Consumption of drugs for Alzheimer's disease on the Brazilian private market.

OBJECTIVE: To analyze the consumption of drugs for Alzheimer's disease on the Brazilian private market and its geographical distribution from 2014 to 2020. METHODS: National data from the Brazilian National System of Controlled Product Management were used, regarding sales of donepezil, galantamine, rivastigmine, and memantine from January 2014 to December 2020. Sales data were used as a proxy for drug consumption and expressed as defined daily dose/1,000 inhabitants/year at national, regional, federative unit and microregion levels. RESULTS: Drug consumption went from 5,000 defined daily doses/1,000 inhabitants, in 2014, to more than 16,000/1,000 inhabitants, in 2020, and all federative units showed positive variation. The Brazilian Northeast had the highest cumulative consumption in the period but displayed microregional disparities while the North region had the lowest consumption. Donepezil and memantine were the most consumed drugs, with the highest growth in consumption from 2014 to 2020. CONCLUSION: The consumption of medicines indicated to treat Alzheimer's disease tripled in Brazil between 2014 and 2020, which may relate to the increase in the prevalence of the disease in the country, greater access to health services, and inappropriate use. This challenges managers and healthcare providers due to population aging and the increased prevalence of chronic-degenerative diseases.

Determination of ptaquiloside in ten species of Pteris in northwestern Argentina.

The toxic effect of ferns of the genus of Pteris in bovines is caused by ptaquiloside, the main carcinogenic toxin. In this study, ten species of Pteris fern in different phenologic stages and plant conditions were collected in northwest Argentina. The phytochemical analysis showed the presence of Pt in the recent collected samples (adults and young plants) but not in the herbarium specimens. The results show a great variation of Pt concentration that depends on the phenologic stage, plant condition, and collection site. Pt was measured in 6-4326 µg/g concentration, with a mean concentration of 644 µg/g. No Pt was detected in eight species of Pteris collected from herbarium samples; such results may be a false negative. It is important to notice that analysis of herbarium samples for Pt may not be a reliable method to determine its presence. It is important to further understand the potential toxicity caused by these ferns because of their effect on animals, public health, and the environment.

Development of an Amplicon-Based Next-Generation Sequencing Protocol to Identify Leishmania Species and Other Trypanosomatids in Leishmaniasis Endemic Areas.

Trypanosomatid infections are an important public health threat affecting many low-income countries across the tropics, particularly in the Americas. Trypanosomatids can infect many vertebrate, invertebrate, and plant species and play an important role as human pathogens. Among these clinically relevant pathogens are species from the genera Leishmania and Trypanosoma. Mixed trypanosomatid infections remain a largely unexplored phenomenon. Herein, we describe the application of an amplicon-based next-generation sequencing (NGS) assay to detect and identify trypanosomatid species in mammalian reservoirs, human patients, and sand fly vectors throughout regions of Leishmania endemicity. Sixty-five samples from different departments of Colombia, including two samples from Venezuela, were analyzed: 49 samples from cutaneous leishmaniasis (CL) patients, 8 from sand flies, 2 from domestic reservoirs (Canis familiaris), and 6 from wild reservoirs (Phyllostomus hastatus). DNA from each sample served to identify the presence of trypanosomatids through conventional PCR using heat shock protein 70 (HSP70) gene as the target. PCR products underwent sequencing by Sanger sequencing and NGS, and trypanosomatid species were identified by using BLASTn against a reference database built from trypanosomatid-derived HSP70 sequences. The alpha and beta diversity indexes of amplicon sequence variants were calculated for each group. The results revealed the presence of mixed infections with more than two Leishmania species in 34% of CL samples analyzed. Trypanosoma cruzi was identified in samples from wild reservoirs, as well as in sand fly vectors. Coinfection events with three different Leishmania species were identified in domestic reservoirs. These findings depose the traditional paradigm of leishmaniasis as being a single-species-driven infection and redraw the choreography of host-pathogen interaction in the context of multiparasitism. Further research is needed to decipher how coinfections may influence disease progression. This knowledge is key to developing an integrated approach for diagnosis and treatment. IMPORTANCE Traditionally, there has been a frequent, yet incorrect assumption that phlebotomine vectors, animal reservoirs, and human hosts are susceptible to Leishmania infection by a single parasite species. However, current evidence supports that these new vector-parasite-reservoir associations lend vectors and reservoirs greater permissiveness to certain Leishmania species, thus promoting the appearance of coinfection events, particularly in disease-endemic regions. The present study describes the application of an amplicon-based next-generation sequencing (NGS) assay to detect and identify trypanosomatid species in mammalian reservoirs, human patients, and sand fly vectors from regions of endemicity for leishmaniasis. This changes our understanding of the clinical course of leishmaniasis in areas of endemicity.

