Design and synthesis of forsythin derivatives as anti-inflammatory agents for acute lung injury.

Acute lung injury (ALI) is a clinically high mortality disease, which has not yet been effectively treated. The development of anti-ALI drugs is imminent. ALI can be effectively treated by inhibiting the inflammatory cascade and reducing the inflammatory response in the lung. Forsythia suspense is a common Chinese herbal medicine with significant anti-inflammatory activity. Using forsythin as the parent, 27 Forsythin derivatives were designed and synthesized, and the anti-AIL activity of these compounds was evaluated. Among them, compound B5 has the best activity to inhibit the release of IL-6, and the inhibition rate reaches 91.79% at 25 µM, which was 7.5 times that of the parent forsythin. In addition, most of the compounds have no significant cytotoxicity in vitro. Further studies showed that compound B5 had a concentration-dependent inhibitory effect on NO, IL-6 and TNF-α. And the IC50 values of compound B5 for NO and IL-6 are 10.88 µM and 4.93 µM, respectively. We also found that B5 could significantly inhibit the expression of some immune-related cytotoxic factors, including inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, B5 inhibits NF-κB/MAPK signaling pathway. In vivo experiments showed that B5 could alleviate lung inflammation in LPS-induced ALI mice and inhibit IL-6, TNF-α, COX-2 and iNOS. In summary, B5 has anti-inflammatory effects and alleviates ALI by regulating inflammatory mediators and inhibiting MAPK and NF-κB signaling pathways.

Pharmacological overview of hederagenin and its derivatives.

Hederagenin is a pentacyclic triterpenoid isolated from plants and widely distributed in a variety of medicinal plants. By integrating and analyzing external related literature reports, the latest research progress on the pharmacological effects and structural modification of hederagenin was reviewed. Hederagenin has a wide range of pharmacological activities, including antitumor, anti-inflammatory, antidepressant, anti-neurodegenerative, antihyperlipidemic, antidiabetic, anti-leishmaniasis, and antiviral activities. Among them, it shows high potential in the field of anti-tumor treatment. This paper also reviews the structural modifications of hederagenin, including carboxyl group modifications and two hydroxyl group modifications. Future research on hederagenin will focus on prolonging its half-life, improving its bioavailability and structural modification to enhance its pharmacological activity, accelerating the preclinical research stage of hederagenin for it to enter the clinical research stage as soon as possible.

Arctigenin: pharmacology, total synthesis, and progress in structure modification.

Arctium lappa L. is a prevalent medicinal herb and a health supplement that is commonly used in Asia. Over the last few decades, the bioactive component arctigenin has attracted the attention of researchers because of its anti-inflammatory, antioxidant, immunomodulatory, multiple sclerosis fighting, antitumor, and anti-leukemia properties. After summarising the research and literature on arctigenin, this study outlines the current status of research on pharmacological activity, total synthesis, and structural modification of arctigenin. The purpose of this study is to assist academics in obtaining a more comprehensive understanding of the research progress on arctigenin and to provide constructive suggestions for further investigation of this useful molecule.

Research and Development of Natural Product Tanshinone I: Pharmacology, Total Synthesis, and Structure Modifications.

Salvia miltiorrhiza (S. miltiorrhiza), which has been used for thousands of years to treat cardiovascular diseases, is a well-known Chinese medicinal plant. The fat-soluble tanshinones in S. miltiorrhiza are important biologically active ingredients including tanshinone I, tanshinone IIA, dihydrotanshinone, and cryptotanshinone. Tanshinone I, a natural diterpenoid quinone compound widely used in traditional Chinese medicine, has a wide range of biological effects including anti-cancer, antioxidant, neuroprotective, and anti-inflammatory activities. To further improve its potency, water solubility, and bioavailability, tanshinone I can be used as a platform for drug discovery to generate high-quality drug candidates with unique targets and enhanced drug properties. Numerous derivatives of tanshinone I have been developed and have contributed to major advances in the identification of new drugs to treat human cancers and other diseases and in the study of related molecular mechanisms. This review focuses on the structural modification, total synthesis, and pharmacology of tanshinone I. We hope that this review will help understanding the research progress in this field and provide constructive suggestions for further research on tanshinone I.

