Microwave Assisted Synthesis and Pharmacological Evaluation of Few 4-Quinazolinone Derivatives

 

Dinesh D. Rishipathak1*, Trupti A. Jadhav2, Sonal P. Tathe2, Pavan B. Udavant3

1Associate Professor, Department of Pharmaceutical Chemistry, Department of Pharmacology, MET’s Institute of Pharmacy, Savitribai Phule Pune University, Pune, Adgaon, Tal. Nashik, Dist. Nashik-422003,

Maharashtra, India.

2PG Scholar, Department of Pharmaceutical Chemistry, MET’s Institute of Pharmacy, Savitribai Phule Pune University, Pune, Adgaon, Tal. Nashik, Dist. Nashik-422003, Maharashtra, India

3Associate Professor, Department of Pharmacology, MET’s Institute of Pharmacy, Savitribai Phule Pune University, Pune,  Adgaon, Tal. Nashik, Dist. Nashik-422003, Maharashtra, India.

*Corresponding Author E-mail: drishipathak@gmail.com

 

ABSTRACT:

In the present investigation, 3-(4-oxo-2-phenyiquinazolin-3(4H)-yl)-2-(substituted phenyl) thiazolidin -4-one derivatives were synthesized with the aim of achieving compounds with anticonvulsant potential. The docking study was performed by 1KJT receptor and yielded good score. The microwave assisted heating technique used which is rapid and efficient resulting in reduced reaction times and increased yields compared to conventional technique. The synthesized compounds were confirmed on the basis of IR, 1H-NMR and Mass analyses. Some of the synthesized compounds were evaluated for their anticonvulsant effect by PTZ induced convulsions method. The molecular docking studies resulted in highlighting the ligands and their conformations which efficiently fit into the cavity #1 of target protein GABA (A)- receptor- associated protein (1KJT). The pharmacological evaluation of the compounds showed increase in latency (onset time) to induce convulsions; decrease in the number of convulsions and increase in latency of death compared to control. From the series of 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(substitutedphenyl)-thiazolidin-4-ones; compounds viz. AQCI-C2, AQPC-C4, AQBE-C5, AQFU-C6 fitted best into the cavity of 1KJT with lowest dock score. The compound AQBE-9 shows highest latency as 4.16 minutes at the dose of 270mg/kg. The compounds AQCI-4and AQBE-9 showed highest percentage of protection (80%) at the dose of 270 mg/kg among the evaluated compounds compared to control. The analysis of structural features revealed that substitution of cinnamyl group and phenyl group on Thiazolidinone ring showed enhanced the anticonvulsant potential among the synthesized compounds.

 

KEYWORDS: 4-thiazolidinone, Anticonvulsant activity, Docking, Microwave technique.

 

 


INTRODUCTION:

It is now well recognized that cellular excitability leading to convulsive seizures can be attenuated by GABA nergic stimulation in the brain. The GABAA receptor is one of two ligand gated ion channels responsible for mediating the effects of GABA, the major inhibitory neurotransmitter in the brain. Activation of the GABAA/benzodiazepine receptors/ chloride channel complex allows increased chloride conductance, thereby preventing the spread of neuronal excitations. The potential targets for AED’s action on the GABA nergic inhibitory synapses include a) drugs that enhance the biosynthesis of GABA (Gabapentin, Pregabalin and VPA), b) drugs that inhibit GABA degradation (Vigabatrin) c) drugs that inhibit the reuptake of GABA (Tiagabine), d) drugs that bind to an allosteric site on the post synaptic GABAA receptor complex that increase chloride conductance (Barbiturates, BZDs, neurosteroids, FBM, TPM).

 

Quinazolinone are the oxidized form of quinazolines and as such are also part of the quinoline alkaloids. The scaffold that defines a quinazoline consist of fused benzene and pyrimidine bicyclic structure. Quinazolinones have shown that these derivatives possess a wide variety of biological activities such as anti HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti-inflammatory, CNS depressant, antimalarial, antioxidant, antileukemic activity, antileishmanial activity.

 

Thiazolidinones are five membered heterocycles with one nitrogen atom and one sulfur in the ring and consist wide variety of pharmacological activities such as Antimicrobial, Anti-inflammatory, Hypoglycemic activity, Anticonvulsant, Antifungal and Antidepressant. Hence we have synthesized combined macromolecules containing both Quinazolinones and Thiazolidinone performed its pharmacological evaluation for anticonvulsant activity.