New Drugs 2021, Part 2.

ABSTRACT: The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective.

Leishmanicidal and cytotoxic activities and 4D-QSAR of 2-arylidene indan-1,3-diones.

The indan-1,3-dione and its derivatives are important building blocks in organic synthesis and present important biological activities. Herein, the leishmanicidal and cytotoxicity evaluation of 16 2-arylidene indan-1,3-diones is described. The compounds were evaluated against the leukemia cell lines HL60 and Nalm6, and the most effective ones were 2-(4-nitrobenzylidene)-1H-indene-1,3(2H)-dione (4) and 4-[(1,3-dioxo-1H-inden-2(3H)-ylidene)methyl]benzonitrile (10), presenting IC50 values of around 30 µmol/L against Nalm6. The leishmanicidal activity was assessed on Leishmania amazonensis, with derivative 4 (IC50 = 16.6 µmol/L) being the most active. A four-dimensional quantitative structure-activity analysis (4D-QSAR) was applied to the indandione derivatives, through partial least-squares regression. The statistics presented by the regression models built with the selected field descriptors of Coulomb (C) and Lennard-Jones (L) nature, considering the activities against L. amazonensis, HL60, and Nalm6 leukemia cells, were, respectively, R2 = 0.88, 0.92, and 0.98; Q2 = 0.83, 0.88, and 0.97. The presence of positive Coulomb descriptors near the carbonyl groups indicates that these polar groups are related to the activities. Besides, the presence of positive Lennard-Jones descriptors close to substituents R3 or R1 indicates that bulky nonpolar substituents in these positions tend to increase the activities. This study provides useful insights into the mode of action of indandione derivatives for each biological activity involved.

Synthesis, biological activity, and four-dimensional quantitative structure-activity analysis of 2-arylidene indan-1,3-dione derivatives tested against Daphnia magna.

A series of 18 2-arylidene indan-1,3-dione derivatives was synthesized and tested against Daphnia magna to assess the environmental toxicity of these compounds. Aiming to investigate the toxicity mechanism for this series of compounds, a four-dimensional quantitative structure-activity analysis (4D-QSAR) was performed through the partial least square regression (PLS). The best PLS model was built with two factors and the selected field descriptors, of Coulomb (C) and Lennard-Jones (L) nature, describing 77.43% of variance and presenting the following statistics: r 2 = 0.89; SEC = 0.30; Q 2 = 0.81; SEV = 0.36. According to the literature, the bioactivity of α,ß-unsaturated ketones, a functionality present in the series of compounds under investigation, is related to the conjugated double bond with the carbonyl group. The presence of a positive Coulomb descriptor nearby the carbonyl moieties, obtained as a result of the regression model, indicates that these polar groups are also related to the toxicity on D. magna. From the PLS regression model, the toxicity EC50-48 h values increases with the positive Coulomb descriptor and diminishes with the negative Lennard-Jones descriptors. It could be concluded that the presence of small polar groups in the aromatic ring of the arylidene moiety tends to increase the toxicity, while bulkier apolar substituents lead to a decrease of the toxicity.

Ptaquiloside and Pterosin B Levels in Mature Green Fronds and Sprouts of Pteridium arachnoideum.

Pteridium arachnoideum, a fern of the Pteridium aquilinum species complex found in South America, is responsible for several different syndromes of poisoning. Cases of bovine enzootic hematuria and upper alimentary squamous cell carcinoma are both frequent occurrences in Brazil, whereas only bovine enzootic hematuria is noted with any frequency around the world. The reason for the high frequency of upper alimentary squamous cell carcinoma in Brazil is not currently known. One possible explanation may be the higher levels of ptaquiloside and pterosin B in Brazilian Pteridium than those present in the plant in other countries. However, these levels have not yet been determined in P. arachnoideum. Thus, the present study aimed to measure and compare ptaquiloside and pterosin B levels in mature green fronds and sprouts of P. arachnoideum collected from different locations in Brazil. Samples of P. arachnoideum were collected from the states of Minas Gerais and Rio Grande do Sul. A total of 28 mature leaf samples and 23 sprout samples were used. The mean concentrations of ptaquiloside and pterosin B present in the mature green fronds of P. arachnoideum ranged from 2.49 to 2.75 mg/g and 0.68 to 0.88 mg/g, respectively; in P. arachnoideum sprouts, mean concentrations of ptaquiloside and pterosin B ranged from 12.47 to 18.81 mg/g, and 4.03 to 10.42 mg/g for ptaquiloside and pterosin B, respectively. Thus, ptaquiloside and pterosin B levels in P. arachnoideum samples collected in Brazil were higher in sprouts than in mature green fronds, as observed in other countries. However, there was no variation in ptaquiloside levels among plants collected from different cities in Brazil. The high frequency of upper alimentary squamous cell carcinoma in Brazilian cattle may not be attributed to greater levels of ptaquiloside and pterosin B in P. arachnoideum than in other Pteridium species in other countries.

