This review comprehensively summarizes recent advances in the field of hydrazinecarboxamide (semicarbazide) derivatives, highlighting their significant therapeutic potential and a broad spectrum of biological activities. As a promising and privileged scaffold in medicinal chemistry, hydrazinecarboxamides have emerged as a versatile class of compounds with significant bioactive properties. Based on their substitutions, their structural diversity permits extensive chemical modifications to enhance their interactions with various biological targets to combat multiple disorders. Notable, this group of compounds has shown significant efficacy against numerous cancer cell lines through diverse mechanisms of action and potent inhibition of enzymes, including cholinesterases, carbonic anhydrases, cyclooxygenases, lipoxygenases, etc. Beyond these, they have also been investigated for their anticonvulsive, analgesic/anti-inflammatory, and antioxidant properties, with detailed structure-activity relationships. For many applications, the hybridization of hydrazinecarboxamides with other bioactive scaffolds, such as primaquine, is of particular interest and offers advantages. Despite their promises, challenges such as suboptimal physicochemical properties and selectivity issues of certain derivatives require further effort. The review aims to inspire future innovation in the design and development of new potential hydrazinecarboxamide-based drugs, addressing existing challenges and expanding their therapeutic applications.

• Klíčová slova
• Anti-inflammatory activity, Anticancer activity, Anticonvulsive activity, Enzyme inhibition, Hydrazinecarboxamides, Semicarbazides, Structure-activity relationship,
• MeSH
• antiflogistika farmakologie   chemie   MeSH
• antikonvulziva * farmakologie   chemie   MeSH
• antioxidancia * farmakologie   chemie   MeSH
• antitumorózní látky * farmakologie   chemie   MeSH
• hydraziny * chemie   farmakologie   chemická syntéza   MeSH
• inhibitory enzymů farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• semikarbazidy chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antiflogistika MeSH
• antikonvulziva * MeSH
• antioxidancia * MeSH
• antitumorózní látky * MeSH
• hydraziny * MeSH
• inhibitory enzymů MeSH
• semikarbazidy MeSH

There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.

• Klíčová slova
• 6 Hz psychomotor seizures, carbonic anhydrases, cholinesterase inhibitors, mitochondrial potential, total ROS activity,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antikonvulziva chemická syntéza   chemie   farmakologie   MeSH
• antioxidancia chemická syntéza   chemie   farmakologie   MeSH
• bifenylové sloučeniny antagonisté a inhibitory   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• epilepsie farmakoterapie   metabolismus   MeSH
• inhibitory karboanhydras chemická syntéza   chemie   farmakologie   MeSH
• karboanhydrasy metabolismus   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• oxidační stres účinky léků   MeSH
• pikráty antagonisté a inhibitory   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• triazoly chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1,1-diphenyl-2-picrylhydrazyl MeSH Prohlížeč
• 1,2,4-triazole MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antikonvulziva MeSH
• antioxidancia MeSH
• bifenylové sloučeniny MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• inhibitory karboanhydras MeSH
• karboanhydrasy MeSH
• pikráty MeSH
• reaktivní formy kyslíku MeSH
• triazoly MeSH

The prevalence of epilepsy in the world population together with a high percentage of patients resistant to existing antiepileptic drugs (AEDs) stimulates the constant search for new approaches to the treatment of the disease. Previously a significant anticonvulsant potential of cardiac glycoside digoxin has been verified by enhancing a weak activity of AEDs in low doses under screening models of seizures induced by pentylenetetrazole and maximal electroshock. The aim of the present study is to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant activity of valproate, levetiracetam, and topiramate in models of primary generalized seizures with different neurochemical mechanisms. A total of 264 random-bred male albino mice have been used. AEDs were administered 30 min before seizure induction once intragastrically at conditionally effective (ED50) and sub-effective (½ ED50) doses: sodium valproate and topiramate - at doses of 300 and 150 mg/kg; levetiracetam - at doses of 100 and 50 mg/kg. Digoxin was administered once subcutaneously at a dose of 0.8 mg/kg body weight (1/10 LD50) 10-15 min before seizure induction. Picrotoxin (aqueous solution 2.5 mg/kg, subcutaneously), thiosemicarbazide (aqueous solution 25 mg/kg, intraperitoneally), strychnine (aqueous solution 1.2 mg/kg, subcutaneously), camphor (oil solution 1000 mg/kg, intraperitoneally) have been used as convulsive agents for seizure induction. It was found that under the conditions of primary generalized seizures induced by picrotoxin, thiosemicarbazide, strychnine, and camphor, digoxin not only shows its own strong anticonvulsant activity but also significantly enhances the anticonvulsant potential of classical AEDs sodium valproate, levetiracetam, and topiramate. The obtained results substantiate the expediency of further in-depth study of digoxin as an anticonvulsant drug, in particular, the in-depth study of neurochemical mechanisms of its action.

