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A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3-9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50=5.2±1.1 nM) and MAO-B (IC50=43±8.0 nM) and is a moderately potent inhibitor of AChE (IC50=0.35±0.01 μM) and BuChE (IC50=0.46±0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Alzheimer's disease therapy.

Trans unsaturated fatty acids in humans may be originated by two different contributions. The exogenous track is due to dietary supplementation of trans fats and the endogenous path deals with free-radical-catalyzed cis-trans isomerization of fatty acids. Arachidonic acid residue (5c,8c,11c,14c-20:4), which has only two out of the four double bonds deriving from the diet, was used to differentiate the two paths and to assess the importance of a radical reaction. A detailed study on the formation of trans phospholipids catalyzed by the HOCH2CH2S* radical was carried out on L-alpha-phosphatidylcholine from egg lecithin and 1-stearoyl-2-arachidonoyl-L-alpha-phosphatidylcholine (SAPC) in homogeneous solution or in large unilamellar vesicles (LUVET). Thiyl radicals were generated from the corresponding thiol by either gamma-irradiation or UV photolysis, and the reaction course was followed by GC, Ag/TLC, and 13C NMR analyses. The isomerization was found to be independent of cis double bond location (random process) in i-PrOH solution. In the case of vesicles, the supramolecular organization of lipids produced a dramatic change of the isomerization outcome: (i) in egg lecithin, the reactivity of arachidonate moieties is higher than that of oleate and linoleate residues, (ii) in the linoleate residues of egg lecithin, the 9t,12c-18:2 isomer prevailed on the 9c,12t-18:2 isomer (3:1 ratio), and (iii) a regioselective isomerization of SAPC arachidonate residues occurred in the 5 and 8 positions. This effect of "positional preference" indicates that thiyl radicals entering the hydrophobic region of the membrane bilayer start to isomerize polyunsaturated fatty acid residues having the double bonds nearest to the membrane surfaces. We propose that arachidonic acid and its trans isomers can function as biomarkers in membranes for distinguishing the two trans fatty acid-forming pathways.

Tacripyrines (1-14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC(50) 105 +/- 15 nM) is associated to a 30.7 +/- 8.6% inhibition of the proaggregating action of AChE on the Abeta and a moderate inhibition of Abeta self-aggregation (34.9 +/- 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca(2+) channel blocking effect, and cross the blood-brain barrier, emerging as lead candidates for treating AD.