Synergistic anti-inflammatory effects of peimine, peiminine, and forsythoside a combination on LPS-induced acute lung injury by inhibition of the IL-17-NF-κB/MAPK pathway activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythia suspensa (Thunb.) Vahl and Fritillaria thunbergii Miq are traditional Chinese medicines that exhibit the ability to clear heat and toxic material effects. In China, the combination of these two medicines is widely used to treat mucopurulent sputum and bloody phlegm, arising due to phlegm-heat obstruction in respiratory diseases. However, very limited information is available regarding the combined anti-inflammatory effect of important effective components of Forsythia suspensa (Thunb.) Vahl and Fritillaria thunbergii Miq, namely peimine, peiminine, and forsythoside A. AIM OF THIS STUDY: To investigate synergistic anti-inflammatory effects of combined administration of peimine, peiminine, and forsythoside A on LPS-induced acute lung injury compared to combined administration of two compounds or individual administration, and unravel the underlying mechanism. MATERIAL AND METHODS: In the present study, male BALB/c mice received an oral dosage of sodium carboxymethylcellulose (CMC-Na) (0.5%, 1 mL/100 g), peimine, peiminine, forsythoside A, peimine + forsythoside A, peiminine + forsythoside A, and peimine + peiminine + forsythoside A (suspended in CMC-Na; 0.5%), once daily for 7 days. Subsequently, intratracheal instillation of LPS was applied to establish acute lung injury model. After 6 h of administration, the mice were sacrificed, and bronchoalveolar lavage fluid (BALF) and lung tissues were collected. These samples were further used to determine lung W/D (wet/dry) weight ratio, total protein (TP) levels, inflammatory cytokines (IL-6, TNF-α, IL-1ß, and IL-17), and expression of proteins involved in TLR4/MAPK/NF-κB pathway and IL-17 pathway. Further, tissue sections were subjected to H&E staining to assess the pathological alterations induced by LPS. The expression of IL-6 and TNF-α proteins in lung tissues was also analyzed using immunohistochemical staining. RESULTS: A synergistic anti-inflammatory effect of peimine, peiminine, and forsythoside A was observed when administered in combination to LPS-induced acute lung injury. The combined administration of peimine, peiminine, and forsythoside A had a strongly inhibitory effects on the W/D weight ratio, total protein (TP) level and the inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-17) level in acute lung injury mice, compared to combined administration of two compounds or individual administration. The infiltration of inflammatory cells and thickened bronchoalveolar walls induced by LPS were also ameliorated through the combined administration of peimine, peiminine, and forsythoside A. More importantly, the upregulation of protein related to TLR4/MAPK/NF-κB signaling pathway and the activation of IL-17 were significantly suppressed by pretreatment with each of the three compounds alone, while the effects of individual compounds were synergistically augmented by the combined pretreatment of these three compounds. CONCLUSION: The combined administration of peimine, peiminine, and forsythoside A ameliorated inflammatory response in acute lung injury mice induced by LPS in a synergistic manner, the mechanism may be related to the dampening of the TLR4/MAPK/NF-κB signaling pathway and IL-17 activation.

Tanshinone IIA: Pharmacology, Total Synthesis, and Progress in Structure-modifications.

Tanshinone IIA, a major bioactive constituent of Danshen, a Chinese herbal medicine, has gained extensive exploration owing to its unique structural features and multiple promising biological activities. This review focuses on the pharmacology, total synthesis, and structural modifications of tanshinone IIA. We hope this review will contribute to a better understanding of the progress in the field and provide constructive suggestions for further study of tanshinone IIA.

Synthesis and Biological Evaluation of (+)-Usnic Acid Derivatives as Potential Anti-Toxoplasma gondii Agents.