• Klíčová slova
• adjuvant, anticonvulsant, digoxin, levetiracetam, seizures, topiramate, valproate,
• MeSH
• antikonvulziva * terapeutické užití   MeSH
• digoxin * terapeutické užití   MeSH
• kafr terapeutické užití   MeSH
• kardiotonika terapeutické užití   MeSH
• kyselina valproová * terapeutické užití   MeSH
• levetiracetam * terapeutické užití   MeSH
• myši MeSH
• pikrotoxin MeSH
• strychnin MeSH
• topiramat * terapeutické užití   MeSH
• záchvaty * chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva * MeSH
• digoxin * MeSH
• kafr MeSH
• kardiotonika MeSH
• kyselina valproová * MeSH
• levetiracetam * MeSH
• pikrotoxin MeSH
• strychnin MeSH
• topiramat * MeSH

The influence of flumazenil on seizures induced by pentylenetetrazol (PTZ) was studied in rats aged 7, 12, 18, 25, and 90 days. Flumazenil in doses of 25, 37.5, and 50 mg/kg IP injected 10 min before PTZ exhibited a dose-dependent anticonvulsant action in all age groups studied. It was more effective against generalized tonic-clonic than against minimal clonic seizures at all developmental stages studied. In the two youngest groups, minimal seizures were elicited only rarely under control conditions. Pretreatment with the two lower doses of flumazenil resulted in an increased incidence of this type of seizure for these two groups. The anticonvulsant activity found in all age groups is in agreement with data from other benzodiazepines and speaks against a pure benzodiazepine-antagonistic action of flumazenil.

• MeSH
• antikonvulziva farmakologie   MeSH
• epilepsie tonicko-klonická chemicky indukované   prevence a kontrola   MeSH
• flumazenil farmakologie   MeSH
• krysa rodu Rattus MeSH
• pentylentetrazol MeSH
• potkani Wistar MeSH
• stárnutí fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• záchvaty chemicky indukované   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• flumazenil MeSH
• pentylentetrazol MeSH

Within the framework of a structure-effect relationships study in a group of new beta-adrenoreceptor blockers, a series of new derivatives derived from p-hydroxyacetophenone with modifications in the basic moiety of the side chain was prepared. The initial p-hydroxyacetophenone prepared by Fries rearrangement of phenylacetate in a reaction with 2-(chloromethyl)oxirane yields 1-[4-(2-oxiranylmetoxy)phenyl]-1-etanone, which combines with the appropriate amines to produce final substances. They were isolated either in the form of free bases, or salts with fumaric acid. Their structure was confirmed by interpretations of the IR, 1H-NMR and 13C-NMR-spectra. Within the framework of pharmacological evaluation of the prepared agents, the anticonvulsive effect as a protective effect against pentetrazole spasms was examined. The results of the evaluation were compared with the values of their distribution coefficients.

• MeSH
• antikonvulziva chemie   terapeutické užití   MeSH
• beta blokátory chemie   terapeutické užití   MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• beta blokátory MeSH

The anticonvulsant effects and duration of protective action of midazolam against Metrazol induced seizures were studied in 528 rats aged 7,12,18,25 and 90 days. The doses of 0.025, 0.05, 0.25, 0.5 and 1.0 mg/kg were administered immediately before Metrazol (100 mg/kg in all but 18-day-old animals where 90 mg/kg were given) for detection of antimetrazol activity at all age groups. The doses of 0.05, 0.25, and/or 0.5 mg/kg were used to study the time course of the protective action of midazolam. Each experimental group consisted of eight animals. Dose-dependent antimetrazol effects of midazolam till now described only in adult animals were demonstrated at all developmental stages studied. There were no qualitative differences in these effects among age groups studied. Midazolam action was better expressed against major Metrazol seizures than against minimal Metrazol seizures. Duration of the protective action depended on the dose tested at all developmental stages, as a rule, lasted longer in young animals than in adult rats. Only quantitative changes of action were found.

• MeSH
• antikonvulziva farmakologie   MeSH
• inbrední kmeny potkanů MeSH
• injekce intraperitoneální MeSH
• krysa rodu Rattus MeSH
• midazolam aplikace a dávkování   farmakologie   MeSH
• mozek účinky léků   MeSH
• pentylentetrazol antagonisté a inhibitory   MeSH
• růst fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• záchvaty chemicky indukované   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• midazolam MeSH
• pentylentetrazol MeSH

A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.

