Design and synthesis of some phthalimide derivatives for antihyperlipidemic activity

ABSTRACT

To synthesize, explore the pharmacophore and evaluate the Structural Activity Relationship [SAR] of some reported and new N-phthaloylamides and N-phthaloylesters of some amino acids [namely, glycine. 1-alanirie, beta-alanine and y-aminobutyrie acids] aiming to find more effective antihyperlipidemic compounds using molecular overlay studies as a modern technique for drug design. The N-phthaloylamides and esters were synthesized using mixed anhydride method in good to escellent yields. The mixed anhydride method have represented a better and an efficient way for synthesizing such amides and esters than the old procedures. Twenty four of the newly synthesized compounds la-i, IIa-i, IIIa, and IVa were tested for their antihyperlipidemic activity against Triton WR- 1339-induced hyperlipidemia in rats. Triton WR-1339 [Tyloxapol, Sigma] was used to induce the suitable hyperlipidemia within 24 hours. Carboxymethylcellulose sodium [CMC-Na, Sigma] was used as a suspending agent. Male waster rats [6-7 week-old, 210-230 g body weight] were used as experimental animals. Spekol - 11 apparatus [Germany] was used to measure the total triglycerides and total cholesterol in the serum. Centrifuge [UK] was used to prepare the blood serum samples. The test compounds were suspended in carboxymethylcellulose sodium solution in 0.5% in normal saline to give 6% concentrations. Triton was dissolved in normal saline to give 12% solution. One hundred thirty five rats were arranged in 27 groups [5 animals each] and were deprived of food but were allowed free to access to drinking water. Each animal in all groups was injected in the tail vein with a volume of Triton solution equivalent to 300 mg/kg boy weight. The animals of one group were orally administered 1 ml of CMC-Na solution and kept as a control group. Animals in the remaining groups were orally given the test compounds at a dose level of 150 mg/kg boy weight. Alter 24 hours, blood was taken from each animal and centrifuged to obtain the serum. The plasma total cholesterol [TC] and total triglyceride [TG] levels were measured and the rates of decrease [%] were calculated using the following equation Rate of decrease [%] = [I -Vt/Vc] x 100. Where Vt and Vc are the value of TC or TG for the test groups and control group, respectively. The preliminary evaluation of the antihyperlipidemic activity of [1-24] against Triton WR 1339-induced hyperlipidemia in rats showed that several derivatives have demonstrated significant lowering of serum total cholesterol and triglyceride levels comparing to clofibrate. Most of the compounds have shown good to excellent activities. The test compounds have also shown more antitriglyceridimic than anticholestrolemic activities