Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones

Al-Omary, Fatmah A. M.; Abou-Zeid, Laila A.; Nagi, Mahmoud N.; Habib, El‐Sayed E.; Abdel‐Aziz, Alaa A.‐M.; El‐Azab, Adel S.; Abdel-Hamide, Sami G.; Al‐Omar, Mohamed A.; Al‐Obaid, Abdulrahman M.; El‐Subbagh, Hussein I.

doi:10.1016/j.bmc.2010.03.019

Cited by 127 publications

(66 citation statements)

References 43 publications

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“…18,19) This is in addition to the anticonvulsant activity of many quinazolinone derivatives, illustrated in Fig. 2, such as methaquolone I which was an important landmark in the field of synthetic anticonvulsant, and whose quinazoline core was responsible for its activity.…”

Section: )mentioning

confidence: 95%

“…1) Literature survey revealed that quinazoline is a privileged lead molecule for scheming potential bioactive agents that exhibits a broad spectrum of bioactivity such as anti-tumor, 16) anti-inflammatory 17) and antimicrobial activities. 18,19) This is in addition to the anticonvulsant activity of many quinazolinone derivatives, illustrated in Fig. 2, such as methaquolone I which was an important landmark in the field of synthetic anticonvulsant, and whose quinazoline core was responsible for its activity.…”

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confidence: 95%

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Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

Abbas

Awadallah

Ibrahim

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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Series of 2,3-disubstituted quinazolinone derivatives and a [1,2,4]triazino[2,3-c]quinazolinone featuring the pharmacophoric elements of anticonvulsant drugs were designed and synthesized. Target compounds were screened for their anticonvulsant activity using the subcutaneous pentylenetetrazole (s.c. PTZ) and maximal electroshock (MES) models. The s.c. PTZ test showed that the most active compound was the amide derivative 9c having a protective dose 50 (PD 50 ) of 200.53 µmol/kg (PD 50 of phenobarbitone=62.18 µmol/kg); nevertheless, this low potency is outweighed by the much higher safety profile of 9c (LD 50 >3000 mg/kg). In the MES screening, seven compounds were equal to or more active than phenytoin; some of these compounds were less neurotoxic than phenytoin. Few compounds such as 9c and 10 were effective in both models. LD 50 for the most active compounds was calculated.Key words quinazolinone; pentylenetetrazole model; maximal electroshock model; anticonvulsant activity; LD 50 ; neurotoxicity Epilepsy is an all-pervading neurological disorder characterized by recurrent seizures and affecting about 1% of the world's population. In the last few decades, many efforts devoted for the development of novel therapeutics resulted in the availability of several newer agents as promising anticonvulsants.1,2) The efficacy of many of the marketed antiepileptic drugs is greatly compromised by severe side effects such as ataxia, drowsiness, gingival hyperplasia, gastrointestinal disturbances, and megaloblastic anaemia. Moreover, about 30% of patients have uncontrolled seizures.3-8) Therefore, continued search for safer and more effective anticonvulsants is urgently necessary.The insufficient information on the cellular mechanism of epilepsy in human and the complex mechanism of action of most of the antiepileptic drugs makes it difficult to use rational methodologies in the discovery of new antiepileptic drugs. Therefore, another design approach based on the existence of different pharmacophores that were established through the analysis of structural characteristics of clinically effective drugs as well as other antiepileptic compounds was adopted.9-11) In the literatures, it is well documented that one of the important core fragments is defined by the presence of: i) hydrogen donor/acceptor unit (HAD), ii) one electron donor atom (D), and iii) a hydrophobic domain (A) (aryl ring substituted/unsubstituted).12-15) These structural features were found in the first generation drugs including the well-established antiepileptics such as carbamazepine or phenytoin, and the newest drugs e.g., Felbamate; and in the second generation antiepileptic drugs and the drugs in clinical trial (Fig. 1). Efforts devoted in the recent years based on this pharmacophore model resulted in the availability of several newer drugs (such as retigabine, tiagabine, lamotrigine, pregabalin, stiripentol, zonisamide, topiramate, levetiracetam) as promising antiepileptics. 1)Literature survey revealed that quinazoline is a privileged lead molecule fo...

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Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

Abbas

Awadallah

Ibrahim

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Such medical health problems have encouraged many medicinal chemists to search for novel antibacterial agents other than the analogs of existing antibiotics 7 . Quinazolines are frequently used in medicine because of their wide spectrum of biological activities [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] . Based on the good performances of quinazoline derivatives in anticancer application, development of novel quinazoline derivatives as anticancer drugs is a promising field 9 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies

Alanazi

Abdel‐Aziz

Shawer

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32 mg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.

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“…Several series of substituted-quinazolin-4-ones were designed and evaluated for their in vitro DHFR inhibition in our laboratory [12][13][14][15][16]. Compounds 2-6 ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Dihydrofolate reductase (DHFR) inhibition and molecular modeling study of some 6-bromo- or 6,8-dibromo-quinazolin-4(3H)-ones

Abdelkhalek¹,

Ewida²,

El‐Messery³

et al. 2018

A J Physiol Biochem Pharmacol

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Objectives:The dihydrofolate reductase (DHFR) inhibitory activity of 6-bromo-and 6,8-dibromo-quinazolin-4(3H)-ones (7-25) were studied to define the structural features and requirements that enhance selectivity and specificity for the proper binding to the enzyme active site. Methods:Compounds 7-25 were tested for their in vitro DHFR inhibition. As an application of the use of DHFR inhibitors, in vitro antitumor activity using disease-oriented human cell lines assay was performed. Key findings: Compounds 19, 20, and 22 showed remarkable DHFR inhibitory activity, inhibitory concentration (IC 50 0.6, 0.2, and 0.1 μM, respectively). Compounds 12, 17, 18, 20, and 24 proved to be broad spectrum antitumor with median IC 50 values of 0.6, 0.6, 0.5, 0.6, and 0.7 μM, respectively. Molecular docking study results revealed that the active DHFR inhibitors 22 and 20 bind to DHFR with similar amino acid residues as methotrexate, especially Arg 28. Conclusions:The mono-bromo series proved to be more active than the di-bromo counterparts and the 3-(2-hydrazinyl-acetyl)-is more active than its 3-(acetohydrazide) isoster. The investigated compounds could be used as template model for further optimization. ARTICLE HISTORY

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Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones

Cited by 127 publications

References 43 publications

Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

Design and Synthesis of Some 3-Substituted-2-[(2,4-dichlorophenoxy)-methyl]quinazolin-4(3<i>H</i>)-one Derivatives as Potential Anticonvulsant Agents

Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies

Dihydrofolate reductase (DHFR) inhibition and molecular modeling study of some 6-bromo- or 6,8-dibromo-quinazolin-4(3H)-ones

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