Original article Synthesis and biological evaluation of N-aryl-1,4-dihydropyridines as novel antidyslipidemic and antioxidant agents Atul Kumar a, * , Ram Awatar Maurya a , Siddharth Sharma a , Mukesh Kumar a , Gitika Bhatia b a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, UP 226001, India b Biochemistry Division, Central Drug Research Institute, Lucknow – 226001, India article info Article history: Received 26 May 2009 Received in revised form 16 August 2009 Accepted 22 October 2009 Available online 31 October 2009 Keywords: 1,4-Dihydropyridines Antidyslipidemic Antioxidant abstract N-aryl-1,4-dihydropyridines 2a–n were synthesized via iodine catalyzed three-component reaction of cinnamaldehydes, anilines and 2-keto esters in methanol. The synthesized compounds were screened for their antidyslipidemic and antioxidant activity in vivo and in vitro. Compounds 2a, 2g, and 2l have exhibited promising lipid and TG lowering activity, whereas compounds 2m and 2n have showed potent antioxidant activity. Ó 2009 Elsevier Masson SAS. All rights reserved. 1. Introduction Atherosclerosis and related diseases represent the prevalent cause of morbidity and mortality in industrialized countries [1–4]. Elevated level of plasma concentration of cholesterol, especially low density lipoprotein (LDL) and triglyceride along with free radical oxidative stress are recognized as leading cause in the development of atherosclerosis and coronary heart disease [5–10]. There is now an increasing amount of experimental and clinical evidences which shows the involvement of oxidative modifications of low density lipoproteins (LDL) in the pathogenesis of athero- sclerosis. In most cases, oxidative damage takes place in the low density lipoprotein (LDL) of plasma by the hydroxyl radicals generated by the metal ions present in the serum due to the alterations in their oxidation states [11,12]. The drugs, currently being used in the treatment of dyslipidemia [13–19], act by lowering cholesterol or by lowering triglyceride levels in plasma. The commonly used antidyslipidemic statins have several side effects like myositis, arthralgias, gastrointestinal upset and elevated liver function tests. Therefore, there is need to discover potentially better antidyslipidemic agents with minimum side effects. The involvement of hydroxyl free radicals has been shown to be a major contributing factor for the peroxidative damage to lipoproteins present in the blood, which are responsible for the initiation and progression of atherosclerosis [20]. Hyperlipidemia may also induce other abnormalities like oxidation of free fatty acids, leading to the formation of ketone bodies as well as masking liver and muscles resistance to insulin which initiates the progress of diabetes in patients [21]. Furthermore, in hyperglycemic patients, several non-enzymatic glycosylation occurs accompanied by glucose oxidation catalyzed by Cu 2þ and Fe 2þ resulting in the formation of O 2  and  OH radicals which further accelerates the risk of cardiac diseases in dyslipidemic patients [22]. Therefore, besides cholesterol lowering property, a hypolipidemic agent incorporating antioxidant activity will be able to protect endothelial and myocardial function and could serve as a better antiatherosclerotic agent. Hantzsch 1,4-dihydropyridines (1,4-DHPs) 1 are an important class of biologically active heterocycles. The 1,4-DHPs 1 have been shown to possess diverse range biological activities like anti- hypertension [23], antitubercular, antioxidant [24,25], antiviral [26], and anticancer activity [27]. Many members of this series (1,4- DHPs) such as nifedipine, nicardipine, amlodipine, and felodipine are clinically approved as drugs for the treatment of hypertension and cardiovascular diseases. Cerivastatin (Fig. 1) was a synthetic member of the class of statins, used to lower cholesterol and prevent cardiovascular disease. It was withdrawn from the market in 2001 because of the high rate of serious side effects [28]. Although Hantzsch 1,4-DHPs 1 have been extensively studied, the corresponding N-aryl, 5 or 5,6-unsubstituted 1,4-DHPs 2 (Fig. 1) are * Corresponding author. Tel.: þ91 522 2612411; fax: þ91 522 2623405. E-mail address: dratulsax@gmail.com (A. Kumar). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ejmech.2009.10.036 European Journal of Medicinal Chemistry 45 (2010) 501–509