Increase in oxidative stress implicated in several other metabolic risk factors such as diabetes and coronary heart disease. Reactive oxygen metabolites, such as hydrogen peroxide (H2O2), superoxide anions (O2-) or hydroxyl radicals (⋅OH), as a by-product of oxidative metabolism can damage the cells resulting lipid peroxidation, modification of protein and nucleic acids. Excess of hydroxyl free radicals are the major factor for the peroxidative damage to lipoproteins present in the blood, which are responsible for the initiation and progression of atherosclerosis in the hyperlipidemic conditions . Therefore, it is envisaged that, if a chemical compound has cholesterol lowering, hypolipidemic and antioxidant properties it will be able to protect endothelial and myocardial function as well as endow with as a better anti-atherosclerotic agent.
Several drugs contain indole moiety, either as a basic pharmocophore or as an attached templete to exhibit specific properties. Indole and their derivatives are known to exert antihypertension, antitubercular , anticancer , antiviral , antioxidant properties , and free radical induced lipid peroxidation . Furthermore, fluvastatin which is a statin class of drug also contain this important scaffold
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On the other hand, Benzofuran derivatives are versatile biodynamic agents both from synthetic as well as natural origin . During the recent decades, great attention has been given to studies focused on the synthesis of benzofuran-containing agents and their pharmacological activities. In addition, natural product tournefolic acids A and B have shown potent anti-lipid-peroxidative properties . Furthermore, a literature survey and based on the framework reveals that benzofuran ring containing moiety, exhibit antihyperlipidemic activity (Fig. 1) . In continuation of our drug discovery programme on new antidyslipidemic agents , and our laboratory experiences on molecular hybridization approach , we herein report the synthesis and biological evaluation of benzofuran-bisindole hybrids as antidyslipidemic agents.(our prototype in Fig. 1)
The synthesis of target and intermediate compounds is outlined in the scheme 1. The Duff reaction  on ortho-substituted phenols (1a-f) in the presence of hexamethylenetetraamine (HMTA) and TFA at 120 °C gave aromatic dicarbaldehyde (2a-f). The Rap-Stoermer reaction  on compounds (2a-f) with different phenacylbromides in the presence of K2CO3 furnished benzofuran carbaldehyde derivatives (3a-j) in quantitative yields. Furthermore, introduction of indole templete was achieved by the reaction of different indoles in the presence of iodine and acetonitrile as a solvent at room temperature to give the final benzofuran-bisindole hybrids 4a-s. All the synthesized compounds were characterized using 1H NMR, 13C NMR, IR spectroscopy and ESI-MS.
The present study has been undertaken to evaluate the lipid lowering activity of benzofuran-bisindole hybrids (4a-4s) in an acute triton induced hyperlipidemic model. Administration of triton WR-1339 in rats induced markedly increased the plasma level of total cholesterol TC (4.05 fold), phospholipids PL (3.31 fold) and triglyceride TG (2.67 fold) and plasma post heparin lipolytic activity (PHLA) (28%) as compared to control Treatment of hyperlipidemic rats with benzofuran-bisindole hybrids (4a-4s) at the dose of 100 mg/kg p.o. reversed the plasma levels of lipid with varying extents. The synthesized derivatives inhibited lipoprotein cholesterol metabolism and activity of lipolytic enzymes to early clearance of lipids from blood circulation in triton induced hyperlipidemia. Compound 4j was found to be the most potent in the series as it showed 28%, 29% and 28%, lowering in TC, PL and TG respectively, while compounds 4a, 4c and 4h showed significantly 23%, 24% and 24% by lowering of TC levels, 23%, 23%, and 23% by lowering of PL levels, 24%, 23% and 23% lowering of TG levels respectively. These data were comparable with standard hypolipidemic drug gemfibrozil which at the dose of 100 mg/kg decreased levels of TC, PL and TG in plasma by 34%, 35% and 34%, respectively. Compounds 4a, 4c, 4h and 4j showed significant reversal of PHLA in plasma of hyperlipidemic rats by 16%, 17%, 16% and 18% respectively, comparable to gemfibrozil, which caused 20% reversal of activity of this enzyme as compared to control group and the results are summarised in Table 1.
