Hypolipidemic effect of novel 2,5-bis-1,3,4-thiadiazole as potential peroxisome proliferation-activated receptor-[alpha] agonist in acute hyperlipidemic rat model

• Published in: Molecular and cellular biochemistry Vol. 458; no. 1-2; p. 39
• Main Authors: Hamadneh, Lama A, Sabbah, Dima A, Hikmat, Suhair J, Al-Samad, Luma A, Hasan, Mariam, Al-Qirim, Tariq M, Hamadneh, Imad M
• Format: Journal Article
• Language: English
• Published: Springer 01.08.2019
• Subjects: Fatty acids; Fenofibrate; Gene expression; Low density lipoproteins; Nuclear magnetic resonance spectroscopy; Physiological aspects; Schiff bases
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-019-03528-5

The development of new antihyperlipidemic agents with higher potency and lower side effects is of high priority. In this study, 1,3,4 thiadiazole Schiff base derivatives were synthesized as potential peroxisome proliferation-activated receptor-[alpha] (PPAR[alpha]) agonists and characterized using elemental analysis, FTIR, .sup.1H-NMR, .sup.13C-NMR and mass spectroscopy and then tested for their hypolipidemic activity in Triton WR-1339-induced acute hyperlipidemic rat model in comparison with bezafibrate. The compounds showed significant hypolipidemic activity. Induced fit docking showed that the compounds are potential activators of PPAR[alpha] with binding scores - 8.00 Kcal/mol for 2,5-bis(4-hydroxybenzylidenamino)-1,3,4-thiadiazole. PCR array analysis showed an increase in the expression of several genes involved in lipid metabolism through mitochondrial fatty acid [beta] oxidation and are part of PPAR[alpha] signaling pathway including Acsm3, Fabp4 and Hmgcs1. Gene expression of Lrp12 and Lrp1b involved in LDL uptake by liver cells and Cyp7a1 involved in cholesterol catabolism were also found to be upregulated.