Design, graph theoretical analysis, density functionality theories, Insilico modeling, synthesis, characterization and biological activities of novel thiazole fused quinazolinone derivatives

Article abstract of DOI:10.1002/ddr.21460

(Table presented.). A series of 2-(2-substituted benzylidenehydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolo din-3-yl]phenyl)quinazolin-4(3H)-one 7a-7l were synthesized and characterized by IR, ¹H-NMR, ¹³C-NMR, mass spectroscopy and elemental analyses. In this present study, the density functionality theory was performed to identify drug stability. Further we introduced graph theoretical analysis by utilised Kyoto Encyclopedia of Genes and Genomes (KEGG) database and Cytoscape software to identify drug target. Based on the observed drug target insilico modeling was executed to know effective drug. The antiepileptic effects of title compounds were evaluated by using MES and subcutaneous pentylenetetrazole (scPTZ) test. Acute neurological toxicity of title compounds was studied by using standardized rotorod test. After 0.5 hr of period many of the compounds showed anticonvulsant activity at MES or scPTZ test. Comparison of the biological activity of test compounds with its chemical structures indicates that, compounds possessing electron donating group exhibited superior activity than the analogs having electron withdrawing moieties. Among the electron donating group tested, amino derivative exhibited good activity than rest of derivatives. From the study it was concluded that, the compound 7j was established as very potent compared with rest of the compounds and standard drugs subjected to biological studies. Thus the compound 2-(2-[4-aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one (7j) came out as pilot derivative without any neurotoxicity with a wide spectrum of antiepileptic activity. Highlights: The performed work is having great significance in terms of Graph theoretical analysis used to identify drug target In silico modeling used to identify designed drug interaction with identify target Density functionality studies used to identify synthesized compound energy band gap which is correlate with enhancement of its biological activity Antiepileptic effects of entire synthesized quinazolinone scaffolds were evaluated by MES and scPTZ test 2-(2-[4-aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one (7j) was established as very potent compared to the rest of the compounds and standard drugs which were subjected to biological studies.

Full text of DOI:10.1002/ddr.21460

Received: 6 July 2018
Revised: 31 July 2018
Accepted: 5 August 2018
DOI: 10.1002/ddr.21460
R E S E A R C H A R T I C L E
Design, graph theoretical analysis, density functionality
theories, Insilico modeling, synthesis, characterization and
biological activities of novel thiazole fused quinazolinone
derivatives
Govindaraj Saravanan1 | Theivendren Panneerselvam2 | Veerachamy Alagarsamy1 |
Selvaraj Kunjiappan3 | Pavadai Parasuraman4 | Indhumathy Murugan5 |
Pandurangan Dinesh Kumar6
Enabling Technologies
Strategy, Management & Health Policy
Hit, Lead &
Candidate Discovery
Preclinical Research
& Development
Clinical
Research
Post-Market
Research
1Department of Pharmaceutical Chemistry,
MNR College of Pharmacy, Sangareddy,
Telangana, India
Abstract
A series of 2-(2-substituted benzylidenehydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolo
din-3-yl]phenyl)quinazolin-4(3H)-one 7a-7l were synthesized and characterized by IR, 1H-NMR,
13C-NMR, mass spectroscopy and elemental analyses. In this present study, the density
functionality theory was performed to identify drug stability. Further we introduced graph
theoretical analysis by utilised Kyoto Encyclopedia of Genes and Genomes (KEGG) data-
base and Cytoscape software to identify drug target. Based on the observed drug target
insilico modeling was executed to know effective drug. The antiepileptic effects of title
compounds were evaluated by using MES and subcutaneous pentylenetetrazole (scPTZ) test.
Acute neurological toxicity of title compounds was studied by using standardized rotorod test.
After 0.5 hr of period many of the compounds showed anticonvulsant activity at MES or scPTZ
test. Comparison of the biological activity of test compounds with its chemical structures indicates
that, compounds possessing electron donating group exhibited superior activity than the analogs
having electron withdrawing moieties. Among the electron donating group tested, amino deriva-
tive exhibited good activity than rest of derivatives. From the study it was concluded that, the
compound 7j was established as very potent compared with rest of the compounds and standard
drugs subjected to biological studies. Thus the compound 2-(2-[4-aminobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one (7j) came out as
pilot derivative without any neurotoxicity with a wide spectrum of antiepileptic activity.
2Department of Pharmaceutical Chemistry,
Karavali College of Pharmacy, Mangalore,
Karnataka, India
3International Research Center, Kalasalingam
University, Krishnan Koil, Tamil Nadu, India
4Department of Pharmaceutical Chemistry,
Faculty of Pharmacy, M .S. Ramaiah University
of Applied Sciences, Bengaluru, Karnataka,
India
5Department of Biotechnology, P.S.R
Engineering College, Sivakasi, Tamilnadu, India
6Hindu College of Pharmacy, Guntur, Andhra
Pradesh, India
Correspondence
T. Panneerselavm, Department of
Pharmaceutical Chemistry, Karavali College of
Pharmacy, Vamanjoor, Mangalore-575028,
Karnataka, India.
Email: tpsphc@gmail.com
Funding information
College of Pharmacy;
Highlights
The performed work is having great significance in terms of
•
•
•
Graph theoretical analysis used to identify drug target
In silico modeling used to identify designed drug interaction with identify target
Density functionality studies used to identify synthesized compound energy band gap which
is correlate with enhancement of its biological activity
•
Antiepileptic effects of entire synthesized quinazolinone scaffolds were evaluated by MES
and scPTZ test
Drug Dev Res. 2018;1–15.
wileyonlinelibrary.com/journal/ddr
© 2018 Wiley Periodicals, Inc.
1

2
SARAVANAN ET AL.
•
2-(2-[4-aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phe-
nyl) quinazolin-4(3H)-one (7j) was established as very potent compared to the rest of the com-
pounds and standard drugs which were subjected to biological studies
KEYWORDS
anticonvulsant activity, density functionality theories, graph theoretical analysis, MES test,
Quinazolin-4(3H)-one, scPTZ test and neurotoxicity, Thiazolidin-4-one
2
| EXPERIMENTAL
1
| INTRODUCTION
In world's population about 1% of people were affected by epi-
lepsy which is general neurologic affection categorized by
2.1 | Chemistry
a
By using Thomas Hoover melting point apparatus, in open capillary
tubes melting points (m.p.) were determined and are uncorrected. Using
a Jasco FT-IR 410 (JASCO Corporation, Tokyo, Japan) spectrometer IR
spectra were recorded in potassium bromide disks or film. In Bruker
Avance-500 NMR (Bruker, Optics-Beijing, China) spectrometer using
CDCl3 NMR spectra were recorded with CDCl3 for 13C-NMR and TMS
(tetramethylsilane) for 1H-NMR as an internal standard. Using FAB posi-
tive (fast atom bombardment) in JEOL-SX-102 instrument mass spectra
was recorded. Perkin-Elmer 2,400 analyzer (Perkin Elmer, Foster City,
Calif) was utilized for micro analysis (C, H, and N). From Merck ready-
made silica gel plates were obtained and monitored the development of
entire chemical reactions. Iodine and UV lamp were used as a develop-
ing agent. From SD Fine Chem (Worli Road, Mumbai, India), CDH,
E. Merck India Ltd., and Qualigens, all chemicals and reagents were pro-
cured and were used without further purification.
extreme temporary neuronal discharge (Fisher et al., 2005). Still
there is a critical need for the improvement of more safer and
effective Anti epileptic drugs (AEDs) regardless of many available
AEDs because available AEDs not controlling seizure in about 30%
epileptic patients (Sander, 2003). In addition, only 60–80% of
patients are effective towards numerous AEDs such as Phenytoin,
Felbamate, Phenobarbital, Valproate, Lamotrigine, Carbamazepine,
and Vigabatrin, which possess a few undesirable side effects, for
instance nausea, gingival hyperplasia, headache, hirsutism, gastro-
intestinal disturbance, hepatotoxicity, drowsiness, ataxia, and
anorexia (Brodie, Elder, & Kwan, 2009; Holmes, 2008; Majoie, de
Baets, Renier, Lang, & Vincent, 2006). Hence, there is a massive
require for the improvement of novel AEDs with more potency
and minimal side effects. The conformational analysis (Bruno-
Blanch, Galvez, & Garcıa-Domenech, 2003; Estrada & Peña, 2000)
of the available AEDs demonstrated that the pharmacophoric
model for anticonvulsant activity, must consist of (a) Electron
donor atom, (b) Hydrogen bond acceptor/donor unit, and
(3) Substituted/unsubstituted hydrophobic aryl ring system
(Figure. 1). Literature survey indicates that quinazolines and con-
densed quinazolines possess excellent anticonvulsant activity
(Hisano, Ichikawa, Kito, & Nishi, 1972; Jatav, Mishra, Kashaw, &
Stables, 2008; Srivastava & Chandra, 2002; Srivastava & Kumar,
2002). Thiazolidin-4-ones are five member ring systems possessing
nitrogen and sulphur hetero atom which established a lot attention
of medicinal chemists owing to its excellent pharmacological prop-
erties. Various substituents at C-2 and C-3 of thiazolidinones
results in potent anticonvulsant activities (Hisano et al., 1972;
Kaur et al., 2010; Shingalapur, Hosamani, Keri, & Hugar, 2010). In
present work it was predicted that presence of above mentioned
pharmacophore could be benefit for a drug molecule because it
might have anticonvulsant property. Person involved in a research
plan aspiring to find out novel structure pilot that would act as
powerful anticonvulsant agents, it was of curiosity to produce a
number of new thiazolidin-4-one substituted quinazolinones as a
test to get potent and safer anticonvulsant agents. As well the
neurotoxicity of the derivatives was determined. The general
chemical structure of the title quinazolinones aimed to synthesize
and its vital structural features are highlighted in Figure 1.
2.2 | Graph theoretical analysis
The graph theoretical analysis (Kanehisa & Goto, 2000) was engaged by
use of Kyoto Encyclopedia of Genes and Genomes (KEGG) database
and protein interaction network in Homo sapiens was (hsa: 05152) cho-
sen to recognize the significant proteins. The lane was rehabilitated to
a graph with proteins (nodes) and interactions (edges) and it was men-
tioned in Table 1 and Figure 2. The identified nodes (69) and edges
(81) in the network were calculated by centrality of degree, between-
ness, eigenvector, radiality, stress, and closeness. Based on the mea-
surements of its threshold values α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) was identified as convulsant drug tar-
get. The identified AMPA has more noticed because of its interaction
between convulsant proteins. The graph theoretical analysis report of
AMPA was very understandable that indicates AMPA is a significant
target to identify active quinazolinone motifs.
2.3 | Density functionality theory
Computational calculations of the synthesized and standard compounds
were performed using GaussView molecular visualized program
ꢀ
(Güntepe, Saraçoglu, Çalıs¸kan, Yüksektepe, & Cukurovali, 2012) and
Gaussian 03 W package (İnkaya, Dinçer, Ekici, & Cukurovali, 2012) on
the personal computer (Processor [Intel(R) Core(TM)2 Duo CPU E7200

