O
(Substituited methylamino)-(3H)-quinazolin- lower activity. All the compounds showed
4-ones 12 by condensing the active hydrogen significant anti-inflammatory activity. The
atom of the amino group of 3-amino-2- compounds exhibited moderate to good
methyl-(3H)-quinazolin-4-one with activity against S. typhimurium, P. aeruginosa,
formaldehyde and appropriate amines S. paratyphi B, Proteus vulgaris, E. tarda and
(Figure 7). Investigation of antimicrobial Bacillus subtilis.63
activity of the test compounds were Similarly another series of novel 2-
performed by agar dilution method against 7 methyl-3-substituted quinazolin-4-(3H)-ones
pathogenic bacteria (K. Pneumoniae, P. 14 have been synthesized by treating (2-
aeruginosa, E. tarda, B. subtilis, S. methyl-4-oxo-3H-quinazolin-3-yl) dithio
typhimurium, P. vulgaris and S. paratyphi) carbamic acid methyl ester with different
and 3 pathogenic fungi (C. albicans, A. niger amines, the starting material dithio
and M. audouinii). All compounds showed carbamate was synthesized from anthranilic
moderate activity against the tested bacteria acid. The compounds synthesized (Figure 9)
and fungi. Anti-HIV activity of the test were investigated for analgesic, anti-
compounds was also performed against inflammatory and antibacterial activities.
replication of HIV-I (IIIB) and HIV-II (ROD) in The compound with methyl substitution 14a
MT-4 cells. Few compound showed 25% shown good analgesic activity, with the
against HIV-I (IIIB) and HIV-II (ROD).62 increased liphophilicity (dimethyl group),
compound 14b shown increased activity.
Anti-inflammatory and Analgesic Activity Further increase in liphophilicity (diethyl
Bacterial infections often produce group) 14c led to further increase in
inflammation and pain. In normal practice, analgesic activity. Substitution with alicyclic
two groups of agents (Chemotherapeutic, amines retains the activity. Placement of
analgesic and anti-inflammatory) are alicyclic amines with additional heteroatom
prescribed simultaneously. The compounds led to further decrease in activity. The anti-
possessing all three activities are not inflammatory activity data revealed that all
common.63,64 the test compounds protected rats from
In view of these facts a series of novel 2- carrageenan-induced inflammation and were
phenyl-3-substituted quinazolin-4(3H)-ones more potent than the earlier reported 2-
13 have been synthesized by treating methyl- phenyl-3-subtituted quinazolines.66 The
N-(2-phenyl quinazolin-3-yl-4(3H)- result of antibacterial activity indicates that
one)dithiocarbamate with different amines, all the test compounds exhibited moderate
the starting material dithiocarbamate was activity against the tested bacteria, S.
synthesized from anthranilic acid. The title typhimurium, P. aeruginosa, S. paratyphi B,
compounds (Figure 8) were investigated for Proteus vulgaris, E. tarda and Bacillus subtilis.
analgesic, anti-inflammatory and The results of analgesic and anti-
antibacterial activities. The compound with inflammatory activities indicate that the
methyl substitution 13a shown good replacement of C-2 phenyl group of 2-
analgesic activity, with the increased phenyl-3-substituted quinazolines by C-2
liphophilicity (dimethyl group) compound methyl group showed increase in activity.64
13b shown increased activity. Further
increase in liphophilicity (diethyl group) 13c Antitumor Activity
led to further increase in analgesic activity. Structure modification of folic acid led to the
Substitution with alicyclic amines led to discovery of a number of antifolates as
decrease in activity. Placement of alicyclic efficient anticancer agents.65 Recently,
amines with additional heteroatom led to Brassinin68615 (Figure 10), a PARP-1 (IC50: 21 nM), and exhibited an
further decrease in activity. In general the dithiocarbamate isolated from cabbage, was
compounds with aliphatic open chain reported to have cancer chemo-preventive
substitution showed the better analgesic activity, and its structural modification led to
activity. Aromatic substitution showed still the design and synthesis of a potential cancer
Inventi Rapid: Med Chem Vol. 2, Issue 1
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(Figure 9). More recently, a series of
dithiocarbamate compounds have been
synthesized and found to possess in vitro and
