Current Topics in Medicinal Chemistry - Volume 11, Issue 22, 2011

Although the single-target approach still remains the current drug discovery strategy in medicinal chemistry for the development of new bioactive molecules, there is increasing recognition that this is the main reason of a lack of a successful therapy for the treatment of multifactorial, complex diseases such as cancer or Alzheimer. Thus, an alternative approach, routinely named the “Multi-target Directed Ligand” (MTDL), based on the use of “multifunctional” or “pluripotential” drugs, is attracting the interest of the researchers in academia, and in the pharmaceutical companies. The idea now would be designing single molecules able to bind or interact with several of the diverse enzymatic systems or receptors implicated in the pathology of the disease. The advantages (and limitations also) of these drugs have been highlighted, and can be summarized in the simplification of dosing regimens, improve the patient comfort, avoiding the challenge of administering various single-drugs showing diverse bioavailability, pharmacokinetic and metabolic profiles. In this special issue of Current Topics in Medicinal Chemistry, a series of leading authors in their areas of research, present their ideas on the theme “hybrid-based drugs”, that we hope catch the attention of the interested reader, and gain new enthusiastic practioners Certainly, neurodegenerative disorders, such as Alzheimer's disease (AD), have concentrated most of the review articles shown here, submitted by Rampa, Gutschow, Bolognesi, Binda, and de los Rios. Rampa describes the progresses in medicinal chemistry over the last few years on the design of molecules incorporating in a single scaffold two pharmacophores from known chemical entities with well established biological activities for AD. Based on this strategy, acetylcholinesterase inhibitors have been extensively coupled with appropriate selected biological active molecules to give homo- and heterodimers endowed with increased potency. In addition, particular attention has been devoted to show the number of AChE inhibitors able to contact the peripheral anionic site of AChE, and consequently, able to prevent the AChE-mediated aggregation of the β-amyloid peptide into the senile plaques, which is a key event in the neurotoxic cascade of AD.

Progresses in medicinal chemistry over the last few years have focused on the design and synthesis of hybrid compounds, molecules encompassing in a single scaffold two pharmacophores from known entities endowed with well established biological activities. The interest in this topic is related to the increasing emphasis on the identification of the different factors involved in a number of disorders, such as the complex multifactorial Alzheimer's disease (AD), and hybrid- based strategy has become a focal point in this medicinal chemistry field since it could lead to derivatives with an improved biological profile. Using this strategy, acetylcholinesterase inhibitors (AChEIs) have been extensively coupled with properly selected bioactive molecules to obtain homo- and heterodimers endowed with increased potency together with supplementary actions. In the past decade the inhibition of the AChE induced aggregation of the β-amyloid peptide into the senile plaques, which is a key event in the neurotoxic cascade of AD, has been considered a relevant approach leading to several dual binding site inhibitors, able to contact both the peripheral anionic site of AChE and the active site. In recent years, pioneering efforts have been performed to obtain novel AChEIs that, beyond the capability to inhibit AChE, were able to hit a number of specific AD targets. In particular, these compounds proved to possess antioxidant, anti-inflammatory, or neuroprotective activities, useful to block or revert the progression of the disease. This review summarizes the progresses that have been made in the design of hybrid molecules for the treatment of AD.

The occurrence of orthosteric and allosteric binding sites is a characteristic common feature of several acetylcholine- binding proteins, like acetylcholinesterase or the nicotinic and muscarinic acetylcholine receptors. These proteins are involved in a number of neurological disorders, such as Alzheimer's disease, and represent important therapeutic targets for the development of heterodimeric ligands addressing both of their binding sites. Among the pharmacophores, which have been combined in such heterodimers, the tetrahydroacridine derivative tacrine has attracted particular interest. This review discusses the chemistry behind the linker connection of tacrine to other pharmacophores and summarizes the types of linkers established to date. Especially, the development of a hydrazide linker for tacrine-derived heterodimers is highlighted by applications in the inhibition of cholinesterases, the bivalent binding to nicotinic and muscarinic acetylcholine receptors, as well as the histochemical imaging of acetylcholinesterase and amyloid-β.

The development of ligands that as single chemical entities are able to modulate multiple epigenetic targets simultaneously (designed epigenetic multiple ligands) is still in its infancy. We are witnessing some advances with combinations of the fused or linked pharmacophores of an epi-drug and other anticancer agents. More recently, however, a very promising approach has been developed in which a single chemical entity exerts several therapeutic activities simultaneously, such as a compound that inhibits several epigenetic enzymes and as a consequence displays multiple biological profiles that address synergistically a particular multifactorial disease. Despite their promiscuity, these multiple epigenetic ligands have exciting conceptual advantages, as they (i) lower the risk of drug-drug interactions compared to cocktails or multicomponent drugs and facilitate ADMET and toxicology studies, (ii) minimize the development of drug resistance, (iii) exploit synergies between the targeted pathways/factors and (iv) can generally be used at lower therapeutically effective concentrations than the single target drugs. The obvious problem with such compounds is to find/design drugs which target multiple effectors with high selectivity and efficiency without displaying extensive off-target effects. In addition, the rational design of multiple epi-ligands is a major challenge. In this review we provide structurally-based principles and the optimization of activities towards the different epigenetic targets.

