Synthesis and Pharmacological Evaluation of Novel Substituted and Unsubstituted N-(Benzoylphenyl)-1H-indole-2-carboxamides as Potent Antihypertriglyceridemic Agents

Abstract

The N-(benzoylphenyl)-1H-indole-2-carboxamide derivatives 1 -6 were synthesized, and the lipid-lowering effects of two of these novel compounds were studied using hyperlipidemic rats as an experimental model. Treatment of ethyl-1H-indole-2-carboxylate with aminobenzophenones in the presence of sodium ethoxide and DMF, followed by purifi cation using column chromatography, gave the target compounds in good yields. The tested animals were divided into control, hyperlipidemic, compounds 2-, 3-and bezafi brate-treated groups. At a dose of 15 mg/kg body weight, compounds 2, 3 and bezafi brate signifi cantly reduced the elevated plasma triglyceride levels after 7 and 24 h. Furthermore, the high-density lipoprotein-cholesterol levels were remarkably increased in all treated groups after 7 and 24 h compared to the hyperlipidemic control group. However, only compounds 2-and 3-treated groups obviously showed a signifi cant reduction in plasma total cholesterol levels after 24 h. It is therefore reasonable to assume that 2 and 3 may have a promising potential in the treatment of hyperlipidemia and coronary heart diseases.

Synthesis and <i>in Vivo</i> Lipid-Lowering Activity of Novel Imidazoles-5-carboxamide Derivatives in Triton-WR-1339-Induced Hyperlipidemic Wistar Rats

“…These findings are in accordance with formerly published data. 11) In addition, the replacement of the heterocyclic aromatic rings with imidazole nucleus has led to compounds with improved water solubility in comparison with those already reported in the literature [7][8][9][10][12][13][14][15] as shown in the water solubility study test. The enhanced water solubility possibly contributes to the pharmacological activity improvement.…”

“…Synthesis Activation of both 1H-imidazole-5-carboxylic acid (1) and 4-methyl-1H-imidazole-5-carboxylic acid (8) in to the acyl chloride was obtained by using oxalyl chloride in excess in the presence of few drops of DMF. The mixture was refluxed under stirring for 90 min to give the corresponding imidazole carbonyl chloride (Charts 1, 2) according to a procedure reported by Berger.…”

“…5,6) Our previous published data has shown that many of the synthesized carboxamide derivatives exhibited noticeable antihyperlipidemic activity. [7][8][9][10][11][12] It was postulated that the hypolipidemic activity of the carboxamides is correlated with the presence of three essential parts: a large lipophilic moiety, an aromatic carboxamide linker along with a heterocyclic ring. 11) Although the significant biological activity, almost all earlier developed carboxamides suffered from water solubility deficiencies hindering biological testing and affecting negatively pharmacological activity.…”

“…These observed deficiencies inspired the design and synthesis of novel compounds with improved water solubility profile. In a first attempt there was the design of benzimidazole-2-carboxamide derivatives that showed improved water solubility over all previous derivatives providing both feasible pharmacological testing due to easier solubilization and comparable pharmacological profile, 13) this has led to the introduction of the imidazole-5-carboxamides possessing an imidazole ring which is characterized by a low pK a value (pK a =6.9) in comparison with the pK a values of the previous aromatic heterocyclic rings (Benzimidazole pK a =16.4, indole pK a =21, furan pK a =35.6, and thiophene pK a =33) present on the previously published carboxamide derivatives [6][7][8][9][10][12][13][14] (Fig. 1).…”

Lipid lowering activity of novelN-(benzoylphenyl)pyridine-3-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats

“…The aim of this study is to identify a new class of nicotinic acid carboxamide derivatives acting as a potential lipid lowering agents starting from nicotinic acid (niacin). The choice of carboxamide derivatives was based on results obtained by the same research group on indol carboxamide derivatives, where they found also that these compounds possessed lipid-lowering effects 11,12,23,24 . So in this study we decided to prepare a hybrid chemical scaffold of two effective hypolipidemic agents using a well-established nucleus (nicotinic acid nucleus) as our starting point to synthesize a novel nicotinic carboxamide derivative bearing the benzophenone unit of fenofibrate drug ( Figure 1).…”