in vivo antitumor activity.68,69
In an effort to look for the possible
nonclassical antifolates acting as antitumor
agents, Cao et al. incorporated
dithiocarbamate moiety with 4(3H)-
quinazolinone. A series of 4(3H)-
derivatives 17 with
dithiocarbamate side chains were
synthesized and tested for their in vitro
antitumor activity against human
(3-(4,5-dimethylthiazo-2-yl) -2 , 5- diphenyl-
tetrazolium bromide) assay.70 Among them,
(3,4-dihydro-2-methyl -4-oxoquinazolin-6-
yl)-methyl-4-(4-fluorophenyl)- piperazine-1-
carbodithioate 17a (Figure 11) exhibited
significant inhibitory activity against K562
cells with IC50 value of 0.5 µM.65
Poly (ADP-Ribose) Polymerase Inhibitory
Activity
Poly(ADP-ribose) polymerase (PARP) is an
abundant nuclear enzyme in eukaryotic cells
that has been implicated to become activated
in response to DNA damage. Activated PARP
catalyzes the transfer of ADP-ribose units
from nicotinamide adenine dinucleotide
(NAD+) to nuclear acceptor proteins such as
histones, topoisomerases, DNA polymerases,
DNA ligases and PARP itself. Excessive
activation of PARP consumes NAD+ and
consequently ATP, culminating in cell
dysfunction or necrosis. Furthermore, PARP
has also been implicated in a caspase-
independent apoptosis pathway mediated by
apoptosis-inducing factor.71 PARP inhibitors
provided remarkable protection from tissue
damage in various forms of reperfusion
injury, inflammation and neurotoxicity in
animal models.72 Thus, inhibition of PARP by
pharmacological agents could be useful in the
treatment of inflammatory disease,
neurodegenerative disease and several other
diseases involved in PARP activation.73
Iwashita et al. had recently discovered
two classes of quinazolinone structure and
quinoxaline structure as potent and brain
penetrable PARP-1 inhibitors which can
represent an attractive therapeutic candidate
for neurodegenerative disorders such as
cerebral ischemia or Parkinson’s disease.73
They also discriminated between PARP-1
and PARP-2 using SBDD analysis by a
combination of X-ray analysis and homology
modeling. In general, the inhibitory potency
of these derivatives was found to be largely
dependent on the unique linker of the
quinazolinone ring. Quinazolinone linked
with a 4-phenyl-tetrahyropyridine moiety 18
(Figure 12) exhibited strong potency against
appropriately 30-fold less potency against
PARP-2 (IC50: 608 nM). The addition of a
chloro group at the 8-position 19, which is
important for bioavailability and brain
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 REVIEW ARTICLE
penetration, resulted in almost the same
activity and selectivity, while the addition of
a chloro group at the 5-position 20 and a
methyl group at the 8-position 21 showed 3
times lower selectivity than 18.73
Leishmanicidal Activity
It has been found that compounds possessing
structural unit 22a and 22b (Figure 13)
either in flexible or in rigid forms express
potent leishmanicidal activity.74 Repetition of
such unit often enhances leishmanicidal
activity. The antiparasitic activity of azoles
such as imidazoles, thiazoles and thiadiazoles
is well documented75,76 and their fusion with
other heterocycles often ameliorate or
diminish the bioresponses depending upon
the nature of substituents and position of
their fusion.
Ram et al. synthesized compounds of
prototypes: quinazolin-4-one, 1,2,4-
triazolo[4,3-a] quinazolin-5-one and 1-(4-
quinazolinon-2-yl)-1,2.4-triazolo[4,3-
a]quinazolin-5-one only compounds of
prototype second displayed high order of
leishmanicidal activity while others were
either inactive or poorly active. The most
potent compound 23 exhibited 95% of
inhibition, closer to pentamidine. The other
two compounds 24 (81%) and 25 (80%) also
demonstrated the activity nearly of the same
order (Figure 14).77
Structure activity relationship showed
that the compounds only with 1,2,4-triazolo[
4,3-a] quinazolinone skeleton display potent
leishmanicidal activity. The order of activity
varies with nature and position of the
substituent. Methyl substituent at position 4
alone or together with any of the
substituents CH3, SH and CH2Cl at position 1
ameliorate the activity. The degree of
leishmanicidal activity due to mere change in
substituent at position 1 in 23, 24 and 25
decreases in the order of CH2Cl > H > SH.
