Direct- And Spacer-Coupled Codrug Strategies for the Treatment of Alzheimer’s Disease

Review Article

Austin Alzheimers J Parkinsons Dis. 2014;1(2): 9.

Direct- And Spacer-Coupled Codrug Strategies for the Treatment of Alzheimer’s Disease

Fornasari E, Di Stefano A and Cacciatore I*

Department of Pharmacy, University “G. d’Annunzio” of Chieti-Pescara, Italy

*Corresponding author: Cacciatore I, Department of Pharmacy, University of Chieti-Pescara, via Dei Vestini 31, 66100 Chieti Scalo (CH), Italy.

Received: August 18, 2014; Accepted: October 01, 2014; Published: October 06, 2014


Over the last years, the ‘multi-target-directed ligand’ strategy has been exploited by many researchers to develop novel attractive tools in the search for new agents for Alzheimer’s disease (AD). Small molecules that concurrently target and modulate AD multiple pathological factors can be synthesized using such strategy. This paper will mainly focus on direct- and spacer-coupled codrug approaches that we recently rationally used to design multifunctional molecules able to contrast oxidative stress, neuroinflammation, glutamate toxicity, and metal dyshomeostasis, as a function of the structural elements introduced in the chemical framework.

Although the potential use of these strategies needs further exhaustive studies, it may offer a promising therapeutic alternative for increasing neuronal protection and preventing AD progression.

Keywords: Alzheimer’s disease; Multi target direct ligand strategy; Codrug; Glutathione; Lipoic acid


Alzheimer’s disease (AD) is a disabling brain disorder that is going to involve 100 million people all over the world by 2050 [1]. AD is marked by gradual memory loss and cognitive decline connected to a decrement of cholinergic neurons and acetylcholine (AChE) levels. Neuritic plaques – composed of amyloid- β protein (Aβ) – and Neurofibrillary Tangles (NFT) – formed by hyperphosphorylated tau proteins (t) – characterize AD affected brain [2]. Among different isoforms produced by the consecutive hydrolysis of the Aβ precursor (AβPP) mediated by β- and γ-secretases [3,4], the Aβ1-42 isoform in the brain intensifies the tendency for peptide aggregation [5] leading to a quickened formation of small Aβ oligomers [6,7]. In addition, after hyperphosphorylation, t-protein detaches from the microtubules and forms NFT intracellular neurotoxic aggregates [8]. These last, together with Aβ oligomers, are connected to neurotoxicity in AD brains.

The etiology of AD still remains obscure, but several events – for instance oxidative stress, Aβ plaques, metal dyshomeostasis, excitotoxicity, protein misfolding, and inflammatory processes – play a strategic role in the advancement of AD [9,10]. It is intricate to found the right succession of these events, but it was proved that oxidative damage is one of the initial pathological markers [11- 15]. Oxidative stress arises when the normal equilibrium between oxidative events and antioxidant defenses is interrupted either by deficiency of antioxidant enzymes or by incremented production of Reactive Oxygen Species (ROS).

In these pathological conditions, ROS react with lipids, proteins, nucleic acids, and other molecules thus altering their structure and function [16]. ROS generation in AD brains could be produced by high amounts of metal ions (Fe, Al, and Hg) or by Aβ aggregates [17]. In fact, the incubation of Cu(II), Zn(II), or Fe(III) with Aβ oligomers promotes the development of Aβ1-40 and Aβ1-42 deposits; notably, the deposition of fibrillar amyloid plaques is enhanced by Fe(III), while the formation of amorphous aggregates is induced by Cu(II) and Zn(II) [18]. Besides, Aβ plaques are responsible for inflammation in AD brains: in vitro studies on astrocytes have convincingly demonstrated that Aβ and APP activate glia in a dose- and timedependent manner, as measured by morphological response and expression of potent pro-inflammatory cytokines and TNF-α [19]. Neuroinflammatory processes that characterize AD might also be responsible for the depletion of Glutathione (GSH), the main tripetide able to counteract the oxidant injury [20,21]; effectively, some researchers found lowered GSH levels in AD brains [22,23]. Altogether, these data confirm that reduced antioxidant systems, metal ion dyshomeostasis, neuroinflammation, and Aβ aggregation generate a vicious circle closely related to the onset of AD.

Multi-Target Therapy for the Cure of AD

Current cure for AD focuses on symptomatic aspects of the pathology and four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) and Memantine (MEM) are the only drugs approved by FDA. Acetylcholinesterase inhibitors enhance cholinergic neurotransmission through inhibition of acetylcholinesterase, thus decreasing the breakdown of ACh [24,25]. MEM - an uncompetitive N-methyl-D-aspartate (NMDA) antagonist - is the only drug employed in the therapy of moderate to severe dementia [26,27]. Nevertheless, all these drugs are not satisfactory to heal AD or to stop its progression. In fact, as AD is featured by a multifactorial nature, drugs are required to hit the pathology at different levels simultaneously [28].

In recent years, several medicinal chemistry approaches were proposed in the search for novel drug candidates [29]. Among them, the ‘Multi-Target-Directed Ligand’ (MTDL) strategy [30-33] is drawing attention of many researchers (Figure 1). Indeed, small molecules that concurrently target and modulate the AD pathological factors can be designed using this methodology. Hybrids and codrugs are examples of MTDLs [34]: the first ones are constituted by two diverse pharmacophores joined via a permanent bond, and that exert a dual effect resulting from a single chemical entity acting on different biological targets without undergoing enzymatic cleavage; on the other hand, codrugs consist of two or more pharmacophores direct-and/or spacer-coupled via a covalent chemical linkage that, after enzymatic biotransformation, explicate their biological effects. The major limitation of this approach is the requirement of welldesigned groups for the linker [34], whereas the main advantage is represented by the advancement of pharmacokinetic profiles of the single drugs. Figure 1 reports a schematic representation regarding the different ways of action of both hybrids and codrugs. Many examples of hybrids were proposed for the cure of AD and the most successful ones were reported in Table 1 [36-46].