The Cream of the Crop of the Medicinal Chemistry Section of Molecules 2019

The MDPI journal Molecules is organized into 25 sections that cover many different areas of the broad field of chemistry. Among them, the Medicinal Chemistry section is one of the most classical. The overarching aim of this section is the publication of original re-search and review articles that increase our knowledge on how the chemical structure of molecules can be advantageously modulated to enhance their physicochemical and pharmacokinetic properties and/or their interaction with particular biological targets of therapeutic or diagnostic interest. With Medicinal Chemistry being multidisciplinary in essence, the contents of the articles published in this section partly overlap with those of other sections namely, organic, natural products, bioorganic, and computational theo-retical chemistry or chemical biology, which contributes to the integration and coherence among the different areas of the journal. Driven by a very active board of Academic Editors and imaginative section Managing Editors, new actions are continuously undertaken to attract, visualize, and promote high quality articles and reviews, with the final goal of disseminating in open access medicinal chemistry of excellence. On this line, we are initiating a series of Editorials to highlight the most influential articles, overall or considering specific topics, published in the Medicinal Chemistry section of Molecules in a particular year. We will start with the articles published in 2019, now that all of them have had an exposure to readers of at least one year

Acetylcholinesterase: A versatile template to coin potent modulators of multiple therapeutic targets

The enzyme acetylcholinesterase (AChE) hydrolyzes the neurotransmitter acetylcholine (ACh) at cholinergic synapses of the peripheral and central nervous system. Thus, it is a prime therapeutic target for diseases that occur with a cholinergic deficit, prominently Alzheimer’s disease (AD). Working at a rate near the diffusion limit, it is considered one of nature’s most efficient enzymes. This is particularly meritorious considering that its catalytic site is buried at the bottom of a 20-Å-deep cavity, which is preceded by a bottleneck with a diameter shorter than that of the trimethylammonium group of ACh, which has to transit through it. Not only the particular architecture and amino acid composition of its active site gorge enable AChE to largely overcome this potential drawback, but it also offers plenty of possibilities for the design of novel inhibitor drug candidates.In this Account, we summarize our different approaches to colonize the vast territory of the AChE gorge in the pursuit of increased occupancy and hence of inhibitors with increased affinity. We pioneered the use of molecular hybridization to design inhibitors with extended binding at the CAS, reaching affinities among the highest reported so far. Further application of molecular hybridization to grow CAS extended binders by attaching a PAS-binding moiety through suitable linkers led to multisite inhibitors that span the whole length of the gorge, reaching the PAS and even interacting with midgorge residues. We show that multisite AChE inhibitors can also be successfully designed the other way around, by starting with an optimized PAS binder and then colonizing the gorge and CAS. Molecular hybridization from a multicomponent reaction-derived PAS binder afforded a single-digit picomolar multisite AChE inhibitor with more than 1.5 million-fold increased potency relative to the initial hit. This illustrates the powerful alliance between molecular hybridization and gorge occupancy for designing potent AChE inhibitors.Beyond AChE, we show that the stereoelectronic requirements imposed by the AChE gorge for multisite binding have a templating effect that leads to compounds that are active in other key biological targets in AD and other neurological and non-neurological diseases, such as BACE-1 and the aggregation of amyloidogenic proteins (β-amyloid, tau, α-synuclein, prion protein, transthyretin, and human islet amyloid polypeptide). The use of known pharmacophores for other targets as the PAS-binding motif enables the rational design of multitarget agents with multisite binding within AChE and activity against a variety of targets or pathological events, such as oxidative stress and the neuroinflammation-modulating enzyme soluble epoxide hydrolase, among others.We hope that our results can contribute to the development of drug candidates that can modify the course of neurodegeneration and may inspire future works that exploit the power of molecular hybridization in other proteins featuring large cavities

Development of hybrid compounds to tackle Alzheimer’s disease

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/128014Alzheimer’s disease (AD) is the main neurodegenerative disorder worldwide. Its pathogenesis involves a network where various mechanisms are interconnected. This complex pathological network makes it extremely challenging to find an efficacious treatment. Herein, we give an overview on the design of the so-called multi-target-directed ligands, i.e. compounds that concurrently hit several key pathogenic factors within the network, as a realistic option to tackle AD, with a particular emphasis on some structural classes of multitarget hybrids recently developed in our group

