2H-chromene and 7H-furo-chromene derivatives selectively inhibit tumour associated human carbonic anhydrase IX and XII isoforms.

Tumour associated carbonic anhydrases (CAs) IX and XII have been recognised as potential targets for the treatment of hypoxic tumours. Therefore, considering the high pharmacological potential of the chromene scaffold as selective ligand of the IX and XII isoforms, two libraries of compounds, namely 2H-chromene and 7H-furo-chromene derivatives, with diverse substitution patterns were designed and synthesised. The structure of the newly synthesised compounds was characterised and their inhibitory potency and selectivity towards human CA off target isoforms I, II and cancer-associated CA isoforms IX and XII were evaluated. Most of the compounds inhibit CA isoforms IX and XII with no activity against the I and II isozymes. Thus, while the potency was influenced by the substitution pattern along the chromene scaffold, the selectivity was conserved along the series, confirming the high potential of both 2H-chromene and 7H-furo-chromene scaffolds for the design of isozyme selective inhibitors.

Design of 3-Phenylcoumarins and 3-Thienylcoumarins as Potent Xanthine Oxidase Inhibitors: Synthesis, Biological Evaluation, and Docking Studies.

Coumarin scaffold has proven to be promising in the development of bioactive agents, such as xanthine oxidase (XO) inhibitors. Novel hydroxylated 3-arylcoumarins were designed, synthesized, and evaluated for their XO inhibition and antioxidant properties. 3-(3'-Bromophenyl)-5,7-dihydroxycoumarin (compound 11) proved to be the most potent XO inhibitor, with an IC50 of 91 nM, being 162 times better than allopurinol, one of the reference controls. Kinetic analysis of compound 11 and compound 5 [3-(4'-bromothien-2'-yl)-5,7-dihydroxycoumarin], the second-best compound within the series (IC50 of 280 nM), has been performed, and both compounds showed a mixed-type inhibition. Both compounds present good antioxidant activity (ability to scavenge ABTS radical) and are able to reduce reactive oxygen species (ROS) levels in H2 O2 -treated cells. In addition, they proved to be non-cytotoxic in a Caco-2 cells viability assay. Molecular docking studies have been carried out to correlate the compounds' theoretical and experimental binding affinity to the XO binding pocket.

Propargylamine: an important moiety in drug discovery.

Propargylamine is a chemical moiety whose properties have made it a widely distributed group within the fields of medicinal chemistry and chemical biology. Its particular reactivity has traditionally popularized the preparation of propargylamine derivatives using a large variety of synthetic strategies, which have facilitated the access to these compounds for the study of their biomedical potential. This review comprehensively covers and analyzes the applications that propargylamine-based derivatives have achieved in the drug discovery field, both from a medicinal chemistry perspective and from a chemical biology-oriented approach. The principal therapeutic fields where propargylamine-based compounds have made an impact are identified, and a discussion of their influence and growing potential is included.

Phytochemical Analysis and Antiproliferative Activity of Ulex gallii Planch. (Fabaceae), a Medicinal Plant from Galicia (Spain).

The genus Ulex comprises thirteen accepted species of perennial shrubs in the family Fabaceae. In Galicia (Spain) many of these are considered spontaneous colonizing species, which are easy to establish and maintain. Among them, Ulex gallii Planch. is used in traditional medicine for the same anti-infective, hypotensive and diuretic purposes as Ulex europaeus L., which is the most studied species. Likewise, some studies have described the antitumoral properties of several species. However, there are few scientific studies that justify the use of Ulex gallii Planch. and nothing has been reported about its composition to date. In our study, the entire plant was extracted with methanol and the crude extract was subjected to liquid phase extraction with distinct solvents, yielding three fractions: hexane (H), dichloromethane (D) and methanol (M), which were subsequently fractionated. The dichloromethane (D5, D7 and D8) and methanol (M4) sub-fractions showed antiproliferative activity on A549 (lung cancer) and AGS (stomach cancer) cell lines, and caspase 3/7 activity assessment and DNA quantification were also performed. Targeted analysis via UHPLC-QToF, in combination with untargeted analysis via MS-Dial, MS-Finder and Global Natural Products Social Molecular Networking (GNPS), allowed us to tentatively identify different metabolites in these sub-fractions, mostly flavonoids, that might be involved in their antiproliferative activity.

8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies.

Psychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 µL min-1 mg-1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression.