Presence of bulky substituent like (4-
quinazolinon-2-yl)thiomethyl at position 1
led to complete loss of activity possibly due
to poor solubility and steric effect. Thus
1,2,4-triazolo[4,3-a]quinazolin-5-one
skeleton with chloromethyl and methyl
substituents at positions 1 and 4 respectively
are optimal requirements for potent
leishmanicidal activity.77
Growth Hormone Secretagogues
Growth hormone (GH) secretagogues have
received considerable attention in the last
several years based on promising
applications of recombinant GH in animals
and in humans. Potential therapeutic
indications for GH secretagogues in human
health include idiopathic GH defciency states
in children and adults, stimulation of
anabolic processes in the elderly and
supportive therapy in catabolic wasting
conditions including AIDS and
osteoporosis.78,79
Ye et al. designed and synthesized
quinazolinone-based compounds as a new
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class of non-peptidic human GH
secretagogues receptor agonists that evolved
from a directed screening lead 26 (hGHSr
IC50=3.5 mM, Figure 15).
Modeling guided design of quinazolinone
compound 27 led to a potency enhancement
of greater than 200-fold compared to
human growth hormone secretagogue
affinity of the screening lead 26.80
Compound 27 is the first reported non-
peptidic agonist of the human GH
secretagogue receptor. Introduction of a
phenyl group at the C-6 position of the
quinazolinone core and extension of the
amine side-chain improved the binding
activity of lead compound 26 against the GH
secretagogue receptor. It was found that in
all quinazolinone-type analogues, activities
on the human GH secretagogue receptor
increased when a phenethyl group was
positioned at the C-2 position.80
Antitubercular Activity
Tuberculosis (TB) is one of the oldest and
most pervasive diseases in history.81,82 The
Directly Observed Treatment, short-course
(DOTS) strategy, constitutes the cornerstone
of the current protocol for control of TB.
However, the three key drugs, isoniazide,
pyrazinamide and rifampicin, used in the
regimen are potentially hepatotoxic and may
lead to drug associated hepatitis.83 Despite
the undoubted success of DOTS strategy, the
emergence of multi drug resistant strains,
recurrently isolated from patient's sputum,
darken the future. Furthermore, one of the
main causes for the prevalence of TB is
synergy with Human Immunodeficiency
Virus (HIV) epidemic where 31% of new TB
cases were attributable to HIV co-infection.84
It was reported recently that 2 and/or 4-
substituted thioquinazoline derivatives were
identified as a possible pharmacophore for
antitubercular activity.85-88 In the quest for
biologically potent anti-tubercular agents, Al-
Deeb et al. synthesized and screened some 2-
alkylthio-6-iodo-3-substituted-quinazolin-4-
one derivatives (Figure 16) to mimic those
reported as potential antitubercular agents.
The results indicate that compounds 28, 29
and 30 showed 96%, 97% and 94%
inhibition, respectively, at a concentration of
6.25µg/ml. SAR observation showed that, an
electron withdrawing group on the sulphur
atom at position 2 in addition to an allyl
and/or benzyl moiety at position 3 has a
positive impact on the antitubercular
activity.89
CONCLUSION
Given the advances in synthetic methodology
and technology in recent years and the
continued interest in the quinazoline
skeleton in medicinal chemistry and drug
development, the development of efficient
and reliable methods for the construction of
these molecules will ensure that this is an
active and important area of research in
heterocyclic chemistry.
REFERENCES AND NOTES
1. Griess, P. Ber. Dtsch. Chem. Ges. 1903, 36, 800.
2. Oriefs, Ber. Dtsch. Chem. Ges. 1869, 2, 416.
3. Dewick, P. M.; Medical Natural Products John
Wiley & Sons Ltd.: U.K, 2009, pp 395-397.
4. Griess, P. Ber. Dtsch. Chem. Ges. 1869, 2, 415.
5. Wiklund, P.; Bergman, J. Curr. Org. Synth. 2006,
3, 379.
6. Leong, S.; Schürer, J.; Briberg, A. J. Nat. Prod.
2008, 71, 1445.
7. Weber, C.; Demeter, A.; Szendrei, G.; Greiner, I.
Tetrahedron Lett. 2003, 44, 7533.
8. Bogert, M. T.; Seil, H. A. J. Am. Chem. Soc. 1907,
29, 517.
9. Bogert, M. T.; May, C. E. J. Am. Chem. Soc. 1909,
31, 507.
10. Reddy, P. S.; Reddy, P. P.; Vasantha, T.
Heterocycles 2003, 60(1), 183.
11. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem.
Rev. 2003, 103(3), 893.
12. Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte,
E.; Vericant, M. L.; Conte Ramis, J.; Merlos, M.;
Gracia-Rafanell, J. F. J. Med. Chem. 1998, 41, 1869.
13. Shiba, S., El-Khamry, A. A.; Shaban, M. E.; Atia, K.
S. Pharmazie 1997, 52, 189.
14. Abdel-Hamid, S. G.; J. Indian Chem. Soc. 1997, 74,
613.
15. Barker, A. Journal Eur. Pat. Chem. Abstr. 1995,
122, 214099.
16. Bekhit, A. A.; Khalil, M. Pharmazie 1998, 53,
539.
17. Gursoy, A.; Karali, N. Farmaco, 1995, 50, 857.
18. Fisnerova, L.; Grimova, J.; Roubal, Z.; Maturova
E.; Brunova, B. Cesk. Farm. 1986, 35, 447.
19. Kumar, A.; Sharma, S.; Bajaj, A. K.; Sharma, S.;
Panwar, H.; Singh, N.; Srivastava, V. K. Bioorg. &
Med. Chem. 2003, 11, 5293.
20. Terashima, K.; Shimamura, H.; Kawase, A;
Tanaka, Y.; Ishizuka, Y.; Sato, M. Chem. Pharm.
Bull. 1995, 43, 2021.
21. Raffa, D.; Dailone, G.; Maggio, B.; Sehillaci, D.;
Plescia, F. Arch Pharm. 1999, 332, 317.
22. Hour, M. J.; Huang, L. J.; Kuo, S. C.; Xia, Y.;
Bastow, K.; Nakanishi, Y.; Hamel, E.; Lee, K. H. J.
Med. Chem. 2000, 43, 4479.
23. Kumar, S.; Shrivastava, A. K.; Sarkar, P. C. Indian
J. Heterocycl. Chem. 1997, 7, 51.
24. Ghorab, M. M.; Abdel-Hamide, S. G.; El-Hakim A.
E.; Indian J. Heterocycl. Chem. 1995, 5, 115.
25. Gao, X.; Cai, X.; Yan, K.; Song, B.; Gao, L.; Chen, Z.
Molecules 2007, 12, 2621.
26. Loscher, W. Eur. J. Pharmacol. 1998, 342, 1.
27. Leppik, I. E. Epilepsia 1994, 35, 29.
28. Chen, L.; Sun, X. Y.; Chai, K.Y. Bioorg. Med. Chem.
2007, 15, 6775.
29. Kubota, M.; Sakakihora, Y. Brain Dev.2000, 22,
230.
30. French, J. A. Epilepsia 1999, 40, 11.
31. Patil, V. M.; Sinha, R.; Masand, N. Digest Journal of
Nanomaterials and Biostructures, 2009, 4(3), 471.
32. Boltze, K. H.; Dell, H. D.; Lehwald, H.; Loranz, D.
Arzneim-Forsch/Drug Res. 1963, 13, 688.
33. Wolfe, J.F.; Rathman ,T.L.; Sleevi, M.C.; Campbell,
J.A.; Grenn Wood ,T.D. J. Med. Chem. 1990, 33,
161.
34. H. Georgey; N. Abdel-Gawad; S. Abbas.
Molecules, 2008, 13, 2557.
35. Kacker, I.K.; Zaheer, S.H. J. Ind. Chem. Soc. 1951,
28, 344.
36. Angelos, S.A.; Meyers, J.A. J. Forensic Sci. 1985,
30, 1022.
37. Ager, R.; Harrison, D.R.; Kennwell, P.D.; Taylor,
J.B. J. Med. Chem. 1977, 20, 379.
38. Abbas S.E. Bull. Fac. Pharm. Cairo Univ. 2007, 45,
119.
39. Seshavataram, S. K. V.; Rao, N. V. S. Proc. Indian
Acad. Sci. Sec-A 1977, 85, 81.
40. Said, M. M.; Hussein, M. M. Bull. Fac. Pharm.
1994, 32, 341.
2011mc055, CCC: $10 © Inventi Journals (P) Ltd
Published on Web 25/03/2011, www.inventi.in
 REVIEW ARTICLE
41. Mishra, P.; Paneerselvam, P.; Jain, S. J. Indian
Chem. Soc. 1995, 72, 559.