• Klíčová slova
• Anticonvulsant agent, Cardiac safety, Disopyramide, Drug discovery, Drug repositioning, Medicinal Chemistry, Refractory epilepsy, Sodium channel blocker, Structure-activity relationships, Voltage-gated sodium channel,
• MeSH
• acetamidy aplikace a dávkování   chemie   terapeutické užití   MeSH
• antikonvulziva aplikace a dávkování   chemie   terapeutické užití   MeSH
• disopyramid aplikace a dávkování   chemie   terapeutické užití   MeSH
• elektrický šok MeSH
• injekce intraperitoneální MeSH
• injekce subkutánní MeSH
• krysa rodu Rattus MeSH
• molekulární struktura MeSH
• myši MeSH
• pentylentetrazol aplikace a dávkování   MeSH
• potkani Wistar MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• záchvaty chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetamidy MeSH
• antikonvulziva MeSH
• disopyramid MeSH
• pentylentetrazol MeSH

A novel anticonvulsant benzodiazepine bretazenil (Ro 16-6028) was studied electrophysiologically in a model of human absence seizures: rhythmic metrazol activity (RMA) in rats. The effects of Ro 16-6028 pretreatment (0.01, 0.05, or 0.1 mg/kg intraperitoneally, i.p.) were compared with those of clonazepam (CZP, 0.02 or 0.1 mg/kg i.p.), valproate (VPA, 200, 300, or 400 mg/kg) and ethosuximide (ESM, 31.25, 62.5, or 125 mg/kg i.p.) in 45 rats with implanted electrocorticographic electrodes. RMA was elicited by an injection of pentylenetetrazol (metrazol, PTZ) in a dose of 40 or 35 mg/kg i.p. The effects of Ro 16-6028 were similar to those of CZP and VPA, i.e., suppression of RMA episodes, an increase in latency and a decrease in number, and total as well as mean duration. On the other hand, ESM differed from these antiepileptic drugs (AEDs) in inability to shorten the duration of RMA episodes. Based on these results, Ro 16-6028 might be predicted to be efficient against human absence seizures.

• MeSH
• absentní epilepsie chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• antikonvulziva farmakologie   MeSH
• benzodiazepinony farmakologie   MeSH
• elektroencefalografie účinky léků   MeSH
• epilepsie chemicky indukované   prevence a kontrola   MeSH
• klonazepam farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina valproová farmakologie   MeSH
• pentylentetrazol * MeSH
• potkani Wistar MeSH
• receptory GABA účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• antikonvulziva MeSH
• benzodiazepinony MeSH
• bretazenil MeSH Prohlížeč
• klonazepam MeSH
• kyselina valproová MeSH
• pentylentetrazol * MeSH
• receptory GABA MeSH

In spite of use of cannabidiol (CBD), a non-psychoactive cannabinoid, in pediatric patients with epilepsy, preclinical studies on its effects in immature animals are very limited. In the present study we investigated anti-seizure activity of CBD (10 and 60 mg/kg administered intraperitoneally) in two models of chemically induced seizures in infantile (12-days old) rats. Seizures were induced either with pentylenetetrazol (PTZ) or N-methyl-D-aspartate (NMDA). In parallel, brain and plasma levels of CBD and possible motor adverse effects were assessed in the righting reflex and the bar holding tests. CBD was ineffective against NMDA-induced seizures, but in a dose 60 mg/kg abolished the tonic phase of PTZ-induced generalized seizures. Plasma and brain levels of CBD were determined up to 24 h after administration. Peak CBD levels in the brain (996 ± 128 and 5689 ± 150 ng/g after the 10- and 60-mg/kg doses, respectively) were reached 1-2 h after administration and were still detectable 24 h later (120 ± 12 and 904 ± 63 ng/g, respectively). None of the doses negatively affected motor performance within 1 h after administration, but CBD in both doses blocked improvement in the bar holding test with repeated exposure to this task. Taken together, anti-seizure activity of CBD in infantile animals is dose and model dependent, and at therapeutic doses CBD does not cause motor impairment. The potential risk of CBD for motor learning seen in repeated motor tests has to be further examined.

• Klíčová slova
• NMDA, PTZ, cannabidiol, epilepsy, immature rats, pentylentetrazole, seizures,
• MeSH
• antikonvulziva farmakologie   MeSH
• epilepsie farmakoterapie   MeSH
• kanabidiol farmakokinetika   farmakologie   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• mozek účinky léků   MeSH
• N-methylaspartát farmakologie   MeSH
• pentylentetrazol farmakologie   MeSH
• potkani Wistar MeSH
• záchvaty farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• kanabidiol MeSH
• N-methylaspartát MeSH
• pentylentetrazol MeSH

A variety of 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethines and 1,3-dihydro-2H-1,4-benzodiazepin-2-one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin-induced seizure model. The prepared 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7-{(E)-[(4-nitrophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-{(E)-[(4-bromo-2,6-difluorophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 7-[(E)-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.

• Klíčová slova
• 1,3-dihydro-2H-1,4-benzodiazepin-2-ones, anticonvulsant, azomethine, epilepsy, molecular docking,
• MeSH
• antikonvulziva chemická syntéza   chemie   farmakologie   MeSH
• azepiny chemická syntéza   chemie   farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu Rattus MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• pikrotoxin aplikace a dávkování   MeSH
• potkani Wistar MeSH
• Schiffovy báze chemická syntéza   chemie   farmakologie   MeSH
• záchvaty chemicky indukované   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• azepiny MeSH
• pikrotoxin MeSH
• Schiffovy báze MeSH