In silico studies, X-ray diffraction analysis and biological investigation of fluorinated pyrrolylated-chalcones in zebrafish epilepsy models

Epilepsy is the third most common known brain disease worldwide. Several antiepileptic drugs (AEDs) are available to improve seizure control. However, the associated side effects limit their practical use and highlight the ongoing search for safer and effective AEDs. Eighteen newly designed fluorine-containing pyrrolylated chalcones were extensively studied in silico, synthe-sized, structurally analyzed by X-ray diffraction (XRD), and biologically and toxicologically tested as potential new AEDs in zebrafish epilepsy in vivo models. The results predicted that 3-(3,5-difluorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (compound 8) had a good drug-like profile with binding affinity to gamma-aminobutyric acid receptor type-A (GABAA,-8.0 kcal/mol). This predicted active compound 8 was effective in reducing convulsive behaviour in pentylenetetrazol (PTZ)-induced larvae and hyperactive movements in zc4h2 knockout (KO) zebrafish, experi-mentally. Moreover, no cardiotoxic effect of compound 8 was observed in zebrafish. Overall, pyrrolylated chalcones could serve as alternative AEDs and warrant further in-depth pharmaco-logical studies to uncover their mechanism of action.

Automated summary

Epilepsy is a common brain disease and the available antiepileptic drugs often have side effects. In this study, 18 newly designed fluorine-containing pyrrolylated chalcones were tested as potential new AEDs. Compound 8 showed good drug-like properties and binding affinity to GABAA receptor. It effectively reduced convulsive behavior in zebrafish models and had no cardiotoxic effects. Pyrrolylated chalcones could be alternative AEDs and further studies are needed to understand their mechanism of action.