42. Oza, H. B.; Joshi, D. G.; Parekh, H. H. Heterocycl.
Commun. 1997, 3, 239.
43. Kumar, P.; Nath, C.; Bhargava, K. P.; Shanker, K.
Pharmazie 1982, 37, 802.
44. Roubinek, F.; Vavrina, J.; Budesinsky, Z.; Collect.
Czec. Chem. Commun. 1982, 47, 630.
45. Elliot, M. L.; Welch, W. M. Pct. Int. Appl. WO
9743276, 1997.
46. Zhixiong, G. Y.; Bakshi, R. K.; Chen, M.; Rohrer, S.
P.; Feighner, S. D.; Pong, S. S.; Howard, A. D.;
Blake, A.; Birzin, E. T.; Locco, L.; Parmar, R. M.;
Chan, W. W. S.; Schaeffer, J. M.; Smith, R. G.;
Patchett, A. A.; Nargaund, R. P. Bioorg. Med.
Chem. Lett. 2000, 10, 5.
47. Varma R. S., Prakash R., Prasad C. R. J. Chem. Soc.
Pak. 1986, 8, 117.
48. Chohan, Z. H.; Supuran, C.T.; Scozzafava, A;
Farroq, M.A. J. Enzym. Inhib. Med. Chem. 2002,
17, 1.
49. Nanda, A.K.; Ganguli, S.; Chakraborty, R.
Molecules 2007, 12, 2413.
50. Neunhoeffer, H. In Comprehensive Heterocyclic
Chemistry, Katritzky, A. R.; Rees, C. W. Eds.;
Pergamon Press: London, 1984, Vol. 3, p. 531.
51. Kane, J. M.; Dudley, M. W.; Sorenson, S. M.;
Miller, P. F. J. Med. Chem. 1988, 31, 1253.
52. Unangst, P. C.; Shurum, G. P.; Connor, D. T.;
Dyer, R. D.; Schrier, D. J. J. Med. Chem. 1992, 35,
3691.
53. Hunt, J. T.; Mitt, T.; Borzilleri, R.; Brown, J. G.;
Fink, B.; Bhide, R. J. Med. Chem. 2004, 47, 4054.
54. Sztanke, K.; Rzymowska, J.; Niemczyk, M.; Dybala,
I.; Koizoi, A. Eur. J. Med. Chem. 2006, 41, 1373.
55. Brand, W. W.; Lovell, J. B. U.S. Patent 4, 1977,
004-017, Chem. Abstr. 1977, 87, 39704d.
56. Kumar, R.; Giri, S.; Nizamuddin, Agric. Biol.
Chem. 1988, 52, 621.
57. C.K. Ryu, J.Y. Lee, R.E. Park, M.Y. Ma, J.H. Nho,
Bioorg. Med. Chem. Lett. 2007, 17, 127.
Inventi Rapid: Med Chem Vol. 2, Issue 1
[ISSN 0976-3821]
58. Pandey, S. K.; Singh, A.; Singh, A.; Nizamuddin.
Eur. J. Med. Chem. 2008, 20, 1.
59. Shakya, A. K.; Patnaik, G. K.; Mishra, P. Eur. J.
Med. Chem., 1992, 27, 1.
60. Mishra, P.; Shakya, A. K.; Agarwal, R. K. J. Indian
Chem. Soc., 1990, 67, 520.
61. Jatav, V.; Jain, S. K.; Kashaw, S. K.; Mishra, P.
Indian J. Pharm. Sci. 2006, 68(3), 360.
62. Alagarsamy, V.; Murugeasn, S.; Dhanabal, K.;
Murugan, M.; De Clercq, E. Indian J. Pharm. Sci.
2007, 69(2), 304.
63. Alagarsamy, V.; Salomon, V. R.; Vanikavitha, G.;
Paluchamy, V.; Ravi Chandran, M.; Sujin, A. A.;
Thangathiruppathy, A.; Amuthalakshmi, S.;
Revathi, R. Biol. Pharm. Bull. 2002, 25(11), 1432.
64. Alagarsamy, V.; Murugananthan, G.;
Venkateshperumal, R. Biol. Pharm. Bull. 2003,
26(12), 1711.
65. Cao, S. L.; Feng, Y. P.; Jiang, Y. Y.; Liu, S. Y.;
Dingb, G. Y.; Lic, R. T. Bioorg & Med. Chem. Lett.
2005, 15, 1915.
66. Moriarty, R. M.; Mehta, R. G.; Liu, J.
Carcinogenesis 1995, 16, 399.
67. Gerhauser, C.; You, M.; Pezzuto, J. M. Cancer Res.
1997, 57, 272.
68. Li, R. T.; Cheng, T. M.; Cui, J. R. C. N. Patent
01118399.3, 2004.
69. Guo, W.; Ran, F. X.; Wang, R. Q.; Cui, J. R.; Li, R. T.;
Cheng, T. M.; Ge, Z. M. Chin. J. Clin. Pharmacol.
Ther. 2004, 9, 59.
70. Niu, Y. L.; Jiang, Y. Y.; Cao, S. L.; Du, W.; Zhao, Y.
F. Chin. Sci. Bull. 2003, 48, 869.
71. Yu, S.W., Wang, H., Poitras, M.F., Coombs, C.,
Bowers, W.J., Federoff, H.J., Poirier, G.G.,
Dawson, T.M. and Dawson, V.L. Science 2002,
297, 259.
72. Szabo, C.; Dawson, V. L. Trends Pharmacol. Sci.
1998, 19, 287.
73. Iwashitaa, A.; Hattorib, K.; Yamamotob, H.;
Ishidab, J.; Kidob, Y.; Kamijob, K.; Muranob, K.;
Miyakeb, H.; Kinoshitac, T.; Warizayac, M.;
Ohkuboc, M.; Matsuokaa, N.; Mutoha, S. FEBS
Letters, 2005, 579, 1389.
74. Ram, V. J.; Singha, U. K.; Guru, P. Y. Eur. J. Med.
Chem. 1990, 25, 533.
75. Gosh, B. K.; Ray, D. H.; Chatterjee, A. N. J. Trop.
Med. Hyg. 1989, 92, 383.
76. Steck, E. A. Progress in Drug Research, 1974, 18,
290.
77. Ram, V. J.; Goel, A.; Verma, M. Bioorg & Med.
Chem. Lett. 1994, 4(17), 2087.
78. Rosen, T.; Johannsson, G.; Johannsson, J.-O.;
Bengtsson, B.-A. Horm. Res. 1995, 43, 93.
79. Strobl, J. S.; Thomas, M. J. Pharmacol. Rev. 1994,
46, 1.
80. Ye, Z.; Gao, Y.; Bakshi, R. K.; Chen, M.; Rohrer, S.
P.; Feighner, S. D.; Pong, S. S.; Howard, A. D.;
Blake, A.; Birzin, E. T.; Locco, L.; Parmar,R. M.;
Chan,W.; Schaeffer, J. M.; Smith,R. G.; Patchett, A.
A.; Nargund, R. P. Bioorg & Med. Chem. Lett.
2000, 10, 5.
81. Okunade, A. L.; Elvin-Lewis, M. P. F.; Lewis, W.
H. Phytochemistry, 2004, 65, 1017.
82. Yves, L. J.; Bioorg. Med. Chem. 2007, 15, 2479.
83. Yew, W.W.; Leung, C. C. Respirology, 2003, 11,
699.
84. Espinal, A.M.; Tuberculosis, 2003, 83, 44.
85. Kunes, J.; Bazant, J.; Pour, M.; Waisser, K.;
Slosarek, M.; Janota, J. Il Farmaco, 2000, 55,
725.
86. Waisser, W.; Bures, O.; Holý, P.; Kunes, J.;
Oswald, R.; Jirásková, L.; Pour, M.; Klimesová,
V.; Palát, K.; Kaustová, J.;. Danse, H. M.;
Möllmann, U.; Pharmazie, 2003, 58(2), 83.
87. Waisser, K.; Perina, M.; Kunes, J.; Klimesová, V.;
Kaustová, J. Il Farmaco, 2003, 58, 1137.
88. Waisser, K.; Matyk, J.; Divisová, H.; Husáková,
P.; Kunes, J.;. Klimesová, V.; Palát, K.;
Kaustová, J. Arch. Pharm. (weinheim), 2007,
340(5), 264.
89. Al-Deeb, A. O.; Alafeefy, A. M. World Applied
Sciences Journal, 2008, 5(1), 94.
2011mc055, CCC: $10 © Inventi Journals (P) Ltd
Published on Web 25/03/2011, www.inventi.in