Pharmacological Evaluation of Novel Isonicotinic Carboxamide Derivatives as Potential Anti‐Hyperlipidemic and Antioxidant Agents

Abstract

Hyperlipidemia and oxidative stress have been implicated as contributing factors to the development of atherosclerosis and cardiovascular diseases (CVDs). Currently, a large number of antihyperlipidemic medications are conveniently available in the market. Nonetheless, the majority of antihyperlipidemics lack the desired safety and efficacy. Thus, the present study was undertaken to evaluate the potential effect of novel N-(benzoylphenyl)pyridine-4-carboxamide and N-(9,10-dioxo-9,10-dihydroanthracenyl)pyridine-4-carboxamide derivatives in controlling hyperlipidemia and oxidative stress using the Triton WR-1339-induced hyperlipidemic rat model for antihyperlipidemic activity and the DPPH radical scavenging assay for antioxidant activity. This study revealed the antihyperlipidemic activities of some of the newly synthesized, novel carboxamide derivatives, mainly C4 and C12 (p < 0.05). The majority of the compounds displayed a relatively low or no DPPH radical scavenging effect, with C20 possessing the best radical scavenging effect (22%) among all. This research opens the door for new potential antihyperlipidemic compounds derived from isonicotinic acid. N-(3-Benzoylphenyl)pyridine-4-carboxamide (C4) was found to have promising lipid-lowering and antioxidant effects, which may create a protective effect against CVDs, by reducing the LDL-C levels and diminishing the generation of reactive oxygen species.

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

“…Referring to the previously reported derivatives [8][9][10][11][12][13][14][15] and in addition to these new derivatives, we can conclude preliminary SAR criteria for active hits, including 5 or 6-ring heterocycle (A) with H-B acceptor atom, carboxamide linker (B), lipophilic side chain (C) with H-B acceptor bridge in addition to limited size to one or two rings, and nally extended linear structure (Fig. 8).…”

“…1. [8][9][10][11][12][13][14][15] All compounds were evaluated by Triton WR-1339-induced hyperlipidemic rats, a well-known model used in screening new agents with a potential lipid-lowering activity, Fig. 2.…”

“…2. [8][9][10][11][12][13][14][15] As compared with the standard control group (NG) in Fig. 2, Triton WR-1339 leads to a remarkable increase in triglyceride (TG) (p < 0.0001) and total cholesterol (TC) (p < 0.0001) plasma concentrations when measured 7 h aer Triton intraperitoneal injection (i.p.).…”

“…The hypolipidemic activity of carboxamide derivatives was attributed to three essential components: a heterocyclic ring, a sizeable lipophilic moiety, and a carboxamide linker. 15 The previous publications [8][9][10][11][12][13][14][15] have focused on carboxamide as a linker with either benzophenone or anthraquinone substitutions.…”

“…It was found that furan benzophenone exhibited excellent antihyperlipidemic activity. 14 This initial investigation of furan, which considers similar isosteric heterocycles to indole, pyrole, and benzofuran, showed excellent antihyperlipidemic activity in our previous work, [8][9][10][11][12][13][14][15] in addition to its small size as a ring, its exibility compared to the previous heterocycle ring, and the established pharmacological importance and the wide diversity of biological activities exhibited by heterocyclic carboxamide derivatives prompted this search to synthesize furan as the heterocyclic system with amide or ester linkers and investigate their effects on the activity and explore different substituents in the lipophilic part (Scheme 1). On the other hand, three picolinic-2-carboxamide derivatives have been synthesized and tested in this work as an initial investigation of a new class of different heterocycle rings.…”