Molecular Docking, Synthesis and Biological Evaluation of Some Novel 2-Substituted-3-allyl-4(3H)-quinazolinone Derivatives as Anticonvulsant Agents

Abulkhair, Hamada S.; El‐Gamal, Kamal M.; El‐Adl, Khaled; Fadl, Mohamed F

doi:10.4172/2161-0444.1000404

Cited by 12 publications

(3 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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“…The final precipitates were filtered under a vacuum, dried and crystallized from dioxane. Compounds 1a, 3a, and 4a were reported in the literature by using a resembling protocol [30]. Using a different protocol, the compounds 2a, 3a, and 4a were reported in the literature [31].…”

Section: Synthesis Of Compounds 1a-9amentioning

confidence: 99%

Synthesis, In Vivo Anticonvulsant Activity Evaluation and In Silico Studies of Some Quinazolin-4(3H)-One Derivatives

Pele,

Marc,

Mogoșan

et al. 2024

Molecules

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Two series, “a” and “b”, each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1–3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a–9a and 1b–9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the “b” series, particularly for compound 8b.

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“…Quinazoline derivatives are biologically important heterocycles and are known to possess a variety of biological activities such as antitumor (Fedorov et al 2014), antimicrobial (Sun et al 2011;, anti-inflammatory (Sun, Hu, et al 2010), antihistaminic (Awadallah, El-Eraky, and Saleh 2012), antidepressant (Olmo et al 2006), anticonvulsant (Abulkhair et al 2016) and antihypertensive (Holló et al 2014). Quinazoline scaffold is in the core structure of many commercially available anticancer drugs like, Gefitinib (1) (Eldehna et al 2017) Erlotinib (2) (Gaber et al 2018), and Lapatinib (3) (Figure 1) which were approved by FDA in the last decade for the treatment certain types of cancers (wood E. R. et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Some New 1,2,4-Triazolo Quinazoline Derivatives

Abulkhair

2021

Al-Azhar Journal of Pharmaceutical Sciences

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Cancer is a major public health problem in all countries and remains as one of the top leading causes of death worldwide. Herein we report the synthesis of novel series of triazoloquinazolines as potential anticancer agents. Structures of this set of compounds were confirmed by different spectral data including IR, 1 H NMR, 13 C NMR, Mass spectra, and elemental analyses. All the newly synthesized compounds were evaluated for their antiproliferative activity against four human cancer cell lines namely; Hepatocellular carcinoma (HePG-2), Mammary gland breast cancer (MCF-7), Human prostate cancer (PC3) and Colorectal carcinoma (HCT-116)). Results of cytotoxicity evaluation showed that the synthesized compounds displayed moderate cytotoxic activity against the selected cancer cell lines. Compound 9 showed the highest anti-proliferative effect followed by compound 7 against colorectal carcinoma cell line (HCT-116) with IC 50 values of 17.35 and 27.05 µM respectively. As well, both compounds showed moderate activity against hepatocellular carcinoma (HePG2) with IC 50 values of 29.47 and 39.41 µM respectively.

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Molecular Docking, Synthesis and Biological Evaluation of Some Novel 2-Substituted-3-allyl-4(3H)-quinazolinone Derivatives as Anticonvulsant Agents

Cited by 12 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

Synthesis, In Vivo Anticonvulsant Activity Evaluation and In Silico Studies of Some Quinazolin-4(3H)-One Derivatives

Synthesis and Pharmacological Evaluation of Some New 1,2,4-Triazolo Quinazoline Derivatives

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