Synthesis and Anticonvulsant Properties of New Mannich Bases Derived from 3,3-Disubstituted Pyrrolidine-2,5-diones. Part IV

A library of 21 new N-Mannich bases of 3,3-diphenyl- (5a-g), 3-methyl-3-phenyl- (6a-g), and 3-ethyl-3-methylpyrrolidine-2,5-diones (7a-g) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The acute neurological toxicity was determined applying the rotarod screen. The results in mice showed that 13 compounds were effective in the MES or/and scPTZ screen. From these, seven molecules were tested in the MES seizures after oral administration in rats. The quantitative studies showed that N-[{4-(2-hydroxyethyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6c) and N-[(4-benzylpiperidin-1-yl)-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6f) revealed higher protection in the MES and scPTZ tests than valproic acid or ethosuximide which were used as reference antiepileptic drugs. Four compounds (5c, 6c, 6e, 6f) showed high effectiveness in the 6-Hz psychomotor seizure model of partial and therapy resistant epilepsy.     

Synthesis and Anticonvulsant Properties of New N‐Mannich Bases Derived from 3,3‐Diphenyl‐ and 3‐Ethyl‐3‐methyl‐pyrrolidine‐2,5‐diones. Part III

Twenty‐four new N‐[(4‐phenylpiperazin‐1‐yl)‐methyl] derivatives of 3,3‐diphenyl‐ ( 7 – 18 ) and 3‐ethyl‐3‐methyl‐pyrrolidine‐2,5‐dione ( 19 – 30 ) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurological toxicity was determined using the rotorod screen. Eleven compounds were active and revealed protection only in electrically induced seizures (MES). In the whole series the most effective compound was N‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3,3‐diphenyl‐pyrrolidine‐2,5‐dione ( 14 ) with an ED₅₀ value of 30.3 mg/kg (p.o. rats) in the MES test. To explain the possible mechanism of action, for chosen active derivatives 7 , 8 , 9 , 11 , 14 , 23 , and 26 , their influence on Na_V1.2 sodium channel currents was evaluated in vitro. The crystallographic structures for several molecules ( 8 , 10 , and 11 ) were solved.     

Design,Synthesis, and In‐Vivo Pharmacological Screening of N,3‐(Substituted Diphenyl)‐5‐phenyl‐1H‐pyrazoline‐1‐carbothioamide Derivatives

Various 3,5‐(substituted diphenyl)‐4,5‐dihydro‐pyrazole‐1‐carbothioic acid phenylamides were synthesized starting from substituted acetophenones. Structures of the compounds were confirmed on the basis of spectral data. The compounds were evaluated for their anticonvulsant and antidepressant activity. Interestingly, out of 26 compounds, four ( 3f , 3g , 3t , and 3u ) were found to protect 100% of the animals in the MES screen at a dose of 25 mg/kg. They were also found to have appreciable anticonvulsant activity in scPTZ screen. Two compounds, 3j and 3o , significantly reduced the duration of the immobility time at 25 mg/kg dose, when compared to control.     

Synthesis and evaluation of anticonvulsant activities of 7‐phenyl‐4,5,6,7‐tetrahydrothieno[3,2‐b ]pyridine derivatives

A series of 7‐phenyl‐4,5,6,7‐tetrahydrothieno[3,2‐b]pyridine derivatives containing triazole and other heterocycle substituents (methyltriazole, tetrazole, and triazolone) is described. Two experimental methods, maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ), were used to evaluate the anticonvulsant activity of the target compounds. Moreover, the neurotoxicity (NT) was tested using the Rotarod test. 5‐(4‐Chlorophenyl)‐4,5‐dihydrothieno[2,3‐e][1,2,4]triazolo[4,3‐a]pyridine ( 6c ) showed the best anticonvulsant activity. In the MES and PTZ experiments, the 50% effective dose (ED₅₀) values of compound 6c were 9.5 and 20.5 mg/kg, respectively. From the therapeutic index (PI) values, 6c (MES and PTZ with PI values of 48.0 and 22.2, respectively) showed better safety than the clinical drugs carbamazepine (MES with PI value of 6.4) and ethosuximide (PTZ with PI value of 3.2). The biological activities of the compounds were verified by using molecular docking studies. Compound 6c showed significant interactions with residues at the benzodiazepine‐binding site on gamma‐aminobutyric acid A (GABA_A) receptors. The results of in vivo GABA estimation and bicuculline‐induced seizures showed that 6c may have an effect on the GABA system. The physicochemical and pharmacokinetic properties of the target compounds were predicted.     

