Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H)-ones

Ibrahim, Mohamed‐Kamal; El‐Adl, Khaled; Al‐Karmalawy, Ahmed A.

doi:10.1016/j.bfopcu.2015.05.001

Cited by 45 publications

(31 citation statements)

References 27 publications

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“…The small‐molecules and protein were minimized using the OPLS 2005 force field. The default settings in Glide Docking were used to generate grid considering the active site residues as explored by Ibrahim et al and Abulkhair et al to define the center of the grid box (20 Å × 20 Å × 20 Å). Prepared small molecules were docked into the protein structure using Glide 6.3 XP docking .…”

Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

Sahu

Siddiqui

Naim

et al. 2017

Archiv der Pharmazie

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A series of new pyrimidine-triazine hybrids (4a-t) was designed and synthesized, from which potent anticonvulsant agents were identified. Most of the compounds exhibited promising anticonvulsant activity against the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, along with minimal motor impairment with higher safety compared to the standard drugs, phenytoin and carbamazepine. In the series, 5-(4-(4-fluorophenyl)-6-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4o) and 5-(6-(4-hydroxy-3-methoxyphenyl)-4-(4-hydroxyphenyl)-2-thioxo-5,6-dihydropyrimidin-1(2H)-yl)-1,2-dihydro-1,2,4-triazin-3(6H)-one (4s) emerged as most potent anticonvulsant agents with median doses of 22.54 and 29.40 mg/kg (MES ED ), 285.02 and 293.42 mg/kg (scPTZ ED ), and 389.11 and 412.16 mg/kg (TD ), respectively. Docking studies were also performed for all synthesized compounds to get insight into the binding pattern toward the GABA receptor as a possible mechanism of their anticonvulsant action, and in silico ADME studies were carried out to predict the safety and stability of the molecules. The increased GABA level in the experimental animals in the neurochemical estimation assay confirmed their GABAergic modulating activity. The most potent compounds were also evaluated for their neurotoxic and hepatotoxic effects. Fortunately, they did not show any sign of neurotoxicity or hepatotoxicity, suggesting that they have a broad spectrum of anticonvulsant activity with a large safety margin. Together, this research suggested that 4o and 4s may serve as leads in the discovery and development of new anticonvulsant drugs.

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Section: Methodsmentioning

confidence: 99%

Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

Sahu

Siddiqui

Naim

et al. 2017

Archiv der Pharmazie

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“…Unlike Compound IIIg, Compound IIIh showed moderate protection at 3o min and 4 hr in maximum electro shock seizure which is due to the presence of amine group at the 3 rd position of quinazoline ring. The amine group is an electron donor and increases the hydrogen bonding interaction with the target proteins or receptor for better CNS activity [22]. Finally, it may be concluded that IIc, IIg, IIj, IIIg, IIIh displayed better activity profiles compared with other derivatives as anti-convulsants with a sustained action.…”

Section: Anticonvulsant Activitymentioning

confidence: 97%

Design and Synthesis of 4-Substituted Quinazoline Derivatives for Their Anticonvulsant and CNS Depressant Activities

Dash¹,

Dash²,

Laloo³

2016

Int J Pharm Pharm Sci

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Objective: The present work is designed to synthesise some isomeric new series of Quinazoline-4-one/4-thione derivatives, based on the pharmacophoric model of central nervous system (CNS) activity by structural modifications retaining the essential structural features for the activity and evaluated for their anticonvulsant and CNS depressant properties. Methods:A series of 7-chloro-3-[substituted (amino/phenylamino)]-2-phenyl quinazolin-4 (3H)-one/thione derivatives and 1-(7-chloro-4-oxo/-2-phenylquinazoline-3 (4H-yl)) substituted urea derivatives were prepared. The reaction scheme proceeds through the intermediateThe structures of the newly synthesised compounds were characterized from infrared (IR), 1 H nuclear magnetic resonance (NMR) and mass spectra (m/z) and elemental analysis. The anti-convulsant and CNS depressant activity were investigated by maximum electroshock (MES) seizure test and porsolt's behavioural despair test (forced swimming) respectively. The rota-rod test was performed to assess any probable changes in motor coordination induced by the test compounds. Results:The physicochemical and spectroscopic data clearly confirmed the synthesis of quinazoline derivatives with a common skeleton. The synthesised compounds were evaluated for their anticonvulsant and CNS depressant properties. Among them, six compounds (IIc, IIg, IIj, IIIc, IIIg, IIIj) exhibited a good activity profile in CNS depressant activity. Five compounds (IIc, IIg, IIj, IIIg, IIIh) showed protection against MES-induced seizures. Conclusion:The Quinazoline derivatives obtained from this research work indicates that the methyl/methoxy group in phenyl ring, amine and thiourea substitution at 3 rd position of quinazoline derivatives are essential for CNS depressant activity as well as anticonvulsant activity. Compounds IIc, IIg, IIj, IIIc, IIIg, IIIj, and IIIh were found to be a potent compound which may be effective as a potential source for the development of CNS depressant and anti-convulsant drugs with lesser side effects.