SARAVANAN ET AL.
3
@ 2.53 DHz]). The molecular structures of the synthesized and standard
in the ground state were optimized by density functional theory using
B3LYP functional with 6-311G (d,p) basis set. The frontier molecular
orbital energies (EHOMO, ELUMO & their energy gap [Eg]) of all molecules
were derived from the optimized structures. The obtained molecular
orbital energy diagrams of the synthesized and standard molecules were
visualized from GaussView molecular visualized program.
2 & C0-6), 119.3 (C-10), 115.4 (C’3 & C0-5), 24.9 [CH3]. EI-MS m/z:
251 [M+]. Anal. Cald for C15H13N3O: C, 71.70; H, 5.21; N, 16.72.
Found: C, 71.92; H, 5.19; N, 16.67.
2.7 | Synthesis of 2-methyl-3-(4-[4-oxo-
2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-
one (4)
3-(4-Aminophenyl)-2-methylquinazolin-4(3H)-one 3 (2.51 g, 0.01 mol)
and benzaldehyde (1.06 g, 0.01 mol) was dissolved in ethanol (20 mL).
To this thioglycolic acid (0.92 g, 0.01 mol) in ethanol (10 mL) and zinc
chloride (0.25 g) in tetrahydrofuran (10 mL) was added with vigorous
stirring and refluxed for 12 hr. The resulting solution was cooled, poured
in crushed ice and stirred well. The product 4 separated was filtered,
dried, and recrystallised using methanol. Yield: 70% (2.89 g), m.p.:
209–211 ꢀC, Rf value: 0.89 (Ethyl acetate: Benzene [5:5]). IR (KBr,
cm−1): 3094 (Ar CH), 2,970 (CH3 CH), 1,706 (C O), 1,658 (C N),
1,613 (C C). 1H NMR (CDCl3, 500 MHz) δ ppm: 2.27 (s, 3H, CH3), 3.90
(s, 2H, CH2 of thiazolidine), 6.05 (s, 1H, CH of thiazolidine), 7.12–8.09
2.4 | Molecular docking studies
Molecular docking was performed to get clear idea about the binding
mode of our designed compounds. The crystal structures used was, x-ray
structure of AMPA subtype ionotropic glutamate receptor in complex
with competitive antagonist ZK 200775 (PDB ID: 3KG2) (Gasteiger &
Marsili, 1980). From the protein data bank the proteins were obtained
for the docking studies. For docking the proteins were primed by remov-
ing water molecules and adding polar hydrogen atom by using Gasteiger-
Huckel charges. SYBYL program (Tripos Inc., St. Louis, Missouri) was
used to draw the 3D structures of compounds and the process of energy
minimization. Surflex-Dock program with Sybyl-X 2.0. (T. SYBYL-X,
2012) was used for molecular docking with default values, miscellaneous
parameters and it was represented in Table 2.
(m, 13H, Ar H). 13
C NMR (CDCl3, 500 MHz) δ ppm: 172.3 (C-4 of thi-
azole), 161.7 (C-4), 154.9 (C-2), 147.3 (C-9), 140.1 (C00-1), 139.6 (C0-4),
133.0 (C-7), 131.8 (C-5), 131.2 (C00-2 & C00-6), 130.9 (C00-3 & C00-5),
129.5 (C0-1), 125.1 (C-6), 124.7 (C00-4), 122.6 (C-8), 120.5 (C0-2, C0-3, C0-
5 & C0-6), 118.4 (C-10), 68.9 (C-2 of thiazole), 31.1 (C-5 of thiazole),
23.0 (CH3). EI-MS m/z: 413 [M+]. Anal. Cald for C24H19N3O2S: C,
69.71; H, 4.63; N, 10.16. Found: C, 69.47; H, 4.64; N, 10.19.
2.5 | Synthesis of 2-methyl-benzo-(1,3)-oxazin-
4-one (2)
To a 0.01 mol (1.37 g) anthranilic acid taken in 250 mL round bottom
flask, 0.1 mol (10.2 mL) acetic anhydride (10.2 mL) was added and refluxed
on water bath for 1 hr. Under reduced pressure excess acetic anhydride
was distilled off. Petroleum ether was added to dissolve the residue left
and kept aside for 1 hr. Filtered and dried the light brown solid 1 which
obtained. Yield: 71% (1.15 g), m.p.: 181–183 ꢀC, Rf value: 0.34 [Ethyl ace-
tate: Hexane: Formic acid (4:4:2)]. IR (KBr, cm−1): 3096 (Ar CH), 2,882
2.8 | Synthesis of 2-(3-chloro-2-oxopropyl)-
3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl)
quinazolin-4(3H)-one (5)
2-Methyl-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl)quinazolin-4(3H)-
one 4 (4.13 g, 0.01 mol) and chloroacetyl chloride (0.01 mol) in ethanol
(25 mL) was refluxed for 5 hr in water bath. The solution obtained was
cooled to room temperature and poured in crushed ice. The separated
solid product 5 was filtered, dried, and recrystallised using ethanol. Yield:
77% (3.76 g), m.p.: 155–157 ꢀC, Rf value: 0.52 (Ethyl acetate: Benzene
[5:5]). IR (KBr, cm−1): 3062 (Ar CH), 2,876 (CH2 CH), 1,735 (C O),
1,640 (C N), 1,628 (C C), 729 (C Cl). 1H NMR (CDCl3, 500 MHz) δ
ppm: 3.05 (s, 2H, CH2 of CH2CO), 3.68 (s, 2H, CH2 of thiazolidine), 5.13
(s, 2H, CH2 of CH2Cl), 6.26 (s, 1H, CH of thiazolidine), 6.82–8.23 (m,
13H, Ar H). 13C-NMR (CDCl3, 500 MHz) δ ppm: 195.6 (CH2COCH2Cl),
170.8 (C-4 of thiazole), 168.2 (C-2), 159.4 (C-4), 149.7 (C-9), 138.1 (C00-
1), 137.9 (C0-4), 135.5 (C-7), 130.3 (C-5), 130.0 (C00-2 & C00-6), 129.6 (C00-
3 & C00-5), 128.8 (C0-1), 128.2 (C-6), 127.5 (C00-4), 123.3 (C-8), 120.7 (C0-
2, C0-3, C0-5 & C0-6), 120.2 (C-10), 67.4 (C-2 of thiazole), 50.1
(CH2COCH2Cl), 38.3 (CH2COCH2Cl), 34.8 (C-5 of thiazole). EI-MS m/z:
489 [M+], 491 [M+2]. Anal. Cald for C26H20ClN3O3S: C, 63.73; H,
4.11; N, 8.58. Found: C, 63.95; H, 4.10; N, 8.56.
(CH3 CH), 1,712 (C O), 1,636 (C N), 1,600 (C C), 1,055 (C
O
C). 1H
NMR (CDCl3, 500 MHz) δ ppm: 2.38 (s, 3H, CH3), 6.92–7.40 (m, 4H,
Ar H). 13C NMR (CDCl3, 500 MHz) δ ppm: 163.4 (C-2), 162.9 (C-4),
147.2 (C-9), 138.5 (C-7), 128.1 (C-5), 126.8 (C-6), 120.2 (C-8), 117.6
(C-10), 23.4 (CH3). EI-MS m/z: 161 [M+]. Anal. Cald for C9H7NO2: C,
67.07; H, 4.38; N, 8.69. Found: C, 67.16; H, 4.40; N, 8.66.
2.6 | Synthesis of 3-(4-aminophenyl)-2-methyl
quinazolin-4(3H)-one (3)
To a mixture of 0.01 mol (1.61 g) 2-methyl-benzo-(1,3)-oxazin-4-one 1 and
0.01 mol (1.08 g) p-phenylenediamine in 250 mL round bottom flask,
50 mL pyridine (anhydrous) was added and heated on sand bath for 6 hr.
Using ice bath resulting mixture was cooled, and treated with 100 mL
hydrochloric acid (dilute). Filtered the solid 2 separated out, washed with
water, and crystallized using ethanol. Yield: 73% (1.82 g), m.p.: 226–228 ꢀC,
Rf value: 0.36 (Ethyl acetate: Hexane: Formic acid [5:3:2]). IR (KBr, cm−1):
3380 and 3,274 (NH), 3,068 (Ar CH), 2,954 (CH3 CH), 1,730 (C O),
1,641 (C N), 1,609 (C C). 1H NMR (CDCl3, 500 MHz) δ ppm: 2.63 (s, 3H,
CH3), 3.76 (s, 2H, NH2), 6.92–7.97 (m, 8H, Ar-H). 13C NMR (CDCl3,
500 MHz) δ ppm: 165.3 (C-4), 150.6 (C-2), 148.0 (C-9), 144.2 (C0-4),
135.7 (C-7), 129.4 (C-5), 127.2 (C-6), 125.1 (C0-1), 124.5 (C-8), 123.7 (C0-
2.9 | Synthesis of 2-(3-hydrazino-2-oxopropyl)-
3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl)
quinazolin-4(3H)-one (6)
Hydrazine hydrate (0.50 g, 0.01 mol) was added to a solution con-
taining 2-(3-chloro-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]