Modulation of sphingosine-1-phosphate in ulcerative colitis.

Introduction: Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid signaling molecule implicated in various physiological and pathological processes, such as regulation of the immune, cardiovascular, pulmonary, and nervous systems and theoretical cancer-related risks, through extracellular activation of S1P1-5 receptors.Areas covered: S1P receptor agonism is a novel strategy for the treatment of UC targeting lymphocyte recirculation, through blockade of lymphocyte egress from lymph nodes. We conducted an extensive literature review on PUBMED on currently available data on molecular aspects of S1P modulation, the mechanisms of action of S1PR agonists (fingolimod, ozanimod, etrasimod, and KRP-203), and their potential efficacy and safety for the treatment of patients with ulcerative colitis.Expert opinion: Selective S1P modulators have emerged to enlarge the efficacy and safety profile of this class of agents. Phase 3 programs should add the potential body of evidence to prove their benefit for the management of UC patients.

What is happening with not recommended drugs for dementia in Argentina? Prescription patterns and direct costs analysis.

OBJECTIVES: The only recommended pharmacological treatments for specific dementias are donepezil, galantamine, rivastigmine, and memantine (recommended drugs, RD). However, other drugs without recommendations (not recommended drugs, NRD) are often used to treat patients with cognitive impairment (CI) in Argentina. The INSSJyP is the largest health insurance in Argentina. The objective of this study is to analyze the prescription pattern, cost, and implications of NRD used for the treatment of CI in the INSSJyP. MATERIALS: This is a retrospective, population-based study of the INSSJyP outpatients' prescriptions database for drugs usually prescribed for CI during 2015. These data were compared with the same database in 2009. The number of "prescriptions" always refers to dispensed packages. RESULTS: A total of 3 255 438 packages of drugs usually indicated for CI were prescribed during 2015: 1 912 476 packages of RD (59%) and 1 342 962 packages of NRD (41%).Comparing the results with those obtained in 2009, there is a 148% gross increase in the prescription of both RD and NRD for CI, although the rates/1000 affiliates/year show a lesser rise for NRD (70.1%) compared to RD (103.9 %).The expenditure on CI drugs prescribed during 2015 was 77 million USD. NRD cost represented approximately 20 million USD. CONCLUSION: Inappropriate drug use increases health costs in developing countries. We found a high number of patients with a probable diagnosis of CI treated with NRD. It is extremely relevant that all the healthcare professionals can update their knowledge and modify behavioral insights about appropriate prescription for specific dementias.

Conduta terapêutica em pacientes com doença pulmonar obstrutiva crônica: monoterapia ou terapia cominada? / Therapy for chronic obstructive pulmonary disease patients: monotherapy or combination therapy?

Objetivo: Comparar a dupla terapia broncodilatadora com glicopirrônio mais indacaterol à monoterapia com glicopirrônio em pacientes portadores de doença pulmonar obstrutiva crônica. Métodos: Estudo clínico prospectivo, unicêntrico, controlado, cruzado, randomizado e duplo-cego realizado com 14 pacientes com diagnóstico de doença pulmonar obstrutiva crônica grau II. Os participantes receberam cada um dos tratamentos durante 30 dias. Antes de cada terapia, realizou-se período de wash-out por 7 dias, com broncodilador de curta ação. Antes e após cada intervenção, os pacientes passaram por exame de espirometria e responderam ao questionário COPD Assessment Test. Resultados: Observou-se melhora na função pulmonar medida por meio do volume expiratório forçado no primeiro segundo de 19mL (±36) para a monoterapia e 87mL (±33) para a terapia dupla. O ganho foi de 67mL (p=0,042) da associação dos medicamentos em relação ao glicopirrônio isolado. A melhora na qualidade de vida, medida a partir das pontuações do questionário, foi de 4,7 (±8,9) pontos para a monoterapia e 5,2 (±11) pontos para a dupla terapia (p=0,08). Conclusão: Ambos os tratamentos demonstram melhora na função pulmonar dos pacientes.