Six series of (+)-usnic acid derivatives were synthesized. The IC50 values of these compounds were determined in T. gondii infected HeLa cells (µM) and in HeLa cells (µM), and their selectivity indexes (SI) were calculated. In vitro, most of the derivatives tested in this study exhibited more anti activity than that of the parent compound (+)-usnic acid and the positive control drugs. Among these derivatives, methyl (E)-(1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)phenylalaninate (D3) showed the most effective anti-T. gondii activity (selectivity >2.77). In comparison with the clinically used positive control drugs sulfadiazine (selectivity 1.15), pyrimethamine (selectivity 0.89), spiramycin (selectivity 0.72), and the lead compound (+)-usnic acid (selectivity 0.96), D3 showed better results in vitro. Furthermore, D3 and (E)-6-acetyl-7,9-dihydroxy-8,9b-dimethyl-2-(1-(quinolin-6-ylamino)ethylidene)dibenzo[b,d]furan-1,3(2H,9bH)-dione (F3) had greater inhibitory effects on T. gondii (inhibition rates 76.0% and 64.6%) in vivo in comparison to spiramycin (inhibition rate 55.2%); in the peritoneal cavity of mice, the number of tachyzoites was significantly reduced (p < 0.001) in vivo. Additionally, some biochemical parameters were measured and spleen indexes were comprehensively evaluated, and the results indicated that mice treated with both compound D3 and compound F3 showed reduced hepatotoxicity and significantly enhanced antioxidative effects in comparison to the normal group. Granuloma and cyst formation were effected by the inhibition of compound D3 and compound F3 in liver sections. Overall, these results indicated that D3 and F3 for use as anti-T. gondii agents are promising lead compounds.

Imperatorin suppresses proliferation and angiogenesis of human colon cancer cell by targeting HIF-1α via the mTOR/p70S6K/4E-BP1 and MAPK pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Angelica dahurica is a commonly used traditional Chinese medicine to treat migraine headache, toothache and cancer. Imperatorin is an active natural furocoumarin component originating from Angelica dahurica and has been shown to exhibit multiple bioeffector functions, including anti-cancer activity. However, the mechanism by which imperatorin inhibits tumor growth is not fully understood. AIM OF THE STUDY: The aim of this study was to investigate the effectiveness of imperatorin as a treatment of cancer and to identify the underlying mechanisms of its anticancer activity. MATERIALS AND METHODS: HCT116, HeLa, and Hep3B cells were used in this study. Major assays were promoter-reporter gene assay, MTT, western blot analysis, immunofluorescence assay, reverse transcription-PCR (RT-PCR), flow cytometric analysis, clonogenic assay, EdU labeling and immunofluorescence, xenografted assay, and VEGF ELISA. RESULTS: We here demonstrated the effect of imperatorin on hypoxia-inducible factor-1 (HIF-1) activation. Imperatorin showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1ß and topoisomerase-I (Topo-I). Further analysis revealed that imperatorin inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Moreover, the phosphorylation levels of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), eIF4E binding protein-1 (4E-BP1), eukaryotic initiation factor 4E (eIF4E), extracellular signal-regulated kinase-1/2 (ERK1/2), SAPK/JNK and p38 were significantly suppressed by imperatorin. Furthermore, imperatorin prevented hypoxia-induced expression of HIF-1 target genes and flow cytometric analysis indicated that imperatorin induced G1 phase arrest in human colon cancer cell (HCT116). We found that imperatorin administration inhibits tumor growth and blocks tumor angiogenesis in a xenograft tumor model. CONCLUSIONS: These results show that imperatorin inhibited HIF-1α protein synthesis by downregulating the mTOR/p70S6K/4E-BP1 and MAPK pathways. These conclusions suggest that imperatorin is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.

Involvement of norepinephrine and serotonin system in antidepressant-like effects of oleoylethanolamide in the mice models of behavior despair.