4
SARAVANAN ET AL.
SCHEME 1 Thiazole fused quinazolinone derivatives
phenyl)quinazolin-4(3H)-one 5 (4.89 g, 0.01 mol) in ethanol (25 mL).
The above solution was refluxed for 10 hr and poured in ice cold
water. The product separated was filtered, dried and recrystallised
using methanol. Yield: 72% (3.49 g), m.p.: 218–220 ꢀC, Rf value: 0.48
(Benzene: Acetic acid [4:6]). IR (KBr, cm−1): 3341 & 3,278 (NH), 3,043
(Ar CH), 2,890 (CH2 CH), 1,716 (C O), 1,662 (C N), 1,615 (C C).
1H NMR (CDCl3, 500 MHz) δ ppm: 2.06 (s, 2H, NH2 of NHNH2), 2.79 (s,
1H, NH of NHNH2), 3.14 (s, 2H, CH2 of CH2CO), 3.90 (s, 2H, CH2 of
thiazolidine), 4.37 (s, 2H, CH2 of CH2NH), 6.12 (s, 1H, CH of thiazolidine),
7.03–8.38 (m, 13H, Ar H). 13
C NMR (CDCl3, 500 MHz) δ ppm: 210.5
(CH2COCH2NHNH2), 172.3 (C-4 of thiazole), 166.8 (C-2), 162.0 (C-4),
146.8 (C-9), 140.4 (C00-1), 138.6 (C0-4), 136.2 (C-7), 131.7 (C-5), 131.4

SARAVANAN ET AL.
5
FIGURE 1 Pharmacophoric pattern of known antiepileptic drugs & title compounds (7a-7l) [Color figure can be viewed at wileyonlinelibrary.com]
(C00-2 & C00-6), 131.0 (C00-3 & C00-5), 126.9 (C0-1), 126.5 (C-6), 126.2 (C00-
4), 124.0 (C-8), 122.8 (C0-2, C0-3, C0-5 & C0-6), 121.5 (C-10), 66.1 (C-2 of
thiazole), 61.7 (CH2COCH2NHNH2), 43.5 (CH2COCH2NHNH2), 34.9 (C-
5 of thiazole). EI-MS m/z: 485 [M+]. Anal. Cald for C26H23N5O3S: C,
64.31; H, 4.77; N, 14.42. Found: C, 64.52; H, 4.76; N, 14.38.
The dried product was recrystallised using ethanol. The method used
for the preparation and isolation of the compounds gave materials
of good purity, as evidenced by their spectral analyses and by thin
layer chromatography.
2.11 | 2-(2-[Benzylidene]hydrazinyl-2-oxopropyl)-
3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl)
quinazolin-4(3H)-one (7a)
2.10 | Synthesis of 2-(2-[substitutedbenzylidene]
hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-
2-phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one
(7a-7l)
Yield: 78% (4.47 g), m.p.: 254–256 ꢀC, Rf value: 0.76 [Benzene: Acetic
acid (4:6)]. IR (KBr, cm−1): 3356 (NH), 3,055 (Ar CH), 2,901
(CH2 CH), 1,674 (C O), 1,549 (C C), 1,532 (CH N). 1H NMR
(CDCl3, 500 MHz) δ ppm: 2.15 (s, 1H, NH of CH2NH), 3.02 (s, 2H,
CH2 of CH2CO), 3.78 (s, 2H, CH2 of thiazolidinone), 4.29 (s, 2H, CH2
of CH2NH), 6.20 (s, 1H, CH of thiazolidinone), 6.91–8.20 (m, 18H,
2-(3-Hydrazino-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl)
quinazolin-4(3H)-one 6 (4.85 g, 0.01 mol) and different aromatic
aldehyde (0.01 mol) in ethanol (50 mL) was taken in round bottomed
flask. To this glacial acetic acid (1 mL) was added and refluxed for
overnight and kept aside for 24 hr. Then the solution was poured in
ice cold water, stirred well and separated product 7a-7l was filtered.
Ar H), 8.39 (s, 1H, CH N). 13
C NMR (CDCl3, 500 MHz) δ ppm: 208.1
(CH2COCH2NHN CH), 170.5 (C-4 of thiazole), 167.6 (C-2), 162.3

6
SARAVANAN ET AL.
609 [M+2]. Anal. Cald for C33H26ClN5O3S: C, 65.18; H, 4.31; N, 11.52.
Found: C, 65.41; H, 4.30; N, 11.49.
TABLE 1 Antiepileptic activity and neurotoxicity of compounds (7a–
7l) administered intraperitoneally to mice
scPTZb
screening
MESa
NTc
2.13 | 2-(2-[4-Dimethylaminobenzylidene]
hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenyl
thiazolidin-3-yl]phenyl)quinazolin-4(3H)-one (7c)
Compounds
0.5 hrd 4.0 hrd 0.5 hrd 4.0 hrd 0.5 hrd 4.0 hrd
7a
300
300
30
–
300
–
300
–
300
300
300
300
–
–
–
7b
ND
–
ND
300
ND
ND
ND
–
Yield: 79% (4.87 g), m.p.: 273–275 ꢀC, Rf value: 0.80 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3334 (NH), 3,069 (Ar CH), 2,927
(CH2 CH), 1,741 (C O), 1,568 (C C), 1,530 (CH N). 1H NMR
(CDCl3, 500 MHz) δ ppm: 2.24 (s, 1H, NH of CH2NH), 3.29 (s, 2H,
CH2 of CH2CO), 3.52 (s, 6H, N[CH3]2), 3.73 (s, 2H, CH2 of thiazolidi-
none), 4.21 (s, 2H, CH2 of CH2NH), 6.18 (s, 1H, CH of thiazolidinone),
6.86–7.92 (m, 17H, Ar H), 8.45 (s, 1H, CH N). 13C-NMR (CDCl3,
500 MHz) δ ppm: 206.4 (CH2COCH2NHN CH), 171.9 (C-4 of thia-
zole), 165.1 (C-2), 161.2 (C-4), 154.8 (C00’-4), 148.6 (C-9), 142.9
(CH2COCH2NHN CH), 140.5 (C00-1), 136.3 (C0-4), 134.2 (C-7), 132.7
(C00’-2 & C00’-6), 129.3 (C-5), 129.1 (C00-2 & C00-6), 128.5 (C00-3 & C00-5),
128.3 (C0-1), 126.9 (C-6), 126.7 (C00-4), 125.4 (C00’-1), 121.8 (C-8),
121.4 (C0-2, C0-3, C0-5 & C0-6), 119.5 (C-10), 117.1 (C00’-3 & C00’-5),
64.3 (C-2 of thiazole), 62.6 (CH2COCH2NHN CH), 43.1 (N[CH3]2),
40.8 (CH2COCH2NHN CH), 35.4 (C-5 of thiazole). EI-MS m/z:
616 [M+]. Anal. Cald for C35H32N6O3S: C, 68.16; H, 5.23; N, 13.63.
Found: C, 68.39; H, 5.24; N, 13.60.
7c
100
300
300
–
100
–
7d
ND
ND
ND
300
–
7e
–
300
–
7f
–
–
7g
100
100
30
30
300
30
30
–
300
300
100
30
100
100
100
100
–
300
300
300
300
300
300
–
7h
–
7i
–
300
–
7j
–
7k
–
ND
300
100
–
ND
–
7l
300
30
100
–
Phenytoine
Ethosuximidef
100
–
–
100
300
The sign – (en-dash) represents an absence of activity at maximum dose
administered (300 mg/kg). ND = Not determined.
Maximal electroshock test (administered intraperitoneally to mice at
doses ranging from 30 to 300 mg/kg).
Subcutaneous pentylenetetrazole test (administered intraperitoneally to
mice at doses ranging from 30 to 300 mg/kg).
Neurotoxicity (administered intraperitoneally to mice at doses ranging
a
b
c
from 30 to 300 mg/kg).
Time of test after drug administration.
Reference drug, data for Phenytoin.
Reference drug, data for Ethosuximide.
d
e
2.14 | 2-(2-[4-Nitobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7d)
f
(C-4), 148.9 (C-9), 145.2 (CH2COCH2NHN CH), 141.4 (C00-1), 139.1 (C0-
4), 135.0 (C00’-1), 134.7 (C-7), 133.4 (C00’-4), 131.3 (C00’-2 & C00’-6), 130.8
(C00’-3 & C00’-5), 130.2 (C-5), 129.9 (C00-2 & C00-6), 129.6 (C00-3 &
C00-5), 129.1 (C0-1), 127.4 (C-6), 127.0 (C00-4), 123.8 (C-8), 122.5
(C0-2, C0-3, C0-5 & C0-6), 119.3 (C-10), 68.7 (C-2 of thiazole), 64.0
(CH2COCH2NHN=CH), 41.2 (CH2COCH2NHN=CH), 34.6 (C-5 of
thiazole). EI-MS m/z: 573 [M+]. Anal. Cald for C33H27N5O3S: C,
69.09; H, 4.74; N, 12.21. Found: C, 68.87; H, 4.75; N, 12.25.
Yield: 73% (4.51 g), m.p.: 229–231 ꢀC, Rf value: 0.53 (Benzene:
Acetic acid [4:6]). IR (KBr, cm−1): 3357 (NH), 3,042 (Ar CH), 2,944
(CH2 CH), 1,727 (C O), 1,675 (C C), 1,586 (CH N), 1,520 & 1,342
(NO2). 1H NMR (CDCl3, 500 MHz) δ ppm: 2.10 (s, 1H, NH of
CH2NH), 2.83 (s, 2H, CH2 of CH2CO), 3.50 (s, 2H, CH2 of thiazolidi-
none), 4.42 (s, 2H, CH2 of CH2NH), 6.03 (s, 1H, CH of thiazolidi-
none), 6.95–8.37 (m, 17H, Ar H), 8.86 (s, 1H, CH N). 13C NMR
(CDCl3, 500 MHz) δ ppm: 207.2 (CH2COCH2NHN CH), 172.6 (C-4 of
thiazole), 163.9 (C-2), 160.1 (C-4), 153.5 (C00’-4), 146.0 (C-9), 144.8
(CH2COCH2NHN=CH), 141.3 (C00’-1), 140.7 (C00-1), 138.4 (C0-4),
133.8 (C-7), 131.9 (C00’-2 & C00’-6), 130.2 (C-5), 130.0 (C00-2 & C00-
6), 129.8 (C00-3 & C00-5), 129.5 (C0-1), 128.7 (C-6), 128.4 (C00-4),
123.1 (C-8), 120.6 (C0-2, C0-3, C0-5 & C0-6), 120.0 (C00’-3 & C00’-5),
119.3 (C-10), 66.5 (C-2 of thiazole), 62.8 (CH2COCH2NHN CH),
38.4 (CH2COCH2NHN CH), 33.2 (C-5 of thiazole). EI-MS m/z:
618 [M+]. Anal. Cald for C33H26N6O5S: C, 64.07; H, 4.24; N,
13.58. Found: C, 64.31; H, 4.23; N, 13.56.
2.12 | 2-(2-[4-Chlorobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7b)
Yield: 75% (4.55 g), m.p.: 190–192 ꢀC, Rf value: 0.35 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3390 (NH), 3,116 (Ar CH), 2,904 (CH2 CH),
1,738 (C O), 1,551 (C C), 1,527 (CH N), 762 (C Cl). 1H NMR (CDCl3,
500 MHz) δ ppm: 2.08 (s, 1H, NH of CH2NH), 2.97 (s, 2H, CH2 of
CH2CO), 3.51 (s, 2H, CH2 of thiazolidinone), 4.06 (s, 2H, CH2 of CH2NH),
6.05 (s, 1H, CH of thiazolidinone), 7.19–8.34 (m, 17H, Ar H), 8.72 (s,
1H, CH N). 13C NMR (CDCl3, 500 MHz)
δ
ppm: 205.9
2.15 | 2-(2-[3-Nitrobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7e)
(CH2COCH2NHN=CH), 173.2 (C-4 of thiazole), 162.5 (C-2), 160.7 (C-4),
145.1 (C-9), 144.0 (CH2COCH2NHN=CH), 139.8 (C00-1), 138.4 (C0-4),
137.5 (C00’-4), 135.3 (C-7), 132.6 (C00’-1), 131.0 (C00’-2 & C00’-6), 130.4 (C00’-
3 & C00’-5), 127.0 (C-5), 126.7 (C00-2 & C00-6), 126.2 (C00-3 & C00-5), 125.5
(C0-1), 125.1 (C-6), 124.6 (C00-4), 123.0 (C-8), 122.2 (C0-2, C0-3, C0-5 & C0-
6), 121.4 (C-10), 67.8 (C-2 of thiazole), 60.3 (CH2COCH2NHN=CH), 39.9
(CH2COCH2NHN CH), 32.5 (C-5 of thiazole). EI-MS m/z: 607 [M+],
Yield: 77% (4.76 g), m.p.: 245–247 ꢀC, Rf value: 0.71 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3292 (NH), 3,105 (Ar CH), 2,913
(CH2 CH), 1,746 (C O), 1,574 (C C), 1,538 (CH N), 1,519 & 1,331
(NO2). 1H NMR (CDCl3, 500 MHz) δ ppm: 2.32 (s, 1H, NH of CH2NH),