Synthesis and Anticonvulsant Properties of New Mannich Bases Derived from 3‐Aryl‐pyrrolidine‐2,5‐diones. Part 1

A series of new Mannich bases of N‐[(4‐arylpiperazin‐1‐yl)‐methyl]‐3‐(chlorophenyl)‐pyrrolidine‐2,5‐diones 10–23 have been synthesized and evaluated for their anticonvulsant activity in maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure threshold tests. Their neurotoxicity was determined using a rotorod screen. Several molecules showed a promising anticonvulsant profile especially in the MES‐test. In this model of seizures, the most active were N‐[{4‐(4‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione 16 and N‐[{4‐(3‐trifluoromethylphenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(3‐chlorophenyl)‐pyrrolidine‐2,5‐dione 17 with ED₅₀ values of 21.4 mg/kg and 28.83 mg/kg, respectively. Selected derivatives 10 , 14 , and 16 were tested in the psychomotor seizure 6‐Hz test from which N‐[{4‐(2‐chlorophenyl)‐piperazin‐1‐yl}‐methyl]‐3‐(2‐chlorophenyl)‐pyrrolidine‐2,5‐dione 10 revealed the highest protection with an ED₅₀ of 78 mg/kg. Compounds 10 , 12 , and 17 were also tested in the pilocarpine‐induced status PIPS test. Furthermore, 17 was examined in the hippocampal kindling screen after i. p. administration to rats.     

Synthesis, characterization, and biological-pharmacological evaluation of new phosphazenes bearing dioxybiphenyl and schiff base groups

A new spirocyclophosphazene, 2,2‐bis(2‐formylphenoxy)‐4,4,6,6‐bis[spiro(2′,2″‐dioxy‐1′‐1″‐biphenylyl)]cyclotriphosphazene ( 3 ), was obtained from the reaction of 2,2‐dichloro‐4,4,6,6‐bis[spiro(2′,2″‐dioxy‐1′‐1″‐biphenylyl)]cyclotriphosphazene ( 2 ) with 2‐hydroxybenzaldehyde. New phosphazene derivatives bearing Schiff base and dioxybiphenyl groups have been synthesized by the reactions of 3 with different amines. The structures of the compounds were defined by elemental analysis, IR, ¹H, ¹³C, and ³¹P NMR spectroscopy. All the synthesized compounds were screened for their antibacterial activity against both types of Gram‐negative and Gram‐positive bacteria. The most potent antibacterial compound of this series was compound 12 which has the low MIC value of 3.75–0.9375 µg / mL. Both minimal inhibitory concentrations (MIC) and inhibition zones were determined in order to monitor the efficacy of the synthesized compounds. New compounds were also screened for anticonvulsant, CNS depressant, and sedative‐hypnotic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight phosphazenes were examined in the maximal electroshock‐induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. Compounds 4 , 5 , and 11 were found to be active in both MES screen and scPTZ screen at 0.5 h. All except 12 showed more than 44% decrease in locomotor activity after 1 h of compound administration via actophotometer screen. CNS‐depressant activity screened with the help of the forced swim method resulted in some potent compounds. Except for 7 and 12 other tested compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time.     

Synthesis and Anticonvulsant Activity Evaluation of 5‐Phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amines

In the present study we describe the syntheses and anticonvulsant activity evaluation of 5‐phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amine derivatives. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of these compounds, the most promising was compound 8h , which showed an ED₅₀ value of 27.4 mg/kg and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED₅₀ and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti‐MES efficacy, the potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide were also established, with the results suggesting that the GABAergic system‐mediated mechanisms might be involved in its anticonvulsant activity.     

Anticonvulsant and neurotoxicity evaluation of some 6-substituted benzothiazolyl-2-thiosemicarbazones

Various 6-substituted benzothiazolyl-2-thiosemicarbazones were synthesized and screened for anticonvulsant activity in maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. The 6-methyl benzothiazolyl-2-thiosemicarbazones showed anticonvulsant activity in both mice i.p. and rat oral MES screen. The 6-nitro benzothiazolyl thiosemicarbazone derivative 1a emerged as the most promising one with anti-MES activity in mice i.p., rat i.p. and rat p.o. evaluations. All the compounds exhibited lesser or no neurotoxicity compared to phenytoin. The isatinimino derivatives had shown better activity when compared to the benzylidene or acetophenone derivatives.     

Synthesis and Evaluation of 3‐[(2,4‐Dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile Derivatives as Potential Anticonvulsants

New 3‐[(2,4‐dioxo‐1,3,8‐triazaspiro[4.6]undec‐3‐yl)methyl]benzonitrile derivatives 8 – 37 were synthesized and their pharmacological activities were determined with the objective to better understand their structure–activity relationship (SAR) for anticonvulsant activity. All the compounds were evaluated for their possible anticonvulsant activity by maximal electroshock seizure (MES) and pentylenetetrazole (PTZ) test. Compounds 11 , 18 , 31 , and 32 showed significant and protective effect on seizure, when compared with the standard drug valproate. The same compounds were found to exhibit advanced anticonvulsant activity as well as lower neurotoxicity than the reference drug. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a hydrophobic center, and a two‐electron donor.     