Oleoylethanolamide (OEA) is an endocannabinoid analogy that belongs to a family of endogenous acylethanolamides. Increasing evidence suggests that OEA may act as an endogenous neuroprotective factor and participate in the control of mental disorder-related behaviors. In the present study, we investigated the antidepressant- like potential of OEA in mice in comparison with clomipramine (Cp). 50 mice were randomly divided into 5 groups, and treated with a vehicle (0.3% methyl cellulose, 20 mL/kg, p.o.), OEA (2.5, 5-10mg/kg, p.o.), or Cp (10mg/kg, p.o.) for 7 days. The immobility was used to evaluate depressive-like behaviors in tail suspension test (TST) and forced swimming test (FST). ELISA detected changes in cerebral noradrenaline (NE) and serotonin (5-HT) levels. Likewise, in the drug-induced model of depression, OEA was given once daily at 10mg/kg (p.o.) for 7 consecutive days. Then, the mice received reserpine (4 mg/kg, i.p.) and the rectal temperature was measured at different time points. Consequently, head twitch behavior induced by intraperitoneal injection of 5-hydroxy-tryptophan (5-HTP; 300 mg/kg) were determined. The experimental data showed that OEA (2.5-10mg/kg) treatment significantly decreased the immobility as compared to the control group, and OEA (10mg/kg) treatment significantly increased 5-HTP-induced head twitch behavior and reversed reserpine-induced hypothermia and increased cerebral levels of NE and 5-HT. Thus, the antidepressant effects of OEA may be related to regulating central monoamine neurotransmitters.

Synthesis and evaluation of the anticonvulsant activity of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives.

Two series of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives (6a-q and 7a-q) were synthesized and evaluated for their anticonvulsant activity using the maximal electroshock (MES) method. All of the compounds prepared were effective in the MES screens. Among which, compound 7j was considered as the most promising one with an ED50 value of 26.3 mg/kg and a superior protective index value of 12.6. The potency of compound 7j against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid and bicuculline suggested that two different mechanisms of action might potentially be involved in its anticonvulsant activity, including the inhibition of voltage-gated ion channels and the modulation of GABAergic activity. A computational study was also conducted to predict the pharmacokinetic properties of the compounds prepared, with the results supporting the use of these compounds as a group of promising antiepileptic agents.

Synthesis and anticonvulsant activity of 7-alkoxy-triazolo-[3, 4-b]benzo[d]thiazoles.

The present study describes the chemical synthesis and anticonvulsant activity evaluation of a series of 7-alkoxy-triazolo-[3, 4-b]benzo[d]thiazoles. Most compounds exhibited good anticonvulsant activity in the Maximal electroshock (MES) test. And the structure-activity relationships (SAR) were analyzed. Among the compounds studied, 7-octyloxy-triazolo-[3, 4-b]benzo[d]thiazole (5g) was found to be the most potent compound with a median effective dose (ED(50)) value of 8.0 mg/kg and a protective index (PI) value of 15.0, possessing better anticonvulsant activity and higher safety than marketed drugs carbamazepine and phenytoin. The mechanism study of compound 5g showed that it displayed broad spectrum activity in several models, and it is likely to have several mechanisms of action (including inhibiting voltage-gated ion channels and GABAergic activity).

Synthesis and anti-inflammatory activity evaluation of some novel 6-alkoxy(phenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine derivatives.

Starting from phthalic anhydride, several new 6-alkoxy(phenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine derivatives were synthesized as potent anti-inflammatory agent. The study showed that the compounds 6h (6-(2-chlorophenoxy)-[1,2,4]triazolo[3,4-a]phthalazine-3-amine) and 6s (6-(4-aminophenoxy)-[1,2,4] triazolo[3,4-a]phthalazine-3-amine) exhibited the highest anti-inflammatory activity (81% and 83% inhibition, respectively, at 0.5 h after i.p. administration) which were slightly more potent than the reference drug Ibuprofen (61%). Furthermore, the peak activity of 6h and 6s was observed at the 3 h after p.o. administration, and they exhibited stronger anti-inflammatory activity than Ibuprofen at the dose of 50 mg/kg at the peak time.

Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-a]quinoline derivatives.

Using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material, a series of 1-formamide-triazolo[4, 3-a]quinoline derivatives (6a-6n) was synthesized, the anticonvulsant effect and neurotoxicity of the compounds was calculated with maximal electroshock test and rotarod tests with intraperitoneally injected in KunMing mice. The results demonstrated that compound 7-(hexyloxy)-4,5-dihydro-[1,2,4] triazolo[4,3-a]quinoline-1-carboxamide (6d) was the most active one and also had the lowest toxicity. In the anti-maximal electroshock potency test, it showed median effective dose (ED(50)) of 30.1 mg/kg, median toxicity dose (TD(50)) of 286 mg/kg, and the protective index of 9.5 which is greater than the reference drug carbamazepine with the protective index value of 6.0.

Synthesis and anticonvulsant activity of some 7-alkoxy-2H-1,4-benzothiazin-3(4H)-ones and 7-alkoxy-4H-[1,2,4]triazolo[4,3-d]benzo[b][1,4]thiazines.

A series of 7-alkoxy-2H-1,4-benzothiazin-3(4H)-ones and a new series of 7-alkoxy-4H-[1,2,4]triazolo[4,3-d]benzo[b][1,4]thiazine derivatives were synthesized using 5-methoxybenzo[d]thiazol-2-amine as starting material. The structures of the compounds were elucidated by IR, (1)H-NMR spectroscopic data and microanalyses. The anticonvulsant activity of these compounds was evaluated by maximal electroshock (MES) test and rotarod test following intraperitoneal injection in KunMing mice. Among the synthesized compounds 3a-v, 7-(hexyloxy)-2H-benzo[b][1,4]thiazin-3(4H)-one (3f) could be considered potentially the most useful and safe therapeutic compound. Among the synthesized compounds 4a-u, compound 7-(2-fluorobenzyloxy)-4H-[1,2,4]triazolo[4,3-d]benzo[b][1,4]thiazine (4k) was the most active compound with an ED(50) of 17.0 mg/kg, TD(50) of 243.9 mg/kg and protective index (PI) of 14.3. Its neurotoxicity was lower than all the other synthesized compounds and also markedly lower than that of the reference drug carbamazepine.

Synthesis and anticonvulsant activity of a new 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine.

A series of 6-alkoxy-[1,2,4]triazolo[4,3-b]pyridazine derivatives were synthesized. In initial screening and quantitative evaluation, compound 2r was among the most active agents, exhibiting in the same time the lowest toxicity. In the anti-maximal electroshock test, it showed median effective dose (ED50) of 17.3 mg/kg and median toxicity dose (TD50) of 380.3 mg/kg, and the protective index (PI) of 22.0, which is much better than PI of the reference drugs. In a subsequent test, compound 2r had median hypnotic dose (HD50) of 746.6 mg/kg, thus demonstrating much better margin of safety compared to reference drugs. Compound 2r also showed oral activity against MES-induced seizures and lower oral neurotoxicity. For explanation of the putative mechanism of action, compound 2r was tested in chemical induced models.

Synthesis and evaluation on anticonvulsant and antidepressant activities of 5-Alkoxy-tetrazolo[1,5-a]quinazolines.

Several 5-alkoxy-tetrazolo[1,5-a]quinazoline derivatives have been synthesized by reacting 2,4-dichloroquinazoline with various phenols or aliphatic alcohol and then with sodium azide. The structures of these compounds have been confirmed by IR, MS,( 1)H-NMR, and elementary analysis. Anticonvulsant activities were evaluated using the maximal electroshock (MES) test. Most of the synthesized compounds displayed weak anticonvulsant activity at a dose of 300 mg/kg. Antidepressant activities were investigated by forced swimming test. Two compounds, namely 5-(hexyloxy)tetrazolo[1,5-a]quinazoline and 5-(4-methoxyphenoxy)tetrazolo[1,5-a]quinazoline, showed significant antidepressant activity, which decreased the immobility time by 62.2 and 51.7% at 100 mg/kg dose level.

