Azoles display promising anticonvulsant effects through possible PPAR-α activation


SARI S., Yurtoğlu S., ZENGİN M., Marcinkowska M., Siwek A., Saraç S.

Neuroscience Letters, vol.828, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 828
  • Publication Date: 2024
  • Doi Number: 10.1016/j.neulet.2024.137750
  • Journal Name: Neuroscience Letters
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Animal Behavior Abstracts, BIOSIS, CAB Abstracts, Chemical Abstracts Core, Veterinary Science Database
  • Keywords: 6 Hz, Azoles, Blood–brain barrier molecular docking, Epilepsy, MES, PPAR-α
  • Hacettepe University Affiliated: Yes

Abstract

Azoles such as nafimidone, denzimol and loreclezole are known for their clinical efficacy against epilepsy, and loreclezole acts by potentiating γ-aminobutyric acid (GABA)-ergic currents. In the current study, we report a series of azole derivatives in alcohol ester and oxime ester structure showing promising anticonvulsant effects in 6 Hz and maximal electro shock (MES) models with minimal toxicity. The most promising of the series, 5f, was active in both 6 Hz and MES tests with a median effective dose (ED50) of 118.92 mg/kg in 6 Hz test and a median toxic dose (TD50) twice as high in mice. The compounds were predicted druglike and blood–brain barrier (BBB) penetrant in silico. Contrary to what was expected, the compounds showed no in vitro affinity to GABAA receptors (GABAARs) in radioligand binding assays; however, they were found structurally similar to peroxisome proliferator-activated receptors alpha (PPAR-α) agonists and predicted to show high affinity and agonist-like binding to PPAR-α in molecular docking studies. As a result, 5f emerged as a safe azole anticonvulsant with a wide therapeutic window and possible action through PPAR-α activation.