Design, synthesis, and potential CNS activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea

Twelve new 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea were synthesized and screened for anticonvulsant, CNS depressant, and sedative-hypnotic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-Disubstituted-quinazolin-4(3H)-one were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data and elemental analysis were consistent with the newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. M3, M4, and M10 were found to be active in both MES screen and scPTZ screen at 0.5 h. All except M11 showed more than 44% decrease in locomotor activity after 1 h of compound administration via actophotometer screen. CNS-depressant activity screened with the help of the forced swim method resulted into some potent compounds. Except for M6 and M11 other tested compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time. It can be concluded that newly synthesized compounds possessed sedative-hypnotic and CNS depressant activities.     

6-取代苯基-3(2H)哒嗪酮的合成、抗惊活性及其构效关系的研究

本文报道了14个6-取代苯基-4,5-二氢-3(2H)哒嗪酮和15个6-取代苯基-3(2H)哒嚎酮的合成及其抗电惊活性。其ED₅₀值表明,以2′,4′-二氯苯基-3(2H)哒嗪酮的抗惊作用为最强。构效分析表明,苯环上的取代基对化合物的抗惊活性有明显影响,吸电子取代基和疏水性参数值较大的取代基有利于提高化合物的抗惊活性。     

Anticonvulsant properties of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methyl-piperazin-1-yl)propyl] derivatives of 3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione

Two series of N-(4-methylpiperazin-1-yl)- and N-[3-(4-methylpiperazin-1-yl)-propyl]-3-aryl- and 3-spirocycloalkyl-pyrrolidine-2,5-dione derivatives were synthesized and tested for anticonvulsant activity in the maximum electroshock (MES) seizure and pentetrazole (sc PTZ) seizure threshold tests. Compounds with an aromatic ring at position-3 of pyrrolidine-2,5-dione exhibited anticonvulsant activity in the MES test. For that series of compounds, ED50 values were determined. The most potent in the series were derivatives and with a chlorine atom at position-3 or 4 of the aromatic ring. Those compounds exhibited strong anticonvulsant activity, and their ED50 values ranged from 29 to 48 mg/kg. Introduction of the spirocycloalkyl ring into the position-3 of pyrrolidine-2,5-dione made those compounds inactive.     

Design, synthesis and screening of quinoline-incorporated thiadiazole as a potential anticonvulsant

A series of quinoline-incorporated substituted thiadiazole were designed and synthesized using appropriate synthetic route keeping in view the structural requirement of pharmacophore and evaluated for anticonvulsant and CNS activities. After intraperitoneal injection to mice, some synthesized derivatives were examined in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazol (scPTZ)-induced seizure and neurotoxicity screens. Those found potent were also evaluated for behavioural impairment and depression activity. Among the compounds tested, 6d and 6e showed protection from seizures in both the animal models at dose level of 30 mg/kg while 7f showed protection against both models at 100 mg/kg dose level. These compounds exhibited lesser CNS depression and neurotoxicity compared with clinically effective drug.     

anticonvulsant and toxicity evaluation of newer 4H-benzo[1,4]oxazin-3-ones: The effect of two hydrogen bonding domains

A series of (Z)-2-(substituted aryl)-N-(3-oxo-4-(substituted carbamothioyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) hydrazine carboxamides (6a-r) was synthesized using 2-amino-5-nitrophenol as a starting material. All the synthesized compounds possessed two hydrogen-bonding domains and their effect on the activity was studied thereof. The anticonvulsant activity was assessed by the maximal electroshock test (MES), subcutaneous pentylenetetrazole test (scPTZ) and intraperitoneal thiosemicarbazide test (ipTSC). Compounds (6b, 6h, 6i, and 6p) were found to be the most potent of the series as they showed 83-100% protection in the MES test. They also displayed considerable activity in the chemically induced seizure tests. Most of the tested compounds were devoid of the neurotoxic and hepatotoxic effects.     

