Oxidation-labile linkers for controlled drug delivery.

The continuous symbiosis throughout chemical biology and drug discovery has led to the design of innovative bifunctional molecules for targeted and controlled drug delivery. Among the different tools, protein-drug and peptide-drug conjugates are trend approaches to achieve targeted delivery, selectivity and efficacy. To meet the main goals of these bioconjugates, the selection of the appropriate payloads and linkers is crucial, as they must provide in vivo stability, while they may also help to achieve the therapeutic target and action. In neurodegenerative diseases or some cancer types, where oxidative stress plays an important role, linkers sensitive to oxidative conditions may be able to release the drug once the conjugate achieves the target. Considering specially this specific application, this mini-review covers the most relevant publications on oxidation-labile linkers.

Thiocoumarins: From the Synthesis to the Biological Applications.

Coumarin is a privilege scaffold in medicinal chemistry. Coumarin derivatives are still an emerging class of highly potent pharmaceutical drugs, best known in the field of antimicrobials and anticoagulants. Thiocoumarins are a particular class of coumarins in which one or two of the oxygen atoms are replaced by a sulfur. They are chemically subdivided in three groups: Thiocoumarins, 2-thioxocoumarins, and dithiocoumarins. This review emphasizes the rationale behind the synthesis and biological applications of the most relevant publications related to this family of compounds. Particular attention has been given to their potential as drug candidates, with particular emphasis in the last 5 years. This article is based on the most relevant information collected from multiple electronic databases, including SciFinder, Pubmed, Espacenet, and Mendeley.

3-Phenylcoumarins as a Privileged Scaffold in Medicinal Chemistry: The Landmarks of the Past Decade.

3-Phenylcoumarins are a family of heterocyclic molecules that are widely used in both organic and medicinal chemistry. In this overview, research on this scaffold, since 2010, is included and discussed, focusing on aspects related to its natural origin, synthetic procedures and pharmacological applications. This review paper is based on the most relevant literature related to the role of 3-phenylcoumarins in the design of new drug candidates. The references presented in this review have been collected from multiple electronic databases, including SciFinder, Pubmed and Mendeley.

Computer-aided Design of Coumarins for Neurodegenerative Diseases: Trends of the Last Decade.

Computer-aided design of new drugs is an exponentially growing field, especially in the last decade. The support of theoretical tools may accelerate the drug discovery process, which is a long and very expensive journey. Tools as QSAR and docking calculations are on the top of the list for helping medicinal chemists to find more potent and selective molecules as potential leads for facing challenging diseases. Coumarins have been an important source of inspiration for the design of new drugs. Due to their chemical properties and their affinity to some targets, special attention has been paid to their role against neurodegenerative diseases. Therefore, the authors provide an overview of the scientific reports describing the research and development of new drug design tools supporting the discovery of coumarins as enzymatic inhibitors or receptor ligands involved in these diseases. This review emphasizes the rationale behind the design of new drug candidates, and particular attention is paid to the search for new leads over the last 10 years. QSAR and docking studies are discussed, as well as new technologies applied for the research in this field. The manuscripts discussed in this review have been collected from multiple electronic databases, including Pubmed, SciFinder, and Mendeley.

Trending Topics on Coumarin and Its Derivatives in 2020.

Coumarins are naturally occurring molecules with a versatile range of activities. Their structural and physicochemical characteristics make them a privileged scaffold in medicinal chemistry and chemical biology. Many research articles and reviews compile information on this important family of compounds. In this overview, the most recent research papers and reviews from 2020 are organized and analyzed, and a discussion on these data is included. Multiple electronic databases were scanned, including SciFinder, Mendeley, and PubMed, the latter being the main source of information. Particular attention was paid to the potential of coumarins as an important scaffold in drug design, as well as fluorescent probes for decaging of prodrugs, metal detection, and diagnostic purposes. Herein we do an analysis of the trending topics related to coumarin and its derivatives in the broad field of drug discovery.

Structure-Based Optimization of Coumarin hA3 Adenosine Receptor Antagonists.

Adenosine receptors participate in many physiological functions. Molecules that may selectively interact with one of the receptors are favorable multifunctional chemical entities to treat or decelerate the evolution of different diseases. 3-Arylcoumarins have already been studied as neuroprotective agents by our group. Here, differently 8-substituted 3-arylcoumarins are complementarily studied as ligands of adenosine receptors, performing radioligand binding assays. Among the synthesized compounds, selective A3 receptor antagonists were found. 3-(4-Bromophenyl)-8-hydroxycoumarin (compound 4) displayed the highest potency and selectivity as A3 receptor antagonist (Ki = 258 nM). An analysis of its X-ray diffraction provided detailed information on its structure. Further evaluation of a selected series of compounds indicated that it is the nature and position of the substituents that determine their activity and selectivity. Theoretical modeling calculations corroborate and explain the experimental data, suggesting this novel scaffold can be involved in the generation of candidates as multitarget drugs.

