5 h 4.0 he 0.5 h 4.0 h 0.5 h 4.0 he (3 S ,5 S )-3a 30 0/1 0/1 0/1 0/1 0/4 0/2 0.80 100 2/3 0/3 0/1 0/1 0/8 0/4 300 1/1 0/1 0/1 0/1 4/4 f, g 0/2 (3 S ,5 R )-3a 30 0/1 0/1 0/1 0/1 0/4 0/2 0.80 100 0/3h 0/3 1/5 i 0/1 0/8 0/4 300 1/1 0/1 0/1 0/1 2/4 0/2 (3 S ,5 S )-3b 30 0/1 0/1 0/1 0/1 0/4 0/2 1.19 100 0/3 0/3 0/1 0/1 0/8 0/4 300 1/1 0/1 0/1 0/1 3/4 f 0/2 (3 S ,5 S )-3c 30 0/1 0/1 0/1 0/1 0/4 0/2 1.19 100 0/3 0/3 0/1 0/1 0/8 0/4 300 0/1 0/1 0/1 0/1 2/4 0/2 (3 S ,5 S )-3d 30 0/1 0/1 0/1 0/1 0/4 0/2 1.61 100 0/3 0/3 0/1 0/1 0/8 0/4 300 1/1 0/1 0/1 0/1 0/4 0/2 (3 S ,5 S )-3e 30 0/4 0/4 – – 0/8 0/8 2.12 100 2/4 1/4 – – 0/8 0/8 300 4/4 4/4 – – 2/8 1/8 (3 S ,5 R )-3e 30 0/4 0/4 – – 0/8 0/8 2.12 100
0/4 0/4 – – 0/8 0/8 300 1/4 0/4 – Selleckchem VS-4718 – 0/8 0/8 rac -3f 30 0/4 0/4 – – 0/8 0/8 2.29 100 0/4 0/4 – – 0/8 0/8 300 0/4 3/4 Selleck AUY-922 – – 0/8 0/8 rac -3g 30 0/1 0/1 0/1 0/1 0/4 0/2 2.12 100 0/3 0/3 0/1 0/1 0/8 0/4 300 0/1
0/1 0/1 0/1 0/4 0/2 Ratios where at least one animal was protected or displayed neurotoxicity have been highlighted in bold to enhance data readability and interpretation aMaximal electroshock test (find more number of animals protected/number of animals tested) bSubcutaneous metrazole test (number of animals protected/number of animals tested) cNeurotoxicity test (number of animals exhibiting neurological toxicity/number of animals tested) dTheoretical logP value calculated by a logarithm included in HyperChem 7.5 package eCompounds (3 S ,5 S )-3e, (3 S ,5 R )-3e and rac -3f were tested at 2.0 h post administration fUnable to grasp rotorod gLoss of righting reflex hActive also in 1/3 at 0.25 h post administration iMyoclonic jerks Table 2 Anticonvulsant activity and neurotoxicity of compounds in the 6 Hz model following intraperitoneal (ip) administration in mice Compounds Testa 0.25 h 0.5 h 1.0 h 2.0 h 4.0 h (3 S ,5 S )-3a 6 Hzb 2/4 1/4 0/4 0/4 0/4 TOXc 0/4 0/4 0/4 0/4 0/4 (3 S ,5 S )-3e 6 Hz – 0/4 – 0/4 – TOX – 0/8 – 0/8 – Ratios where at least one animal was protected or displayed
neurotoxicity have been highlighted in bold to enhance data readability and interpretation aAt dose 100 mg/kg b6 Hz test, 32 mA (number of animals protected/number of animals tested) cNeurotoxicity test (number of animals exhibiting PIK3C2G neurological toxicity/number of animals tested) As shown in Table 1, compounds 3a, b, d–f exhibited weak to good anticonvulsant activities in the MES model in mice.