Recent advances in pharmaceutical sciences VII

The E-book series Recent Advances in Pharmaceutical Sciences reports research contributions from different areas of the multidisciplinary field of Pharmaceutical Sciences. This seventh volume consists of nine chapters, mainly dealing with the fields of botany, physiology, food science, biochemistry & molecular biology, plant physiology, microbiology, parasitology, pharmacology, and medicinal chemistry

Recent advances in pharmaceutical sciences IV

Reproducció del llibre publicat a: http://www.trnres.com/ebookcontents.php?id=234Like in the three previous editions, this E-book compiles a series of contributions in the multidisciplinary research arena of Pharmaceutical Sciences. The E-book has been organized in 12 chapters, whose main topics belong to the fields of pharmacology, physical chemistry, plant physiology, microbiology, physiology, preventive medicine and public health, food science, botany, clinical pharmacy and pharmacotherapy, organic chemistry, biochemistry and molecular biology, and parasitology..

Recent advances in pharmaceutical sciences V

Reproducció del llibre publicat a: http://www.trnres.com/ebookcontents.php?id=249This E-book is the fifth volume of a series that compiles contributions from different areas of the multidisciplinary field of Pharmaceutical Sciences. The E-book consists of 11 chapters that cover the areas of organic chemistry, health and environmental management, plant physiology, food science, toxicology, botany, parasitology, physiology, biochemistry and molecular biology, microbiology, and pharmacology

Recent Advances in Pharmaceutical Sciences VIII

This E-book is the eighth volume of a series that compiles contributions from different areas of the multidisciplinary field of Pharmaceutical Sciences. The E-book consists of 7 chapters that cover the areas of organic chemistry, health and environmental management, plant physiology, food science, toxicology, botany, parasitology, physiology, biochemistry and molecular biology, microbiology, and pharmacology

Ultra rapid in vivo screening for anti-Alzheimer anti-amyloid drugs

More than 46 million people worldwide suffer from Alzheimer's disease. A large number of potential treatments have been proposed; among these, the inhibition of the aggregation of amyloid β-peptide (Aβ), considered one of the main culprits in Alzheimer's disease. Limitations in monitoring the aggregation of Aβ in cells and tissues restrict the screening of anti-amyloid drugs to in vitro studies in most cases. We have developed a simple but powerful method to track Aβ aggregation in vivo in realtime, using bacteria as in vivo amyloid reservoir. We use the specific amyloid dye Thioflavin-S (Th-S) to stain bacterial inclusion bodies (IBs), in this case mainly formed of Aβ in amyloid conformation. Th-S binding to amyloids leads to an increment of fluorescence that can be monitored. The quantification of the Th-S fluorescence along the time allows tracking Aβ aggregation and the effect of potential antiaggregating agents

