Anticonvulsant activities of 4-(4?-fluorophenoxy) benzaldehyde semicarbazone

Dimmock, Jonathan R.; Puthucode, R. N.; Tuchek, John M.; Baker, Glen B.; Hinko, Christine N.; Steinmiller, Caren L.; Stables, James P.

doi:10.1002/(sici)1098-2299(199902)46:2<112::aid-ddr4>3.0.co;2-n

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…The scaffold has advantageous properties: low molecular weight, reasonable C log P , good hydrogen bond donating and accepting capabilities, and easy, economical synthetic routes. The closely related semicarbazone scaffold has been evaluated for clinical use as an antihypertensive, anticonvulsant, and antiallodynic agent . For example, the semicarbazone compound 4-[4-fluorophenoxy]benzaldehyde semicarbazone has entered clinical trials for the treatment of neuropathic pain .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationship Study of Potent Trypanocidal Thio Semicarbazone Inhibitors of the Trypanosomal Cysteine Protease Cruzain

et al. 2002

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American trypanosomiasis, or Chagas' disease, is the leading cause of heart disease in Latin America. Currently there is an urgent need to develop antitrypanosomal therapy due to the toxicity of existing agents and emerging drug resistance. A novel series of potent thio semicarbazone small-molecule inhibitors of the Trypanosoma cruzi cysteine protease cruzain have been identified. Some of these inhibitors have been shown to be trypanocidal. We initially discovered that 3'-bromopropiophenone thio semicarbazone (1i) inhibited cruzain and could cure mammalian cell cultures infected with T. cruzi. 3'-Bromopropiophenone thio semicarbazone showed no toxicity for mammalian cells at concentrations that were trypanocidal. Following this lead, more than 100 compounds were designed and synthesized. A specific structure-activity relationship (SAR) was established, and many potent analogues with IC(50) values in the low nanomolar range were identified. Eight additional analogues were trypanocidal in a cell culture assay, and this indicates that aryl thio semicarbazone is a productive scaffold for killing the parasites. Kinetic studies show that these are time-dependent inhibitors. Molecular modeling studies of the enzyme-inhibitor complex have led to a proposed mechanism of interaction as well as insight into the SAR of the thio semicarbazone series. The nonpeptide nature of this series, small size, and extremely low cost of production suggest this is a promising direction for the development of new antitrypanosome chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationship Study of Potent Trypanocidal Thio Semicarbazone Inhibitors of the Trypanosomal Cysteine Protease Cruzain

et al. 2002

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“…In the conventional screening process, 4-(4-fluorophenoxy) benzaldehyde semicarbazone was discovered as a lead molecule against the electroshock (MES) seizure test. The protective index of this compound is higher than that of carbamazepine, phenytoin and valproate (55). Later on, a large number of scholars have attempted to find new molecules with significant anticonvulsant activity (Table III).…”

Section: Semi-and Thiosemi-carbazones As Anticonvulsant Agentsmentioning

confidence: 99%

An overview of structurally diversified anticonvulsant agents

Alotaibi

2019

Acta Pharmaceutica

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There are several limited approaches to treat epilepsy in hospitals, for example, using medicines, surgery, electrical stimulation and dietary interventions. Despite the availability of all these new and old approaches, seizure is particularly difficult to manage. The quest for new antiepileptic molecules with more specificity and less CNS toxicity continues for medicinal chemists until a new and ideal drug arrives. This review covers new antiseizure molecules of different chemical classes, the exact mode of action of which is still unidentified. Newer agents include sulfonamides, thiadiazoles, semi- and thiosemicarbazones, pyrrolidine-2,5-diones, imidazoles, benzothiazoles and amino acid deriva tives. These new chemical entities can be useful for the design and development of forthcoming antiseizure agents.

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“…A major achievement of Dimmock (28) was the identification of 4-(4'-fluorophenoxy) benzaldehyde semicarbazone as a lead molecule. Derivatives of this molecule were highly potent and were patented (29).…”

Section: Dimmock's Early Work On Semicarbazonesmentioning

confidence: 99%

Semicarbazone – a versatile therapeutic pharmacophore for fragment based anticonvulsant drug design

Pandeya¹

2012

Acta Pharmaceutica

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During the last fifteen years, semicarbazones have been extensively investigated for their anticonvulsant properties. 4-(4-Flurophenoxy) benzaldehyde semicarbazone (C0102862, V102862) was discovered as a lead molecule and is being developed as a potent antiepileptic drug, with maximal electroshock (MES) ED50 of i.p. 12.9 mg kg-1. In MES (oral screen), this compound has a protective index (PI = TD50/ED50 > 315) higher than carbamazepine (PI 101), phenytoin (PI > 21.6) and valproate (PI 2.17). The compound is a potent sodium channel blocker. Other semicarbazones have demonstrated activity in various chemoshock screens, like subcutaneous pentylenetetrazole, subcutaneous strychnine, subcutaneous picrotoxin and subcutaneous bicculine. Semicarbazones are also GABA-transaminase inhibitors. Extensive structure- -activity relationship has demonstrated that F, Cl, Br and NO2 substituents in the arylhydrophobic pocket and a hydrogen bonding domain (HBD) are generally found in active anticonvulsant agents.

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Anticonvulsant activities of 4-(4?-fluorophenoxy) benzaldehyde semicarbazone

Cited by 8 publications

References 41 publications

Synthesis and Structure−Activity Relationship Study of Potent Trypanocidal Thio Semicarbazone Inhibitors of the Trypanosomal Cysteine Protease Cruzain

Synthesis and Structure−Activity Relationship Study of Potent Trypanocidal Thio Semicarbazone Inhibitors of the Trypanosomal Cysteine Protease Cruzain

An overview of structurally diversified anticonvulsant agents

Semicarbazone – a versatile therapeutic pharmacophore for fragment based anticonvulsant drug design

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