 

MATERIALS AND METHODS:

Materials:

All the chemicals were of laboratory reagent grade and were obtained from Thomas Baker, Loba Chemical and Sigma-Aldrich. Melting points were taken in melting point apparatus (omega scientific industries) and were uncorrected. Analytical thin-layer chromatography was performed on 60F254 Precoated silica gel plates (Merck) to establish identity of reactants and products monitored in between reactions as well at the end for completion of reaction. The spots were visualized in UV chamber or by iodine vapors in an enclosed chamber. The solvent system used for Thin-Layer Chromatography was A) Chloroform: Acetone (4.5:0.5) B) Benzene: Methanol (4:1) C) Benzene: Ethyl Acetate (7:3). Infra-Red spectra of compounds were recorded on DRS on a shimadzu 1000 FTIR spectrometer in the range of 4000-200 cm-1. Proton (1H) Nuclear Magnetic Resonance spectra of compounds were recorded on Bruker Advance II 400 NMR Spectrophotometer using DMSO solvent, at SAIF, Punjab University, Chandigarh. Mass spectra of compounds were recorded on WATERS, Q-TOF MICROMASS (LC-MS) at SAIF, Punjab University, Chandigarh. All microwave reactions were carried on ‘Catalyst System’ CATA 2R- Scientific Microwave Synthesizer with power setting from P-1 to H (700 W). The completion of the reaction was monitored by TLC.

 

Methods:

Synthesis of 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(substituted phenyl) thiazolidin-4-one:

Step 1: Synthesis of 2-phenyl-3, 1-benzoxazin-4-one.

 

 

To a solution of anthranilic acid (0.01mol) in pyridine (0.03mol) was added benzoyl chloride (0.02 mol), and the mixture was shaken for 5 min and then kept aside Room temperature for further 25 min with occasional shaking. The reaction mixture was treated with 5% NaHCO3 solution (15 ml), filtered, washed with water, dried and the crude product was recrystallized from absolute ethanol. Purity of the product was checked by TLC (solvent system B).

 

Step 2: Synthesis of 3-amino-2-phenylquinazolin-4(3H)-one

 

 

In Microwave flask, benzoxazinone (0.01mol) was dissolved in sufficient ethanol and added hydrazine hydrate (99%) (0.02mol). The Reaction mixture was irradiated under microwave at power 350 W for 8 min. The crude solid product obtained was air dried and recrystallized from ethanol. Purity of the product was checked by TLC (solvent system B).

 

Step 3: Synthesis of 3-(substituted benzylidene)-amino-2-phenylquinazolin-4(3H)-one

 

 

A mixture of Quinazolinone and various substituted aromatic aldehydes in ratio (1:1) was irradiated under microwave in ethanol at power and time mentioned in the Table 1 The reaction mixture was cooled to room temperature. Solid thus obtained was filtered, air dried and recrystallized from Ethanol. Purity of the product was checked by TLC (solvent system A).

 

Table 1: Microwave assisted reaction conditions for Synthesis of 3-(substituted benzylidene)-amino-2-phenylquinazolin-4(3H)-one

 

 

 

Compound

code

Ar

Power (watt)

Time (min)

QME-1

p -OCH3-C6H5-

455

35

QPF-2

p-F-C6H5-

455

32

QPC-3

p–Cl-C6H5-

455

20

QCI-4

-CH=CHC6H5

455

25

QPN-5

m-NO2-C6H5-

455

30

QPH-6

p-OH-C6H5-

455

30

QFU-7

-C4H4O

455

35

QMC-8

m-Cl-C6H5-

455

30

QBE-9

C6H5-

455

25

 

Step 4: Synthesis of 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(substituted phenyl) thiazolidin-4-one from 3-(benzylidene amino)-2-phenylquinazolin-4(3H)-one

A 3-(benzylideneamino)-2-phenylquinazolin-4(3H)-one (0.01mol) and thioglycolic acid (0.01mol) in presence of pinch of anhydrous Zinc Chloride in methanol was irradiated under microwave at 455 W power and time mentioned in the Table 2. The reaction mixture was cooled, poured into crushed ice. Solid thus obtained was filtered, air dried and recrystallized from Ethanol. Purity of the product was checked by TLC (solvent system A).

