Furvina inhibits the 3-oxo-C12-HSL-based quorum sensing system of Pseudomonas aeruginosa and QS-dependent phenotypes.

Disruption of cell-cell communication or quorum sensing (QS) is considered a stimulating approach for reducing bacterial pathogenicity and resistance. Although several QS inhibitors (QSIs) have been discovered so far their clinical use remains distant. This problem can be circumvented by searching for QSI among drugs already approved for the treatment of different diseases. In this context, antibiotics have earned special attention. Whereas at high concentrations antibiotics exert a killing effect, at lower concentrations they may act as signaling molecules and as such can modulate gene expression. In this study, the antibiotic furvina was shown to be able to cause inhibition of the 3-oxo-C12-HSL-dependent QS system of Pseudomonas aeruginosa. Furvina interacts with the LasI/LasR system. The data were validated by modeling studies. Furvina can also reduce biofilm formation and decrease the production of QS-controlled virulence factors.

Effect of Sublethal Nickel Chloride Exposure on Crayfish, Astacus leptodactylus Ovary: An Ultrastructural, Autometallographic, and Electrophoretic Analyses.

Cytological responses in different organs of sentinel organisms have proven to be useful tools for characterizing the health status of those organisms and assessing the impact of environmental contaminants. Our study shows that nickel (II) accumulated in both germ cells (oogonia and developing oocytes) and somatic cells (muscle cells, follicle cells) in the Astacus leptodactylus ovary. Muscle cells from ovarian wall show disorganization and the disruption of cytoplasmic microtubules and pyknosis of the cell nucleus. Follicle cells, both those that surround the developing oocytes and also those that are not associated with the oocytes contained within the cytoplasm vacuoles of different sizes, degenerated mitochondria, myelin bodies, disorganized microtubules, and pyknotic nuclei. The most evident pathological phenomenon was the alteration and disorganization of the basal matrix, which separates the ovarian interstitium from ovarian follicles compartment. Exposure to nickel induces cytoplasmic vacuolation in oogonia and developing oocytes, structural alteration of the developing yolk granules and condensation of the nucleoli. Ultrastructural autometallography has shown grains of silver-enhanced nickel inside the cytoplasm of the muscle cells with altered morphology, including the cytoplasm, nucleus, and basal matrix of the follicle cells, and in intracisternal granules and developing yolk granules of the oocytes.

Biological and Medicinal Properties of Natural Chromones and Chromanones.

Emerging threats to human health require a concerted effort to search for new treatment therapies. One of the biggest challenges is finding medicines with few or no side effects. Natural products have historically contributed to major advances in the field of pharmacotherapy, as they offer special characteristics compared to conventional synthetic molecules. Interest in natural products is being revitalized, in a continuous search for lead structures that can be used as models for the development of new medicines by the pharmaceutical industry. Chromone and chromanones are recognized as privileged structures and useful templates for the design of diversified therapeutic molecules with potential pharmacological interest. Chromones and chromanones are widely distributed in plants and fungi, and significant biological activities, namely antioxidant, anti-inflammatory, antimicrobial, antiviral, etc., have been reported for these compounds, suggesting their potential as lead drug candidates. This review aims to update the literature published over the last 6 years (2018-2023) regarding the natural occurrence and biological activity of chromones and chromanones, highlighting the recent findings and the perspectives that they hold for future research and applications namely in health, cosmetic, and food industries.

Drug Development for Alzheimer's and Parkinson's Disease: Where Do We Go Now?

Neurodegenerative diseases (NDs) are a set of progressive, chronic, and incurable diseases characterized by the gradual loss of neurons, culminating in the decline of cognitive and/or motor functions. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common NDs and represent an enormous burden both in terms of human suffering and economic cost. The available therapies for AD and PD only provide symptomatic and palliative relief for a limited period and are unable to modify the diseases' progression. Over the last decades, research efforts have been focused on developing new pharmacological treatments for these NDs. However, to date, no breakthrough treatment has been discovered. Hence, the development of disease-modifying drugs able to halt or reverse the progression of NDs remains an unmet clinical need. This review summarizes the major hallmarks of AD and PD and the drugs available for pharmacological treatment. It also sheds light on potential directions that can be pursued to develop new, disease-modifying drugs to treat AD and PD, describing as representative examples some advances in the development of drug candidates targeting oxidative stress and adenosine A2A receptors.

Synthesis and NMR studies of novel chromone-2-carboxamide derivatives.