Modulating Cytotoxicity with Lego-like Chemistry: Upgrading Mitochondriotropic Antioxidants with Prototypical Cationic Carrier Bricks.

Although the lipophilic triphenylphosphonium (TPP+) cation is widely used to target antioxidants to mitochondria, TPP+-based derivatives have shown cytotoxicity in several biological in vitro models. We confirmed that Mito.TPP is cytotoxic to both human neuronal (SH-SY5Y) and hepatic (HepG2) cells, decreasing intracellular adenosine triphosphate (ATP) levels, leading to mitochondrial membrane depolarization and reduced mitochondrial mass after 24 h. We surpassed this concern using nitrogen-derived cationic carriers (Mito.PICO, Mito.ISOQ, and Mito.IMIDZ). As opposed to Mito.TPP, these novel compounds were not cytotoxic to SH-SY5Y and HepG2 cells up to 50 µM and after 24 h of incubation. All of the cationic derivatives accumulated inside the mitochondrial matrix and acted as neuroprotective agents against iron(III), hydrogen peroxide, and tert-butyl hydroperoxide insults. The overall data showed that nitrogen-based cationic carriers can modulate the biological performance of mitochondria-directed antioxidants and are an alternative to the TPP cation.

Hydroxy-3-Phenylcoumarins as Multitarget Compounds for Skin Aging Diseases: Synthesis, Molecular Docking and Tyrosinase, Elastase, Collagenase and Hyaluronidase Inhibition, and Sun Protection Factor.

Skin aging is a progressive biological process of the human body, and it is not only time-dependent. Differently substituted 3-phenylcoumarins proved to efficiently inhibit tyrosinase. In the current work, new substitution patterns have been explored, and the biological studies were extended to other important enzymes involved in the processes of skin aging, as elastase, collagenase and hyaluronidase. From the studied series, five compounds presented inhibitory activity against tyrosinase, one compound against elastase, eight compounds against collagenase and two compounds against hyaluronidase, being five compounds dual inhibitors. The 3-(4'-Bromophenyl)-5,7-dihydroxycoumarin (1) and 3-(3'-bromophenyl)-5,7-dihydroxycoumarin (2) presented the best profiles against tyrosinase (IC50 = 1.05 µM and 7.03 µM) and collagenase (IC50 = 123.4 µM and 110.4 µM); the 3-(4'-bromophenyl)-6,7-dihydroxycoumarin (4) presented a good inhibition against tyrosinase and hyaluronidase; the 3-(3'-bromophenyl)-6,7-dihydroxycoumarin (5) showed an effective tyrosinase and elastase inhibition; and 6,7-dihydroxy-3-(3'-hydroxyphenyl)coumarin (11) presented a dual profile inhibition against collagenase and hyaluronidase. Furthermore, considering the overall activities tested, compounds 1 and 2 proved to be the most promising anti-aging compounds. These compounds also showed to have a photo-protective effect, without being cytotoxic to human skin keratinocyte cells. To predict the binding site with the target enzymes, computational studies were also carried out.

Synthesis and Vasorelaxant Activity of Nitrate-Coumarin Derivatives.

Due to the need for new chemical entities for cardiovascular diseases, we have synthesized a new series of nitrate-coumarins and evaluated their vasorelaxant activity in contraction-relaxation studies using rat aorta rings precontracted with phenylephrine or by depolarization with a high concentration of potassium chloride. Four of the new compounds were able to relax smooth vascular muscle with a similar profile and potency to glyceryl trinitrate (IC50 =12.73 nM) and sodium nitroprusside (IC50 =4.32 nM). Coumarin-7-yl-methyl nitrate (4), the best compound within the series, was able to relax smooth vascular muscle in the low nanomolar range (IC50 =1.92 nM). The mechanisms of action have been explored, being the activation of sGC and the opening of K+ channels involved. Our studies indicate that the new nitrate derivatives are reversible and not deleterious for aortic rings, suggesting that these compounds have a potential interest for the development of new and highly efficient vasodilator drugs.

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.

Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties.

The absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug-like profile, and for the first time we obtained potent and selective chromone 2-phenylcarboxamides acting in the low nanomolar range. Compounds 5-hydroxy-4-oxo-N-phenyl-4H-chromene-3-carboxamide (38) (IC50 = 13.0 nM) and N-(4-chlorophenyl)-5-hydroxy-4-oxo-4H-chromene-3-carboxamide (41) (IC50 = 8.3 nM) stood out as reversible, potent, selective and non-cytotoxic MAO-B inhibitors bearing a favourable drug-like profile. Both compounds displayed cytoprotective effects towards iron(III) oxidative stressor.

