Elena Simoni

Inhibition of Acetylcholinesterase, β-Amyloid Aggregation, and NMDA Receptors in Alzheimer's Disease : A Promising Direction for the Multi-target-Directed Ligands Gold Rush

Alzheimers disease (AD) is a multifactorial syndrome with several target proteins contributing to its etiology. To confront AD, an innovative strategy is to design single chemical entities able to simultaneously modulate more than one target. Here, we present compounds that inhibit acetylcholinesterase and NMDA receptor activity. Furthermore, these compounds inhibit AChE-induced Abeta aggregation and display antioxidant properties, emerging as lead candidates for treating AD.

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-d-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cell-based assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDA-induced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC(50) = 0.28 nM).

Exploiting the lipoic acid structure in the search for novel multitarget ligands against Alzheimer’s disease

Lipoic acid (LA) is a natural antioxidant. Its structure was previously combined with that of the acetylcholinesterase inhibitor tacrine to give lipocrine (1), a lead compound multitargeted against Alzheimers disease (AD). Herein, we further explore LA as a privileged structure for developing multimodal compounds to investigate AD. First, we studied the effect of LA chirality by evaluating the cholinesterase profile of 1s enantiomers. Then, a new series of LA hybrids was designed and synthesized by combining racemic LA with motifs of other known anticholinesterase agents (rivastigmine and memoquin). This afforded 4, which represents a step forward in the search for balanced anticholinesterase and antioxidant capacities.

Multifunctional Tacrine Derivatives in Alzheimer’s Disease

Tacrine (1) was the first acetylcholinesterase inhibitor (AChEI) introduced in therapy for the treatment of Alzheimers disease (AD), but similarly to the most recent approved AChEIs and memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, it does not represent an effective drug in halting the progression of AD. The continuous research in this field has contributed to delineate AD as a multifactorial syndrome with several biological targets involved in its etiology. On these bases, the development of new effective therapeutics becomes crucial and the design of molecules that address more than one specific AD target should represent thus a succeeded strategy for AD treatment. This review will focus on and summarize multifunctional 1 derivatives starting from our last paper published on the same topic in 2010. In the last three years, the design and synthesis of 1 homo- and heterodimers, as well as of 1-hybrid structures for AD therapy, was aimed mainly to discover safer drugs, with decreased hepatotoxicity in comparison to 1, taking also into account the multifactorial pathogenesis of the disease. Most of these new hetero/homo-dimers and/or hybrids of 1, although addressed mainly to acetylcholinesterase (AChE) and Aβ aggregation inhibition, are able to hit additional targets relevant to AD, among which, β-secretase (BACE1), reactive oxygen species (ROS), calcium channels, NMDAR and M1- muscarinic receptors.

Multi-target Design Strategies in the Context of Alzheimer’s Disease: Acetylcholinesterase Inhibition and NMDA Receptor Antagonism as the Driving Forces

In recent years, the multi-target-directed ligand concept has been used to design a variety of molecules hitting different biological targets for Alzheimer’s disease. We have sought to combine, in the same molecule, the neuroprotective action of N-methyl-d-aspartate receptor antagonism with the symptomatic relief offered by cholinergic activity through acetylcholinesterase inhibition. This strategy could potentially maintain the positive outcomes of memantine–acetylcholinesterase inhibitor combinations, but with the benefits of a single molecule therapy. Herein, we discuss selected examples of multifunctional compounds, which we rationally designed to simultaneously modulate these targets. We also examine the intertwined relationship between acetylcholinesterase, N-methyl-d-aspartate receptors, and other active players in the neurotoxic cascade.

Polyamine Conjugation of Curcumin Analogues toward the Discovery of Mitochondria-Directed Neuroprotective Agents†

Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery.

Multitarget-Directed Ligands: Innovative Chemical Probes and Therapeutic Tools Against Alzheimer's Disease

Multitarget agents directed at selected molecular targets involved in the pathogenic cascade of Alzheimers disease (AD) have been increasingly sought after in recent years, with the aim of achieving enhanced therapeutic efficiency with respect to single-target drugs and drug candidates. At the same time, much attention has been devoted to identifying high quality pharmacological tools to help explore the molecular mechanisms underlying AD without being exposed to physicochemical challenges. Herein, we discuss several examples of both types of compounds, taken from our own research and derived from the leads memoquin, lipocrine and bis(7)tacrine.