Chromones are heterocyclic compounds of natural or synthetic origin that possess relevant pharmacological activities. Versatile functionalization of the chromone nucleus allows attaining of a chemical diversity suitable to perform structure-activity relationships in drug discovery and development programs. Accordingly, the synthesis and identification of novel chromone carboxamide derivatives with electron-donating and electron-withdrawing substituents in different positions of the exocyclic ring are reported in this work. Their complete structural characterization was performed using one-dimensional and two-dimensional resonance techniques. The data acquired are useful for a prompt analysis of related compounds that encompass our integrated medicinal chemistry sketch.

4-Oxo-N-phenyl-4H-chromene-2-carboxamide and of a new polymorph of 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide and its hemihydrate.

4-Oxo-N-phenyl-4H-chromene-2-carboxamide, C16H11NO3, crystallizes in the space group P2(1)/n and its derivative 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide, C18H15NO4, forms two polymorphs which crystallize in the space groups P2(1)/c and P1. The structures have an anti-rotamer conformation about the C-N bond; however, the amide O atom can be either trans- or cis-related to the O atom of the pyran ring. The latter compound also crystallizes as a hemihydrate, C18H15NO4·0.5H2O, in the space group C2/c. This compound has a similar structure to that of the unsolvated compound.

The Effect of a Single Bout of Resistance Exercise with Blood Flow Restriction on Arterial Stiffness in Older People with Slow Gait Speed: A Pilot Randomized Study.

Purpose: Low-intensity resistance exercise with moderate blood-flow restriction (LIRE-BFR) is a new trending form of exercises worldwide. The purpose of this study was to compare the acute effect of a single bout of traditional resistance exercise (TRE) and LIRE-BFR on arterial stiffness in older people with slow gait speeds. Methods: This was a randomized, controlled clinical study. Seventeen older adults (3 men; 14 women; 82 ± 5 years old) completed a session of TRE (n = 7) or LIRE-BFR (n = 10). At baseline and after 60 min post-exercise, participants were subject to blood pressure measurement, heart rate measurements and a determination of arterial stiffness parameters. Results: There was no significant difference between the TRE and LIRE-BFR group at baseline. Pulse-wave velocity increased in both groups (p < 0.05) post-exercise with no between-group differences. Both exercise modalities did not produce any adverse events. The increase in systolic blood pressure, pulse pressure, augmentation pressure and pulse wave velocity (all p > 0.05) were similar after both TRE and LIRE-BFR. Conclusion: TRE and LIRE-BFR had similar responses regarding hemodynamic parameters and pulse-wave velocity in older people with slow gait speed. Long-term studies should assess the cardiovascular risk and safety of LIRE-BFR training in this population.

Chromone 3-phenylcarboxamides as potent and selective MAO-B inhibitors.

Monoamine oxidase (MAO) is an enzyme, present in mammals in two isoforms MAO-A and MAO-B. These isoforms have a crucial role in neurotransmitters metabolism, representing an attractive drug target in the therapy of neurodegenerative diseases (MAO-B) and depression (MAO-A). In this context, our work has been focused on the discovery of new chemical entities (NCEs) for MAO inhibition, based on the development of chromone carboxamides. Chromone derivatives with a carboxamide function located in position 2- and 3- of the benzo-γ-pyrone core, (compounds 2-6 and 8-12) were synthesized, with moderate/good yields, by a one-pot condensation reaction using phosphonium salts as coupling reagents. The synthetic compounds were screened towards human MAO isoforms (hMAO) to evaluate their potency and selectivity. The chromone-3-carboxamides show high selectivity to hMAO-B, with compounds 9 and 12 displaying IC(50) values at nanomolar range.

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.

Mapping Chromone-3-Phenylcarboxamide Pharmacophore: Quid Est Veritas?

Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.

Chromone-2- and -3-carboxylic acids inhibit differently monoamine oxidases A and B.

Chromone carboxylic acids were evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. The biological data indicated that only chromone-3-carboxylic acid is a potent hMAO-B inhibitor, with a high degree of selectivity for hMAO-B compared to hMAO-A. Conversely the chromone-2-carboxylic acid resulted almost inactive against both MAO isoforms. Docking experiments were performed to elucidate the reasons of the different MAO IC(50) data and to explain the absence of activity versus selectivity, respectively.

The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-di-methyl-anilino)-N-(3,4-di-methyl-phen-yl)quinoline-3-carboxamide.

