Structure–activity relationships of memoquin: Influence of the chain chirality in the multi-target mechanism of action Maria Laura Bolognesi * , Manuela Bartolini, Michela Rosini, Vincenza Andrisano, Carlo Melchiorre Department of Pharmaceutical Sciences, Alma Mater Studiorum-Bologna University, Via Belmeloro 6, I-40126 Bologna, Italy article info Article history: Received 22 April 2009 Revised 19 May 2009 Accepted 20 May 2009 Available online 28 May 2009 Keywords: Alzheimer’s disease Acetylcholinesterase Butyrylcholinesterase Amyloid-beta Small molecule protein-protein interaction inhibitors abstract The present article expands on the study of structure–activity relationships of the novel class of quinone- bearing polyamines, as multi-target-directed ligands against Alzheimer’s disease. Namely, the effect of inserting a methyl substituent at the a position of the terminal benzyl amine moieties of lead candidate 1 (memoquin) was evaluated at the multiple targets involved in the multifunctional mechanism of action. The RR stereoisomer 2 resulted more effective than 1 in reverting two important effects mediated by acetylcholinesterase (AChE), that is, acetylcholine hydrolysis and AChE-induced amyloid-b aggregation. Ó 2009 Elsevier Ltd. All rights reserved. Despite the huge research effort and the considerable strides already made, Alzheimer’s disease (AD) still is an incurable pathol- ogy which provokes considerable concern inside the pharmaceuti- cal community. 1,2 Over the past decade, trying to address the pitfalls that have long hindered the identification of effective ther- apeutic tools, we developed an innovative concept, which embod- ies in the design of Multi-Target Directed Ligands (MTDLs) as response to the multifactorial nature of AD. 3 This approach has proven particularly fruitful and allowed the identification of several MTDLs, some of which have emerged as interesting phar- macological tools for the investigation of neurodegenerative disor- ders, or as innovative drug candidates for combating AD. 3–5 Among them, memoquin (1) is a promising new chemical entity that has been rationally designed with the deliberate aim of creat- ing a multifunctional small molecule acting at different levels of the neurodegenerative cascade underlying AD pathology. 6 By inserting the antioxidant benzoquinone moiety of the prom- ising drug candidate ubiquinone (2,3-dimethoxy-5-methyl-6- decaprenyl-1,4-benzoquinone) into a polyamine scaffold endowed with acetylcholinesterase (AChE) inhibition activity 1 was gener- ated (Fig. 1). An in-depth in vitro and in vivo characterization has confirmed its multifunctional mechanism of action and verified the interaction of 1 with different crucial molecular targets in AD neurotoxic pathways, such as AChE and b-secretase (BACE-1) en- zymes, b-amyloid (Ab) and oxidative processes. 7 The ability of 1 to exert a positive pharmacological effect on AD neurodegenera- tion in vivo was verified by extending the studies to different ani- mal models for AD. 7 Administration of 1 to anti NGF AD11 mice showed that it is able to ameliorate neuropathological signs and cognitive deficits, confirming its capability to impinge on different points of the cascade/s leading to neurodegeneration. 6,7 In a search of memoquin derivatives with an improved MTDL profile, we previously synthesized a small unbiased library of 1-derivatives, and analyzed the contributions of the different 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.05.087 * Corresponding author. Tel.: +39 051 2099718; fax: +39 051 2099734. E-mail address: marialaura.bolognesi@unibo.it (M.L. Bolognesi). O O N H N H N N 1 O O O O N H N H N N * * O O 2: RR 3: SS 4: RS Figure 1. Chemical structures of 1 and its chiral derivatives 2–4. Bioorganic & Medicinal Chemistry Letters 19 (2009) 4312–4315 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl