Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents

• Published in: Bioorganic chemistry Vol. 112; p. 104943
• Main Authors: Emami, Saeed, Valipour, Mehdi, Kazemi Komishani, Fatemeh, Sadati-Ashrafi, Fatemehsadat, Rasoulian, Maria, Ghasemian, Majid, Tajbakhsh, Mahmood, Honarchian Masihi, Patrick, Shakiba, Aidin, Irannejad, Hamid, Ahangar, Nematollah
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2021
• Subjects: Anticonvulsant agents; Epilepsy; Hydrazide-hydrazones; MES; PTZ; MES; Anticonvulsant agents; Epilepsy; PTZ; Hydrazide-hydrazones
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.104943

[Display omitted] •(Z)-Isatin aroylhydrazones (5a-e and 6a-e) were synthesized as anticonvulsant agents.•Most of compounds were effective against MES-induced seizures.•Compounds 6a and 6e showed 100% protection at the dose of 5 mg/kg.•Pharmacokinetics properties of 6a and 6e were evaluated computationally and experimentally.•6a and 6e had no significant cytotoxicity against neuronal and hepatic cells at conventional doses. In this study, a series of new isatin aroylhydrazones (5a-e and 6a-e) was synthesized and evaluated for their anticonvulsant activities. The (Z)-configuration of compounds was confirmed by 1H NMR. In vivo studies using maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy in mice revealed that while most of compounds had no effect on chemically-induced seizures at the higher dose of 100 mg/kg but showed significant protection against electrically-induced seizures at the lower dose of 5 mg/kg. Certainly, N-methyl analogs 6a and 6e were found to be the most effective compounds, displaying 100% protection at the dose of 5 mg/kg. Protein binding and lipophilicity(logP) of the selected compounds (6a and 6e) were also determined experimentally. In silico evaluations of title compounds showed acceptable ADME parameters, and drug-likeness properties. Distance mapping and docking of the selected compounds with different targets proposed the possible action of them on VGSCs and GABAA receptors. The cytotoxicity evaluation of 6a and 6e against SH-SY5Y and Hep-G2 cell lines indicated safety profile of compounds on the neuronal and hepatic cells.