SARAVANAN ET AL.
7
FIGURE 2 The AMPA pathway with nodes and edges interaction [Color figure can be viewed at wileyonlinelibrary.com]
2.80 (s, 2H, CH2 of CH2CO), 3.64 (s, 2H, CH2 of thiazolidinone), 4.38
(s, 2H, CH2 of CH2NH), 6.25 (s, 1H, CH of thiazolidinone), 7.02–8.19
(m, 17H, Ar H), 8.63 (s, 1H, CH N). 13C NMR (CDCl3, 500 MHz) δ
ppm: 205.7 (CH2COCH2NHN=CH), 169.4 (C-4 of thiazole), 163.0 (C-2),
161.5 (C-4), 150.1 (C00’-3), 148.3 (C-9), 142.9 (CH2COCH2NHN=CH),
140.6 (C00-1), 138.2 (C0-4), 136.0 (C00’-6), 135.4 (C00’-1), 134.7 (C-7),
131.8 (C00’-5), 129.3 (C-5), 129.0 (C00-2 & C00-6), 128.6 (C00-3 & C00-5),
128.1 (C0-1), 127.8 (C-6), 127.3 (C00-4), 126.2 (C00’-2), 125.5 (C00’-4),
120.3 (C-8), 119.8 (C0-2, C0-3, C0-5 & C0-6), 119.1 (C-10), 65.4 (C-2 of
thiazole), 61.9 (CH2COCH2NHN CH), 39.0 (CH2COCH2NHN CH),
34.8 (C-5 of thiazole). EI-MS m/z: 618 [M+]. Anal. Cald for
140.8 (C00-1), 139.4 (C0-4), 134.3 (C00’-5), 132.9 (C-7), 131.7 (C00’-1), 129.2
(C00’-6), 127.5 (C-5), 127.4 (C00-2 & C00-6), 127.0 (C00-3 & C00-5), 126.6 (C0-
1), 125.1 (C-6), 124.9 (C00-4), 124.3 (C00’-1), 123.8 (C-8), 122.5 (C0-2, C0-3,
C0-5 & C0-6), 122.0 (C00’-3), 118.7 (C-10), 63.1 (C-2 of thiazole), 60.9
(CH2COCH2NHN CH), 36.4 (CH2COCH2NHN CH), 30.2 (C-5 of thia-
zole). EI-MS m/z: 618 [M+]. Anal. Cald for C33H26N6O5S: C, 64.07; H,
4.24; N, 13.58. Found: C, 64.30; H, 4.25; N, 13.54.
2.17 | 2-(2-[4-Methoxybenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7g)
C33H26N6O5S: C, 64.07; H, 4.24; N, 13.58. Found: C, 63.84; H,
Yield: 79% (4.76 g), m.p.: 238–240 ꢀC, Rf value: 0.64 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3348 (NH), 3,042 (Ar CH), 2,924
(CH2 CH), 1,745 (C O), 1,550 (C C), 1,526 (CH N), 1,053
4.25; N, 13.62.
2.16 | 2-(2-[2-Nitrobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7f )
(C
O
C). 1H NMR (CDCl3, 500 MHz) δ ppm: 2.38 (s, 1H, NH of
CH2NH), 2.84 (s, 2H, CH2 of CH2CO), 3.70 (s, 2H, CH2 of thiazolidi-
none), 4.05 (s, 3H, OCH3), 4.27 (s, 2H, CH2 of CH2NH), 6.02 (s, 1H,
CH of thiazolidinone), 7.13–8.36 (m, 17H, Ar H), 8.75 (s, 1H, CH N).
13C NMR (CDCl3, 500 MHz) δ ppm: 202.5 (CH2COCH2NHN CH),
174.9 (C-4 of thiazole), 161.4 (C-2), 160.1 (C00’-4), 158.7 (C-4), 150.2
(C-9), 145.0 (CH2COCH2NHN CH), 140.6 (C00-1), 138.4 (C0-4), 134.0
(C-7), 132.5 (C00’-2 & C00’-6), 130.1 (C-5), 129.8 (C00-2 & C00-6), 129.6
(C00-3 & C00-5), 129.1 (C0-1), 127.6 (C-6), 126.9 (C00-4), 125.7 (C00’-1),
123.0 (C-8), 122.9 (C0-2, C0-3, C0-5 & C0-6), 121.5 (C-10), 118.2 (C00’-
3 & C00’-5), 64.7 (C-2 of thiazole), 60.6 (CH2COCH2NHN CH), 52.0
(OCH3), 43.1 (CH2COCH2NHN CH), 37.8 (C-5 of thiazole). EI-MS m/z:
Yield: 70% (4.33 g), m.p.: 201–203 ꢀC, Rf value: 0.42 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3375 (NH), 3,051 (Ar CH), 2,908
(CH2 CH), 1,730 (C O), 1,572 (C C), 1,529 (CH N), 1,504 & 1,337
(NO2). 1H NMR (CDCl3, 500 MHz) δ ppm: 2.13 (s, 1H, NH of CH2NH),
3.06 (s, 2H, CH2 of CH2CO), 3.59 (s, 2H, CH2 of thiazolidinone), 4.05
(s, 2H, CH2 of CH2NH), 6.27 (s, 1H, CH of thiazolidinone), 6.84–8.01
(m, 17H, Ar H), 8.30 (s, 1H, CH N). 13C NMR (CDCl3, 500 MHz) δ
ppm: 207.3 (CH2COCH2NHN CH), 173.6 (C-4 of thiazole), 164.7 (C-2),
159.9 (C-4), 147.2 (C00’-2), 146.5 (C-9), 144.1 (CH2COCH2NHN CH),

