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

Hyperlipidemia is an elevation of one or more of the plasma lipids, including triglycerides, cholesterol, cholesterol esters and phospholipids (Raasch, 1988). This pathological condition has been ranked as one of the most important risk factors contributing to the prevalence and severity of coronary heart diseases (Goldstein et al., 1973; Frishman, 1998). These diseases along with stroke, atherosclerosis, and hypertension are found to be one of the main causes of death worldwide (Smith et al., 2004; Braunwald, 1997). Previous studies showed that a single parenteral administration of Triton WR-1339 to adult rats produces hyperlipidemia in which cholesterol, triglycerides, and phospholipid levels increase to a maximum within about 20 h and decrease thereafter (Schurr et al., 1972). This activity of Triton WR-1339 was found to be due to its inhibitory effect on lipoprotein lipase (Schotz et al., 1957). Therefore Triton WR-1339-induced hyperlipidemic rats are widely used as a model to screen for or to differentiate the mechanism of action of potential hypolipidemic agents (Paoletti, 1962; Kalopissis et al., 1980). Fibrates and their derivatives are a group of drugs, which have been widely used for a long time to treat hyperlipoproteinemia, among which is the well-known commercially available drug bezafi brate (Frick et al., 1987). Fibric acids enhance the fatty acid catabolism and accordingly reduce the plasma lipid levels, predominantly triglyceride levels (Rubins et al., 1999). The main mechanism was found to be through decreasing the synthesis of apoC-III and increasing the activity of lipoprotein lipase, which together enhance the clearance of circulating triglyceride-rich lipoproteins (Schoonjans et al., 1996). Some indole derivatives are well known for their diverse pharmacological effects including a hypolipidemic effect (Al-Qirim et al., 2009; Bosies et al., 1980; Sher and Ellsworth, 2004; Kopin et al., 2006; Dasseux and Oniciu, 2002). But to the best of our knowledge N-(benzoylphenyl)-1Hindole-2-carboxamide derivatives have not been Synthesis and Pharmacological Evaluation of Novel Substituted and Unsubstituted N-(Benzoylphenyl)-1H-indole-2-carboxamides as Potent Antihypertriglyceridemic Agents Moyad Shahwan, Ghassan Shattat, Tariq Al-Qirim*, Ghassan Abu Sheikha, Yusuf Al-Hiari, Waseem El-Huneidi, Anan Jarab, and Manal Al-Najdawi