The structure of the title quinoline carboxamide derivative, C26H25N3O, is described. The quinoline moiety is not planar as a result of a slight puckering of the pyridine ring. The secondary amine has a slightly pyramidal geometry, certainly not planar. Both intra- and inter-molecular hydrogen bonds are present. Hirshfeld surface analysis and lattice energies were used to investigate the inter-molecular inter-actions.

The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease.

The discovery and development of multitarget-directed ligands (MTDLs) is a promising strategy to find new therapeutic solutions for neurodegenerative diseases (NDs), in particular for Alzheimer's disease (AD). Currently approved drugs for the clinical management of AD are based on a single-target strategy and focus on restoring neurotransmitter homeostasis. Finding disease-modifying therapies AD and other NDs remains an urgent unmet clinical need. The growing consensus that AD is a multifactorial disease, with several interconnected and deregulated pathological pathways, boosted an intensive research in the design of MTDLs. Due to this scientific boom, the knowledge behind the development of MTDLs remains diffuse and lacks balanced guidelines. To rationalize the large amount of data obtained in this field, we herein revise the progress made over the last 5 years on the development of MTDLs inspired by drugs approved for AD. Due to their putative therapeutic benefit in AD, MTDLs based on MAO-B inhibitors will also be discussed in this review.

The Effects of Resistance Exercise With Blood Flow Restriction on Flow-Mediated Dilation and Arterial Stiffness in Elderly People With Low Gait Speed: Protocol for a Randomized Controlled Trial.

BACKGROUND: During aging, a significant loss of muscle mass, strength, and power is associated with a decline in daily functional capacities. Traditionally, resistance training is prescribed to prevent or reverse the skeletal muscle weakness, but the required training intensity may be too demanding for older people with poor physical performance. Resistance exercise with blood flow moderation (KAATSU training), originally developed in Japan, combines resistance exercise with blood flow restriction. It has been reported that KAATSU training enhances muscle hypertrophy in many populations. However, few studies have evaluated the effects of resistance exercises with blood flow restriction in elderly people and how this affects vascular structure and function. OBJECTIVE: The aim of this study was to evaluate (1) the acute and chronic effects of resistance exercise with blood flow restriction on vascular health in elderly people with low gait speed and (2) whether low-load resistance training with blood flow restriction elicits similar strength and gait speed gains to those elicited by conventional resistance training without blood flow restriction. METHODS: This is an ongoing randomized controlled trial in elderly people with low gait speed. Overall, two study arms of 13 participants each perform resistance exercise with and without blood flow restriction. The 2 groups are as follows: the control group will perform conventional resistance exercise (60% of 1 repetition maximum) and the KAATSU group will perform the low-load resistance exercise with blood flow restriction (20% of 1 repetition maximum) for 12 weeks. Pulse wave velocity, venous occlusion plethysmography, and flow-mediated dilation are used to assess arterial stiffness, muscle blood flow, and endothelial function, respectively. The secondary outcomes are gait speed, strength, and quality of life. All measures will be performed before and after the training program. RESULTS: This research study is in progress. Recruitment has started, and data collection is expected to finish in August 2020. CONCLUSIONS: The findings of this study will have important implications for the rehabilitation of elderly people. TRIAL REGISTRATION: ClinicalTrials.gov NCT03272737; https://clinicaltrials.gov/ct2/show/NCT03272737. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14691.

Searching for new cytotoxic agents based on chromen-4-one and chromane-2,4-dione scaffolds.

Cancer is a major cause of death worldwide and novel anticancer agents for its better management are much needed. Benzopyrone-based compounds, such as chromones, possess several distinctive chemical and biological properties, of which the cytotoxicity against cancer cells seems to be prominent. In this study, two series of compounds based on chromen-4-one (3-10) and chromane-2,4-dione (11-18) scaffolds were synthesized in moderate/high yields and evaluated for cytotoxicity against HL-60, MOLT-4, and MCF-7 cancer cells using MTT assay. In general, the compounds exhibited moderate cytotoxic effects against the cancer cell lines, among which, a superior potency could be observed against MOLT-4 cells. Chroman-2,4-dione (11-18) derivatives had overall higher potencies compared to their chromen-4-one (3-10) counterparts. Compound 13 displayed the lowest IC50 values against HL-60 (IC50, 42.0 ± 2.7 µM) and MOLT-4 cell lines (IC50, 24.4 ± 2.6 µM), while derivative 11 showed the highest activity against MCF-7 cells (IC50, 68.4 ± 3.9 µM). In conclusion, this study provides important information on the cytotoxic effects of chromone derivatives. Benzochroman-2,4-dione has been identified as a promising scaffold, which its potency can be modulated by tailored synthesis with the aim of finding novel and dissimilar anticancer compounds.

