Review, reevaluation, and new results in quantitative structure-activity studies of anticonvulsants

Hadjipavlou‐Litina, Dimitra

doi:10.1002/(sici)1098-1128(199803)18:2<91::aid-med1>3.0.co;2-m

Cited by 40 publications

(24 citation statements)

References 41 publications

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“…Asalreadymentioned,a rylalkylimidazolesand (thio)semicarbazonesw erep repared in various studiest oe valuatetheiranticonvulsantactivity.Thisist he first time thatbothstructuresw ereg athering in the same compound and the increaseo fanticonvulsantactivity was predicted. First of all,the lipophilicity of the compounds wasani mportantfactorforeasilycrossing the bloodbrain barrier.Itwasanticipated thataneurologicallyactivecompound should haveasuitable logP.Nafimidone hasac logPof 2.35 [41]a nd the calculationsof the logP showed thatthe synthesized compoundshavesimilarlipophilicity toanticonvulsantdrugs(see Table 1). The anticonvulsantactivity of the compoundsw as evaluated against the twomost adopted seizuremodels, MES and scPTZ tests,induced 0.5 and 4hafteradministration att hree graded doses(30,100 and 300 mg/kg), using Swiss albino male mice( 20 ±2g).…”

Section: 2anticonvulsantactivitymentioning

confidence: 99%

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

Calis

Septioglu²,

Aytemir³

2011

Arzneimittelforschung

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A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N-substi-tuted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ). Title compounds were prepared by the reaction of appropriate (thio)semicarba-zides with ketones. Neurotoxicity was screened by the rotarod test. The structure of compounds was confirmed by elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. As a result of activity studies, when the thiosemicar-bazone compounds were compared at different doses, 2-(1H-imidazole-1-yl)-1-(2-naphthyl)ethane-1-one N-(3-chloro-phenyl)thiosemicarbazone (3) and 2-(1H-imidazole-1-yl)-1-(2-biphenyl)ethane-1-one N-(4-fluorophenyl)thiosemicarba-zone (12) were found selective and highly active compounds against MES-induced seizures after 0.5 h and 4 h, respectively. Beside this, 2-(1H-imidazole-1-yl)-1-(1-biphenyl)ethane-1-one N-(4-methylphe-nyl)thiosemicarbazone (14) was the most active compound in the scPTZ-induced seizure test after 4 h. The 2,4-dichloro-phenyl (9) and 2-fluorophenyl (10) substituted biphenyl derivatives of thiosemi-carbazone compounds showed neurotoxicity at higher doses

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Section: 2anticonvulsantactivitymentioning

confidence: 99%

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

Calis

Septioglu²,

Aytemir³

2011

Arzneimittelforschung

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“…Quantitative structure–activity relationship (QSAR) models, mathematical equations relating chemical structure to their biological activity, give information that is useful for drug design and medicinal chemistry (11,12). A major step in constructing the QSAR model is to find a set of molecular descriptors representing the higher impact on the biological activity of interest (13–16).…”

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Research article: QSAR Study of Phenoxypyrimidine Derivatives as Potent Inhibitors of p38 Kinase Using different Chemometric Tools

et al. 2007

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Selective inhibition of the CSBP/p38 mitogen-activated protein kinase pathway may be an attractive target for the development of therapeutic agents to treat chronic inflammatory disease. A series of Phenoxypyrimidine Derivatives as Potent Inhibitors of p38 Kinase was subjected to quantitative structure-activity relationship (QSAR) analysis to find the structural requirements for ligand binding. A collection of chemometrics methods including multiple linear regression (MLR), factor analysis-based multiple linear regression (FA-MLR), principal component regression and partial least squared combined with genetic algorithm for variable selection (GA-PLS) were employed to make connections between structural parameters and enzyme inhibition. The results revealed the significant roles of steric effect, hydrogen bonding and electronic properties on the p38 inhibitory activity of the studied molecules. The most significant QSAR model, obtained by GA-PLS, could explain and predict 98% and 87% of variances in the pIC(50) data, respectively.

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“…Insilico ADMET prediction of drug molecules help to assess the Pharmacokinetic (PK) profile and drug likeliness of molecules [28]. The composition of Docking and Pharmacophore Modelling with QSAR studies can be applied to gain more precise information on the interactions between the ligand and the receptor [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Pharmacophore modelling, QSAR study, molecular docking and insilico ADME prediction of 1,2,3-triazole and pyrazolopyridones as DprE1 inhibitor antitubercular agents

Panigrahi¹,

Mishra²,

Sahu

2020

SN Appl. Sci.

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Tuberculosis (TB) is a chronic lung infected airborne disease caused by Mycobacterium tuberculosis (MTB). The development of resistance towards available antitubercular agents leads to the discovery of new drugs for treatment against these resistant bacteria. Decaprenyl phosphoryl-β-D-Ribose 20-epimerase (DprE1) is a vulnerable target for the design of antitubercular agents which are more acting against multidrug resistant bacterial pathogens. DprE1 is an oxidase involved in the synthesis of arabinogalactan. Inhibition of DprE1 leads to blocking off cell wall synthesis, causing the death of the bacteria. A series of 50 DprE1 inhibitors having activity were subjected to 2D, 3D QSAR, Pharmacophore Modeling, Molecular Docking and in silico ADME studies. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. 2D-QSAR and 3D-QSAR models developed by Partial Least Square associated with the Sphere Exclusion method (PLS-SE) and StepWise variable selection method (SW-kNN MFA) based on k-Nearest Neighbor technique are more significant which have cross-validated squared correlation coefficient (q2), coefficient of determination (r2), Fisher ratio (F) values as 0.7499, 0.8917 and 85.04 and the internal (q2 = 0.8198), external (pred_r2 = 0.6109) model validation correctly predicts activity ~ 81% and ~ 61% for the training and test set, respectively. Pharmacophore model was developed with two aromatic regions (Aro), one aliphatic (Ala) and one hydrogen donor (HDr). Docking studies of the selected inhibitors with the active site of DprE1 enzyme showed hydrogen bond interaction with Gly-116, His-131, Arg-118, Thr-117 and Gln-299 residues present at the active site. The results of the present work provide more useful information and important structural insights for designing DprE1 inhibitors with much more enhanced potency.

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Review, reevaluation, and new results in quantitative structure-activity studies of anticonvulsants

Cited by 40 publications

References 41 publications

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole

Research article: QSAR Study of Phenoxypyrimidine Derivatives as Potent Inhibitors of p38 Kinase Using different Chemometric Tools

Pharmacophore modelling, QSAR study, molecular docking and insilico ADME prediction of 1,2,3-triazole and pyrazolopyridones as DprE1 inhibitor antitubercular agents

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