8
SARAVANAN ET AL.
TABLE 2 Antiepileptic activity and neurotoxicity of selected
2.19 | 2-(2-[4-Hydroxybenzylidene]hydrazinyl-
compounds administered orally (30 mg/kg) to rats
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
MESa
phenyl)quinazolin-4(3H)-one (7i)
Compounds
0.25 hrc
0.5 hrc
3/4
1 hrc
3/4
1/4
1/4
2/4
3/4
2/4
3/4
2 hrc
3/4
1/4
1/4
2/4
4/4
2/4
3/4
4 hrc
3/4
0/4
0/4
3/4
4/4
3/4
3/4
NTb
Yield: 76% (4.48 g), m.p.: 281–283 ꢀC, Rf value: 0.59 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3528 (OH), 3,359 (NH), 3,047 (Ar CH),
2,910 (CH2 CH), 1,734 (C O), 1,576 (C C), 1,521 (CH N). 1H NMR
(CDCl3, 500 MHz) δ ppm: 2.03 (s, 1H, NH of CH2NH), 3.15 (s, 2H,
CH2 of CH2CO), 3.52 (s, 2H, CH2 of thiazolidinone), 4.36 (s, 2H, CH2
of CH2NH), 5.29 (s, 1H, OH), 6.14 (s, 1H, CH of thiazolidinone),
6.98–8.03 (m, 17H, Ar H), 8.37 (s, 1H, CH N). 13C NMR (CDCl3,
500 MHz) δ ppm: 204.2 (CH2COCH2NHN CH), 172.5 (C-4 of thia-
zole), 163.8 (C-2), 162.4 (C-4), 162.0 (C00’-4), 145.5 (C-9), 141.6
(CH2COCH2NHN CH), 138.5 (C00-1), 137.1 (C0-4), 131.8 (C-7), 129.2
(C00’-2 & C00’-6), 126.7 (C-5), 126.5 (C00-2 & C00-6), 126.1 (C00-3 & C00-5),
125.9 (C0-1), 125.3 (C-6), 125.0 (C00-4), 124.4 (C00’-1), 121.5 (C-8),
121.0 (C0-2, C0-3, C0-5 & C0-6), 120.6 (C-10), 118.3 (C00’-3 & C00’-5),
66.7 (C-2 of thiazole), 63.2 (CH2COCH2NHN CH), 40.9
(CH2COCH2NHN CH), 35.6 (C-5 of thiazole). EI-MS m/z:
589 [M+]. Anal. Cald for C33H27N5O4S: C, 67.22; H, 4.62; N,
11.88. Found: C, 67.04; H, 4.61; N, 11.92.
7c
1/4
0/4 (−)d
0/4 (−)d
0/4 (−)d
0/4 (−)d
0/4 (−)d
0/4 (−)d
0/4 (−)d
7g
0/4
0/4
7h
0/4
0/4
7i
1/4
1/4
7j
1/4
3/4
7l
1/4
1/4
Phenytoin
1/4
4/4
a
Maximal electroshock test (dose of 30 mg/kg was administrated. The
data indicate: number of rats protected /number of rats tested).
Neurotoxicity (number of rats protected /number of rats tested).
Time of test after drug administration.
(−) No neurotoxicity at dose tested.
Reference drug, data for Phenytoin.
b
c
d
e
603 [M+]. Anal. Cald for C34H29N5O4S: C, 67.64; H, 4.84; N, 11.60.
Found: C, 67.87; H, 4.83; N, 11.56.
2.18 | 2-(2-[4-Methylbenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7h)
2.20 | 2-(2-[4-Aminobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7j)
Yield: 72% (4.23 g), m.p.: 184–186 ꢀC, Rf value: 0.31 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3281 (NH), 3,064 (Ar CH), 2,917
(CH2 CH), 1,722 (C O), 1,565 (C C), 1,513 (CH N). 1H NMR
(CDCl3, 500 MHz) δ ppm: 2.26 (s, 1H, NH of CH2NH), 2.61 (s, 3H,
CH3), 2.92 (s, 2H, CH2 of CH2CO), 3.58 (s, 2H, CH2 of thiazolidinone),
4.40 (s, 2H, CH2 of CH2NH), 6.39 (s, 1H, CH of thiazolidinone),
7.27–8.48 (m, 17H, Ar H), 8.84 (s, 1H, CH N). 13C NMR
(CDCl3, 500 MHz) δ ppm: 207.8 (CH2COCH2NHN CH), 170.3
(C-4 of thiazole), 165.1 (C-2), 159.6 (C-4), 150.9 (C-9), 142.5
(CH2COCH2NHN CH), 141.3 (C00’-4), 137.8 (C00-1), 136.0 (C0-4),
135.2 (C-7), 132.7 (C00’-1), 130.4 (C00’-3 & C00’-5), 130.1 (C00’-2 &
C00’-6), 127.9 (C-5), 127.6 (C00-2 & C00-6), 127.2 (C00-3 & C00-5),
126.8 (C0-1), 126.0 (C-6), 125.4 (C00-4), 121.9 (C-8), 119.3 (C0-2,
C0-3, C0-5 & C0-6), 118.7 (C-10), 68.1 (C-2 of thiazole), 63.9
(CH2COCH2NHN CH), 41.5 (CH2COCH2NHN CH), 32.4 (C-5 of
thiazole), 28.2 (CH3). EI-MS m/z: 587 [M+]. Anal. Cald for
Yield: 70% (4.12 g), m.p.: 268–270 ꢀC, Rf value: 0.87 [Benzene: Acetic
acid (4:6)]. IR (KBr, cm−1): 3356 & 3,249 (NH), 3,025 (Ar CH), 2,972
(CH2 CH), 1,741 (C O), 1,627 (C C), 1,587 (CH N). 1H NMR
(CDCl3, 500 MHz) δ ppm: 2.21 (s, 1H, NH of CH2NH), 2.69 (s, 2H,
CH2 of CH2CO), 3.30 (s, 2H, CH2 of thiazolidinone), 4.52 (s, 2H, CH2
of CH2NH), 4.93 (s, 2H, NH2), 6.37 (s, 1H, CH of thiazolidinone),
7.04–8.32 (m, 17H, Ar H), 8.85 (s, 1H, CH N). 13C NMR (CDCl3,
500 MHz) δ ppm: 205.6 (CH2COCH2NHN CH), 171.0 (C-4 of thia-
zole), 162.3 (C-2), 161.8 (C-4), 153.5 (C00’-4), 149.0 (C-9), 143.9
(CH2COCH2NHN CH), 140.4 (C00-1), 139.7 (C0-4), 135.6 (C-7), 132.9
(C00’-2 & C00’-6), 130.0 (C-5), 129.8 (C00-2 & C00-6), 129.5 (C00-3 & C00-5),
128.4 (C0-1), 126.2 (C-6), 125.8 (C00-4), 124.6 (C00’-1), 123.1 (C-8),
122.5 (C0-2, C0-3, C0-5 & C0-6), 121.0 (C-10), 115.7 (C00’-3 & C00’-5),
63.9 (C-2 of thiazole), 60.4 (CH2COCH2NHN CH), 40.6
(CH2COCH2NHN CH), 34.3 (C-5 of thiazole). EI-MS m/z:
588 [M+]. Anal. Cald for C33H28N6O3S: C, 67.33; H, 4.79; N, 14.28.
Found: C, 67.56; H, 4.80; N, 14.23.
C
34H29N5O3S: C, 69.49; H, 4.97; N, 11.92. Found: C, 69.70; H,
4.95; N, 11.94.
2.21 | 2-(2-[3-Chlorobenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7k)
TABLE 3 The results of threshold parameter values of the network
analysis
Centrality measures
Betweenness
Closeness
Maximum
2,645.299482
0.36363636
15
Mean
Minimum
0
192.1188
0.2183
Yield: 74% (4.49 g), m.p.: 199–201 ꢀC, Rf value: 0.79 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3367 (NH), 3,109 (Ar CH), 2,905
(CH2 CH), 1,732 (C O), 1,556 (C C), 1,534 (CH N), 750 (C-Cl). 1H
NMR (CDCl3, 500 MHz) δ ppm: 2.19 (s, 1H, NH of CH2NH), 3.05
(s, 2H, CH2 of CH2CO), 3.62 (s, 2H, CH2 of thiazolidinone), 4.24 (s,
2H, CH2 of CH2NH), 6.23 (s, 1H, CH of thiazolidinone), 7.20–8.35
(m, 17H, Ar H), 8.41 (s, 1H, CH=N). 13C NMR (CDCl3, 500 MHz)
0.139059
1
Degree
2.347826
0.072565
0.65078
518.4928
0.123434
EigenVector
Radiality
0.607887948
0.84090909
6,780
2.60E-04
0.437166
0
Stress
Eccentricity
0.166666667
0.090909

SARAVANAN ET AL.
9
TABLE 4 Surflex docking score (kcal/Mol) of the quinazoline derivatives on PDB ID: 3KG2
Compounds
C Scorea
10.74
10.24
10.16
9.58
Crash Scoreb
−1.13
−3.87
−3.01
−2.07
−2.34
−3.64
−1.83
−2.68
−2.55
−2.56
−3.20
−4.58
Polar Scorec
6.32
D Scored
−168.916
−2.5.030
−204.220
−190.616
−153.240
−191.490
−167.745
−184.203
−170.811
174.064
PMF Scoree
−111.870
−120.392
−125.007
−114.656
−69.354
G Scoref
Chem Scoreg
−41.394
−45.076
−44.327
−41.419
−33.111
−42.832
−43.832
−48.919
−37.062
−42.768
−36.064
−50.331
7d
7l
−225.659
−317.747
−278.769
−263.959
−319.010
−305.331
−250.196
−291.240
−260.470
−258.897
−304.559
−335.116
5.84
7e
7g
7c
7b
7a
7k
7h
7j
5.59
4.92
9.08
3.25
8.81
4.34
−119.136
−112.536
−116.609
−94.071
8.42
4.22
8.38
3.98
8.24
4.11
7.98
4.72
−116.776
117.609
7i
7.98
2.49
−190.877
−2.6.629
7f
7.56
4.03
−116.488
a
b
c
CScore (Consensus Score) integrates a number of popular scoring functions for ranking the affinity of ligands bound to the active site of a receptor and
reports the output of total score.
Crash-score revealing the inappropriate penetration into the binding site. Crash scores close to zero are favorable. Negative numbers indicate
penetration.
Polar indicating the contribution of the polar interactions to the total score. The polar score may be useful for excluding docking results that make no
hydrogen bonds.
D-score for charge and van der Waals interactions between the protein and the ligand (work of Kuntz).
PMF-score indicating the Helmholtz free energies of interactions for protein-ligand atom pairs (Potential of Mean Force, PMF) (work of Muegge and
Martin).
d
e
f
G-score showing hydrogen bonding, complex (ligand-protein), and internal (ligand–ligand) energies (work of Willett's group).
δ ppm: 208.3 (CH2COCH2NHN CH), 173.8 (C-4 of thiazole), 168.5
(C-2), 163.2 (C-4), 150.6 (C-9), 143.1 (CH2COCH2NHN CH), 142.7
(C00-1), 140.3 (C0-4), 136.9 (C00’-1), 135.4 (C00’-3), 134.6 (C-7), 133.0
(C00’-4), 131.9 (C00’-5), 130.3 (C00’-2), 129.5 (C-5), 129.4 (C00-2 & C00-6),
128.6 (C00-3 & C00-5), 128.1 (C0-1), 127.8 (C-6), 127.0 (C00’-6), 126.5
(C00-4), 124.7 (C-8), 123.7 (C0-2, C0-3, C0-5 & C0-6), 121.9 (C-10), 66.0
(C-2 of thiazole), 62.8 (CH2COCH2NHN CH), 42.0 (CH2COCH2NHN CH),
33.9 (C-5 of thiazole). EI-MS m/z: 607 [M+], 609 [M+2]. Anal. Cald
for C33H26ClN5O3S: C, 65.18; H, 4.31; N, 11.52. Found: C, 64.97; H,
4.30; N, 11.55.
2H, CH2 of CH2CO), 3.45 (s, 2H, CH2 of thiazolidinone), 4.53 (s, 2H,
CH2 of CH2NH), 5.38 (s, 1H, OH), 6.06 (s, 1H, CH of thiazolidinone),
6.82–8.19 (m, 17H, Ar H), 8.68 (s, 1H, CH N). 13C NMR (CDCl3,
500 MHz) δ ppm: 207.9 (CH2COCH2NHN CH), 172.1 (C-4 of thia-
zole), 166.6 (C-2), 161.5 (C-4), 160.2 (C00’-3), 148.3 (C-9), 145.7
(CH2COCH2NHN CH), 140.0 (C00-1), 139.8 (C0-4), 137.4 (C00’-1),
134.9 (C-7), 133.0 (C00’-5), 130.8 (C-5), 130.2 (C00-2 & C00-6), 129.7 (C00-
3 & C00-5), 128.5 (C0-1), 127.9 (C-6), 126.2 (C00-4), 124.3 (C-8), 123.2
(C0-2, C0-3, C0-5 & C0-6), 123.0 (C00’-6), 122.8 (C-10), 119.5 (C00’-4),
116.1 (C00’-2), 68.5 (C-2 of thiazole), 64.7 (CH2COCH2NHN CH), 42.3
(CH2COCH2NHN CH), 33.1 (C-5 of thiazole). EI-MS m/z:
589 [M+]. Anal. Cald for C33H27N5O4S: C, 67.22; H, 4.62; N, 11.88.
Found: C, 67.41; H, 4.63; N, 11.85.
2.22 | 2-(2-[3-Hydroxybenzylidene]hydrazinyl-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]
phenyl)quinazolin-4(3H)-one (7l)
2.23 | Pharmacology
Yield: 80% (4.71 g), m.p.: 252–254 ꢀC, Rf value: 0.68 (Benzene: Acetic
acid [4:6]). IR (KBr, cm−1): 3531 (OH), 3,383 (NH), 3,056 (Ar CH),
2,929 (CH2 CH), 1,725 (C O), 1,558 cm−1 (C C), 1,520 (CH N). 1H
NMR (CDCl3, 500 MHz) δ ppm: 2.27 (s, 1H, NH of CH2NH), 3.21 (s,
Institutional Animal Ethical Committee approved all the animal tests
which are performed as per international valid guidelines. Before
1 week of experiment, in restricted access room using wire mesh
FIGURE 3 Docked view of all the compounds at the active site of the enzyme PDB: 3KG2 [Color figure can be viewed at wileyonlinelibrary.com]

