Synthesis and biological evaluation of new antiseizure compounds derived from valproic acid

GAROFALO, FEDERICO M; SBARAGLINI, MARÍA L; BARRIONUEVO, EMILIA M; PERALTA, ESTEFANÍA; BONIFAZI, EVELYN L; TALEVI, ALAN; GAVERNET, LUCIANA

Future Medicinal Chemistry

Newlands Press Ltd

Año: 2023 vol. 15 p. 735 - 743

1756-8919

Background: New hybrid compounds were synthesized by linking the valproic acid (VPA) structure with other anticonvulsant/anti-inflammatory scaffolds. Materials & methods: The chemistry involved the incorporation of the linker oxymethyl ester into VPA, followed by reaction with the second scaffold. The antiseizure effects were investigated by the maximal electroshock seizure test, and the most active compound was additionally evaluated in the 6 Hz test and pentylenetetrazol test in mice. Results: The compounds showed protection against seizures. The hybrid structure with the butylparaben scaffold exhibited an ED50 of 8.265 mg/kg (0.0236 mmol/Kg) in the maximal electroshock seizure test and 50.00 mg/kg (0.147 mmol/kg) in the 6 Hz test. Conclusion: The antiseizure activity of the synthesized compounds highlighted the potential of hybrid structures to treat multifactorial diseases such as epilepsy. Plain language summary This article focuses on the design of new anticonvulsant compounds that combine the chemical structure of valproic acid with other interesting scaffolds with anticonvulsant or anti-inflammatory properties. These compounds protected against in vivo acute seizure models (mice). The results revealed the capacity of combining known scaffolds into a single structure to generate new active compounds with multitarget purposes. Tweetable abstract The article focuses on the design and biological evaluation of new anticonvulsant compounds that share the chemical structure of valproic acid linked to other interesting scaffolds with anticonvulsant or anti-inflammatory properties.