Synthesis, crystal studies and in vivo anti-hyperlipidemic activities of indole derivatives containing fluvastatin nucleus

Abstract

As a part of our efforts to prepare better analogues of fluvastatin for the treatment of hyperlipidemia, we have synthesized some indole derivatives containing a fluvastatin nucleus by methanol mediated Claisen–Schmidt aldol condensation reaction. The newly synthesized molecules are characterized by FT-IR, ¹H NMR, ¹³C NMR and LCMS spectral analyses. The structural parameters of 5b, 5c, 5g and 5h have been elucidated by X-ray diffraction studies. In vivo antihyperlipidemic activity and histopathological studies of all the compounds have been investigated. Among 5a–l, compounds 5c and 5i demonstrated a significant decrease in the serum total cholesterol, triglycerides, low density lipoprotein and very low density lipoprotein besides an increase in serum high density lipoprotein levels. Compounds 5c and 5i displayed significant cytoplasmic fatty infiltration as well as granular degeneration compared to that of a standard fluvastatin drug. It is conceivable that the synthesis of analogues of drugs could result in more efficient therapeutic effects. In addition, the interaction between the most significant antihyperlipidemic agent, 5c and human serum albumin, HSA has been investigated. Compound 5c could reversibly bind with HSA mainly via a mechanism involving the formation of a complex, in which both hydrogen bonds and hydrophobic interactions are the main acting forces.