Coumarin-Resveratrol-Inspired Hybrids as Monoamine Oxidase B Inhibitors: 3-Phenylcoumarin versus trans-6-Styrylcoumarin.

Monoamine oxidases (MAOs) are attractive targets in drug design. The inhibition of one of the isoforms (A or B) is responsible for modulating the levels of different neurotransmitters in the central nervous system, as well as the production of reactive oxygen species. Molecules that act selectively on one of the MAO isoforms have been studied deeply, and coumarin has been described as a promising scaffold. In the current manuscript we describe a comparative study between 3-phenylcoumarin (endo coumarin-resveratrol-inspired hybrid) and trans-6-styrylcoumarin (exo coumarin-resveratrol-inspired hybrid). Crystallographic structures of both compounds were obtained and analyzed. 3D-QSAR models, in particular CoMFA and CoMSIA, docking simulations and molecular dynamics simulations have been performed to support and better understand the interaction of these molecules with both MAO isoforms. Both molecules proved to inhibit MAO-B, with trans-6-styrylcoumarin being 107 times more active than 3-phenylcoumarin, and 267 times more active than trans-resveratrol.

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.

Curcumin-Coumarin Hybrid Analogues as Multitarget Agents in Neurodegenerative Disorders.

Neurodegenerative diseases have a complex nature which highlights the need for multitarget ligands to address the complementary pathways involved in these diseases. Over the last decade, many innovative curcumin-based compounds have been designed and synthesized, searching for new derivatives having anti-amyloidogenic, inhibitory of tau formation, as well as anti-neuroinflammation, antioxidative, and AChE inhibitory activities. Regarding our experience studying 3-substituted coumarins with interesting properties for neurodegenerative diseases, our aim was to synthesize a new series of curcumin-coumarin hybrid analogues and evaluate their activity. Most of the 3-(7-phenyl-3,5-dioxohepta-1,6-dien-1-yl)coumarin derivatives 11-18 resulted in moderated inhibitors of hMAO isoforms and AChE and BuChE activity. Some of them are also capable of scavenger the free radical DPPH. Furthermore, compounds 14 and 16 showed neuroprotective activity against H2O2 in SH-SY5Y cell line. Nanoparticles formulation of these derivatives improved this property increasing the neuroprotective activity to the nanomolar range. Results suggest that by modulating the substitution pattern on both coumarin moiety and phenyl ring, ChE and MAO-targeted derivatives or derivatives with activity in cell-based phenotypic assays can be obtained.

New benzimidazolequinones as trypanosomicidal agents.

Herein, the design and synthesis of new 2-phenyl(pyridinyl)benzimidazolequinones and their 5-phenoxy derivatives as potential anti-Trypanosoma cruzi agents are described. The compounds were evaluated in vitro against the epimastigotes and trypomastigote forms of Trypanosoma cruzi. The replacing of a benzene moiety in the naphthoquinone system by an imidazole enhanced the trypanosomicidal activity against Trypanosoma cruzi. Three of the tested compounds (11a-c) showed potent trypanosomicidal activity and compound 11a, with IC50 of 0.65 µM on the trypomastigote form of T. cruzi, proved to be 15 times more active than nifurtimox. Additionally, molecular docking studies indicate that the quinone derivatives 11a-c could have a multitarget profile interacting preferentially with trypanothione reductase and Old Yellow Enzyme.

Combined 3D-QSAR and docking analysis for the design and synthesis of chalcones as potent and selective monoamine oxidase B inhibitors.