Synthesis and anticonvulsant activity of N-(2-hydroxy-ethyl)amide derivatives.

A series novel of N-(2-hydroxyethyl)amide derivatives was synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, and their neurotoxicity was evaluated by the rotarod test (Tox). The maximal electroshock test showed that N-(2-hydroxyethyl)decanamide 1g, N-(2-hydroxyethyl)palmitamide 1l, and N-(2-hydroxyeth-yl)stearamide 1n were found to show a better anticonvulsant activity and also had lower toxicity than the marked anti-epileptic drug valproate. In the anti-MES potency test, these compounds exhibited median effective doses (ED50) of 22.0, 23.3, 20.5 mg/kg, respectively, and median toxicity doses (TD50) of 599.8, >1000, >1000 mg/kg, respectively, resulting in a protective index (PI) of 27.5, >42.9, >48.8, respectively. This is a much better protective index than that of the marked anti-epileptic drug valproate (PI = 1.6). To further investigate the effects of the anticonvulsant activity in several different models, compounds 1g, 1l, and 1n were tested having evoked convulsions with chemical substances, including pentylenetetrazloe, isoniazide, 3-mercaptopropionic acid, bicuculline, thiosemicarbazide, and strychnine.

Synthesis of some quinoline-2(1H)-one and 1, 2, 4 - triazolo [ 4 , 3 -a ] quinoline derivatives as potent anticonvulsants.

PURPOSE: A new series of substituted quinoline-2(1H)-one and 1,2,4-triazolo[4,3-a]-quinoline derivatives were designed and synthesized to meet the structural requirements essential for anticonvulsant properties. METHODS: 4-substituted-phenyl-3,4-dihydro-2(1H)-quinolines, 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3a]quinolines and 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo-[4,3-a]quinoline-1-(2H)-ones derivatives were synthesized using 3-substituted-phenyl-N-phenyl-acrylamide as a starting material. Their anticonvulsant activity were evaluated by maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxic effects were determined by the rotarod neurotoxicity test. RESULTS: The compounds 4-substitued-phenyl-3,4-dihydro-2(1H)-quinolines (2a-f) had increased anticonvulsant effects compared to the parental compounds. The compounds 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quinolines (3a-f) had significantly increased anticonvulsant activity compared to 2a-f. However, the compounds 5-substituted-phenyl-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoline-1(2H)-ones(4a-f), exhibited no anticonvulsant effects even under a high dose of 300 mg/kg. CONCLUSIONS: The triazole, but not the triazolone, modified series showed stronger anticonvulsant effects than the parent compounds. Among them, compound (3f), 5-(p-fluorophenyl)-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoline, showed the strongest anticonvulsant effect with ED50 of 27.4mg/kg and 22.0mg/kg in the anti-MES and anti-PTZ test, respectively.

Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones.

To further investigate anticonvulsant activity of quinoline derivatives, a series of 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one derivatives was synthesized starting from 7-hydroxyl-3,4-dihydro-2(1H)-quinoline. In initial (phase I) screening and quantitative (phase II) evaluation, compound 7-benzyloxyl-4,5-dihydro-[1,2,4]thiazolo[4,3-a]quinoline-1(2H)-one (3f) was among the most active but also has the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 12.3 mg/kg, median toxicity dose (TD(50)) of 547.5 mg/kg, and the protective index (PI) of 44.5, which is much greater than PI of the prototype drugs phenytoin, phenobarbital, carbamazepin, and valproate. Compound 3f was chosen for further evaluation. In phase III pharmacological test, the compound had median hypnotic dose (HD(50)) and median lethal dose (LD(50)) of 1204 mg/kg and >3000 mg/kg, respectively, thus demonstrating much greater margin of safety compared to prototype drugs. The compound 3f also showed significant oral activity against MES-induced seizures and low oral neurotoxicity in mice in phase IV pharmacological test. Possible structure-activity relationship was discussed.