Future Medicinal Chemistry Preliminary Communication part of Donepezil–ferulic acid hybrids as anti-Alzheimer drugs Mohamed Benchekroun 1 , Lhassane Ismaili* ,1 , Marc Pudlo 1 , Vincent Luzet 1 , Tijani Gharbi 1 , Bernard Refouvelet 1 & José Marco-Contelles 2 1 NanoMedicine, Imagery & Therapeutics Lab EA 4662, Laboratoire de Chimie Organique et Thérapeutique UFR SMP, CHU Jean Minjoz, Université de Franche-Comté, 19 rue Ambroise Paré, 25030-Besançon, France 2 Laboratorio de Química Médica (IQOG, CSIC), C/ Juan de la Cierva 3, 28006-Madrid, Spain *Author for correspondence: lhassane.ismaili@univ-fcomte.fr 15 Future Med. Chem. (2015) 7(1), 15–21 ISSN 1756-8919 10.4155/FMC.14.148 © 2015 Future Science Ltd ti- Background: Due to the complex nature of Alzheimer’s disease, there is a renewed and growing search for multitarget drugs. Results: Donepezil–ferulic acid hybrids (DFAHs) were prepared by the one-pot Ugi-4CR in low-to-moderate yields. DFAHs are potent antioxidant agents, showing oxygen radical absorbance capacity values in the range 4.80–8.71 trolox equivalents, quite higher compared with those recorded for ferulic acid and melatonin. From the ChEs inhibition studies, we conclude that DFAH 8, bearing an ethylene linker, and DFAH 12, bearing a propylene linker, both substituted with a melatonin motif, are the most potent inhibitors, in the nanomolar range. Conclusion: We have identified DFAH 8 as a very potent antioxidant, and totally selective equineButyrylCholinEsterase (eqBuChE) inhibitor. Alzheimer’s disease (AD) is the major cause of dementia, rising exponentially with age [1] . Post-mortem brains of AD patients reveal the presence of amyloid plaques of β-amyloid peptide (Aβ), neuroibrillary tangles composed of hyperphosphorylated tau protein [2,3] , a dramatic loss of synapses, and a decrease of neurons. AD is clinically characterized by progressive deterioration of memory and cognition. A deiciency in cholinergic neurotransmission is considered to be one of the major hallmarks of memory impairments in the patients with AD. Con- sequently, AD patients have been treated with acetylcholinesterase inhibitors such as tacrine, galantamine, rivastigmine and donepezil [4] , based on the ‘one molecule, multiple targets’ paradigm, but with limited therapeutic success. This might be due to the multifactorial nature of AD, a fact that has urged the search for new multitarget-directed ligands, able to interact with different enzymatic systems or receptors closely related to the progress and development of AD [5] . Oxidative stress is included in all the patho- physiological hypotheses for AD. The free rad- ical and oxidative stress theory of aging [6] sug- gests that oxidative damage plays a pivotal role in neuronal degeneration, and several studies have demonstrated that the oxidative stress is an early occurring condition in AD [7] . Thus, in this context, multifunctional molecules able to restore acetylcholine (ACh) level and reduce oxidative stress have been developed [8–10] . Among them, tacrine–ferulic/caffeic acids [11–14], tacrine–melatonin [15,16] and curcumin–melatonin [17] hybrids have been described, showing great power to reduce oxi- dative stress, and protect neuronal cells against toxic insults. Surprisingly, hybrids from done- pezil, such as the cholinesterase (ChE) motif, and ferulic acid or melatonin, as the antioxi- dant agent, have not yet been described in the literature, but should offer clear advantages compared with tacrine hybrids, due to the potential hepatotoxicity of these ones. Acetylcholinesterase (AChE) inhibitor donepezil is the second drug approved by US FDA for the treatment of mild-to-mod- erate AD, and marketed in the USA and in some European and Asian countries under the trade name of Aricept ® . Donepezil has N-benzylpiperidine and an indanone moi- eties, shows a greater selectivity for AChE than for butyrylcholinesterase (BuChE) [18] , and has been used in many multitarget drugs for AD [19] .