Objective: To compare dual bronchodilator therapy (Glycopyrronium with Indacaterol) versus Glycopyrronium monotherapy in patients with chronic obstructive pulmonary disease. Methods: This was a prospective, unicentric, controlled, crossover, randomized, and double-blind clinical trial with 14 patients diagnosed with grade II chronic obstructive pulmonary disease. The participants received each treatment during the period of 30 days. Before each therapy, a 7-day wash-out period with a short-acting bronchodilator was instituted. Before and after each intervention, the patients underwent spirometry and answered the COPD Assessment Test questionnaire. Results: An improvement in pulmonary function measured by forced expiratory volume during the first second of 19mL (±36) for monotherapy, and 87mL (±33) for dual therapy was observed. The gain was of 67mL (p=0.042) in the association of the drugs in relation to Glycopyrronium alone. The mean improvement in quality of life measured from the questionnaire scores was 4.7 (±8.9) points for monotherapy and 5.2 (± 11) points for dual therapy (p=0.08). Conclusion: Both treatments show improvement in the patients' pulmonary function.

Discovery of novel West Nile Virus protease inhibitor based on isobenzonafuranone and triazolic derivatives of eugenol and indan-1,3-dione scaffolds.

The West Nile Virus (WNV) NS2B-NS3 protease is an attractive target for the development of therapeutics against this arboviral pathogen. In the present investigation, the screening of a small library of fifty-eight synthetic compounds against the NS2-NB3 protease of WNV is described. The following groups of compounds were evaluated: 3-(2-aryl-2-oxoethyl)isobenzofuran-1(3H)-ones; eugenol derivatives bearing 1,2,3-triazolic functionalities; and indan-1,3-diones with 1,2,3-triazolic functionalities. The most promising of these was a eugenol derivative, namely 4-(3-(4-allyl-2-methoxyphenoxy)-propyl)-1-(2-bromobenzyl)-1H-1,2,3-triazole (35), which inhibited the protease with IC50 of 6.86 µmol L-1. Enzyme kinetic assays showed that this derivative of eugenol presents competitive inhibition behaviour. Molecular docking calculations predicted a recognition pattern involving the residues His51 and Ser135, which are members of the catalytic triad of the WNV NS2B-NS3 protease.

Bronchodilators for hyperinflation in COPD associated with biomass smoke: clinical trial.

Introduction: The efficacy of long-acting bronchodilators for COPD associated with biomass (BE-COPD) has not been properly evaluated. Objective: To determine the acute effect of indacaterol (IND) 150 µg q.d and tiotropium (TIO) 18 µg q.d. on lung hyperinflation, walking distance (WD) and dyspnea during the six-minute walking test (6MWT) in moderate BE-COPD at 30, 60 and 240 mins post-drug administration. Design: Randomized, controlled, open-level, crossover noninferiority clinical trial. Forty-two women with BE-COPD were randomly assigned to a bronchodilator sequence: IND-TIO or vice versa. Results: There were statistically significant changes over time in inspiratory capacity (IC) (p<0.0001), FEV1 (p<0.0001) and FVC (p<0.0001) when IND was used. When TIO was administered, an increase over all time periods was observed only for FEV1 (p<0.0001) and FVC (p<0.0001), whereas for IC an increase was observed only at 30 mins and 24 hrs after TIO administration. We did not find clinically significant increases in WD and dyspnea after the administration of both bronchodilators. Conclusion: Both IND and TIO showed significant and fast onset improvement in hyperinflation. Therefore, either of them may be recommended as a first line of treatment for COPD associated with BE-COPD.

Influence of DRD1 and DRD3 Polymorphisms in the Occurrence of Motor Effects in Patients with Sporadic Parkinson's Disease.

Parkinson's disease (PD) is a multisystem disorder that affects 2-3% of the population ≥ 65 years of age. The main pharmacologic agent use in the treatment of clinical symptoms of PD is levodopa (L-DOPA). However, the chronic use of L-DOPA might result in the emergence of motor complications such as motor fluctuation and dyskinesia. Previous studies have shown that the inter-individual variability and pharmacogenetic profile of PD patients seem to influence the occurrence of motor complications. For these reasons, the purpose of this study was to evaluate a possible relationship between DRD1 A48G and DRD3 Ser9Gly genetic variants with the occurrence of motor complications in PD patients in a Brazilian population. A total of 228 patients with idiopathic PD were enrolled. Patients were genotyped for DRD1 A48G and DRD3 Ser9Gly polymorphisms using PCR-RFLP. The univariate and multivariate analyses were performed to assess the association of these polymorphisms with the occurrence of motor fluctuation and dyskinesia in PD patients. Multiple Poisson regression analyses showed a protector effect to the occurrence of dyskinesia for individuals carrying of the DRD1 G/G genotype (PR 0.294; CI 0.09-0.87; p ≤ 0.020) after the threshold Bonferroni's. Besides, we verified risk increased to the occurrence of motor complications with daily L-DOPA dosage, disease duration, and users of rasagiline, selegiline, or entacapone (p < 0.05 for all). Our results suggest that the DRD1 A48G polymorphism and the presence of extrinsic and intrinsic factors may role an effect in the occurrence of dyskinesia in PD patients.

Studies of 4-arylthiazolylhydrazones derived from 1-indanones as Trypanosoma cruzi squalene epoxidase inhibitors by molecular simulations.

Chagas disease or American trypanosomiasis is a parasitic disease caused by the protozoan Trypanosoma cruzi. Its squalene epoxidase (SE) is a target for drug design and development because it is a key enzyme in the biosynthetic pathway of ergosterol, which is essential for the life cycle of the parasite. Previously, we reported that some 4-arylthiazolylhydrazones derived from 1-indanones (TZHs) active against T. cruzi are able to accumulate squalene probably by SE inhibition. In this work, we performed a series of theoretical studies to verify that TZHs act as inhibitors of this enzyme. Since the crystal structure of SE is unknown for all species, we built a 3D enzyme model of T. cruzi SE by homology modeling. Based on this model, we carried out docking, molecular dynamics, and MM/PBSA calculations and the results were compared with those found for the reference inhibitor compound terbinafine (Tbf). The binding free energy values allowed the discrimination between accumulators and non-accumulators of squalene compounds, in agreement with the experimental findings. Pairwise residue free energy decomposition showed that the key amino acids involved in inhibitor binding for TZHs and Tbf were the same. Also, molecular superposition analysis between these compounds revealed high structural similarity. In addition, we proposed a pharmacophore model for T. cruzi SE inhibitors, which confirmed that TZHs and Tbf share chemical features with respect to their biochemical interaction characteristics at similar positions in 3D space. All theoretical calculations suggest that the experimentally observed squalene accumulation is produced by T. cruzi SE inhibition.

Release of taurine and glutamate contributes to cell volume regulation in human retinal Müller cells: differences in modulation by calcium.

Neuronal activity in the retina generates osmotic gradients that lead to Müller cell swelling, followed by a regulatory volume decrease (RVD) response, partially due to the isoosmotic efflux of KCl and water. However, our previous studies in a human Müller cell line (MIO-M1) demonstrated that an important fraction of RVD may also involve the efflux of organic solutes. We also showed that RVD depends on the swelling-induced Ca2+ release from intracellular stores. Here we investigate the contribution of taurine (Tau) and glutamate (Glu), the most relevant amino acids in Müller cells, to RVD through the volume-regulated anion channel (VRAC), as well as their Ca2+ dependency in MIO-M1 cells. Swelling-induced [3H]Tau/[3H]Glu release was assessed by radiotracer assays and cell volume by fluorescence videomicroscopy. Results showed that cells exhibited an osmosensitive efflux of [3H]Tau and [3H]Glu (Tau > Glu) blunted by VRAC inhibitors 4-(2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl)-oxybutyric acid and carbenoxolone reducing RVD. Only [3H]Tau efflux was mainly dependent on Ca2+ release from intracellular stores. RVD was unaffected in a Ca2+-free medium, probably due to Ca2+-independent Tau and Glu release, but was reduced by chelating intracellular Ca2+. The inhibition of phosphatidylinositol-3-kinase reduced [3H]Glu efflux but also the Ca2+-insensitive [3H]Tau fraction and decreased RVD, providing evidence of the relevance of this Ca2+-independent pathway. We propose that VRAC-mediated Tau and Glu release has a relevant role in RVD in Müller cells. The observed disparities in Ca2+ influence on amino acid release suggest the presence of VRAC isoforms that may differ in substrate selectivity and regulatory mechanisms, with important implications for retinal physiology. NEW & NOTEWORTHY The mechanisms for cell volume regulation in retinal Müller cells are still unknown. We show that swelling-induced taurine and glutamate release mediated by the volume-regulated anion channel (VRAC) largely contributes the to the regulatory volume decrease response in a human Müller cell line. Interestingly, the hypotonic-induced efflux of these amino acids exhibits disparities in Ca2+-dependent and -independent regulatory mechanisms, which strongly suggests that Müller cells may express different VRAC heteromers formed by the recently discovered leucine-rich repeat containing 8 (LRRC8) proteins.