10
SARAVANAN ET AL.
FIGURE 4 Docked view of compound 7d at the active site of the enzyme PDB: 3KG2 [Color figure can be viewed at wileyonlinelibrary.com]
cages animals were retained with stable conditions at 45–55% relative
humidity, 25 ꢁ2 ꢀC, sustained under 12 hr dark and light cycle. Puri-
fied water ad libitum and standard lab pellets were given to animals.
Animals were fasted prior to the experiments for 12 hr.
mice are primarily tested by i.p. injection at 30 mg/kg, 100 mg/kg and
300 mg/kg dose of title compounds. Whereas rats are primarily
examined at 0.25 hr, 0.5 hr, 1 hr, 2 hr, and 4 hr time intervals by oral
route at 30 mg/kg dose. Phenytoin was used as reference standard
for comparison of title compounds and the outcomes are depicted in
Table 3.
2.24 | Acute toxicity
Acute toxic class method was used to assess the acute toxicity of the
title compounds (Tice et al., 2000). By a step wise procedure the toxicity
of the quinazolinone analogs were tested by using three single sex mice.
3–4 hr prior to dosing the mice was fasted (with held food but not
water). After completion of 3–4 hr fasting, the mice were weighed and
the title compounds were administered at 2000 mg/kg dose orally. Dur-
ing the first 30 min after dosing mouse was observed individually; dur-
ing the first 4 hr special attention were given and periodically over
24 hr. Thereafter for 14 days the mouse were monitored periodically.
3.2 | The subcutaneous pentylenetetrazole
seizure test
The test compounds ability to elevate the seizure threshold of mice which
results in protection of clonic seizure was detected by subcutaneous pen-
tylenetetrazole (scPTZ) method. Test compounds were administered to
animals by i.p. injection at 30 mg/kg, 100 mg/kg and 300 mg/kg dose
into a loose fold of skin present in the midline of the neck of mice,
85 mg/kg dose of Pentylenetetrazole is injected. To minimize stress the
mice are positioned in isolation cages and observed the presence or
absence of a seizure at 0.5 hr and 4 hr intervals (Swinyard, Clark, Miya-
hara, & Wolf, 1961). A 3–5 s clonic spasms episode of the hind and/or
forelimbs, jaws or vibrissae is taken as the endpoint. Mice which do not
display these signs are considered protected. Ethosuximide was used as
reference standard and the datas are depicted in Table 3.
3
| ANTICONVULSANT ACTIVITY
3.1 | The maximal electroshock test
MES seizures are exceptionally reproducible and with human seizures
these are electro physiologically reliable. In this method before placing
corneal electrodes, a drop of 0.5% tetracaine hydrochloride in 0.9%
saline was applied to the eyes of all animals. For mice 50 m Ampere,
60 Hz electrical stimulus and for rats 150 m Ampere, 60 Hz, electrical
stimulus was transported for 0.2 s by Woodbury and Davenport
described apparatus (White, Johnson, Wolf, & Kupferberg, 1995;
Woodbury & Davenport, 1952). The endpoint is the eradication of
tonic hindleg extensor phase in seizure. At 0.5 hr and 4 hr intervals
3.3 | Neurotoxicity (minimal motor impairment)
The rotorod test was performed in mice to evaluate MMI (minimal
muscular impairment)
/ MNI (minimal neurological impairment
(Dunham & Miya, 1957). At 0.5 hr and 4 hr intervals mice are pre-
treated by i.p. injection at 30 mg/kg, 100 mg/kg and 300 mg/kg dose
of title compounds. In a 6 rpm rotating rod when mice placed sustain
its balance for extended periods of time. During a period of 1 min if
FIGURE 5 Docked view of compound 7l at the active site of the enzyme PDB: 3KG2 [Color figure can be viewed at wileyonlinelibrary.com]

SARAVANAN ET AL.
11
FIGURE 6 A) Hydrophobic and B) hydrophilic amino acids surrounded around the compounds 7d (green colour) and 7l (cyan colour) (PDB: 3KG2)
[Color figure can be viewed at wileyonlinelibrary.com]
the animal falls three times then the analog is considered toxic. Addi-
tionally the animals may also show changes in muscle tone, abnormal
body posture, circular or zigzag gait, catalepsy, tremors, stupor, som-
nolence, hyperactivity, lack of exploratory behavior, spread of the legs,
and loss of placing response. Phenytoin (Yogeeswari et al., 2005) and
Ethosuximide (Rajak et al., 2009) was used as reference standard and
the outcomes are depicted in Table 4.
represents the docked view of all the synthesized compounds at the
active site of the enzyme PDB ID 3KG2.
As depicted in the Figure. 5a–c, compound 7d at active site of
enzyme (PDB ID: 3KG2) makes eight hydrogen bonding interactions,
oxygen atom of carbonyl group at quinazoline ring makes two hydro-
gen bonding interactions with hydrogens of THR480 and one with
ARG485 (C O------H-THR480, 2.50 Å and 2.36 Å;
C O-----H-
ARG485). C-4 nitro moiety of the phenyl ring makes three hydrogen
bonding interactions with hydrogens of GLU705 and one with
4
| RESULTS AND DISCUSSION
THR655 (O
N
O------H-GLU705, 1.95 Å, 2.06 Å and O2N-------H-
O-----H-THR655, 2.31 Å) and remaining
GLU705 2.34 Å;
O
N
4.1 | Density functionality studies
another hydrogen bonding interaction raised from the carbonyl group
of thiazolidine ring with hydrogen of THR482 (C O ----- H-THR482,
1.84 Å). As depicted in Figure. 6a–c, compound 7l makes 11 hydrogen
bonding interactions at the active site of the enzyme (PDB ID: 3KG2),
among those three interactions were of carbonyl group present at the
quinazoline ring with hydrogens of SER654 and THR655 (C O-------
In general the energies of highest occupied molecular orbital (HOMO) &
lowest unoccupied molecular orbital (LUMO) are very vital in the con-
nection compound biological significance, their energies and HOMO–
LUMO energy gap are calculated by B3LYP level with 6-311G (d, p)
basis set & the HOMO–LUMO diagram of synthesized and standard
were shown in Figure. 3a,b. The calculated frontier molecular orbital
energies (HOMO, LUMO) and their energy gap (ΔE) of synthesized com-
pound were − 0.2675, −0.1878 and 2.1688 eV, respectively. For the
parent standard energies were − 0.2515, −0.1859 and 1.7851 eV. In π–
electron systems for forecasting the most reactive position and in conju-
gated system to elucidate several kinds of reactions the electron densi-
ties of the FMOs (frontier molecular orbitals) were used. The chemical
reactivity and ΔE of test compounds were reflected through the energy
values of the EHOMO (highest occupied molecular orbital) and the ELUMO
(lowest unoccupied molecular orbital). The bioactivity from intramolecu-
lar charge transfer (ICT) was recently proved by using the energy gap
among LUMO and HOMO. The comparison study of standard com-
pound and synthesized compound report is showing that the synthe-
sized compound is having more energy band gap and it was enhances
its biological activity.
H-SER654, 1.94 Å and 2.13 Å;
C O-------H-THR655, 2.52 Å).
Carbonyl group of 2-oxo propionyl makes three hydrogen bonding
interactions with hydrogens of ARG485 and THR480 (C O-------H-
ARG485, 1.77 Å and 2.38 Å; C O-------H-THR480, 2.50 Å). Hydro-
gen of the amino group of hydrazinyl makes two hydrogen bonding
interactions with oxygen of GLU705 (N H-------O-GLU705, 2.41 Å
and 2.05 Å). C-3 hydroxyl group of phenyl ring makes two hydrogen
bonding interactions with hydrogen of MET708 and THR707
(H O-------H-MET708, 2.06 Å; H O-------H-THR707, 2.64 Å) and
remaining another hydrogen bonding interaction raised from the car-
bonyl group of thiazolidine ring with hydrogen of THR482 (C O -----
H-THR482, 2.24 Å). Figure. 7a,b represents the hydrophobic and
hydrophilic amino acids surrounded to the studied compounds 7d
(green colour) and 7l (cyan colour).
4.3 | Chemistry
4.2 | Molecular docking studies
Variety of new thiazolidin-4-one substituted quinazolinone analogs
Scheme 1 were prepared using a multistep synthesis from anthranilic
acid. In the beginning, acetylation trailed ring closure reaction was used
to synthesize 2-methyl-benzo-(1,3)-oxazin-4-one 2 from anthranilic acid
1 and acetic anhydride. In the next step, 3-(4-aminophenyl)-2-methyl
quinazolin-4(3H)-one 3 was synthesized through the condensation of
compound 2 with p-phenylenediamine in pyridine by loss of one water
Entire derivatives displayed very significant docking score against
AMPA subtype ionotropic glutamate receptor in complex with com-
petitive antagonist ZK 200775. The predicted binding energies of the
compounds are listed in Table 2. The molecules showed consensus
score in the range of 10.74–7.56, indicating the summary of all forces
of interactions between the ligands and the protein. Figure. 4a,b),