 

Table 2

Microwave assisted reaction conditions for Synthesis of 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(substituted phenyl) thiazolidin-4-one from 3-(benzylidene amino)-2-phenylquinazolin-4(3H)-one

 

 

Compound

code

Ar

Power (watt)

Time (min)

AQME-1

455

35

AQPF-2

455

25

AQPC-3

455

30

AQCI-4

455

28

AQPN-5

455

25

AQPH-6

455

30

AQFU-7

455

35

AQMC-8

 

455

35

AQBE9

455

30

 

Pharmacological evaluation:

Acute toxicity of synthesized compounds:

OECD guidelines (No. 425) were followed for acute toxicity studies. Acute toxicity in mice was carried out for determining median Lethal Dose (LD50). Animal were dosed two at time at minimum of 48 hour intervals. Doses were selected from the sequence 2000, 550, 175, 55, 17.5, 5.5, 1.75mg/kg with 5 animals per group. Each animal was observed carefully for signs of toxicity as well as for mortality in the first 30 minutes after dosing and then occasionally for further 4 hours and daily thereafter for a period of 14 days. The number of mice dying during 48 hours was recorded. The test compounds were administered intraperitonially during acute toxicity testing.

 

Anticonvulsant activity: Pentylenetetrazole (PTZ) induced convulsions in mice:

Animals: Swiss albino mice of male sex, weighing 22-30 gm were used. The animals were purchased from National Institute of Bioscience, Pune, India. Animals were housed in different groups consisting of five animals in each group, in plastic cages under good hygienic conditions in registered animal house of MET’s Institute of Pharmacy, Nashik (Registration no. 1344/ac/10/CPCSEA). Bedding, good hygienic conditions, ambient temperature of 25±1ºC, relative humidity of 45-55% and 12 hours light 12 hours dark cycles were maintained in animal house. The animals had free access to water and standard palletized diet, except during experimentation, food and water were withheld. All pharmacological experiments were performed between 11:00 am and 3:00 pm. All experiments were conducted according to the guidelines of Committee for Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environments and Forests, Government of India with their procedures and protocols reviewed and approved by Institutional Animal Ethical Committee (IAEC), constituted under CPCSEA.

 

Preparation of doses:

The drug solutions were freshly prepared. Pentylenetetrazole (Dose: 80 mg/kg, i.p.) solution was prepared by dissolving it in distilled water. Diazepam (Dose: 2 mg/kg, i.p.), a stock solution containing 0.2 mg/mL was prepared by dissolving it in distilled water. All the test compounds were insoluble in water hence they were dissolved in DMSO. The doses of test compounds were selected as 180 mg/kg, i.p. (Dose I, approx. 1/10th of LD50) and 270 mg/kg, i.p. (Dose II, 1.5 times of the dose I) and stock solutions of the test compounds were prepared by dissolving in DMSO.

 

Procedure:

1. The animals were first weighed and were selected for the experiment depending on the weight. The animals were then divided into ten groups as shown in Table 3, of Six animals each one group is used for studying the effects of Pentylenetetrazole alone (Control) and the other for studying the protective effects of Diazepam (Standard). The remaining eight groups were used for studying the effects of synthesized compounds (Test). Two doses, Dose I and Dose II as mentioned above were used for administration of test compounds i.e. quinazolinones.

 

 

 

Table 3 Different groups of mice used for evaluation of anticonvulsant effect

Group

Compound

Dose (mg/Kg) i.p.

1

PTZ (Control)

80

2

Diazepam (Standard)

2

3

AQPF-2

180

4

270

5

AQPC-3

180

6

270

7

AQCI-4

180

8

270

9

AQBE-9

180

10

270

 

2. Pentylenetetrazole (80 mg/kg, body weight) was administered intraperitoneally to induce convulsions in the control and the onset of convulsions, severity of convulsions and mortality was noted.

 

3. PTZ (80 mg/kg, i.p.) was administered half an hour after the administration of Diazepam and the test compounds. In case of Diazepam treated animals, either delay or complete abolition of convulsions was noted. The test group animals were observed for onset of convulsions, number of convulsions and percentage of protection. The Diazepam treated and test animals were observed following PTZ injection up to half an hour. The anticonvulsant potential of the newly synthesized compounds is evaluated on the basis of the following observations:

·      Increase in latency (onset time) to induce convulsions

·      Percentage Protection as compared to control

 

Readings of the test compounds are compared with control.