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“…Some of the potent anticonvulsants with quinazolinone nucleus are depicted in Figure . The substitution of quinazolinone by electron withdrawing halogens at 6 th , 7 th or 8 th positions resulted derivatives with optimum anticonvulsant activity and lower toxicity than phenytoin . Ralitoline is a recently reported AED, found effective in both MES and kindling models of seizures with rodents .…”

Section: Introductionmentioning

confidence: 99%

“…First objective was based on a postulate that aryl ring at second position of quinazolinone is not always necessary for anticonvulsant activity . Second objective was to replace 6,7‐dimethoxy group by using electron withdrawing chlorine atom at 7 th position of quinazolin‐4(3 H )‐one nucleus to enhance anticonvulsant activity with improved side effect profile . In continuation of our research to find novel anticonvulsants with significantly improved therapeutic profile, here we have reported structurally optimized novel 7‐chloroquinazolino‐phenylacetamides by molecular fragmentation approach.…”

Section: Introductionmentioning

confidence: 99%

Exploring Quinazolinones as Anticonvulsants by Molecular Fragmentation Approach: Structural Optimization, Synthesis and Pharmacological Evaluation Studies

et al. 2020

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In recent years, design and synthesis of anticonvulsants effective against multiple seizures has attracted much attention of medicinal chemists. In an attempt to find novel anticonvulsants, herein we have reported structurally optimized sixteen different substituted quinazolinones explored through molecular fragmentation approach. The anticonvulsant activity of synthesized compounds was assessed by using predictable seizure models in mice. Two most promising analogues 8 d (ED50 = 35.1 mg/kg, MES, mice, i. p.; ED50 = 41.5 mg/kg, scPTZ test, mice, i. p.) and 8 l (ED50 = 21.2 mg/kg, MES, mice, i. p.; ED50 = 32.4 mg/kg, scPTZ test, mice, i. p.) exhibited broad spectrum anticonvulsant action in preclinical models of seizures. Compound 8 l was also shown profound activity against pharmaco‐resistant limbic seizures produced in 6 Hz test. Most of the synthesized molecules exhibited moderate to high anticonvulsant activity in all seizure models with no symptoms of neurotoxicity and hepatotoxicity. We have also used in‐silico protocol for prediction of physiochemical and pharmacokinetic properties of synthesized quinazolinones. The promising anticonvulsant activity of synthesized analogues, ex‐vivo toxicity, in‐silico molecular docking, physiochemical and pharmacokinetic predictions make us to anticipate emergence of synthesized quinazolinones as valid leads for the treatment of convulsive disorder.

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Design, synthesis, molecular docking and anticonvulsant evaluation of novel 6-iodo-2-phenyl-3-substituted-quinazolin-4(3H)-ones

Cited by 45 publications

References 27 publications

Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

Design, Synthesis, and Docking Study of Pyrimidine–Triazine Hybrids for GABA Estimation in Animal Epilepsy Models

Design and Synthesis of 4-Substituted Quinazoline Derivatives for Their Anticonvulsant and CNS Depressant Activities

Exploring Quinazolinones as Anticonvulsants by Molecular Fragmentation Approach: Structural Optimization, Synthesis and Pharmacological Evaluation Studies

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