4.2. Effect of compounds 4a, 4c, 4h and 4j on lipid lowering at different doses in triton induced hyperlipidemic rat.
After the confirmation of the most active compounds in primary screening we further, evaluate the activity of compounds 4a, 4c, 4h and 4j was studied at different doses in 50 to 150 mg/kg body weight. In these compounds 4a, 4c and 4h lowers the TC by 15% to 25%, 20% to 27% and 17% to 24%, respectively, also lowers PL by 17% to 24%, 20% to 23% and 18% to 26% respectively, and further lowers TG by 16% to 25%, 21% to 24% and 16% to 24% respectively. Similarly most potent compound 4j lowers the TC by 22% to 29%, PL by 20% to 29%, and TG by 20% to 30% respectively. The results are summarised in Fig. 2
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4.3. Effect of compounds 4a, 4c, 4h and 4j on lipoprotein cholesterol level and LCAT activity in triton induced hyperlipidemic rat.
The analysis of hyperlipidemic plasma of triton administered rats showed a significant increase in the level of lipoprotein lipids and these effects were pronounced for VLDL and LDL followed by a decrease in HDL as compared to control rats. After treatment with most active compounds 4a, 4c, 4h and 4j significantly reversed VLDL, LDL and HDL levels as shown in Fig. 2. Furthermore, triton administration markedly decreases the level of LCAT in rat, where as treatment with compounds 4a, 4c, 4h and 4j activity were significantly increased followed by standard drug gimfibrozil (Fig. 3). In our study, most active hybrids at most steadfast dose (100mg/kg) decreased the plasma TC, PL and TG in triton induced hyperlipidemic rats, which may be due to inhibition of exogenous absorption and formation. In addition, compounds 4a, 4c, 4h and 4j increased LCAT activity, which plays a key role in lipoprotein metabolism to contribute an increased level of HDL-C in plasma. .
4.4. Effect of compounds 4a-4s on superoxide anions, hydroxyl radicals and lipid-peroxidation
Antioxidant activities of compounds 4a-4s at 200µg/mL were evaluated by generating free radicals [superoxide ions (O2-), hydroxyl radicals (⋅OH), microsomal lipid peroxidation] in vitro in the absence and presence of these compounds. The results of this study are shown in Fig. 4. Compounds 4a and 4j significantly suppressed the superoxide ions by 33% and 31%, hydroxyl radical's by 30% and 27% and microsomal lipid peroxidation by 31% and 32%, respectively. The standard drug Alloperinol, at 200µg/mL, showed 51% inhibition in superoxide ions, whereas Mannitol and α-tocopherol, at the same dose, showed 49% and 52% inhibition of hydroxyl ions and microsomal lipid peroxidation, respectively in in vitro system. The scavenging potential of the other derivatives was modest at best.
Interestingly, in terms of structure activity relationship, among the series methoxy substituted indole and benzofuran compounds (4a, 4c, 4h and 4j) exhibited potent activity. Furthermore, in the absence of methoxy group or its replacement with electron withdrawing groups results in diminished activity. From the above results reveal that hybrids containing methoxy group were elevate the activity where as indole hybrids containing without methoxy group will decrease the activity.
In conclusion, inspired by the molecular hybridization approach lipid lowering effect of the newly synthesized hybrids were evaluated in triton WR-1339 induced hyperlipidemic rats the most active compounds 4a, 4c, 4h and 4j decreased total cholesterol (TC), phospholipids (PL) and triglycerides (TG), of hyperlipidemic rats significantly, at 100 mg/kg body weight. In addition, treatment with active hybrids effectively reversed the levels of VLDL, LDL and HDL also increased the LCAT activity, which plays a key role in lipoprotein metabolism contributing to an increased level of HDL-C in plasma. Furthermore, the synthesized compounds 4a and 4j exhibited significantly inhibiting superoxide ions, hydroxyl radicals and microsomal lipid peroxidation, which illustrates potent antioxidant properties of hybrids. Moreover these benzofuran-bisindole hybrids, mitigates dyslipidemia via activation of LCAT.