Artificial Intelligence Applied to Flavonoid Data in Food Matrices.

Increasing interest in constituents and dietary supplements has created the need for more efficient use of this information in nutrition-related fields. The present work aims to obtain optimal models to predict the total antioxidant properties of food matrices, using available information on the amount and class of flavonoids present in vegetables. A new dataset using databases that collect the flavonoid content of selected foods has been created. Structural information was obtained using a structural-topological approach called TOPological Sub-Structural Molecular (TOPSMODE). Different artificial intelligence algorithms were applied, including Machine Learning (ML) methods. The study allowed us to demonstrate the effectiveness of the models using structural-topological characteristics of dietary flavonoids. The proposed models can be considered, without overfitting, effective in predicting new values of Oxygen Radical Absorption capacity (ORAC), except in the Multi-Layer Perceptron (MLP) algorithm. The best optimal model was obtained by the Random Forest (RF) algorithm. The in silico methodology we developed allows us to confirm the effectiveness of the obtained models, by introducing the new structural-topological attributes, as well as selecting those that most influence the class variable.

Antibacterial Activity and Molecular Docking Studies of a Selected Series of Hydroxy-3-arylcoumarins.

Antibiotic resistance is one of the main public health concerns of this century. This resistance is also associated with oxidative stress, which could contribute to the selection of resistant bacterial strains. Bearing this in mind, and considering that flavonoid compounds are well known for displaying both activities, we investigated a series of hydroxy-3-arylcoumarins with structural features of flavonoids for their antibacterial activity against different bacterial strains. Active compounds showed selectivity against the studied Gram-positive bacteria compared to Gram-negative bacteria. 5,7-Dihydroxy-3-phenylcoumarin (compound 8) displayed the best antibacterial activity against Staphylococcus aureus and Bacillus cereus with minimum inhibitory concentrations (MICs) of 11 g/mL, followed by Staphylococcus aureus (MRSA strain) and Listeria monocytogenes with MICs of 22 and 44 g/mL, respectively. Moreover, molecular docking studies performed on the most active compounds against Staphylococcus aureus tyrosyl-tRNA synthetase and topoisomerase II DNA gyrase revealed the potential binding mode of the ligands to the site of the appropriate targets. Preliminary structure-activity relationship studies showed that the antibacterial activity can be modulated by the presence of the 3-phenyl ring and by the position of the hydroxyl groups at the coumarin scaffold.

Targeting α -(1,4)-Glucosidase in Diabetes Mellitus Type 2: The Role of New Synthetic Coumarins as Potent Inhibitors.

Diabetes mellitus type 2 (DMT2) is a metabolic disease characterized by a chronic increase in glycemia that promotes several long-term complications and high mortality. Some enzymes involved in glycaemic control, such as α -(1,4)-glucosidase, have now been established as novel pharmacological targets. Coumarins have shown benefits in attenuating signs and complications of DMT2, including inhibition of this enzyme. In this work, new synthetic coumarins (bearing different amide and aryl substituents) were studied in vitro as inhibitors of α-(1,4)-glucosidase. Among them, five molecules proved to be excellent α-(1,4)-glucosidase inhibitors, being compound 7 (IC50 = 2.19 µM) about 200 times more potent than acarbose, a drug currently used for the treatment of DMT2. In addition, most of the coumarins presented uncompetitive inhibition for the α-(1,4)-glucosidase. Molecular docking studies revealed that coumarins bind to the active site of the enzyme in a more external area comparing to the substrate, without interfering with it, and displaying aromatic and hydrophobic interactions, as well as some hydrogen bonds. According to the results, aromatic interactions with two phenylalanine residues, 157 and 177, were the most common among the studied coumarins. This study is a step forward for the understanding of coumarins as potential anti-diabetic compounds displaying α-(1,4)-glucosidase inhibition.

Coumarin derivatives as promising xanthine oxidase inhibitors.

