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A novel series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles 4(a–d) and 7(a–i) were rationally designed through QSAR based pharmacophore approach and synthesized from 5-(1,3-benzodioxol-5-yl)-[1,3,4]thiadiazol-2-amine (1). The structures of these compounds were established by IR, ¹H NMR, ¹³C NMR, HRMS technique. All the compounds were evaluated for their in vitro antihyperlipidemic activity using trition induced hyperlipidemic model. The newly synthesized title compound 7d, 7e and 7h showed a significant decrease in the serum, TCH, TG LDL and VLDL values along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index, LDL:HDL risk ratios and the level of SGOT, SGPT and ALP activities compared to cholesterol induced hyperlipidemic control group.