Synthesis and Anticonvulsant Activity of N-(Substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamides

Article abstract of DOI:10.1002/ardp.201600024

A series of new N-(substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamides were designed, synthesized, and evaluated for their anticonvulsant activity. Most of the synthesized compounds exhibited potent anticonvulsant activities in the maximal electroshock (MES) and pentylenetetrazol (PTZ) test. The most promising compound 4c showed significant anticonvulsant activity with a protective index value of 3.58. The compounds 4a–c were also found to have encouraging anticonvulsant activity in the MES and PTZ screen when compared with the standard drugs, valproate and methaqualone. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drugs.

Full text of DOI:10.1002/ardp.201600024

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Arch. Pharm. Chem. Life Sci. 2016, 349, 1–6
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Full Paper
Synthesis and Anticonvulsant Activity of N-(Substituted)-1-methyl-
2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamides
Hemavathi N. Deepakumari1, Bidarur K. Jayanna2, Maralekere K. Prashanth2,
Hosakere D. Revanasiddappa3, and Bantal Veeresh4
1
Department of Chemistry, Bharathi College, Bharathinagara, Mandya, Karnataka, India
Department of Chemistry, B. N. M. Institute of Technology, Bangaluru, Karnataka, India
Department of Chemistry, University of Mysore, Manasagangothri Mysore, Karnataka, India
Department of Pharmacology, G Pullareddy College of Pharmacy, Mehdipatnam, Hyderabad, India
2
3
4
A series of new N-(substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamides were
designed, synthesized, and evaluated for their anticonvulsant activity. Most of the synthesized
compounds exhibited potent anticonvulsant activities in the maximal electroshock (MES) and
pentylenetetrazol (PTZ) test. The most promising compound 4c showed significant anticonvulsant
activity with a protective index value of 3.58. The compounds 4a–c were also found to have
encouraging anticonvulsant activity in the MES and PTZ screen when compared with the standard
drugs, valproate and methaqualone. The same compounds were found to exhibit advanced
anticonvulsant activity as well as lower neurotoxicity than the reference drugs.
Keywords: Anticonvulsant / Glycosmicine / MES / Neurotoxicity / PTZ
Received: January 29, 2016; Revised: May 3, 2016; Accepted: May 6, 2016
DOI 10.1002/ardp.201600024
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
The structure–activity relationship (SAR) studies of clinically
available AEDs and other anticonvulsant active compounds
Introduction
Epilepsy is a chronic disorder of the brain characterized by
recurrent unprovoked seizures that affects about 1% of the
world’s population [1, 2]. Despite the availability of many
antiepileptic drugs (AEDs), there is still an urgent need for the
development of more effective and safer AEDs, as about
30% of epileptic patients are not seizure-free with the
existing AEDs [3, 4]. Moreover, their usage is associated with
undesirable numerous side effects including drowsiness,
ataxia, gastrointestinal disturbances, hirsutism, and megalo-
blastic anemia [5]. Thus, there is an enormous need for the
development of novel AEDs with fewer side effects and more
effectiveness.
showed that most of these compounds included quinazoli-
none moiety in their molecules. Quinazolinones (metha-
qualone, quinethazone, albaconazole, febrifugine, afloqualone,
fenquizone, raltitrexed, etc.) are considered to be an
important chemical synthon of various physiological signifi-
cance and pharmaceutical utility like anticonvulsant, sedative,
tranquilizing, analgesic, antirheumatic, hypotensive, anti-
allergic, antidiabetic, diuretic, antimalarial, etc. Moreover,
they continued to attract a widespread interest for a long
time due to their diverse pharmacological activities [6]. As
such, quinazoline-2,4(1H,3H)-dione derivatives have been
widely used as key structures in the production of medicinal
drugs [7].
In search of new anticonvulsant agents, the titled com-
pounds (4a–g) possessed all the required pharmacophoric
elements as the phenyl ring attached to the nitrogen moiety
can be referred to the aryl ring (lipophilic aryl ring), the
nitrogen of the amide group can act as a hydrogen bond
donor and the amide keto group can act as a hydrogen bond
acceptor (HBA). The proposed quinazolinone seems to
Correspondence: Dr. Maralekere K. Prashanth, Department
of Chemistry, B. N. M. Institute of Technology, Bangaluru,
Karnataka, India.
E-mail: prashanthmk87@gmail.com
Fax: 91-80-26710881
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resemble better with standards. With this as background and
in continuation of our research program on design and
synthesis of new anticonvulsant agents [8–10], the present
work highlights the importance of the synthesis of prototypes
and coupled to substituted anilines to give desired com-
pounds 4a–g.
Anticonvulsant activity
of
N-(substituted)-1-methyl-2,4-dioxo-1,2-dihydroquinazo-
Maximal electroshock (MES), pentylenetetrazole (PTZ), and
picrotoxin seizure threshold tests were well known to
evaluate the potential anticonvulsant activity of compounds
under investigation [11]. At the present time, there are three
in vivo models that are routinely used by most AED discovery
programs. They include the MES, PTZ, and picrotoxin model.
The anticonvulsant activities of the newly synthesized
compounds were evaluated by the use of standard technique.
The preliminary screening was performed at 1.0 mmol/kg of
all synthesized compounds 4a–g by use of PTZ, MES, and
picrotoxin models of seizures. The MES test is associated with
the electrical induction of the seizure, whereas PTZ and
picrotoxin methods involve a chemical induction to generate
the convulsion [12]. The results are presented in Table 1.
The preliminary anticonvulsant screening showed that
some of these compounds are less active; however, com-
pounds 4a–c and 4e were active against MES, PTZ, and
picrotoxin tests, among which compounds 4a and 4c
presented 100% protection. The compounds 4b and 4e
exhibited 100 and 50% protection, respectively, in MES test.
The compounds (4a–c and 4e) that exhibited significant
line-3(4H)-carboxamides and efficacy of their anticonvulsant
activity.
Result and discussion
Chemistry
Most target N-(substituted)-1-methyl-2,4-dioxo-1,2-dihydro-
quinazoline-3(4H)-carboxamides (4a–g) reported herein were
prepared according to Scheme 1. A variety of combinatorial
approaches have been described by which pharmacophophoric
groups were attached to such relatively rigid scaffold.
The naturally occurring plant-derived 1-methylquinazoline-
2,4(1H,3H)-dione (glycosmicine) 1 used to prepare target
compounds was obtained from synthesized by published
method [7]. The structures of the synthesized compounds
1
were deduced on the basis of H NMR, IR, and mass spectra.
The composition of all the compounds was obtained by
elemental analysis. The proton magnetic resonance spectra
of synthesized compounds have been recorded in CDCl3.
In addition, the chemical shift and multiplicity patterns
correlated well with the proposed structures. The elemental
analysis data showed good agreement between the experi-
mentally determined values and the theoretically calculated
values.
Amino function of compound 1 was reacted with ethyl
chloroformate in dry benzene in the presence of triethyl-
amine at room temperature to afford a quantitative yield
of ethyl 1-methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-
activity were subsequently subjected to
a quantitative
determination of the pharmacological parameters, that is,
median effective dose (ED50) and toxic dose (TD50) in mice.
Results of the quantitative test for these compounds, along
with the data on the current AEDs (methaqualone and
valproate) are shown in Table 2.
The protective index (PI) (TD50/ED50) is considered to be an
index representing the margin of safety and tolerability
between anticonvulsant doses and doses of anticonvulsant
drugs exerting acute adverse effects (e.g., sedation, motor
coordination impairment, ataxia, or other neurotoxic man-
ifestations) [13]. The compound 4e showed a higher PI than
all the standard drugs. The compound 4c gave an ED50 of
0.24 mg/kg and a TD50 of 0.86 mg/kg, resulting in a high PI,
carboxylate (2). Then compound
3 was obtained after
hydrolysis using 1 N sodium hydroxide/ethanol solution at
room temperature for 12 h. Further acid group in compound 3
was converted to their corresponding acid chlorides by
reaction with an excess of thionyl chloride in dichloromethane
Scheme 1. Synthetic route to 4a–g. Reagents and
conditions: (i) ethyl chloroformate, TEA, benzene,
8 h; (ii) SOCl2, EtOH, NaOH, 12 h; (iii) substituted
phenylamine (a–g), SOCl2, CH2Cl2, reflux.
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Table 1. Anticonvulsant activity of the new-synthesized compounds (1.0 mmol/kg), valproate (1.5 mmol/kg), and
methaqualone (1.4 mmol/kg).
Compounds
MESa) (% protection)
PTZb) (% protection)
Pictrotoxin (% protection)
4a
4b
4c
4d
100
100
100
0.0
50
100
70
100
25
100
50
100
0.0
40
4e
67
4f
4g
33
10
100
100
–
66
50
100
100
–
10
0.0
50
100
–
Methaqualone
Valproate
Control
Values are expressed as mean ꢀ SE. n ¼ 6 animals in each group.
a)Maximal electroshock seizure test.
b)Pentylenetetrazole test.
that is, TD50/ED50, of 3.58 when compared to phenobarbital
and valproate. Almost all the PI values of the selected
compounds (2.93, 2.07, 3.58, and 1.41) were higher than or
equal to the reference drugs as compared to 1.14 for
methaqualone and 2.0 for valproate.
In the present series of compounds, the active compounds
possess all the requirements essential for anticonvulsant
activity as proposed by Dimmock and Baker [14]. Thus, our
new proposal for a pharmacophore model includes factors
which are responsible for bioactivity. On correlating the
structures of the synthesized compounds with their biological
activity, it has been observed that compounds bearing the
para-substituted halogens groups like chloro, bromo, and
fluoro on phenyl ring possess high potency in MES, PTZ, and
picrotoxin tests. Introduction of halogen on the phenyl ring
changed (reduced or increased) the anticonvulsant activity at
different levels. The bioevaluation led to an understanding of
the importance of the position of the halogen at the phenyl.
The compounds bearing para-substituted halogens groups
on phenyl ring showed high potency in MES and PTZ tests.
Whereas replacement of para position with halogens groups
on phenyl ring has resulted in compounds with decrease
in anticonvulsant activity. Compounds 4a–c and 4e show
apparent activity in MES, PTZ, and picrotoxin screen, and
which is considered to be the optimum lipophilicity for the
congeners that act on the central nervous system. It may
indicate the importance of lipophilicity as well as electronic
properties of the substituents on the activity of these
compounds.
SAR recommendations withdrawn from those findings
revealed that (i) halogens like chloro, fluoro, and bromo
groups connected to phenyl ring as in para position is essential
for anticonvulsant activity; (ii) the removal of halogen
substitution of para position will yield compounds with
Table 2. Comparison of the anticonvulsant activities (ED50), acute neurotoxic effects (TD50), median lethal doses (LD50),
therapeutic and protective indexes of the most promising anticonvulsant new-synthesized compounds and standards in
mice.
Therapeutic
Compound
ED50 (mg/kg)
TD50 (mg/kg)
LD50 (mg/kg)
index
Protective index
Valproate
Methaqualone
4a
4b
4c
4e
4.8
9.6
11.9
2.00
1.13
1.02
1.18
0.92
2.48
1.40
3.64
2.48
4.91
1.64
2.0
1.40
0.31
0.41
0.24
0.56
1.60
0.91
0.85
0.86
0.79
1.14
2.93
2.07
3.58
1.41
ED50, median effective dose providing anticonvulsant protection in 50% of mice against pentylenetetrazole (PTZ)-induced
seizures; TD50, median toxic dose producing minimal neurological toxicity in 50% of mice subjected to the Chimney test; LD50
,
median lethal dose that causes 50% mortality in mice; therapeutic index, LD50/ED50; protective index, TD50/ED50
.
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decrease in anticonvulsant activity; and (iii) lipophilicity
manipulates the magnitude of anticonvulsant potency of
such chemical synthons.
Preparation of 1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxylic acid (3)
To a solution of compound 2 (10.0 mmol) in EtOH was added
sodium hydroxide (1 N, 10 mL), and the resulting mixture
stirred at room temperature for 12 h. EtOH was removed
under reduced pressure, water was added to the residue
and the mixture was acidified to pH 2 with 2 M HCl and
extracted with ethyl acetate (3 ꢂ 20 mL). The combined
extracts were dried over Na2SO4 and evaporated to give
product 3. Yield: (92%), m.p.: 264°C. Anal. calcd. for
Conclusion
In the current study, a series of novel N-(substituted)-1-
methyl-2,4-dioxo-1,2-dihydroquinazoline-3(4H)-carboxamide
derivatives (4a–g) were designed, synthesized, and evaluated
for anticonvulsant activity. For anticonvulsant evaluation,
three animal models were adopted, namely MES, PTZ, and
picrotoxin (Pic)-induced convulsions. The most active was 4c
which showed a PI of 3.58. This compound showed greater PI
to standard drugs. Additionally, compounds 4a and 4b
showed advanced anticonvulsant activity as well as lower
toxicity than methaqualone and valproate reference drugs.
The obtained results showed that certain compounds could be
useful as a template for future design, modification, and
investigation to produce more active analogs.
C
10H8N2O4: C, 54.55; H, 3.66; N, 12.72. Found: C, 54.35; H,
3.51; N, 12.83. 1H NMR (300 MHz, CDCl3) d: 3.78 (s, 3H, N–CH3),
7.37–7.88 (m, 4H, Ar–H), 11.02 (s, 1H, COOH). IR (Nujol, cmꢁ1):
–
–
3053–2829.5 (Ar C–H), 2738 (COOH), 1708, 1676, 1635 (C O).
MS, m/z: 220 (Mþ1).
General procedure for the synthesis of 4a–g
To the acid (3, 2 mmol) in CH2Cl2 was added an freshly distilled
thionyl chloride and refluxed for 1 h, excess of thionyl chloride
was removed in vacuo and thereafter condensed with
methylenechloride solution of substituted phenylamine
(2 mmol) and stirred for 2 h. The organic layer was washed
with water (2 ꢂ 30 mL), dried over anhydrous Na2SO4, and
concentrated to give crude product and recrystallization from
absolute ethanol gave desired compounds 4a–g.
Experimental
Materials
Elemental analysis (C, H, N) was determined using a Carlo-Erba
1160 elemental analyzer. IR spectra were recorded on a JASCO
FTIR-8400 spectrophotometer using Nujol mulls. The 1H NMR
spectra were recorded on a Varian AC 400 spectrometer
instrument in CDCl3 using TMS as the internal standard. Low
resolution ESI-MS spectra were obtained on a Varian 1200L
model mass spectrometer (solvent: CH3OH). Melting points
were determined with a Buchi 530 melting point apparatus in
open capillaries and are uncorrected. Compound purity was
checked by thin layer chromatography (TLC) on precoated
silica gel plates (Merck, Kieselgel 60 F254, layer thickness
0.25 mm).
N-(4-Chlorophenyl)-1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxamide (4a)
Yield: (81%), m.p.: 281°C. Anal. calcd. for C16H12ClN3O3: C,
58.28; H, 3.67; N, 12.74. Found: C, 58.25; H, 3.59; N, 12.83.
1H NMR (300 MHz, CDCl3) d: 3.69 (s, 3H, N–CH3), 6.19 (s, 1H,
NH), 6.78–7.79 (m, 8H, Ar–H). IR (Nujol, cmꢁ1): 3235 (N–H),
–
3051–2828 (Ar C–H), 1705, 1675, 1637 (C O). MS, m/z: 330
–
(Mþ1).