 

RESULTS AND DISCUSSION:

Table 4: Dock score and binding energy of 2-(4-substituted phenyl)-3-(4-oxo-2- phenylquinazolin-3(4H)-yl) thiazolidin-4-one

 

 

 

Compound Code

Ar

Dock score

∆G (Kcal/mol)

AQCI-C2

-CH=CHC6H5

-5.6

-228

AQPC-C4

p –Cl-C6H5

-5.11

-75

AQBE-C5

C6H5-

-4.9

-91

AQFU-C6

-C4H4O

-4.8

-181

AQMC-C5

m-Cl- C6H5-

-4.7

-87

AQPN-C3

p-NO2-C6H5-

-4.7

-80

AQPF-C5

p-F- C6H5-

-4.38

-87

AQME-C4

p -OCH3-C6H5-

-4.00

-87

AQPH-C6

p-OH-C6H5-

-2.6

-200

 

 

From the observations mentioned in Table 4, for few conformations with dock scores comparable with that of the standard, the binding patterns with the cavity # 1 of the receptor [1KJT] were studied by observing the hydrophobic and Vander Waals interactions, as described in following section.

 

a)    For the compound, 2-(4-chlorophenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) thiazolidin-4-one (AQPC-3), the Hydrophobic (A) and Vander Waals (B) interactions with cavity # 1 of GABA(A)- receptor- associated protein, GABARAP [ PBD ID:1KJT] are shown in Figure 1. The ligand showed hydrophobic interaction with the residues LYS38A, GLU112A and Vander Waals interactions with the residues LYS38A, GLU11.

 

 

(A)

 

(B)

Figure 1

Binding interactions of (AQPC-3) with cavity # 1 of GABA (A)- receptor- associated protein 1KJT (Blue colour dotted lines indicate hydrophobic interactions and Magenta colour dotted lines indicate Vander Waals interactions)

 

b)      For the compound, 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-phenylthiazolidin-4-one (AQBE-4), the Hydrophobic (A) and Vander Waals (B) interactions with cavity # 1 of GABA(A)- receptor- associated protein, GABARAP [ PBD ID:1KJT] are shown in Figure 2 The ligand showed hydrophobic interaction with the residues LYS38A, GLU112A and Vander Waals interactions with the residues LYS38A, GLU11.

c)       

 

(A)

 

(B)

Figure 2

Binding interactions of (AQBE-9) with cavity # 1 of GABA (A)- receptor- associated protein, 1KJT (Blue color dotted lines indicate hydrophobic interactions and Magenta color dotted lines indicate Vander Waals interactions)

 

d)      For the compound, 2-(4-nitrophenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) thiazolidin -4-one (AQPN-5), the Hydrophobic (A) and Vander Waals (B) interactions with cavity # 1 of GABA(A)- receptor- associated protein, GABARAP [ PBD ID:1KJT] are shown in Figure 3 The ligand showed hydrophobic interaction with the residues LYS38A, GLU112A and Vander Waals interactions with the residues LYS38A, GLU112A.

 

 

(A)

 

(B)

Figure 3

Binding interactions of (AQPN-5) with cavity # 1 of GABA (A)- receptor- associated protein, 1KJT (Blue colour dotted lines indicate hydrophobic interactions and Magenta colour dotted lines indicate Vander Waals interactions)

 

e)      For the compound, 2-(2-chlorophenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) thiazolidin-4-one (AQMC-8), the Hydrophobic (A) and Vander Waals (B) interactions with cavity # 1 of GABA(A)- receptor- associated protein, GABARAP [ PBD ID:1KJT] are shown in Figure 4. The ligand showed hydrophobic interaction with the residues LYS38A, GLU112A and Vander Waals interactions with the residues LYS38A, GLU112A.

 

 

(A)

 

(B)

Figure 4

Binding interactions of (AQMC-8) with cavity # 1 of GABA (A)- receptor- associated protein (1KJT) (Blue colour dotted lines indicate hydrophobic interactions and Magenta colour dotted lines indicate Vander Waals interactions)


 

 

Table 5: Physical properties of 2-(4-substituted phenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)- thiazolidin-4-one

 

Sr. No.