Playing a pivotal role in the metabolism of neurotransmitters in the central nervous system, the mitochondrial enzymes monoamine oxidases A and B (MAO A and B) have been for long studied as drug targets for neurodegenerative and neurological diseases. MAO inhibitors (MAOIs) are clinically used to treat Parkinson's disease and depression by blocking the degradation of neuroactive catecholamines and providing a symptomatic relief in the patients. More recent is the idea that the neuroprotective effect of MAOIs may result from the prevention of oxidative stress produced by the MAO reaction rather than being simply related to the inhibition of neurotransmitters degradation. Tranylcypromine and phenelzine are among the first developed MAOI drugs and have been used for years to treat depression. Their usage is now limited to cases of refractory depression because of their negative side effects, which are due to both the lack of MAO A/MAO B selectivity and the inhibition of other enzymes such as the drug-metabolizing cytochromes P450. Although the multi-target action of these MAOIs determines negative implications, the most newly developed compounds have improved properties not only for their specificity relatively to MAO A/MAO B selectivity but also because they function through multiple mechanisms that produce beneficial effects. In particular, safinamide, a MAO B selective inhibitor in clinical trials for Parkinson's disease, is neuroprotective by blocking the voltage-dependent Na+ and Ca2+ channels and the Ca2&plus-mediated glutamate release processes. Rasagiline is a drug used in combination with L-dopa in the treatment of parkinsonian patients and the metabolic products of its degradation exert neuroprotective effects. Moreover, rasagiline scaffold is used to design analogs by addition of pharmacophores that act on other neurological targets. This multi-target approach may prove successful in order to find new and more effective therapies for the complexity of neurodegenerative diseases.

Multitarget agents directed at selected molecular targets involved in the pathogenic cascade of Alzheimer's 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.

The synthesis and the pharmacological evaluation of 1,8-naphthyridine derivatives and related compounds as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as voltage-dependant Ca2+ channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca2+-antagonists 1,4-dihydropyridines. They were obtained from polyfunctionalized 2-amino-3-cyanoheterocycles via Friedlander-type reaction with selected cycloalkanones. Most of the compounds showed moderate inhibitory activity of cholinesterases, with selectivity to the AChE inhibition, and blocked Ca2+ channels, preferentially the Lsubtype, when a 4-aryl-1,4-DHP-like moiety were present in its chemical structure. Taking into account that the regulation of Ca2+ entry to cells has been described to play a key role in cell death/survival processes, some of them were studied as cytoprotective agentes against different toxic stimuli. Specifically, the 1,8-naphthyridine derivative 30 was described to exert a tiny positive effect on Ca2+ entry to cells, as single cell, isolated organ, and 45Ca2+ uptake experiments showed. This slight “Ca2+-promoter” behavior was related to its cytoprotective effect against several toxic stimuli, as Ca2+- chelating and antiapoptotic protein Bcl-2 was overexpressed in bovine chromaffin cells preincubated with 30. In fact, the relationship between small elevations of [Ca2+]c and neuroprotection has been deeply studied by our group and others, concluding that a huge blockade of Ca2+ entry does not have to generate neuroprotection, but the precise regulation, up or down, of such [Ca2+] concentrations.

Of the tropical diseases, trypanosomiases and leishmaniases should most concern the pharmaceutical community because of their high prevalence in developing countries and the lack of effective drug treatments. Despite this, they have not historically received much attention in terms of investment and research effort, nor do they now. In very recent years, thanks to the involvement of several nonprofit organizations, the chemotherapeutic options have expanded with the introduction of the first combination therapy. The optimal efficacy and safety of nifurtimox-eflornithine combination against second-stage human African trypanosomiasis is an encouraging first step towards simpler and more affordable therapies. Along the same line, I propose that single chemical entities able to modulate more than one target may prove more efficacious and tolerable than the available arsenal of drugs. Herein, I discuss the pros and cons of this approach, together with examples taken from the recent literature.

Thromboembolic disorders are still the leading causes of morbidity and mortality in developed societies. Therefore, prophylaxis and treatment of arterial and venous thrombosis are among the main therapeutic challenges nowadays. Simultaneous action on several targets involved in pathology of thrombosis offers potential advantages compared to existing drugs which were developed as selective modulators of single targets. The review focuses on dual inhibitors of coagulation enzymes, dual antiaggregatory compounds exerting their action on different combinations of platelet targets, as well as on anticoagulant/antiaggregatory compounds which interfere with at least one target involved in blood coagulation and at least one target engaged in the process leading to platelet aggregation.