Monoamine oxidases (MAOs) are important targets in medicinal chemistry, as their inhibition may change the levels of different neurotransmitters in the brain, and also the production of oxidative stress species. New chemical entities able to interact selectively with one of the MAO isoforms are being extensively studied, and chalcones proved to be promising molecules. In the current work, we focused our attention on the understanding of theoretical models that may predict the MAO-B activity and selectivity of new chalcones. 3D-QSAR models, in particular CoMFA and CoMSIA, and docking simulations analysis have been carried out, and their successful implementation was corroborated by studying twenty-three synthetized chalcones (151-173) based on the generated information. All the synthetized molecules proved to inhibit MAO-B, being ten out of them MAO-B potent and selective inhibitors, with IC50 against this isoform in the nanomolar range, being (E)-3-(4-hydroxyphenyl)-1-(2,2-dimethylchroman-6-yl)prop-2-en-1-one (152) the best MAO-B inhibitor (IC50 of 170 nM). Docking simulations on both MAO-A and MAO-B binding pockets, using compound 152, were carried out. Calculated affinity energy for the MAO-A was +2.3 Kcal/mol, and for the MAO-B was -10.3 Kcal/mol, justifying the MAO-B high selectivity of these compounds. Both theoretical and experimental structure-activity relationship studies were performed, and substitution patterns were established to increase MAO-B selectivity and inhibitory efficacy. Therefore, we proved that both 3D-QSAR models and molecular docking approaches enhance the probability of finding new potent and selective MAO-B inhibitors, avoiding time-consuming and costly synthesis and biological evaluations.

4-Oxoquinolines and monoamine oxidase: When tautomerism matters.

4-Oxoquinoline derivatives have been often used in drug discovery programs due to their pharmacological properties. Inspired on chromone and 4-oxoquinoline chemical structure similarity, a small series of quinoline-based compounds was obtained and screened, for the first time, toward human monoamine oxidases isoforms. The data showed the N-(3,4-dichlorophenyl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide 10 was the most potent and selective MAO-B inhibitor (IC50 = 5.30 ± 0.74 nM and SI: ≥1887). The data analysis showed that prototropic tautomerism markedly influences the biological activity. The unequivocal characterisation of the quinoline tautomers was performed to understand the attained data. To our knowledge, there have been no prior reports on the characterisation of quinolone tautomers by 2D NMR techniques, namely by 1H-15N HSQC and 1H-15N HMBC, which are proposed as expedite tools for medicinal chemistry campaigns. Computational studies on enzyme-ligand complexes, obtained after MM-GBSA calculations and molecular dynamics simulations, supported the experimental data.

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.

7-Amidocoumarins as Multitarget Agents against Neurodegenerative Diseases: Substitution Pattern Modulation.

This study explores the potential of 7-amidocoumarins as multitarget agents against Parkinson's and Alzheimer's diseases, by modulating the substitution patterns within the scaffold. Sixteen compounds were synthesized via 7-amino-4-methylcoumarin acylation, and in vitro evaluation of the molecules against hMAO-A, hMAO-B, hAChE, hBuChE and hBACE1 was performed. Five compounds turned out to be potent and selective hMAO-B inhibitors in the nanomolar range, six displayed inhibitory activity of hMAO-A in the low micromolar range, one showed hAChE inhibitory activity and another one hBACE1 inhibitory activity. MAO-B reversibility profile of 7-(4'-chlorobenzamido)-4-methylcoumarin (10) was investigated, with this compound being a reversible inhibitor. Neurotoxicity on motor cortex neurons and neuroprotection against H2 O2 were also studied, corroborating the safety profile of these molecules. Finally, theoretical ADME properties were also calculated, showing these molecules as good candidates for the optimization of a lead compound. Results suggest that by modulating the substitution pattern at position 7 of the scaffold, selective or multitarget molecules can be achieved.

Adenosine Receptor Ligands: Coumarin-Chalcone Hybrids as Modulating Agents on the Activity of hARs.

Adenosine receptors (ARs) play an important role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. The different subtypes of ARs and the knowledge on their densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Looking for new scaffolds for selective AR ligands, coumarin-chalcone hybrids were synthesized (compounds 1-8) and screened in radioligand binding (hA1, hA2A and hA3) and adenylyl cyclase (hA2B) assays in order to evaluate their affinity for the four human AR subtypes (hARs). Coumarin-chalcone hybrid has been established as a new scaffold suitable for the development of potent and selective ligands for hA1 or hA3 subtypes. In general, hydroxy-substituted hybrids showed some affinity for the hA1, while the methoxy counterparts were selective for the hA3. The most potent hA1 ligand was compound 7 (Ki = 17.7 µM), whereas compound 4 was the most potent ligand for hA3 (Ki = 2.49 µM). In addition, docking studies with hA1 and hA3 homology models were established to analyze the structure-function relationships. Results showed that the different residues located on the protein binding pocket could play an important role in ligand selectivity.