Development of novel API-ILs for the optimization of anti-Alzheimer drugs

Nowadays, the treatment of Alzheimer’s disease (AD) is focused on targeting neurotransmitter functions by using acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartic acid (NMDA) glutamate receptor antagonists. Four of the five drugs that have been approved by the U.S. Food and Drug Administration (FDA) for AD, including tacrine and donepezil, are AChEIs. This fact together with the results of studies performed in the last decades highlighting the role of AChE enzyme and cholinergic system on Aβ plaques deposition and modulation of regional brain blood flow, respectively, have contributed to the growing interest in AChEIs. [1]

New drugs should not only be able to inhibit the enzyme but also show optimal parameters of solubility and permeability across cellular membranes, since they affect bioavailability. Considering the good properties of ionic liquids (ILs) and the potential advantages of transforming active pharmaceutical ingredients APIs into ILs, a new series of API-ILs based on two AChEIs, tacrine, a commercially available drug, and compound 1, [2] a donepezil analogue, was proposed. The design, synthesis and evaluation of the water solubility of five new API-ILs, four of them derived from tacrine and one of the donepezil analogue 1, were successfully carried out in this work.

[1] a) G. V. De Ferrari, M. A. Canales, I. Shin, L. Weiner, I. Silman and N. C. Inestrosa, Biochemistry 2001, 40, 10447-10457; b) R. M. lane, M. Kivipelto and N. H. Greig, Clin. Neuropharmacol. 2004, 27,141-149.

[2] N. Vila, P. Besada, D. Viña, M. Sturlese, S. Moro and C. Terán, RSC Adv. 2016, 6, 46170-46185