Synthesis of Novel 2,5‐Disubstituted 1,3,4‐Thiadiazoles for Their Potential Anticonvulsant Activity: Pharmacophoric Model Studies

A series of novel N¹‐[5‐(4‐substituted phenyl)‐1,3,4‐thiadiazol‐2‐yl]‐N⁴‐(4‐substituted benzaldehyde)‐semicarbazone 1 – 12 , N¹‐[5‐(4‐substituted phenyl)‐1,3,4‐thiadiazol‐2‐yl]‐N⁴‐[1‐(4‐substituted phenyl)ethanone]‐semicarbazone 13 ‐ 16 , and N¹‐[5‐(4‐substituted phenyl)‐1,3,4‐thiadiazol‐2‐yl]‐N⁴‐[1‐(4‐substituted phenyl) (phenyl) methanone]‐semicarbazone 17 – 20 were synthesized for their anticonvulsant activity. The chemical structures of the compounds were proved by elemental and spectral (IR, ¹H‐NMR, ¹³C‐NMR, and MS) analysis. The anticonvulsant potential of the compounds was investigated using maximal electroshock seizure (MES) and subcutaneous pentylenetrtrazole (scPTZ) models. Compound 19 was found to possess significant anticonvulsant activity in both the models employed for anticonvulsant evaluation. Compounds 8 , 13 , 15 , and 16 also demonstrated a marked anticonvulsant property. The results of the present study validated that the pharmacophore model with four binding sites is essential for anticonvulsant activity. The efforts were also made to establish structure‐activity relationships among the synthesized compounds.     

Synthesis and Anticonvulsant Activity of Ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) Cyclopropanecarboxylate Derivatives

In this study on the development of new anticonvulsants, fourteen ethyl 2,2‐dimethyl‐1‐(2‐substitutedhydrazinecarboxamido) cyclopropanecarboxylate derivatives were synthesized and tested for anticonvulsant activity using the maximal electroshock, subcutaneous pentylenetetrazole screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 6f and 6k showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 6k showed the maximal electroshock‐induced seizures with ED₅₀ value of 9.2 mg/kg and TD₅₀ value of 387.5 mg/kg after intraperitoneally injection to mice, which provided compound 6k with a protective index (TD₅₀/ED₅₀) of 42.1 in the maximal electroshock test.     

Design, synthesis and evaluation of anticonvulsant activity of pyridinyl-pyrrolidones: a pharmacophore hybrid approach

Various 1‐[6‐(4‐substituted phenyl)‐3‐cyano‐4‐(substituted phenyl)‐pyridin‐2‐yl]‐5‐oxopyrrolidine‐3‐carboxylic acids ( 3a–t ) were designed and synthesized by clubbing pyrrolidinones and pyridines, the two active anticonvulsant pharmacophores. All the synthesized compounds fulfilled the requirements of suggested pharmacophoric model for anticonvulsant activity. Their in vivo anticonvulsant evaluation was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. The minimal motor impairment was assessed by rotorod test and the estimation of various liver enzymes was performed to check the magnitude of liver toxicity posed by the synthesized compounds. Compounds 3d and 3k displayed comparable anticonvulsant activity to the standard drugs with ED₅₀ values of 13.4 and 18.6 mg/kg in electroshock screen, repectively. The compounds 3d and 3k were also found to have encouraging anticonvulsant activity (ED₅₀ = 86.1 and 271.6 mg/kg, respectively) in scPTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver.     

Synthesis and anticonvulsant properties of new N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-aryl pyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione

A series of N-[(4-arylpiperazin-1-yl)-methyl] derivatives of 3-arylpyrrolidine-2,5-dione and 2-aza-spiro[4.4]nonane-1,3-dione were synthesized and tested for anticonvulsant activity in the maximum electroshock seizure (MES) and metrazole seizure threshold (sc.MET) tests. The most potent in the series were N-[[4-(3-chlorophenyl)-piperazin-1-yl]-methyl]-3-(2-chlorophenyl)-pyrrolidine-2,5-dione (ED50=14.18 mg/kg) and N-[[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl]-3-(3-bromophenyl)-pyrrolidine-2,5-dione (ED50=33.64 mg/kg). Structures of the novel compounds were confirmed by elemental and spectral analyses.     

Design,synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

A novel series of benzoxazole derivatives containing 1,2,4‐triazolone ( 5a‐m ) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc‐PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti‐MES activities at 100 and 300 mg/kg. Compound 5f , which showed potential anticonvulsant activity in the MES model with ED₅₀ values of 22.0 mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3‐mercaptopropionic acid and BIC was also verified. In an enzyme‐linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ‐aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED₅₀ value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABA_A receptor confirmed possible binding of the compound 5f with BZD receptors.     

Synthesis and anticonvulsant and neurotoxicity evaluation of N4-phthalimido phenyl (thio) semicarbazides.

The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.), maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (sc STY)-induced seizure threshold tests in mice. Compound 2c afforded protection in all the three screens. Compounds except 1d, 2a and 2d showed no neurotoxicity up to 300 mg/kg. Compounds 1a, 1b, 2c, 2d, 2g and 2i were found to show oral MES activity. The compounds exhibited CNS depression and behavioral despair side effects, lesser than the conventional antiepileptic drugs.