Compound code

Ar

Melting point (0C)

% Yield

Solvent system

Rf

1

AQME-1

-p -OCH3-C6H5

108-110

75

A

0.65

2

AQPF-2

-P-F-C6H5

118 -120

85

A

0.7

3

AQPC-3

-p –Cl-C6H5

170-172

70

A

0.7

4

AQCI-4

-C10H12

140-142

65

A

0.65

5

AQPN-5

m-NO2-C6H5

124-126

70

A

0.6

6

AQPH6

p-OH-C6H5

80-82

72

A

0.75

7

AQFU-7

-C4H4O

110-112

75

A

0.77

8

AQMC-8

m-Cl-C6H5

168 -170

70

A

0.70

9

AQBE-9

C6H5

138-140

69

A

0.8

 

 


Characterization of the synthesized compounds:

a)      The 1H-NMR spectrum of the compound 2-(4-methoxyphenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-thiazolidin-4-one (AQME-1) shows, (Ar-Ha) doublet at ᵟ7.60-7.64, (Ar-Hb) doublet at ᵟ7.67, (Ar-HC) doublet at ᵟ6.86-6.89, (Ar-Hd) doublet at ᵟ8.09,(Ar-He) doublet at ᵟ7.79-7.81, (Ar-Hf) doublet ᵟ 7.47-7.49 , (Ar-Hg) doublet at ᵟ7.81,(Ar-Hh)singlet at ᵟ5.92,(Ar-Hi)singlet at ᵟ3.95-3.85, (Ar-Hj)singlet at ᵟ 3.83.

 

b)      The 1H-NMR spectrum of the compound Characterization of 2-(4-flluorophenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-thiazolidin-4-one (AQPF-2) shows, (Ar-Ha) doublet at ᵟ7.60, (Ar-Hb) doublet at ᵟ7.85, (Ar-HC) doublet at ᵟ7.2 , (Ar-Hd) doublet at ᵟ8.09 ,(Ar-He) doublet at ᵟ 7.24 , (Ar-Hf) doublet ᵟ7.58 , (Ar-Hg) doublet at ᵟ7.83 ,(Ar-Hh) singlet at ᵟ5.92,(Ar-Hi) singlet at ᵟ3.85-3.95.

 

 

c)      The 1H-NMR spectrum of the compound NMR Of 2-(4-chlorophenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-thiazolidin-4-one (AQPC-3) shows, (Ar-Ha) doublet at ᵟ7.60, (Ar-Hb) doublet at ᵟ7.70 , (Ar-HC) doublet at ᵟ7.33 , (Ar-Hd) doublet at ᵟ8.09 ,(Ar-He) doublet at ᵟ 7.2 , (Ar-Hf) doublet ᵟ7.50 , (Ar-Hg) doublet at ᵟ6.88 ,(Ar-Hh) singlet at ᵟ5.92,(Ar-Hi) singlet at ᵟ3.85-3.95.

 

d)      The mass spectrum of the compound AQPF-2 (fluorophenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-thiazolidin-4-one (AQPF-2) showed molecular ion peak at m/e 417.6The mass analysis was done by Liquid Chromatography-Mass Spectrometry (LC-MS). The fragment peaks were observed at m/e 352,322.07, 245,144.03, 77.04

 

e)      The mass spectrum of the final compound 2-(4-methoxyphenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-thiazolidin-4-one (AQME-1) showed molecular ion peak at m/e 429.11. The fragment peaks were observed at m/e 352, 322.7, 245, 144.03, 77.0


 

 

Table 6: Anticonvulsant effect of some synthesized 2-(4-substituted phenyl)-3-(4-oxo-2-phenylquinazolin-3(4H)-yl) thiazolidin-4-one in mice using PTZ induced convulsions method.

Code

Dose (mg/Kg, i.p.)