Exploring the effects of isothiocyanates on chemotherapeutic drugs

Introduction: Chemoprevention has emerged as a promising strategy to reduce the risk and to control cancer. In this context, isothiocyanates (ITCs), found in abundance in the form of glucosinolates in cruciferous vegetables, have gained increasing consideration for their chemopreventive activity. ITCs exert their effects mainly by inducing carcinogen metabolism or by inhibiting tumor cell proliferation. Areas covered: In recent years, novel combination treatments, by coupling chemopreventive agents and typical chemotherapeutics, have been exploited to increase the antitumor activities. The aim of this article is to examine the foremost studies carried out, so far, on the effects of dietary and synthetic ITCs on different signaling pathways involved in the pharmacokinetics and pharmacodynamics of chemotherapeutic agents, in order to enhance their effectiveness. Expert opinion: Undoubtedly, the beneficial anticarcinogenic potential of ITCs, both singly and in combination, has emerged in in vitro and in vivo studies. However, only a few clinical trials have been carried out so far with ITCs, which try to better define both the pharmacokinetic and pharmacodynamic impacts in humans. More toxicological evaluations after long-term administration of ITCs in different species are required for the clinical development of ITCs as anticarcinogenic agents.

Multitarget strategies in Alzheimer's disease: benefits and challenges on the road to therapeutics.

Alzheimers disease is a multifactorial syndrome, for which effective cures are urgently needed. Seeking for enhanced therapeutic efficacy, multitarget drugs have been increasingly sought after over the last decades. They offer the attractive prospect of tackling intricate network effects, but with the benefits of a single-molecule therapy. Herein, we highlight relevant progress in the field, focusing on acetylcholinesterase inhibition and amyloid pathways as two pivotal features in multitarget design strategies. We also discuss the intertwined relationship between selected molecular targets and give a brief glimpse into the power of multitarget agents as pharmacological probes of Alzheimers disease molecular mechanisms.

The bivalent ligand approach as a tool for improving the in vitro anti-alzheimer multitarget profile of dimebon

Alzheimer’s disease (AD) is an extremely challenging and often frustrating area of drug discovery. Since the withdrawal of tacrine (Cognex) in 2006, more than 200 AD drug candidates have failed in late-stage clinical trials. The antihistamine drug dimebon (1, Figure 1) belongs to this long list. In 2008, 1 attracted considerable interest within the AD community when it successfully completed a small six-month clinical trial in Russia, in which it showed impressive cognition-enhancing effects in patients suffering from mild to moderate AD. 3] However, these positive outcomes were unconfirmed in a replication trial in the United States. We were particularly interested in 1 because, from initial reports on its in vitro activity profile, it seemed to fulfill the promise of an effective multitarget drug for treating AD. In recent years, multitarget drug development has emerged as an effective approach in the search for disease-modifying drugs against AD. This approach involves the development of single chemical entities that can simultaneously modulate multiple targets critically involved in the neurotoxic pathway. It therefore runs parallel to drug combination in the search for appropriate therapeutic interventions against the complex pathogenesis of AD. 9] Indeed, early research suggested that the clinical benefits of dimebon were related to its ability to simultaneously inhibit two crucial AD molecular targets: acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR). The effectiveness of simultaneous inhibition of both targets was further supported by higher shortand long-term efficacies observed in clinical trials involving co-administration of the NMDAR antagonist memantine and an AChE inhibitor (AChEI). Combining memantine and AChEIs is the current standard of care for AD patients. Furthermore, pre-clinically, the combination was demonstrated to act synergistically, which may explain the observed clinical effects. In this respect, we have already successfully combined the symptomatic relief of AChE inhibition and the neuroprotective action of NMDAR antagonism in a single multitarget molecule. 14] In the case of 1, however, its low in vitro activity against these two key targets (IC50 = 42 mm and 10–70 mm against AChE and NMDAR, respectively) might be one of the causes of its clinical failure. Indeed, Giorgetti et al. demonstrated that the brain concentration reached after acute oral administration of 1 to rats is much lower than that required to significantly affect AChE or NMDA pathways (nanomolar vs. micromolar). Although exposure levels of dimebon in plasma and cerebrospinal fluids in humans have not been published, it has been implied that the same situation might be replicated in the AD patients that were enrolled in the trial. This raised much uncertainty on the real mechanism by which dimebon may beneFigure 1. Design strategy for generating compounds 2–6.