Novel Tacrine−Melatonin Hybrids as Dual-Acting Drugs for Alzheimer Disease, with Improved Acetylcholinesterase Inhibitory and Antioxidant Properties

Abstract

Tacrine and melatonin are well-known drugs with activities as an acetylcholinesterase (AChE) inhibitor and free radical scavenger, respectively. In this work, we report new hybrids of both drugs that display higher in vitro properties than the sum of their parts. As selective inhibitors of human AChE, their IC(50) values range from sub-nanomolar to picomolar. They exhibit a higher oxygen radical absorbance capacity than does melatonin and are predicted to be able to cross the blood-brain barrier to reach their targets in the central nervous system.

Benzothiazepine CGP37157 and Its Isosteric 2′-Methyl Analogue Provide Neuroprotection and Block Cell Calcium Entry

“…60,65 In the last years, this later method was successfully applied by some of us to different classes of compounds. 24,66−69 The in vitro permeability (P e ) values of ITH12505 and CGP37157 through a lipid extract of porcine brain were determined by using PBS/ethanol (70:30) ( Table 1).…”

Tacrine–Melatonin Hybrids as Multifunctional Agents for Alzheimer's Disease, with Cholinergic, Antioxidant, and Neuroprotective Properties

“…Intermediates 31 b,c, 32 b,c, 33 b, 34 b,c, and 35 b were described in a previous work. [24] 5- (1,2,3 at room temperature overnight and then diluted with CH 2 Cl 2 (50 mL). The resulting mixture was consecutively washed with aqueous citric acid (10 %, 3 30 mL), NaHCO 3 (aq) (10 %, 3 30 mL), and H 2 O (30 mL).…”

“…Tacrine-melatonin hybrids 4, 5, 7-11, 15, 16, 18, 19, 21, and 22 were described in a previous work. [24] N-(2-(1H-Indol-3-yl)ethyl)-5- (1,2,3,4-tetrahydroacridin-9-ylamino) 6-(6,8-Dichloro-1,2,3,4-tetrahydroacridin-9-ylamino)-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)hexanamide (20 N-(2-(1H-Indol-3-yl)ethyl)-8-(1,2,3,4-tetrahydroacridin-9 …”

“…[24] Prompted by their promising biological profile, we describe herein the synthesis of new tacrine-melatonin hybrids in order to have a broader chemical structure-biological activity relationship analysis by molecular modeling, and to study additional pharmacological properties such as propidium iodide displacement from AChE, effects on Ab self-aggregation, and cell viability. We also studied the neuroprotective effects of these hybrids against death induced in neuroblastoma cells by various toxic insults related to Ab degeneration (Ab 25-35 ), as well as oxidative stress triggered by hydrogen peroxide and rotenone.…”

Chemical and Pharmacological Studies on Enantiomerically Pure p‐Methoxytacripyrines, Promising Multi‐Target‐Directed Ligands for the Treatment of Alzheimer’s Disease

“…The multifactorial nature of AD has given rise to the rational basis for the development of the most current innovative therapeutic approaches based on the "one molecule, multiple targets" paradigm. [5][6][7][8][9] The multitarget approach [10] has been widely explored leading to the development of several multi-target-direct ligands (MTDLs), which include novel tacrine-melatonin hybrids, [11] dual inhibitors of acetylcholinesterase (AChE) and monoamine oxidase, [12] or serotonin transporters, [13] potent cholinesterase inhibitors with antioxidant and neuroprotective properties, [14] gallamine-tacrine hybrids binding at cholinesterases and M 2 muscarinic receptors, [15] or NO-donor-tacrine hybrids as hepatoprotective anti-AD drugs. [16] Based on the multitarget approach, some years ago we designed and synthesized novel multipotent molecules, called tacripyrines (I), by combination of tacrine and nimodipine, as reference agents with a multipotent cholinergic and calcium antagonism profile, respectively, for the treatment of AD.…”