Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors

A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase1 (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.

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► Aminopropylindenes are a new chemotype of oxidosqualene cyclase inhibitors.
► Depending on the amino group the compounds show selectivity for oxidosqualene cyclases from different organisms.
► A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi oxidosqualene cyclase.
► For two of the inhibitors significant reduction of cholesterol biosynthesis was demonstrated in a whole cell assay.