Discovery of New Cyclopentaquinoline Analogues as Multifunctional Agents for the Treatment of Alzheimer’s Disease

Abstract

Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications of the tetrahydroacridine structure. Next, the biological assessment of each of them was performed. Based on the obtained results we identified 6-chloro-<i>N</i>-[2-(2,3-dihydro-<i>1H</i>-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (<b>3e</b>) as the most promising compound with inhibitory potencies against EeAChE and EqBuChE in the low nanomolar level 67 and 153 nM, respectively. Moreover, <b>3e</b> compound is non-hepatotoxic, able to inhibit amyloid beta aggregation, and shows a mix-type of cholinesterase's inhibition. The mixed type of inhibition of the compound was confirmed by molecular modeling. Then, yeast three-hybrid (Y3H) technology was used to confirm the known ligand-receptor interactions. New derivatives do not show antioxidant activity (confirmed by the use of two different tests). A pKa assay method was developed to identify the basic physicochemical properties of <b>3e</b> compound. A LogP assay confirmed that <b>3e</b> compound fulfills Lipinsky's rule of five.