N-(4-Bromophenyl)-1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxamide (4b)
The InChI codes and NMR spectra of the investigated
compounds are provided as Supporting Information.
Yield: (78%), m.p.: 287°C. Anal. calcd. for C16H12BrN3O3: C,
51.36; H, 3.23; N, 11.23. Found: C, 51.26; H, 3.11; N, 11.39.
1H NMR (300 MHz, CDCl3) d: 3.66 (s, 3H, N–CH3), 6.78–7.92 (m,
8H, Ar–H), 8.65 (s, 1H, NH). IR (Nujol, cmꢁ1): 3230 (N–H), 3052–
Synthesis
Preparation of ethyl 1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxylate (2)
–
2829 (Ar C–H), 1703, 1678, 1632 (C O). MS, m/z: 374 (Mþ1).
–
Compound 1 (15 mmol) was refluxed with ethyl chloroformate
(15.5 mmol) in dry benzene (30mL) and in the presence of
triethylamine. Then the reaction mixture was stirred at room
temperature for about 8 h. After completion of the reaction
(TLC), the reaction mixture was quenched in ice cold water
and extracted with dichloromethane. The organic layer
was washed with 5% NaHCO3 and dried over Na2SO4 and
concentrated in vacuo to give desired product. Yield:
(96%), m.p.: 273°C. Anal. calcd. for C12H12N2O4: C, 58.06; H,
4.87; N, 11.29. Found: C, 58.01; H, 4.73; N, 11.37. 1H NMR
(300 MHz,CDCl3)d:1.36(t, 3H, –CH3),3.78(s, 3H, N–CH3),4.26(q,
2H, COO–CH2), 7.35–7.90 (m, 4H, Ar–H). IR (Nujol, cmꢁ1): 3053–
N-(4-Fluorophenyl)-1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxamide (4c)
Yield: (80%), m.p.: 277°C. Anal. calcd. for C16H12FN3O3: C,
61.34; H, 3.86; N, 13.41. Found: C, 61.21; H, 3.73; N, 13.48.
1H NMR (300 MHz, CDCl3) d: 3.72 (s, 3H, N–CH3), 7.03–7.85 (m,
8H, Ar–H), 8.86 (s, 1H, NH). IR (Nujol, cmꢁ1): 3235 (N–H), 3051–
–
2828 (Ar C–H), 1703, 1675, 1632 (C O). MS, m/z: 314 (Mþ1).
–
N-(3-Chlorophenyl)-1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxamide (4d)
Yield: (81%), m.p.: 280°C. Anal. calcd. for C16H12ClN3O3: C,
58.28; H, 3.67; N, 12.74. Found: C, 58.16; H, 3.54; N, 12.91.
1H NMR (300 MHz, CDCl3) d: 3.70 (s, 3H, N–CH3), 7.01–7.88
–
2829.5 (Ar C–H), 1708, 1675, 1635 (C O). MS, m/z: 249 (Mþ1).
–
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(m, 8H, Ar–H), 8.75 (s, 1H, NH). IR (Nujol, cmꢁ1): 3238 (N–H),
eliciting convulsions in 100% of control mice of dose 8 mg/kg.
Seizures and tonic-clonic convulsions, hypnosis, and death
were recorded. Sodium valproate (200 mg/kg) and methaqua-
lone (300 mg/kg) were used as reference drugs.
–
3055–2830 (Ar C–H), 1704, 1671, 1632 (C O). MS, m/z: 330
–
(Mþ1).
N-(2,5-Difluorophenyl)-1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxamide (4e)
The neurological toxicity
Yield: (80%), m.p.: 298°C. Anal. calcd. for C16H11F2N3O3: C,
58.01; H, 3.35; N, 12.68. Found: C, 57.95; H, 3.23; N, 12.81.
