Semikarbazon – svestrani farmakofor u dizajniranju antikonvulziva

During the last fifteen years semicarbazones have been extensively investigated for their anticonvulsant properties. 4-(4-Flurophenoxy) benzaldehyde semicarbazone (C0102862, V102862) has been discovered as a lead molecule and is being developed as a potent antiepileptic drug, with maximal electroskock (MES) ED50 (i.p. 12.9 mg kg1). In MES (oral screen), this compound has protective index (PI = TD50/ED50 >315) higher than carbamazepine (PI 101), phenytoin (PI >21.6) and valproate (PI 2.17). This compound is a potent sodium channel blocker. Other semicarbazones have demonstrated activity in various chemoshock screens, like subcutaneous pentylenetetrazole (ScPTZ), subcutaneous strychnine (ScSTY), subcutaneous picrotoxine (ScPIC) and subcutaneous bicculline (ScBIC). Semicarbazones are also GABA-transaminase inhibitors. Extensive structure-activity relationship has demonstrated that F, Cl, Br and NO2 substitutents in the arylhydrophobic pocket and a hydrogen bonding domain (HBD) are generally found in active anticonvulsant agents.Tijekom posljednjih petnaest godina intenzivno su istraživana antikonvulzivna svojstva semikarbazona. 4-(4-Flurofenoksi)benzaldehid semikarbazon (C0102862, V102862) otkriven je kao vodeći spoj iz kojeg je razvijen antiepileptik s maksimalnom elektrošok aktivnošću (MES) ED50 12,9 mg kg1 (i.p.) i zaštitnim indeksom (PI = TD50/ED50 > 315) većim od karbamazepina (PI 101), fenitoina (PI > 21,6) i valproata (PI 2,17). Spoj je snažni blokator natrijevih kanala. Drugi su se semikarbazoni pokazali učinkovitima u različitim kemo-šok testovima, kao što su supkutana primjena pentilentetrazola, strihnina, pikrotoksina i bikukulina. Semikarbazoni su također inhibitori GABA-transaminaze. Opširne studije odnosa strukture i djelovanja pokazale su da je za antikonvulzivno djelovanje bitna prisutnost F, Cl, Br i NO2 supstituenata u arilhidrofobnom džepu i domena za vezanje vodikovim vezama (HBD)

Farmakološko djelovanje izatina i njegovih derivata

Isatin is an endogenous compound identified in humans that possesses wide range of biological activities. Isatin has anxiogenic, sedative, anticonvulsant activity and acts as a potent antagonist on atrial natriuretic peptide receptors in vitro. A series of p-substituted isatin semicarbazones have shown anticonvulsant activity in MES, scPTZ and scSTY tests. Various isatin N-Mannich bases of isatin-3-thiosemicarbazones have shown antiviral and tuberculostatic activity. Methisazone is an effective compound against variola and vaccinia viruses. The N-dimethyl and morpholino derivative of 5-methyl isatin and trimethoprim exhibited an EC50 of more than 4.3 and 17.7 microgram mL-1 and 17.7 microgram mL-1, respectively. Isatin (3-o-nitrophenyl)hydrazone has shown activity against Walker carcinoma-256. Various substituted indolinones showed antitubercular activity against M. tuberculosis H37Rv with MIC ranging from 10-20 microgram mL-1. Isatin derivatives of Mannich bases had fibrinolytic, muscle relaxant, antiallergic, immunosuppressant, and antithrombotic activity. Isatin showed cardioinhibitory effect on frog heart, and hypotensive, respiratory depression and antidiuretic effects.Izatin je endogeni spoj prisutan u organizmu čovjeka koji posjeduje niz farmakoloških učinaka. Izatin djeluje kao antioksidans, sedativ i antikonvulziv. In vitro je snažni antagonist na receptorima za natrijeve ione u atriju. Serija p-supstituiranih semikarbazona izatina pokazala je antikonvulzivno djelovanje u MES, scPTZ i scSTY testovima, a N-Mannichove baze izatina i izatin-3-tiosemikarbazona virustatsko i tuberkulostatsko djelovanje. Metisazon je učinkovit protiv infekcija variola i vakcinia virusima. EC50 N-dimetil i morfolino derivata 5-metilizatina i trimetoprima veći je od 4,3, odnosno 17,7 g mL-1. Izatin (3-o-nitrofenilhidrazon) inhibira rast tumorskih stanica Walker-256, a supstituirani indolinoni su aktivni protiv M. tuberculosis H37Rv (MIC vrijednosti 1020 g mL-1. Mannichove baze izatina djeluju kao fibrinolitici, miorelaksansi, antihistaminici, imunosupresivi i antitrombotici. Izatin ima kardioinhibitorni učinak na srce žabe, a djeluje i kao hipotenziv, depresor respiracije i antidiuretik

Antikonvulzivno djelovanje Schiffovih baza- derivata isatina

Schiff bases of N-methyl and N-acetyl isatin derivatives with different aryl amines have been synthesized and screened for anticonvulsant activities against maximal electroshock (MES) and subcutaneous metrazole (ScMet). N-methyl-5-bromo-3-(p-chlorophenylimino) isatin 2 exhibited anticonvulsant activity in MES and ScMet with LD50 > 600 mg kg-1, showing better activity than the standard drugs phenytoin, carbamazepine and valproic acid. Thus, compound 2 may be chosen as a prototype for development of new anticonvulsants.Schiffove baze N-metil i N-acetil derivata izatina s različitim aromatskim aminima sintetizirane su i ispitane na sposobnost suzbijanja konvulzija uzrokovanih elektrošokom (MES) i subkutanom primjenom metrazola (ScMet). N-metil-5-bromo-3-(p-klorofenilimino) izatin 2 pokazao je nisku neurotoksičnost i jače antikonvulzivno djelovanje nego standardni antikonvulzivi fenitoin, karbamazepin i valproična kiselina. Zbog toga se spoj 2 može smatrati prototipom za razvoj novih antikonvulziva

Synthesis and Anticonvulsant Activity (Chemo Shock) of Phenothiazine Amino Acid Derivatives

Abstract: Amino acid derivatives of phenothiazine scaffold were synthesized and screened for their anticonvulsants activity against chemo shock induced screening to study the mechanism of action of anticonvulsants. Strychnine, thiosemicarbazide and 4-aminopyridine were used for induction of seizures. Rotorod test was used to study the neurotoxicity profile of these compounds. All these compounds protected against strychnine and thiosemicarbazide (20 mg/kg) induced seizures at a dose of 30 mg/kg up to 2 h. In case of 4-aminopyridine (13.3 mg/kg) induced seizure, protection was observed only up to 15 minute which was followed by death of the animals