Synthesis of microwave-assisted carboxamides in Triton WR-1339-induced hyperlipidemic rats: possible hypolipidemic heterocyclic compounds

Basmah Al-Jammal; Buthaina Hussein; Yusuf Al-Hiari; Tareq Al-Qirim; Manal Al-Najdawi; Lama Hamadneh; Mohammad Alwahsh; Balqis Ikhmais

doi:10.1039/d3ra03581f

Synthesis of microwave-assisted carboxamides in Triton WR-1339-induced hyperlipidemic rats: possible hypolipidemic heterocyclic compounds

RSC Adv. 2023 Jul 24;13(32):22193-22204. doi: 10.1039/d3ra03581f. eCollection 2023 Jul 19.

Authors

Basmah Al-Jammal¹, Buthaina Hussein², Yusuf Al-Hiari^{1

2}, Tareq Al-Qirim², Manal Al-Najdawi³, Lama Hamadneh⁴, Mohammad Alwahsh², Balqis Ikhmais²

Affiliations

¹ Department of Pharmaceutical Sciences/Faculty of Pharmacy, The University of Jordan Amman-11942 Jordan.
² Faculty of Pharmacy, Al-Zaytoonah University of Jordan Amman-17138 Jordan Buthina.hussein@zuj.edu.jo.
³ Faculty of Pharmacy, Isra University Amman-11622 Jordan.
⁴ Department of Basic Medical Sciences, Faculty of Medicine, Al-Balqa Applied University Al-Salt Jordan.

Abstract

The hypolipidemic effect of furan carboxamide derivatives was investigated using the Triton WR-1339 rat model. Nineteen compounds were synthesized, including furan-2-carboxamides of benzophenones and acetophenones (a(1-4)), anilines and amine derivatives (a(5-9)), picolinic-2-carboxamide derivatives of benzophenones and acetophenone (a(10-12)) and furan-2-carboxylate esters of benzophenones and acetophenones, substituted phenols and alcohols (b(1-7)). All the necessary steps were taken to synthesize, purify, and characterize these compounds. They were synthesized by reacting acyl chlorides of the heterocycles with their corresponding amines in the presence of pyridine and tert-butyl acetate. While the conventional heating method yielded acceptable yields for some of the reactions under reflux, the microwave synthesis reactor achieved significantly higher yields for others. Rats with hyperlipidemia were induced with Triton WR-1339 and then subjected to in vivo testing via an intraperitoneal injection of 200 mg kg^-1 Triton WR-1339. The model was tested using an oral dose of bezafibrate (100 mg kg^-1). After 7 hours of treatment with Triton, the new derivatives represented by compounds a(1-2), a(4-5), a7, and a(10-12) showed significant activity against the complete lipid profile, including a decrease in triglyceride, total cholesterol, and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol plasma levels. At 20 mg kg^-1 dose, these compounds were superior to other lipid-lowering agents in reducing triglyceride levels and slightly increased high-density lipoprotein cholesterol levels. These results indicate a mutual mechanism of action of novel compounds with fibrates, where they have a marked effect on triglyceride and high-density lipoprotein cholesterol levels; for example, a5 causes a significant reduction (p 0.0001) of triglyceride levels by 86%, and a remarkable increase (p 0.0001) in high-density lipoprotein cholesterol plasma levels by 65% as compared to hyperlipidemic rats.