Latency to induce convulsions (Mean ± SEM) (Min)

No. of convulsions

% Protection

PTZ (Control)

80

1.02±0.05

5

0

Diazepam

2

-

0

100

AQPF-2

180

270

2.50±0.45 NS

2.81±0.47 *

4

2

20

60

AQPC-3

180

270

2.60 ±0.35*

2.71 ±0.27 *

3

2

40

60

AQPCI-4

180

270

3.09±0.44 *

4.04±0.54 **

3

1

40

80

AQBE-9

180

270

3.17±0.33 *

4.16±0.45 **

3

1

40

80

N=6, in each group; *: P < 0.05; **: P <0.01; NS: Non significant; One Way ANOVA followed by Dennett’s test. Values expressed as Mean ± SEM

 

 


Anticonvulsant effect of some synthesized 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(substituted phenyl)-thiazolidin-4-ones in mice using PTZ induced method.

 

 

Figure 5: Graphical representation of anticonvulsant effect of some synthesized 3-(4-oxo-2-phenylquinazolin-3(4H)-yl)-2-(substituted phenyl)-thiazolidin-4-ones in mice using PTZ induced convulsions method

 

 

CONCLUSION:

On the basis of the present investigation following conclusions are outlined:

·      The molecular docking studies resulted in highlighting the ligands and their conformations which efficiently fit into the cavity #1 of target protein GABA (A)- receptor- associated protein (1KJT). From the series of 3-(4-oxo-2-phenyiquinazolin-3(4H)-yl)-2-(substituted phenyl)- thiazolidin -4-ones; compounds viz. AQCI-C2, AQPC-C4, AQBE-C5, AQFU-C6 fitted best into the cavity of 1KJT with lowest dock score is indicated in Table 4.

·      The compound AQBE-9 shows highest latency as 4.16 minutes at the dose of 270mg/kg.

·      The pharmacological evaluation of the compounds showed increase in latency (onset time) to induce convulsions; decrease in the number of convulsions and increase in latency of death compared to control.

·      The compounds AQCI-4and AQBE-9 showed highest percentage of protection (80%) at the dose of 270 mg/kg among the evaluated compounds compared to control.

·        The analysis of structural features revealed that substitution of cinnamyl group and phenyl group on Thiazolidinone ring showed enhanced the anticonvulsant potential among the synthesized compounds.

 

ACKNOWLEDGEMENT:

We would like to thanks the MET’s Institute of Pharmacy, Adgoan, Nashik for providing us necessary lab facilities, Grateful thanking for all helping hands, Savitribai Phule Pune University Pune, Maharashtra, India and SAIF, Punjab University, Chandigarh for their assistance in analytical work.

 

 

REFERENCES:

1.     Chawala, A. et al. (2013) ‘Recent advances of Quinazolinone derivatives as marker for various biological activities’. International Research Journal of Pharmacy, 4(3), pp. 49-58

2.     Rajput, R. et al. (2012) ‘A Review on Biological Activity of Quinazolinones’. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 4, no.2, pp. 66-70

3.     Ibrahim, S. et al. (1997) ‘Synthesis and biological evaluation of some new fused quinazoline derivatives. Journal of Chem Res, (5), pp. 1041-1063

4.     Jatav, V. et al, (2008), ‘CNS depressant and Anticonvulsant activity of some novel 3-[5-substituted 1, 3, 4-thiadiazole-2-yl]-2-styryl quinazoline-(4)-3H-one’. European Journal of Medicinal Chemistry, 43(9), pp.1945-1954

5.     Mavandadi, F. et al. (2004) ‘Microwave- assisted chemistry in drug discovery.’ Current Topics in Medicinal Chemistry, 4, pp. 773-792

6.     Paneersalvam, P. et al. (2010) ‘Anticonvulsant activity of Schiff bases of 3-amino-6,8-dibromo-2-phenyl-quinazolin-4(3H)-ones’. Indian Journal of Pharmaceutical Science., (72), pp. 375-378

7.     Venkataraman, S. et al. (2010) ‘Synthesis and biological activity of some novel quinazolinone derivatives’. Journal of Chemical and Pharmaceutical Research, 2(5) pp. 461-475

8.     Wolfe, J. et al. (1990) ‘Synthesis and Anticonvulsant Activity of Some New 2-Substituted 3-Aryl-4(3H)-quinazolinones’. Journal of Medicinal Chemistry; (33) pp. 161- 166

9.     Kashaw, V. et al. (2009) ‘Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea’. European Journal of Medicinal Chemistry, vol.44 pp. 4335–4343

 

 

 

 

 

Received on 19.06.2019        Accepted on 21.07.2019

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2019; 9(3):147-154.

DOI: 10.5958/2231-5691.2019.00023.6