Design and synthesis of novel quinazolinone‐based fibrates as PPARα agonists with antihyperlipidemic activity. Issue 3 (27th December 2021)

• Record Type: Journal Article
• Authors: Hassan, Rasha M.; Ali, Islam H.; Abdel‐Maksoud, Mohammed S.; Abdallah, Heba M. I.; El Kerdawy, Ahmed M.; Sciandra, Francesca; Ghannam, Iman A. Y.
• Is Part Of: Archiv der Pharmazie. Volume 355:Issue 3(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-27
• Subjects: antihyperlipidemia -- fibrates -- PPARα -- quinazolinone -- synthesis; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.202100399
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: Aiming to discover new antihyperlipidemic agents, a new set of quinazolinone‐fibrate hybrids 9a–r bearing the essential features for peroxisome proliferator‐activated receptor‐α (PPARα) agonistic activity was synthesized and the structures were confirmed by different spectral data. All the target compounds were screened for their PPARα agonistic activity. Compounds 9o and 9q exhibited potent activity, with EC50 values better than that of fenofibrate by 8.7‐ and 27‐fold, respectively. Molecular docking investigations were performed for all the newly synthesized compounds in the active site of the PPARα receptor to study their interactions and energies in the receptor. Moreover, the antihyperlipidemic and antioxidant activities of compounds 9o and 9q were determined using Triton WR‐1339‐induced hyperlipidemic rats. Compound 9q exhibited effective hypolipidemic activity in a dose‐dependent manner, where it significantly reduced the serum levels of total cholesterol, triglycerides, low‐density lipoprotein cholesterol, and very‐low‐density lipoprotein cholesterol and increased the level of high‐density lipoprotein cholesterol. Furthermore, it possesses a powerful antioxidant profile where it significantly elevated the levels of reduced glutathione as well as the total antioxidant capacity and significantly decreased the malondialdehyde level. The histopathological studies revealed that compound 9q improved the aortic architecture and hepatic steatosis. These findings support that compound 9q could be a promising lead compound for the development of new antihyperlipidemic agents. Abstract : Eighteen new quinazolinone‐fibrate hybrids 9a–r were synthesized and screened for their peroxisome proliferator‐activated receptor‐α agonistic activity. Compounds 9o and 9q exhibited potent in vitro activity better than that of fenofibrate. Compound 9q displayed effective antihyperlipidemic and antioxidant activities in the Triton WR‐1339‐induced hyperlipidemia model. Histopathological investigations showed that compound 9q improved the aortic architecture and hepatic steatosis.