Trends in Pharmaceutical and Food Sciences I

Podeu consultar el llibre complet a: https://medwinpublishers.com/OAJPR/OAJPR16000eB001.pdfTrends in Pharmaceutical and Food Sciences I is the first issue of an open access E-book devoted to scientific and technical research that covers the entire spectrum of drug and food research, including medicinal chemistry, pharmacology, drug delivery, microbiology and biochemical studies, as well as relevant developments in nutrition, food safety and analytical innovation. The first chapter, Different techniques to detect G protein coupled receptor heteromers, describes state of the art techniques based in biophysical principles applied to detect oligomeric aggregates formed by G-protein coupled receptors in the cell membrane, and describes how the knowledge generated can be applied to design new compounds for the treatment of neurological and mental diseases. Obesity has become a worldwide problem and it is well known that causes and exacerbates many health problems by promoting profound changes in physiological functions. Chapter 2, Analysis of the role of diet in the appearance of neurodegenerative processes, reviews the consequences of these metabolic alterations while considering their effects in the development of Type 2 Diabetes Mellitus, and their role in the appearance of cognitive impairments such as the sporadic forms of Alzheimer’s disease. The development of new cultivars facing climate change is an issue of great interest for the agrochemical industry and can be approached in different ways. Chapter 3, Arabidopsis Thaliana A Model for the Study of Plant Speciation, reviews different aspects of the plant immune system and the different layers of the plant immune response and signaling. The emerging field in plant research that studies how soil microbiota influences plant basic mechanisms is also discussed. Chagas disease is endemic in Latin America, but recently and due to human migrations, it is becoming a global health problem. In chapter 4, Trypanosoma cruzi infection diagnosis: New insights, challenges and perspectives, a group of experts from several institutions describe the different techniques that can be used for the serological diagnosis of the infection and the characterization of Trypanosoma cruzi, discuss the advantages and drawbacks of each method and propose improvements that would entail important savings for health institutions. Chapter 5, Nutrients, Control of Gene Expression and Metabolic Homeostasis, focuses on the molecular mechanisms that control metabolism by means of regulating gene expression in response to dietary inputs, to design new therapeutic strategies based on nutritional interventions against metabolic diseases. In this context, involvement of FGF21 hormone in the regulation of lipid metabolism during amino acid starvation is described, thus reinforcing its important role as an endocrine factor in coordinating energy homeostasis under a variety of nutritional conditions. This raises the possibility of dietary modulation of circulating levels of FGF21 as an alternative approach to its pharmacological administration. Biodegradable polymeric nanoparticles encapsulating neuroprotective drugs have enormous potential to treat neurodegenerative diseases, including Alzheimer´s disease and glaucoma. Recent advances in the field are described in chapter 6, Polymeric nanoparticles for the treatment of neurodegenerative diseases: Alzheimer’s disease and glaucoma, specifically the preparation of engineered polymeric nanoparticles with attached peptides or antibodies to increase their bioavailability, favoring their transport through the blood brain barrier and the blood retinal barrier, avoiding at the same time possible drug adverse and toxic effects. The last chapter, Pentacyclic triterpenes in table olives: Determination of their composition and bioavailability by LC-M, is a review on the pentacyclic triterpenes contained in table olives, natural compounds of enormous interest due to their beneficial effects on human health, including hepatoprotective, anti-diabetic, antiviral, cardioprotective and antitumor activities. Authors describe a selective and sensitive LC–MS method for the simultaneous determination of the main triterpenic compounds present in Olea europaea L. This opens the possibility to bioavailability studies after consumption of different foods, or administration of plants widely used in traditional medicine, with the aim of studying in depth the beneficial effects of these compounds in human beings. We hope that this new volume will attract the interest of all the scientific community, especially those working in the fields of pharmaceutical, medical, biological, chemical and food sciences

Protective Role of a Donepezil-Huprine Hybrid against the β-Amyloid (1-42) Effect on Human Erythrocytes

Aβ(1-42) peptide is a neurotoxic agent strongly associated with the etiology of Alzheimer's disease (AD). Current treatments are still of very low effectiveness, and deaths from AD are increasing worldwide. Huprine-derived molecules have a high affinity towards the enzyme acetylcholinesterase (AChE), act as potent Aβ(1-42) peptide aggregation inhibitors, and improve the behavior of experimental animals. AVCRI104P4 is a multitarget donepezil-huprine hybrid that improves short-term memory in a mouse model of AD and exerts protective effects in transgenic Caenorhabditis elegans that express Aβ(1-42) peptide. At present, there is no information about the effects of this compound on human erythrocytes. Thus, we considered it important to study its effects on the cell membrane and erythrocyte models, and to examine its protective effect against the toxic insult induced by Aβ(1-42) peptide in this cell and models. This research was developed using X-ray diffraction and differential scanning calorimetry (DSC) on molecular models of the human erythrocyte membrane constituted by lipid bilayers built of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). They correspond to phospholipids representative of those present in the external and internal monolayers, respectively, of most plasma and neuronal membranes. The effect of AVCRI104P4 on human erythrocyte morphology was studied by scanning electron microscopy (SEM). The experimental results showed a protective effect of AVCRI104P4 against the toxicity induced by Aβ(1-42) peptide in human erythrocytes and molecular models