Frontiers in Medicinal Chemistry

Oxidative stress is implicated in the pathogenesis of a number of neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis and stroke in the adult as well as in conditions such as periventricular white matter damage in the neonatal brain. It has also been linked to the disruption of blood brain barrier (BBB) in hypoxic-ischemic injury. Both experimental and clinical results have shown that antioxidants such as melatonin, a neurohormone synthesized and secreted by the pineal gland and edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly developed drug, are effective in reducing oxidative stress and are promising neuroprotectants in reducing brain damage. Indeed, the neuroprotective effects of melatonin in many central nervous system (CNS) disease conditions such as amyotrophic lateral sclerosis, PD, AD, ischemic injury, neuropsychiatric disorders and head injury are well documented. Melatonin affords protection to the BBB in hypoxic conditions by suppressing the production of vascular endothelial growth factor and nitric oxide which are known to increase vascular permeability. The protective effects of melatonin against hypoxic damage have also been demonstrated in newborn animals whereby it attenuated damage in different areas of the brain. Furthermore, exogenous administration of melatonin in newborn animals effectively enhanced the surface receptors and antigens on the macrophages/microglia in the CNS indicating its immunoregulatory actions. Not only did melatonin prevent neuronal loss in the brain, but also protected the retinal neurons in ocular diseases such as glaucoma, diabetic retinopathy and age related macular degeneration. Another anti-oxidant, edaravone has been shown to reduce oxidative stress, edema, infarct volume, inflammation and apoptosis following ischemic injury of the brain in the adult as well as decrease free radical production in the neonatal brain following hypoxic-ischemic insult. It can counteract toxicity from activated microglia. This review summarizes the clinical and experimental data highlighting the therapeutic potential of melatonin and edaravone in neuroprotection in various disorders of the CNS.

The therapeutic arsenal for the treatment of Alzheimer’s disease (AD) remains confined to a group of four inhibitors of AChE and one NMDA receptor antagonist, which are used to provide a relief of the very late symptoms of the dementia, i.e. the cognitive and functional decline. In line with the growing body of evidence of the pivotal role of the β-amyloid peptide (Aβ) in the pathogenesis of AD, alternative classes of drugs targeting mainly the formation or the aggregation of Aβ are actively pursued by the pharmaceutical industry, as they could positively modify the course of AD, stopping or slowing down disease progression. While mostly amyloid-directed drug candidates are being scrutinized in the past decades as disease-modifying drugs, mounting preclinical and clinical evidence is pointing towards a disease-modifying role also for currently marketed anti-Alzheimer AChE inhibitors (AChEIs), particularly for donepezil. In this review, the neuroprotective effects exhibited by currently commercialized AChEIs will be briefly discussed, together with the secondary mechanisms through which they could exert such effects. This review will focus also on particular classes of AChEIs, namely dual binding site AChEIs, which are being purposely designed to target Aβ aggregation and/or other biological targets that contribute to AD pathogenesis, thus constituting very promising disease-modifying anti- Alzheimer drug candidates.

Dopamine agonists have been shown to possess neuroprotective properties in different in vitro and in vivo experimental Parkinson’s disease models, because their capability to counteract- neuronal cell death. Here we update the molecular evidence underlying the wide pharmacological spectrum of dopamine agonists currently used for treating Parkinson’s disease patients. In particular, the mechanism of action of different dopamine agonists does not always appear to be restricted to the stimulation of selective dopamine receptor subtypes since at least some of these drugs are endowed with antioxidant, antiapoptotic or neurotrophic properties. These activities are moleculespecific and may contribute to the clinical efficacy of these drugs for the treatment of chronic and progressive neurodegenerative diseases in which oxidative injury and/or protein misfolding and aggregation exert a primary role. However, despite increasing number of experimental results confirm their neuroprotective effects, further studies are needed to definitively confirm dopamine agonists as disease-modifying agents.

Oxytocin (OT) is a neurohypophysial hormone synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OT-like substances have been identified in all vertebrates, OT has been found only in mammals where it plays a major role in the onset and maintaining of behaviors which are typical of these animals, such as labour and lactation. Several data have suggested the involvement of OT in the formation of infant attachment, maternal behavior, pair bonding and, more generally, in linking social signals with cognition, behaviors and reward.

The aim of this paper was to review critically the role of OT in the regulation of different physiological functions and complex behaviors, as well as its possible involvement in the pathophysiology of some neuropsychiatric disorders. MEDLINE and PubMed (1972-2014) databases were searched for English language articles by using the following keywords: oxytocin, physiology, cognitive functions, attachment, psychopathology, psychiatric disorders. Papers were examined that addressed the following aspects of the OT system: synthesis and localization, receptors, physiology. In addition, latest findings showing abnormalities of OT and OT system in several neuropsychiatric disorders, including autism, obsessive-compulsive disorder, eating disorders, addiction, schizophrenia, post-traumatic stress disorder and Prader-Willy syndrome, will be also discussed together with the possible clinical use of OT or its analogues and/or antagonists.

Protein aggregation correlates with the development of several deleterious human disorders such as Alzheimer's disease, Parkinson's disease, prion-associated transmissible spongiform encephalopathies, type II diabetes and several types of cancers. The polypeptides involved in these disorders may be globular proteins with a defined 3Dstructure or natively unfolded proteins in their soluble conformations. In either case, proteins associated with these pathogenesis all aggregate into amyloid fibrils sharing a common structure, in which β-strands of polypeptide chains are perpendicular to the fibril axis. Because of the prominence of amyloid deposits in many of these diseases, much effort has gone into elucidating the structural basis of protein aggregation. A number of recent experimental and theoretical studies have significantly increased our understanding of the process. On the one hand, solid-state NMR, X-ray crystallography and single molecule methods have provided us with the first high-resolution 3D structures of amyloids, showing that they exhibit conformational plasticity and are able to adopt different stable tertiary folds, with impact both their transmissibility and neurotoxicity. On the other hand, several computational approaches have identified regions prone to aggregation in disease-linked polypeptides, predicted the differential aggregation propensities of their genetic variants and simulated the early, crucial steps of the oligomerization reaction. This review summarizes these findings and their therapeutic relevance, as by uncovering specific structural or sequential targets they may provide us with a means to tackle the debilitating diseases linked to protein aggregation.