12
SARAVANAN ET AL.
FIGURE 7 HOMO–LUMO energy gap of standard and synthesized compound [Color figure can be viewed at wileyonlinelibrary.com]
molecule. On treating with benzaldehyde and thioglycolic acid in pres-
ence of zinc chloride and ethanol, compound 3 converted to
2-methyl-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl)quinazolin-4(3H)-
one 4 by a ring closure reaction with a loss of two water molecule. The
compound 4 undergoes simple condensation reaction with chlor-
oacetylchloride in ethanol and yielded 2-(3-chloro-2-oxopropyl)-
3-(4-[4-oxo-2-phenylthiazolidin-3-yl] phenyl)quinazolin-4(3H)-one
5 with a loss of hydrochloric acid. In the pre final step, 2-(3-hydrazino-
2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phenyl) quinazolin-4
(3H)-one 6 was obtained by reacting derivative 5 with hydrazine
hydrate in ethanol with removal of hydrochloric acid. Finally
using Schiff's base reaction the title compounds 7a–7l were syn-
thesized, in which carbonyl compound (different aromatic alde-
Thus the formed hemiaminal undergoes dehydration to generate
2-(2-[substitutedbenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-
phenylthiazolidin-3-yl]phenyl) quinazolin-4(3H)-one 7a–7l by produc-
ing stable imine as per synthetic Scheme 1.
Spectral evidences confirm the assigned structures of the title
compounds. In IR presence of C O and C
O C stretching in
2-methyl-benzo-(1,3)-oxazin-4-one 2 was confirmed by its absorption
peak at 1712 and 1,055 cm−1 respectively. The formation of analog
,
3 was confirmed by absence of peak around 1,050 cm−1 (stretching of
C
O H
C) and presence of peak at 3380 and 3,274 cm−1 (N
stretching of NH2). Also in 1H NMR, two protons singlet peak around
δ 3.76 ppm corresponds to NH2 confirms the formation of three. In
compound 4, absence of absorption band around 3,250–3,400 cm−1
(NH2 moiety) proves the formation of compound 4. Further it was
supported by, appearance of singlet peak in 1H NMR spectra at δ
hydes) and quinazolin-4(3H)-one analog
6 (amino derivative)
undergoes nucleophilic addition with formation of hemiaminal.

SARAVANAN ET AL.
13
FIGURE 8 Schematic representation of SAR of title compounds (7a-7l) [Color figure can be viewed at wileyonlinelibrary.com]
3.90 and 6.05 ppm for C-5 and C-2 protons of thiazolidin-4-one. In IR
spectra appearance of a peak at 729 cm−1 which is assigned to C Cl
group confirms the formation of compound 5. Compound 6 was
proved by absence of peak around 750 cm−1 (absence of chlorine) and
appearance of peak at 3341 and 3,278 cm−1 (presence NH2 moiety). The
IR spectra of title quinazolinones 7a–7l displays absorption peak at
3249–3390 cm−1 (NH), 3,025–3,116 cm−1 (Ar CH), 2,901–2,972 cm−1
(CH2 -CH), 1,674–1,746 cm−1 (C O), 1,549–1,675 cm−1 (C C) and
1,513–1,587 cm−1 (CH N). The conclusions obtained from the 1H-NMR
spectra of synthesized derivatives 7a-7 L are as follows: (a) A singlet
around δ 2.03–2.38 ppm for NH of CH2NH, (b) A singlet around δ
2.69–3.29 ppm for CH2 of CH2CO, (c) A singlet around δ 3.30–3.78 ppm
for CH2 of thiazolidinone, (d) A singlet around δ 4.05–4.53 ppm for CH2
of CH2NH, (e) A singlet around δ 6.02–6.39 ppm for CH of thiazolidi-
none, (f ) A multiplet around δ 6.82–8.48 ppm for Ar H, (g) A singlet
around δ 8.30–8.86 ppm for CH N. More over 13C NMR are in
accordance with chemical structure of title quinazolinones. Further
mass spectrum confirmed their molecular weight. Elemental analyses
of all synthesized compounds were found to be within ꢁ 0.4% with
respect to calculated value which confirmed the purity of synthe-
sized compounds.
studies revealed the non-toxic and well tolerance of test com-
pounds by test animals at tested dose levels.
5
| ANTICONVULSANT ACTIVITY
5.1 | MES test
In MES screening, the majority of test derivatives displayed reason-
able to fine antiepileptic activity. Out of many title compounds tested
in electroshock investigation, four compounds (7c, 7i, 7j, and 7l) were
found to be significantly active because after 0.5 hr they displayed
protection at 30 mg/kg dose (lowest tested dose). At same 30 mg/kg
dose out of these derivatives only one compound (7j) continuously
exhibited protection after 4.0 hr. But after 4.0 hr compounds 7c
and 7i at 100 mg/kg dose (higher dose) sustained to display the
potency; whereas 7l requires a dose of 300 mg/kg for demonstrat-
ing quick onset with extended duration of action. The encouraged
potency of these compounds possibly ascribed to the substituent's
present in benzylidene portion (hydrophobic distal aryl ring). At
the distal aryl ring these derivatives possess electron releasing
group like dimethylamino, hydroxy, and amino moiety. At 100 mg/
kg dose compounds such as 7g and 7h were showed protection
after 0.5 hr signifying the capability of compounds 7g and 7h to
shield from seizures at moderately low dosage. At 300 mg/kg dose
these derivatives were also active after 4.0 hr. At a dose of
300 mg/kg compounds 7a, 7b, 7d, 7e, and 7k were found to be
active after 0.5 hr and/or 4.0 hr. In addition compound 7f was
found to be inactive at the doses tested.
4.4 | Pharmacology
Test compounds were administered intraperitonially in mice for the
recognition of antiepileptic activity & tested by Maximal Electroshock
Seizure (MES) and scPTZ model. Generally the derivatives which show
activity in these tests are useful candidate for the treatment of gener-
alized, partial and even absence seizures. Antiepileptic screening
results of title compounds and standard drugs are presented in
Tables 3 and 4.
5.2 | The subcutaneous pentylenetetrazole
seizure test
Like MES screening many title compounds displayed fair to first-
class activity in scPTZ method also. Protection in scPTZ test by title
compounds revealed their ability to escalating seizure threshold.
Among various tested compounds, 7c, 7 g, 7 h, 7i, 7j, and 7l showed
protection in scPTZ test after 0.5 hr at 100 mg/kg dose. The above
derivatives sustained to exhibit potency at 300 mg/kg dose after
4.5 | Acute toxicity
At a dose of 2000 mg/kg no sign of toxicity observed in group of
animals. The LD50 value of test derivatives may surpass
2000 mg/kg. Hence these derivatives comes under class
5 (2000 mg/kg < LD50 < 2,500 mg/kg). Results of acute toxicity

