Design and synthesis of novel parabanic acid derivatives as anticonvulsants.

In this work a set of novel derivatives of parabanic acid 9a-d, 12a-d and 13a-d was synthesized and their anticonvulsant potential was evaluated. All the compounds under investigation exhibited anticonvulsant activity in both scPTZ and MES tests. In phase II anticonvulsant study, the trimethoxy phenyl derivative 9a evoked the highest potency among the tested compounds in scPTZ test. It displayed 1.72- and 17.05-folds activity more than the standard drugs phenobarbital and ethosuximide, respectively. In addition, the margin of safety for compound 9a is better than that of the reference antiepileptic drug ethosuximide. Also, compound 9a was devoid of hepatotoxicity indicated by measurements of serum level of ALT, AST, ALP, albumin and total protein. Furthermore, treatment with compound 9a significantly increased the GABA brain level by 2.56-folds compared to the control value. Additionally, molecular docking was performed on the active site of GABA-AT to clarify the interactions of the most potent compound 9a with the enzyme. In MES test, compound 12a exhibited the most potent activity against electric stimuli-induced seizures with the lowest ED50 = 13.7 mg/kg and protective index >36.5. Both candidates 9a and 12a could be a good starting point to develop new molecules as novel antiepileptic drugs.

Synthesis, molecular modeling studies and anticonvulsant activity of certain (1-(benzyl (aryl) amino) cyclohexyl) methyl esters.

A series of (1-(benzyl (aryl) amino) cyclohexyl) methyl esters 7a-n were prepared and screened for their anticonvulsant profile. Screening of these esters 7a-n and their starting alcohols 6a and 6b revealed that compound 7k was the most potent one in the scPTZ screening test with an ED50 value of 0.0056mmol/kg being about 10- and 164-fold more potent than phenobarbital (ED50=0.056mmol/kg) and ethosuximide (ED50=0.92mmol/kg) as reference drugs, respectively. Meanwhile, in the MES test, compounds 7b and 7k at doses 0.0821mmol/kg and 0.0334mmol/kg, exerted 66% and 50% protection of the tested mice, respectively, compared with diphenylhydantoin, which exerted 100% protection at dose 0.16mmol/kg. In the neurotoxicity screen test, almost all esters 7a-n did not show any minimal motor impairment at the maximum administrated dose. The anticonvulsant effectiveness of esters 7a-n was higher than their corresponding alcohols 6a and 6b. Compounds 7b and 7k exhibited pronounced anticonvulsant activity devoid of neurotoxicity in minimal motor impairment test and hepatotoxicity in the serum enzyme activity assay. 3D pharmacophore model using Discovery Studio 2.5 programs showed high fit value. The obtained experimental results of sc-PTZ activity of compounds 7a-n was consistent with the molecular modeling study.

Influence of bioactive sulfated polysaccharide-protein complexes on hepatocarcinogenesis, angiogenesis and immunomodulatory activities.

OBJECTIVE: To explore the in vivo anticancer, anti-angiogenesis and immunomodulatory efficacies of the bioactive polysaccharide isolated from cold aqueous extract of Jania rubens (JCEM) and Pterocladia capillacea (PCEM) as well as hot aqueous extract of Enteromorpha intestinalis (EHEM) against hepatocellular carcinoma rat model (HCC) and to study their chemical composition. METHODS: The sugars and amino acids composition of the bioactive polysaccharides of JCEM, PCEM and EHEM were determined using gas liquid chromatography and amino acid analyzer, respectively. These polysaccharide extracts (20 mg/kg b.wt. for 5 weeks) were assessed on hepatocarcinogenesis in rats and α-fetoprotein (AFP), carcinoembryonic antigen (CEA), glypican-3 (GPC-3), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) and Ig G levels were evaluated. RESULTS: The GLC analysis of JCEM, PCEM and EHEM polysaccharide revealed the presence of 10, 9 and 10 sugars, in addition the amino acid analyzer enable identification of 16, 15 and 15 amino acids, respectively. These polysaccharide extracts of JCEM, PCEM and EHEM produced significant decrease in serum AFP, CEA, GPC-3, HGF and VEGF compared with untreated HCC group. JCEM, PCEM and EHEM had an immunostimulatory responses by increasing the IgG levels as compared by naïve value (1.23, 1.53 and 1.17 folds), respectively. The bioactive polysaccharides in HCC induced rats improved the humoral immune response. The photomicrographs of liver tissue sections of the groups of HCC treated with polysaccharide extracts of Jania rubens and Enteromorpha intestinalis showed intact histological structure. Moreover, fractions HE1, HE4, HE7 obtained from polysaccharide of EHEM showed moderate cytotoxic activity against HepG2 in vitro with IC50 73.1, 42.6, 76.2 µg/mL. However, fractions of PCEM and JCEM show no or weak cytotoxicity against HepG2 in vitro where the cytotoxic activity of their crude polysaccharide extract proved synergetic effect. CONCLUSIONS: The pronounced antitumor activity of sulfated polysaccharide-protein complexes of JCEM and EHEM is due to direct cytotoxic activity, anti-hepatocarcinogenesis, and anti-angiogenesis. In addition, JCEM, PCEM and EHEM had an immunostimulatory response and improved the humoral immune response in HCC induced rats.