Alzheimer’s disease (AD) is the most common form of dementia affecting older people (60-80% cases). Besides the neuropathologic hallmark abnormalities that are deposits of the protein fragment β-amyloid (plaques) and twisted strands of the protein tau (tangles), AD is characterized by a consistent deficit in cholinergic neurotransmission, consequently leading to destruction of cholinergic neurons in basal forebrain. Cholinesterases (acetylcholinesterase - AChE, and butyrylcholinesterase - BChE) are serine hydrolases that split acetylcholine (ACh) and terminate its action. Cholinesterase inhibitors increase the levels of ACh and prolong its action. For this reason, they have relevance to the treatment of neurodegenerative disorders. Moreover, AChE inhibition holds a key role to reduce the aggregation of β amyloid and the formation of the neurotoxic fibrils. Recently, researchers move their interest in finding drugs that are able to inhibit both of these events. This chapter covers the current knowledge of natural products as cholinesterase inhibitors and how these compounds could serve as lead compounds for semi-synthetic analogs with improved properties. In particular, studies in the period 2000-2007 and from 2013 until now (2014 first semester) are reported.

Malaria is recognized as the most dangerous disease originating from parasites. Plasmodium falciparum dihydrofolate reductase (PfDHFR) is one of the important targets for anti-malarial drug design. All the reported anti-folates show drug resistance. Mutations in the active-site of PfDHFR enzyme, particularly at 16, 51, 59, 108, and 164 residues, are responsible for the observed resistance. The new strategies for anti-malarial drug discovery include design of leads which are effective against both wild type and mutant PfDHFR. Recent efforts in this direction lead to the identification of P218 as an important lead compound. In addition a set of guanylthiourea derivatives were also reported. Rational lead design strategies are being adopted for the design of PfDHFR inhibitors as anti-malarial agents. In this update, a review of the computeraided drug design which was adopted over the past decade, in the design of PfDHFR inhibitors, are elaborated. Efforts based on molecular docking, pharmacophore mapping, QSAR, homology modeling, and quantum chemical studies are discussed in detail. Special emphasis is given to the importance of drug action while discussing the pharmacoinformatic approaches. In future the rational methods of lead design and lead optimization are expected to increase because sufficient knowledge is already generated on the structural aspects of PfDHFR and its possible inhibitors are already available.

Natural toxins are the product of a long-term evolution, and act on essential mechanisms in the most crucial and vital processes of living organisms. They can attack components of the protein synthesis machinery, actin polymerization, signal transduction pathways, intracellular trafficking of vesicles as well as immune and inflammatory responses. For this reason, toxins have increasingly been used as valuable tools for analysis of cellular physiology, and in the recent years, some of them are used medicinally for the treatment of human diseases.

This review is devoted to protein toxins of bacterial origin, specifically those toxins that are currently used in therapy or those under study for their potential clinical applications. Bacterial protein toxins are all characterized by a specific mechanism of action that involves the central molecular pathways in the eukaryotic cell. Knowledge of their properties could be used for medical purposes.

Taenia solium cysticercosis is a major parasitic disease that severely affects human health and the economy of undeveloped countries. Since pigs are obligate intermediate hosts, it is plausible to curb human transmission by reducing pig cysticercosis through effective vaccination. This article reviews the current knowledge on the development of vaccines against porcine cysticercosis. It highlights the development of plant-based, needle-free vaccine versions as a feasible and affordable approach to reduce the logistic costs of injectable vaccines, while preventing the digestive hydrolysis of vaccine antigens.

The advancements in the molecular pathogenesis and a deeper comprehension of cellular mechanisms of liver fibrosis promise to give new therapeutic approaches to the management of this disease in the future.

Apoptosis, cytokines, oxidants, and inflammosomes play a complex role in favouring or delaying the onset of liver fibrosis; sustained hepatic stellate cell activation and transformation, without forgetting the role of hepatocytes and other complex molecular and cellular mechanisms, are the direction that guides to fibrosis.

Therefore, in this review, after considering the causes of the development of fibrosis as well as the interrelation between molecular and cellular profibrotic mechanisms, we will focus on the part played in counteracting both of these actions by some anti-oxidants and anti-fibrotic molecules such as cytokines, prostacyclin and others.

Further validation in animal studies and confirmation in clinical trials are requested. Some data that are already available from in vitro and animal studies demonstrating the effectiveness of novel approaches to inhibiting or treating liver fibrosis can only offer moderate hope.

Regenerative engineering has recently emerged as the next stage in the evolution of tissue engineering. Advanced materials science is a key component in regenerative engineering. Biologically active materials largely affect cell fate processes and tissue morphogenesis through chemical and biological cues carried by the materials. By physical adsorption of biomolecules on scaffold surface, physical entrapment of biomolecules in polymer microspheres or hydrogels, and chemical immobilization of oligopeptides or proteins on biomaterials, biologically active biomaterials and scaffolds can be derived. These bioactive systems show great potential in regenerative engineering in rendering bioactivity and/or specificity to scaffolds. This review highlights some of the biologically active chitosan systems for regenerative engineering and the associated strategies to develop such bioactive chitosan systems.