14
SARAVANAN ET AL.
4.0 h. The above obtained results were found to equal when com-
pared to Ethosuximide (Standard AED drug for scPTZ test). Except
7f remaining compounds (7a, 7b, 7d, 7e, and 7k) were active at a
dose of 300 mg/kg after 0.5 hr and/or 4.0 hr. From the above
results, we came to know that the most active compounds of these
series contain electron releasing group in distal aryl ring which
improved antiepileptic activity.
substituent moiety of distal aryl ring (benzylidene) direct to a significant
difference in antiepileptic potency. In general it was found that com-
pounds possessing electron donating group displayed more activity than
compounds possessing electron withdrawing groups. For instance sub-
stituent's like amino (electron releasing moiety) improved the pharmaco-
logical potency; whereas substituent's like nitro (electron withdrawing
moiety) made the derivatives less active. The unsubstituted derivative
displayed moderate activity. The boost in antiepileptic potency of quina-
zolinone derivatives with electron releasing group may be accepted
owing to the existence of additional electron donating group on title
compounds (which are not present in compounds containing electron
withdrawing group) which might be responsible for added bonding in
binding site. Additionally it was found that p-substituted compounds
showed enhanced potency than corresponding o & m-substituted com-
pounds. Among the series the most active compound was found to be
2-(2-[4-aminobenzylidene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenyl
thiazolidin-3-yl]phenyl)quinazolin-4(3H)-one 7j, which shows longer
duration of action & more potency than that of standard Phenytoin with-
out showing any neurotoxicity. The SAR of 2-(2-[substitutedbenzyli-
dene]hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-2-phenylthiazolidin-3-yl]phe-
nyl) quinazolin-4(3H)-one 7a–7l was schematically represented in
Figure. 8.
At any one of the doses tested many of the test compounds
showed activity after 0.5 hr either in MES and/or scPTZ model. The
study discloses that 75% of the tested compounds displayed activity
in MES test; while 67% title quinazolinones showed activity in scPTZ
screening at one tested doses. The above outcomes exposed that the
majority of derivatives obsessed some MES selectivity.
5.3 | Neurotoxicity-minimal motor impairment
The neurotoxicity study exposed that most of the derivatives of these
series showed neurotoxicity at higher doses than a dose of generally
prescribed AEDs such as Carbamazepine or Phenytoin; However while
assessing an antiepileptic potency, division among neurotoxic, and antie-
pileptic dosage is enviable. After 0.5 hr and/or 4.0 hr none of the ana-
logs were found to be neurotoxic at a dose of 30 mg/kg. In antiepileptic
activity owing to its poor potency, except 7b, 7d, 7e, 7f, and 7k, remain-
ing derivatives were tested for their neurotoxicity. From the study it
was found that after 0.5 and/or 4.0 hr 7c, 7g, 7i, and 7l were neurotoxic
at 300 mg/kg dose. At maximum administered dose rest of all tested
compounds (7a, 7 h, and 7j) were not found to be neurotoxic.
6
| CONCLUSIONS
In conclusion, a varied novel 7a–7l have been designed and synthesized
based on the pharmacophore requirements of AEDs. Toxicity of title
compounds were evaluated by acute toxicity study at the dose level of
2000 mg/kg orally in mice. The anticonvulsant potency evaluated by
MES and scPTZ seizure method by the dose level of 30, 100, and
300 mg/kg, i.p. at 0.5 hr and 4.0 hr time intervals. Further, neurotoxicity
study was performed by minimal motor impairment test. The observed
SAR studies of tested compounds indicated that electron donating group
displayed more activity than electron withdrawing groups. The neurotox-
icity study exposed that most of the derivatives showed neurotoxicity
only at higher doses than a dose of generally prescribed AEDs such as
Phenytoin/Carbamazepine. From the initial screen identified potent
compounds 7c, 7g, 7h, 7i, 7j and 7l were additionally screened for their
oral availability test by MES and neurotoxicity at 30 mg/kg dose in rats.
The in vivo studies confirmed that the absorption of compounds from
GIT and also their infiltration to CNS. Among the test compounds,
One of the important properties of antiepileptic compound is its
ability to inhibit epilepsy by oral route of administration. This test unveils
the duration, TPE (the approximate time of peak effect), and the time of
onset of neurotoxicity or antiepileptic activity. We identified six com-
pounds (7c, 7g, 7h, 7i, 7j and 7l) from preliminary studies which are fur-
ther screened at 30 mg/kg dose for oral availability in rats by MES test &
neurotoxicity.
From these studies it was identified that the most potent com-
pounds of this series is 7j. This compound protected four out of four
rats (100%) at 2 hr and 4 hr time points, three out of four (75%) at
0.5 hr and 1 hr and one out of four (25%) at 0.25 hr. When compared
to Phenytoin compound 7j was found to exhibit more activity & lon-
ger duration of action. In addition, compound 7c protected 75% (3/4)
of rats at time points 0.5, 1, 2, and 4 hr and 25% (1/4) at 0.25 hr. The
compounds such as 7i and 7l were found to be fairly successful in
screening by MES test (oral route in rat); whereas remaining tested
derivatives (7g and 7h) were found to be least effective. When given
orally entire tested derivatives were nonneurotoxic. The in vivo stud-
ies confirmed the absorption of compounds from GIT and also their
infiltration to CNS. These derivatives may act on voltage depended
sodium ion channels like Phenytoin and other related drugs to inhibit
the electrically induced seizures.
2-(2-[4-aminobenzylidene]
hydrazinyl-2-oxopropyl)-3-(4-[4-oxo-
2-phenylthiazo lidin-3-yl]phenyl) quinazolin-4(3H)-one 7j exhibited the
most potent activity. Based on the biological study report it was con-
cluded that, the compound 7j was found to be very potent compared
with rest of the compounds and standard. Consequently the compound
7j come out as the pilot molecule with broad spectrum antiepileptic
potency and devoid of neurotoxicity for further exploitation.
5.4 | Structure activity relationship studies
ACKNOWLEDGMENT
Structure activity relationship (SAR) studies indicated that various benzy-
lidene derivatives present at C-2 of quinazolin-4(3H)-one nucleus
exerted varied pharmacological activity. The electronic character of the
The authors are thankful to the management of MNR College of
Pharmacy, Karavali College of Pharmacy for providing infrastructure
facilities to carry out this research work. The authors thankfully

SARAVANAN ET AL.
15
Kanehisa, M., & Goto, S. (2000). KEGG: Kyoto encyclopedia of genes and
genomes. Nucleic Acids Research, 28, 27–30.
Kaur, H., Kumar, S., Vishwakarma, P., Sharma, M., Saxena, K., & Kumar, A.
(2010). Synthesis and antipsychotic and anticonvulsant activity of some
new substituted oxa/thiadiazolylazetidinonyl/thiazolidinonylcarbazoles.
European Journal of Medicinal Chemistry, 45, 2777–2783.
admit the Central Instrumentation Facility, IIT Chennai, India. The
authors also thank Kalasalingam University, and Soniya Education
Trust's, College of Pharmacy for providing insilico facilities to carry
out this research work.
Majoie, H. M., de Baets, M., Renier, W., Lang, B., & Vincent, A. (2006).
Antibodies to voltage-gated potassium and calcium channels in epi-
lepsy. Epilepsy Research, 71, 135–141.
CONFLICT OF INTEREST
Rajak, H., Deshmukh, R., Aggarwal, N., Kashaw, S., Kharya, M. D., & Mishra, P.
(2009). Synthesis of novel 2, 5Disubstituted 1, 3, 4Thiadiazoles for their
potential anticonvulsant activity: Pharmacophoric model studies. Archiv der
Pharmazie, 342, 453–461.
Authors declare there is no conflict of interest.
ORCID
Sander, J. W. (2003). The epidemiology of epilepsy revisited. Current Opin-
ion in Neurology, 16, 165–170.
Shingalapur, R. V., Hosamani, K. M., Keri, R. S., & Hugar, M. H. (2010).
Derivatives of benzimidazole pharmacophore: Synthesis, anticonvul-
sant, antidiabetic and DNA cleavage studies. European Journal of
Medicinal Chemistry, 45, 1753–1759.
Theivendren Panneerselvam
http://orcid.org/0000-0002-
8197-4688
REFERENCES
Srivastava, V., & Chandra, R. (2002). A. Kumar. Synthesis of potential quina-
zolinonyl pyrazolines and quinazolinyl isoxazolines as anticonv ulsant
agents, 41B, 2371–2375.
Brodie, M. J., Elder, A. T., & Kwan, P. (2009). Epilepsy in later life. The Lan-
cet Neurology, 8, 1019–1030.
Bruno-Blanch, L., Galvez, J., & Garcıa-Domenech, R. (2003). Topological
virtual screening: A way to find new anticonvulsant drugs from
chemical diversity. Bioorganic & Medicinal Chemistry Letters, 13,
2749–2754.
Dunham, N., & Miya, T. (1957). A note on a simple apparatus for detecting
neurological deficit in rats and mice. Journal of Pharmaceutical Sciences,
46, 208–209.
Srivastava, V., & Kumar, A. (2002). Synthesis of newer thiadiazolyl and
thiazolidinonyl quinazolin-4 (3H)-ones as potential anticonvulsant
agents. European Journal of Medicinal Chemistry, 37, 873–882.
Swinyard, E. A., Clark, L. D., Miyahara, J. T., & Wolf, H. H. (1961). Studies
on the mechanism of amphetamine toxicity in aggregated mice. Journal
of Pharmacology and Experimental Therapeutics, 132, 97–102.
T. SYBYL-X, 1.2; Tripos International, St, Louis, MO, USA, (2012).
Tice, R. R., Agurell, E., Anderson, D., Burlinson, B., Hartmann, A.,
Kobayashi, H., … Sasaki, Y. (2000). Single cell gel/comet assay: Guide-
lines for in vitro and in vivo genetic toxicology testing. Environmental
and Molecular Mutagenesis, 35, 206–221.
White, H., Johnson, M., Wolf, H., & Kupferberg, H. (1995). The early iden-
tification of anticonvulsant activity: Role of the maximal electroshock
and subcutaneous pentylenetetrazol seizure models. The Italian Journal
of Neurological Sciences, 16, 73–77.
Woodbury, L. A., & Davenport, V. D. (1952). Design and use of a new elec-
troshock seizure apparatus, and analysis of factors altering seizure
threshold and pattern. Archives Internationales de Pharmacodynamie et
de Therapie, 92, 97–107.
Estrada, E., & Peña, A. (2000). In silico studies for the rational discovery of
anticonvulsant compounds. Bioorganic
2755–2770.
& Medicinal Chemistry, 8,
Fisher, R. S., Boas, W. V. E., Blume, W., Elger, C., Genton, P., Lee, P., &
Engel, J. (2005). Epileptic seizures and epilepsy: Definitions proposed
by the international league against epilepsy (ILAE) and the International
Bureau for Epilepsy (IBE). Epilepsia, 46, 470–472.
Gasteiger, J., & Marsili, M. (1980). Iterative partial equalization of orbital
electronegativity—A rapid access to atomic charges. Tetrahedron, 36,
3219–3228.
ꢀ
Güntepe, F., Saraçoglu, H., Çalıs¸kan, N., Yüksektepe, Ç., & Cukurovali, A.
(2012). Synthesis, molecular and crystal structure analysis of
2-bromo-4-chloro-6-{[4-(3-methyl-
Yogeeswari, P., Sriram, D., Thirumurugan, R., Raghavendran, J. V.,
3-phenyl-cyclobutyl)-thiazol-2-yl]-hydrazonomethyl}-phenol by experi-
mental methods and theoretical calculations. Journal of Molecular Struc-
ture, 1022, 204–210.
Sudhan, K., Pavana, R. K.,
& Stables, J. (2005). Discovery of
N-(2, 6-dimethylphenyl)-substituted semicarbazones as anticonvul-
sants: Hybrid pharmacophore-based design. Journal of Medicinal
Chemistry, 48, 6202–6211.
Hisano, T., Ichikawa, M., Kito, G., & Nishi, T. (1972). Syntheses and pharma-
cological activities of 2-heterocyclic substituted 4 (3H)-Quinazolinone
derivatives. Chemical and Pharmaceutical Bulletin, 20, 2575–2584.
Holmes, G. L. (2008). Handbook of epilepsy. Philadelphia, USA: Lippincott
Williams & Wilkins.
How to cite this article: Saravanan G, Panneerselvam T,
Alagarsamy V, et al. Design, graph theoretical analysis, density
functionality theories, Insilico modeling, synthesis, characteri-
zation and biological activities of novel thiazole fused quinazo-
linone derivatives. Drug Dev Res. 2018;1–15. https://doi.org/
10.1002/ddr.21460
İnkaya, E., Dinçer, M., Ekici, Ö.,
&
Cukurovali, A. (2012).
N0-(2-methoxy-benzylidene)-N-[4-(3-methyl-3-phenyl-cyclobutyl)-thiazol-
2-yl]-chloro-acetic hydrazide: X-ray structure, spectroscopic characteriza-
tion and DFT studies. Journal of Molecular Structure, 1026, 117–126.
Jatav, V., Mishra, P., Kashaw, S., & Stables, J. (2008). CNS depressant and
anticonvulsant activities of some novel 3-[5-substituted 1, 3,
4-thiadiazole-2-yl]-2-styryl quinazoline-4 (3H)-ones. European Journal
of Medicinal Chemistry, 43, 1945–1954.