Xanthine oxidase (XO) is an interesting target for the synergic treatment of several diseases. Coumarin scaffold plays an important role in the design of efficient and potent inhibitors. In the current work, twenty 3-arylcoumarins and eight 3-heteroarylcoumarins were evaluated for their ability to inhibit XO. Among all the candidates, 5,7-dihydroxy-3-(3'-hydroxyphenyl)coumarin (compound 20) proved to be the best inhibitor with an IC50 of 2.13 µM, being 7-fold better than the reference compound, allopurinol (IC50 = 14.75 µM). To deeply understand the potential of this compound, the inhibition mode was also evaluated. Compound 20 showed an uncompetitive profile of inhibition. Molecular docking studies were carried out to analyze the interaction of compound 20 with the studied enzyme. The binding mode involving residues different from the catalytic site of the binding pocket, is compatible to the observed uncompetitive inhibition. Compound 20 was not cytotoxic at its IC50 value, as demonstrated by the viability of 99.1% in 3 T3 cells. Furthermore, pharmacokinetics and physicochemical properties were also calculated, which corroborated with the potential of the studied compounds as promising XO inhibitors.

Evaluation of Trypanocidal and Antioxidant Activities of a Selected Series of 3-amidocoumarins.

BACKGROUND: Neglected diseases are becoming more prevalent due to globalization. This has inspired active research in the development of new drugs for the treatment of parasitic diseases such as Chagas disease. OBJECTIVES: With the aim of finding new trypanocidal agents, we report the in vitro evaluation of a new series of 3-amidocoumarins with or without hydroxyl substituents at position 4 of the coumarin ring. METHODS: Electrochemical and biological assays were performed in order to assess the antioxidant and trypanocidal potential of these compounds and to better understand the mechanisms involved in their activity. RESULTS: Most of the studied compounds showed high trypanocidal activity against both epimastigote and trypomastigote forms, with IC50 values in the low micromolar range. Some of them have greater activity and selectivity than the reference compound, nifurtimox. CONCLUSION: Compound 2 is the most active of this series, being also non-cytotoxic against murine RAW 264.7 macrophages. Electrochemical and radical scavenging experiments were carried out, providing new information about the profile of the best derivatives, and the potential therapeutic application of the new 3-amidocoumarins.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier.

BACKGROUND: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. METHODS: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. RESULTS: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. CONCLUSION: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Molecular Docking and Drug Discovery in ß-Adrenergic Receptors.

BACKGROUND: Evolution in computer engineering, availability of increasing amounts of data and the development of new and fast docking algorithms and software have led to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Moreover, analysis of protein-ligand recognition through molecular docking has become a valuable tool in drug design. OBJECTIVE: In this review, we focus on the applicability of molecular docking on a particular class of G protein-coupled receptors: the ß-adrenergic receptors, which are relevant targets in clinic for the treatment of asthma and cardiovascular diseases. RESULTS: We describe the binding site in ß-adrenergic receptors to understand key factors in ligand recognition along with the proteins activation process. Moreover, we focus on the discovery of new lead compounds that bind the receptors, on the evaluation of virtual screening using the active/ inactive binding site states, and on the structural optimization of known families of binders to improve ß-adrenergic affinity. We also discussed strengths and challenges related to the applicability of molecular docking in ß-adrenergic receptors. CONCLUSION: Molecular docking is a valuable technique in computational chemistry to deeply analyze ligand recognition and has led to important breakthroughs in drug discovery and design in the field of ß-adrenergic receptors.

New insights into highly potent tyrosinase inhibitors based on 3-heteroarylcoumarins: Anti-melanogenesis and antioxidant activities, and computational molecular modeling studies.

Melanogenesis is a physiological pathway for the formation of melanin. Tyrosinase catalyzes the first step of this process and down-regulation of its activity is responsible for the inhibition of melanogenesis. The search for molecules capable of controlling hyperpigmentation is a trend topic in health and cosmetics. A series of heteroarylcoumarins have been synthesized and evaluated. Compounds 4 and 8 exhibited higher tyrosinase inhibitory activities (IC50=0.15 and 0.38µM, respectively), than the reference compound, kojic acid (IC50=17.9µM). Compound 4 acts as competitive, while compound 8 as uncompetitive inhibitor of mushroom tyrosinase. Furthermore, compounds 2 and 8 inhibited tyrosinase activity and melanin production in B16F10 cells. In addition, compounds 2-4 and 8 proved to have an interesting antioxidant profile in both ABTS and DPPH radicals scavenging assays. Docking experiments were carried out in order to study the interactions between these heteroarylcoumarins and mushroom tyrosinase.

Synthesis, antioxidant and antichagasic properties of a selected series of hydroxy-3-arylcoumarins.

Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2.23) and a high degree of selectivity towards epimastigotes stage of the parasite T. cruzi (IC50=1.31µM), higher than Nifurtimox (drug currently used for treatment of Chagas disease). Interestingly, the current study revealed that small structural changes in the hydroxy-3-arylcoumarin core allow modulating both activities, suggesting that this scaffold has desirable properties for the development of promising classes of antichagasic compounds.

Facing Chagas' disease: trypanocidal properties of new coumarin-chalcone scaffolds.

With the aim of finding new chemical entities based on coumarin and chalcone scaffolds, new hybrid compounds 2-5 were designed and synthesized. The trypanocidal activity of these compounds was tested against the epimastigote, trypomastigote and amastigote stages of the Trypanosoma cruzi parasite. Cytotoxicity assays were also performed in RAW 264.7 and VERO cells. Compound 5 presented the highest trypanocidal activity of the series, with trypanocidal values higher than nifurtimox for the trypomastigote and epimastigote stages., but presenting cytotoxic effects in the mammalian cells. A SAR study suggested that methoxy substitution at positions 2 and 5 in the designed scaffold seemed to be a key feature for the trypanocidal activity. Therefore, the coumarin-chalcone scaffold can be taken into account for further lead optimization and design new and more effective trypanocidal compounds.

3-Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases.

Monoamine oxidase (MAO) generates reactive oxygen species (ROS), which cause neuronal cell death, causing neurodegeneration. Agents that are able to concurrently inhibit MAO and scavenge free radicals represent promising multifunctional neuroprotective agents that could be used to delay or slow the progression of neurodegenerative diseases. In this work, variously substituted 3-amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1-diphenyl-2-picrylhydrazyl (DPPH⋅) radical scavenging assay. Selective and reversible inhibitors of the MAO-B isoform were identified. Interestingly, in the case of the 3-benzamidocoumarins, substitution at position 4 with a hydroxy group abolishes MAO-B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3-heteroarylamide derivatives indicates that it is the nature of the heterocycle that determines the neuroprotective effects. Evaluation in a parallel artificial membrane permeability assay (PAMPA) highlighted the need to further improve the blood-brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski's rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates.

Design, synthesis and antibacterial study of new potent and selective coumarin-chalcone derivatives for the treatment of tenacibaculosis.

With the aim of finding new chemical entities selective for fish pathogens to avoid drug resistance in humans, a series of coumarin-chalcone hybrid compounds with different patterns of substitution were designed and synthesized. Their antibacterial activity was evaluated against important types of human bacteria strains (Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa) and against a fourteen strains of the marine pathogen Tenacibaculum maritimum, responsible for tenacibaculosis in fish, which is an important disease that causes great economical loss in the aquaculture industry. All the amino derivatives 5-12 presented high activity against different strains of T. maritimum, no activity against any of the three human pathogenic bacteria strains and no toxicity. Compounds 6, 7 and 11 were the most promising molecules. The most sensitive strains to these compounds were LL01 8.3.8 and LL01 8.3.1, being compound 11 up to 20 times more active than enrofloxacin. Therefore these scaffolds are good candidates for aquaculture treatments, avoiding possible drug resistance problems in humans.

Synthesis and pharmacological activities of non-flavonoid chromones: a patent review (from 2005 to 2015).

INTRODUCTION: Chromones are one of the major classes of naturally occurring compounds. Their chemistry has been widely explored and extensively reviewed. The following review intends to give a broad overview of the patented chromones. Particular attention has been given to their synthesis, uses and applications in last 10 years. AREAS COVERED: The authors provide an overview of the recent scientific reports describing the obtaining and study of new chromones. The review emphasizes the rationale behind natural sources, synthesis, biological activities and structure-activity relationships of the new chromone derivatives. The article is based on the literature published from 2005 to 2015 related to the development of this family of compounds. The patents presented in this review have been collected from multiple electronic databases including SciFinder, Espacenet and Mendeley. EXPERT OPINION: Although a great number of chromones have been published in bibliographic sources in the last years, there is little innovation in the synthetic methodologies. Some natural sources and isolation techniques were described. Different pharmacological applications have also been claimed. Two of the most studied applications have been the use of these compounds as therapeutic agents for cancer and skin diseases. Some safety requirements need to be developed in order to find new chemical entities as new drugs.

Development of novel adenosine receptor ligands based on the 3-amidocoumarin scaffold.

With the aim of finding new adenosine receptor (AR) ligands presenting the 3-amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1-8 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30-fold selective for the A3 AR (Ki=3.24 µM). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A1, A2A, and/or A3 AR ligands. We also performed docking calculations in hA2A and hA3 to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates.