TY - JOUR

T1 - A facile synthesis of 1,3,4-oxadiazole-based carbamothioate molecules

T2 - Antiseizure potential, EEG evaluation and in-silico docking studies

AU - Rasool, Nasir

AU - Razzaq, Zainib

AU - Gul Khan, Samreen

AU - Javaid, Sana

AU - Akhtar, Naheed

AU - Mahmood, Sadaf

AU - Christensen, Jørn B.

AU - Ali Altaf, Ataf

AU - Muhammad Muneeb Anjum, Syed

AU - Alqahtani, Faleh

AU - AlAsmari, Abdullah F.

AU - Imran, Imran

N1 - Funding Information: This work was funded by Distinguished Scientist Fellowship program at King Saud University, Riyadh, Saudi Arabia through research supporting project Number ( RSP2023R131 ). Funding Information: We are thankful to Mr. Muhammad Imran, an animal house attendant who is responsible for the care of animals in the animal house facility of Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan. This work was funded by Distinguished Scientist Fellowship program at King Saud University, Riyadh, Saudi Arabia through research supporting project Number (RSP2023R131). Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

N2 - In present work, a series of novel structural hybrids of 1,3,4-oxadiazole and carbamothioate was designed by chemical modification of 2-(4-isobutylphenyl)propanoic acid. Target compounds (7a-f) were synthesized in significant yields (84–88 %) by coupling compound (4) with different electrophiles under different reaction conditions. The structures of oxadiazole based carbamothionate derivatives were confirmed by spectroscopic (FTIR, 1H NMR, 13C NMR) and physiochemical methods. During in-vivo experimentation, all synthesized compounds were tested through 6 Hz (32 mA) and PTZ (80 mg/kg) mouse seizure models. The 7b and 7c showed significant outcomes (P < 0.05) in terms of seizure severity, protection and mortality. The behavioural outcomes of PTZ tests were further strengthened with video-electroencephalogram (vEEG) findings in which EEGs were analyzed for epileptic spikes to understand the impact of 7b and 7c treatment on these ictal activities. The 7b was found most efficient in reducing the seizure spiking activity in brains of PTZ-treated mice while both 7b and 7c significantly reduced overall PTZ-induced seizure severity. The molecular docking studies also predicted the BBB permeability, reduced binding energies and good compound interaction with GABAA receptors and SV2A protein. Therefore, the observed pharmacological outcomes might be attributed to the GABAA agonistic and SV2A modulating potential of these oxadiazole-carbamothioate hybrid compounds.

AB - In present work, a series of novel structural hybrids of 1,3,4-oxadiazole and carbamothioate was designed by chemical modification of 2-(4-isobutylphenyl)propanoic acid. Target compounds (7a-f) were synthesized in significant yields (84–88 %) by coupling compound (4) with different electrophiles under different reaction conditions. The structures of oxadiazole based carbamothionate derivatives were confirmed by spectroscopic (FTIR, 1H NMR, 13C NMR) and physiochemical methods. During in-vivo experimentation, all synthesized compounds were tested through 6 Hz (32 mA) and PTZ (80 mg/kg) mouse seizure models. The 7b and 7c showed significant outcomes (P < 0.05) in terms of seizure severity, protection and mortality. The behavioural outcomes of PTZ tests were further strengthened with video-electroencephalogram (vEEG) findings in which EEGs were analyzed for epileptic spikes to understand the impact of 7b and 7c treatment on these ictal activities. The 7b was found most efficient in reducing the seizure spiking activity in brains of PTZ-treated mice while both 7b and 7c significantly reduced overall PTZ-induced seizure severity. The molecular docking studies also predicted the BBB permeability, reduced binding energies and good compound interaction with GABAA receptors and SV2A protein. Therefore, the observed pharmacological outcomes might be attributed to the GABAA agonistic and SV2A modulating potential of these oxadiazole-carbamothioate hybrid compounds.

KW - 1,3,4-oxadiazole

KW - 6 Hz

KW - Electroencephalogram

KW - Epilepsy

KW - PTZ

KW - Seizure

U2 - 10.1016/j.arabjc.2023.104610

DO - 10.1016/j.arabjc.2023.104610

M3 - Journal article

AN - SCOPUS:85147198230

VL - 16

JO - Arabian Journal of Chemistry

JF - Arabian Journal of Chemistry

SN - 1878-5352

IS - 4

M1 - 104610

ER -