Teste de Caminhada de Seis Minutos e Teste de Marcha Estacionária de Dois Minutos em uma população idosa participante de um programa de reabilitação cardíaca / Analysis and correlation of the Six-Minute Walk Test and Two-Minute Step Test in an elderly population participating in a cardiac rehabilitation program

The six-minute walk test (6MWT) and two-minute step test (2MST) are submaximal tests widely used in the elderly population functional capacity evaluation. Objective: To investigate whether the cardiac rehabilitation (CR) program was able to promote an increase in these tests and if there was an association between them; and to compare the hemodynamic stress caused by each of the tests. Methods: Retrospective, observational study in elderly participants in CR program. 24 elderly people were evaluated and classified according to the Fried frailty phenotype. The 6MWT and the 2MST were applied, observing the mean distance walked and the number of steps performed, respectively, as well as the double cardiac product (DP) at the beginning and after 4 months of the CR program. Results: There was an increase of 57 meters in the mean distance covered by the 6MWT (364.31±108.01 vs. 421.65±108.73, P<0.001) and 14 steps performed in the 2MST (62.17±22.50 vs. 76.17±25.56, P= 0.011) after 4 months of CR and we found a significant correlation between the tests and their results (P <0.001). When comparing the DP, both tests had a significant reduction (14469.92±2497.91 vs. 13348.21±2839.36, P= 0.022 and 15744.17±3591.87 vs. 13222.29±2505.39, P<0.001; respectively). Conclusion: A relationship between the number of steps performed in the 2MST with the mean distance covered of 6MWT suggest the use of them as an effective indicator in CR program and the association between them offers greater possibilities for treatment and evaluation of an elderly population.

O teste de caminhada de seis minutos (TC6m) e o teste de marcha estacionária de dois minutos (TME2min) são testes submáximos amplamente utilizados na avaliação da capacidade funcional da população idosa. Objetivo: Investigar se o programa de reabilitação cardíaca (RC) foi capaz de promover melhora nesses testes e se houve associação entre eles; além de comparar o estresse hemodinâmico causado por cada um dos testes nessa população. Métodos: Estudo retrospectivo e observacional em idosos participantes do programa de RC. Foram avaliados 24 idosos e classificados de acordo com o fenótipo de fragilidade de Fried. Foram aplicados o TC6m e o TME2min, observando-se a distância média percorrida e o número de passos realizados, respectivamente, bem como o duplo produto cardíaco (DP) no início e após 4 meses do programa de RC. Resultados: Houve aumento de 57 metros na distância média percorrida no TC6m (364,31±108,01 vs. 421,65±108,73, P<0,001) e 14 passos realizados no TME2min (62,17±22,50 vs. 76,17±25,56, P= 0,011) após 4 meses de RC e encontramos correlação significativa entre os testes e seus resultados (P<0,001). Ao comparar o DP, ambos os testes tiveram redução significativa (14.469,92±2.497,91 vs. 13.348,21±2.839,36, P= 0,022 e 15.744,17±3.591,87 vs. 13.222,29±2.505,39, P<0,001; respectivamente). Conclusão: A relação entre o número de passos realizados no TME2min com a distância média percorrida no TC6m sugere a utilização deles como um indicador eficaz em programa de RC e a associação entre eles oferece maiores possibilidades de tratamento e avaliação de uma população idosa.

Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances.

The use of privileged structures in drug discovery has proven to be an effective strategy, allowing the generation of innovative hits/leads and successful optimization processes. Chromone is recognized as a privileged structure and a useful template for the design of novel compounds with potential pharmacological interest, particularly in the field of neurodegenerative, inflammatory, and infectious diseases as well as diabetes and cancer. This perspective provides the reader with an update of an earlier article entitled "Chromone: A Valid Scaffold in Medicinal Chemistry" ( Chem. Rev. 2014 , 114 , 4960 - 4992 ) and is mainly focused on chromones of biological interest, including those isolated from natural sources. Moreover, as drug repurposing is becoming an attractive drug discovery approach, recent repurposing studies of chromone-based drugs are also reported.