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

Muhammad Syafiq Akmal Mohd Fahmi; Puspanjali Swain; Amirah Hani Ramli; Wan Norhamidah Wan Ibrahim; Nur Atikah Saleh Hodin; Noraini Abu Bakar; Yee Seng Tan; Siti Munirah Mohd Faudzi; Cheol-Hee Kim

doi:10.1016/j.heliyon.2023.e13685

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

Heliyon. 2023 Feb 11;9(2):e13685. doi: 10.1016/j.heliyon.2023.e13685. eCollection 2023 Feb.

Authors

Affiliations

¹ Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
² Department of Biology, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.
³ Natural Medicines and Product Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
⁴ Department of Biology, Faculty of Science, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia.
⁵ Centre of Foundation Studies for Agricultural Science, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia.
⁶ Research Centre for Crystalline Materials, School of Medical and Life Sciences, Sunway University, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia.

Abstract

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, synthesized, 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 γ-aminobutyric acid receptor type-A (GABA_A, -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, experimentally. Moreover, no cardiotoxic effect of compound 8 was observed in zebrafish. Overall, pyrrolylated chalcones could serve as alternative AEDs and warrant further in-depth pharmacological studies to uncover their mechanism of action.

Keywords: Antiepileptic drugs (AEDs); Chalcones; Zebrafish.