Design and synthesis of novel cycloalkanecarboxamide parabanic acid hybrids as anticonvulsants

• Published in: Medicinal chemistry research Vol. 33; no. 1; pp. 89 - 106
• Main Authors: Abd-Allah, Walaa Hamada, Abd El-Maksoud, Mohamed Samir, Elbaset, Marawan A., Hessin, Alyaa F., Hassan, Rasha Mohamed
• Format: Journal Article
• Language: English
• Published: New York Springer US 2024; Springer Nature B.V
• Subjects: Acids; Anticonvulsants; Antiepileptic agents; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Convulsions & seizures; Drug development; Electroconvulsive therapy; Hepatotoxicity; Hybrids; Inorganic Chemistry; Medicinal Chemistry; Molecular docking; Neurotoxicity; Original Research Article; Pentylenetetrazole; Pharmacokinetics; Pharmacology/Toxicology; Screening; Seizures; Serum levels; γ-Aminobutyric acid; Anticonvulsants; Cycloalkanecarboxamides; Synthesis; Epilepsy; Parabanic acids
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-023-03166-z

Aiming to develop novel anticonvulsant agents a new series of novel cycloalkanecarboxamide parabanic acid hybrids series 8 , 9 and 10 possessing the essential structure requirements for anticonvulsant activity was synthesized starting from cycloalkanones. All final target compounds were primary screened for chemically and electrically induced seizures using pentylenetetrazole “scPTZ” and maximal electroshock seizure “MES” models. In phase I anticonvulsant evaluation compounds 8b and 10b exhibited the highest potency among all the target compounds with 100% protection towards chemically induced seizures. Results of phase II anticonvulsant screening showed that compounds 8b and 10b are more potent than standard drug ethosuximide by about 11 and 9 fold, respectively. Regarding MES test, compounds 8b and 9a-d exhibited 100% protection with ED 50 values ranged between 0.107–0.177 mmol/Kg. All final compounds did not display any signs of motor impairment in the neurotoxicity screening test. Also, compounds 8a , 9a-d and 10b were devoid of hepatotoxicity as shown by measurement of serum levels of liver enzymes, albumin as well as total protein. Moreover, the cyclohexyl derivative 10b produced a significant increase of Gamma-aminobutyric acid “GABA” brain’s content of mice compared to control group confirmed its GABAergic modulating activity. Molecular docking, physicochemical and pharmacokinetic properties were carried out for all compounds as well. These outcomes support that cycloalkanecarboxamide parabanic acid hybrid is a promising scaffold to pave the way towards further development of novel class of antiepileptic drugs.