1H NMR (300 MHz, CDCl3) d: 3.70 (s, 3H, N–CH3), 5.63 (s, 1H,
NH), 6.52–7.75 (m, 7H, Ar–H). IR (Nujol, cmꢁ1): 3235 (N–H),
The acute neurotoxicity of the selected compounds was
performed according to a method described by Boissier
et al. [16]. In this test, the animals had to climb backwards up
the tube. Motor impairment was indicated by the inability of
the animals to climb backward up the transparent tube within
30 s. The neurotoxic effects of the tested compounds were
expressed as their median toxic doses (TD50 values), repre-
senting the doses at which the investigated compounds
impaired motor coordination in 50% of the animals.
–
3052–2828 (Ar C–H), 1705, 1671, 1632 (C O). MS, m/z: 332
–
(Mþ1).
N-(3,5-Difluorophenyl)-1-methyl-2,4-dioxo-1,2-
dihydroquinazoline-3(4H)-carboxamide (4f)
Yield: (78%), m.p.: 289°C. Anal. calcd. for C16H11F2N3O3: C,
58.01; H, 3.35; N, 12.68. Found: C, 57.91; H, 3.27; N, 12.83.
1H NMR (300 MHz, CDCl3) d: 3.71 (s, 3H, N–CH3), 6.95–7.84 (m,
7H, Ar–H), 8.73 (s, 1H, NH). IR (Nujol, cmꢁ1): 3235 (N–H), 3052–
Quantification studies
Anticonvulsant activity was expressed in terms of the median
effective dose (ED50), that is, the dose of drug required to
produce the biological responses in 50% of animals,
neurotoxicity was expressed as the median toxic dose
(TD50). Groups of six mice each were given a range of i.p.
doses of the selected drug until at least four points were
established in the range of 10–90% seizure protection or
minimal observed neurotoxicity [17]. From the plot of these
data, the respective ED50 and TD50 values, slope of the
regression line, and standard error of the slope were
calculated by means of a computer program based on the
method described by Finney [18].
–
2828 (Ar C–H), 1705, 1671, 1632 (C O). MS, m/z: 332 (Mþ1).
–
1-Methyl-2,4-dioxo-N-(2,3,4-trifluorophenyl)-1,2-
dihydroquinazoline-3(4H)-carboxamide (4g)
Yield: (80%), m.p.: 291°C. Anal. calcd. for C16H10F3N3O3: C,
55.02; H, 2.89; N, 12.03. Found: C, 54.95; H, 2.11; N, 12.15.
1H NMR (300 MHz, CDCl3) d: 3.77 (s, 3H, N–CH3), 7.05–7.89 (m,
6H, Ar–H), 8.78 (s, 1H, NH). IR (Nujol, cmꢁ1): 3238 (N–H), 3050–
–
2825 (Ar C–H), 1708, 1670, 1632 (C O). MS, m/z: 350 (Mþ1).
–
Pharmacology
The anticonvulsant activity was evaluated by MES and PTZ
tests. Mice (18–20 g) were procured from National Institute of
Nutrition, Hyderabad. The animals were kept in individual
cages for 1 week to acclimatize for laboratory conditions.
They were allowed to free access of water and food. All the
experimental procedures were carried out in accordance with
Committee for the Purpose of Control and Supervision of
Experiments on Animals (CPCSEA) guidelines. The study was
reviewed and approved by the Institutional Animal Ethics
Committee, G Pulla Reddy College of Pharmacy, Hyderabad,
India.
The authors have declared no conflicts of interest.
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0.2 s by means of a convulsiometer through a pair of ear clip
electrodes. The test compounds were administered intraperi-
toneally (i.p.) at dose of 1.0 mmol/kg 30 min before the seizure
induction. The animals were observed closely for 2 min. The
percentage of inhibition of seizure relative to control was
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and methaqualone (300 mg/kg) were used as reference drugs.
The PTZ test was carried out by the i.p. injection of a
convulsant dose of PTZ (100 mg/kg). As with PTZ, the chemo-
convulsants picrotoxin was administered i.p. to mice in a dose
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