Synthesis and biological evaluation of potential acetylcholinesterase inhibitors based on a benzoxazine core.

With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 ± 0.9 µM and 20.2 ± 0.9 µM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues.

Zirconium catalyzed synthesis of 2-arylidene Indan-1,3-diones and evaluation of their inhibitory activity against NS2B-NS3 WNV protease.

A simple and efficient Knoevenagel procedure for the synthesis of 2-arylidene indan-1,3-diones is herein reported. These compounds were prepared via ZrOCl2·8H2O catalyzed reactions of indan-1,3-dione with several aromatic aldehydes and using water as the solvent. The 2-arylidene indan-1,3-diones were obtained with 53%-95% yield within 10-45 min. The synthesized compounds were evaluated as inhibitors of the NS2B-NS3 protease of West Nile Virus (WNV). It was found that hydroxylated derivatives impaired enzyme activity with varying degrees of effectiveness. The most active hydroxylated derivatives, namely 2-(4-hydroxybenzylidene)-1H-indene-1,3(2H)-dione (14) and 2-(3,4-dihydroxybenzylidene)-1H-indene-1,3(2H)-dione (17), were characterized as noncompetitive enzymes inhibitors, with IC50 values of 11 µmol L-1 and 3 µmol L-1, respectively. Docking and electrostatic potential surfaces investigations provided insight on the possible binding mode of the most active compounds within an allosteric site.

Design, synthesis and pharmacological evaluation of N-benzyl-piperidinyl-aryl-acylhydrazone derivatives as donepezil hybrids: Discovery of novel multi-target anti-alzheimer prototype drug candidates.

A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AßO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AßO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.

Biomonitoring levels and trends of PAHs and synthetic musks associated with land use in urban environments.

Polycyclic aromatic hydrocarbons (PAHs) are some of the most studied organic compounds in urban environments, due to their known adverse effects on human health and persistence in environmental matrices. During the last decade, new groups of organic compounds with an intensive use worldwide such as synthetic musks have been raising the interest of the scientific community given their toxicity and health effects. However, literature is still scarce in studies dealing with their concentration in the environment, especially in developing countries, where they are even more rare or non-existing at all. We employed leaves of Ligustrum lucidum to assess the concentrations of PAHs and synthetic musks in different land use areas in Cordoba city, therefore contributing with environmental information in Argentina. We found higher levels of PAHs in urban and industrial areas than in the peri-urban sampling sites, naphthalene being one of the dominant PAHs in all sampling areas. Regarding synthetic musk fragrances, polycyclic musks were the most contributing compounds and the highest levels found in industrial areas as well. A high environmental risk could be expected due to the frequent occurrence of galaxolide in addition to the high hazardous potential of phantolide, which was present in 50% of the samples. The results of the present study indicate that leaves of an urban ubiquitous tree can be used to assess the spatial behavior of both "classic" and "emerging" organic pollutants, allowing an assessment of urban air quality in areas where common air sampling devices are unavailable.

N4 -aryl substituted thiosemicarbazones derived from 1-indanones as potential anti-tumor agents for breast cancer treatment.

Breast cancer is the first cause of cancer death in women. Many patients are resistant to current therapies, and even those were sensitive at first may eventually become resistant later. Thiosemicarbazones (TSCs) are synthetic compounds that exhibit several pharmacological activities. In this study, we investigated the potential anti-tumor activity of a set of N4 -arylsubstituted TSCs (N4 -TSCs) on human breast cancer cell lines. Studies on the effect of N4 -TSCs (T1, T2, and T3) were carried on MCF-7, MDA-MB 231, and BT 474 cell lines which differ in their expression of ER, PR, and Her2/neu. Non-transformed MCF-10A breast cell line were used as normal cells. Action of N4 -TSCs were evaluated by proliferation assay, quantification of apoptosis and cell cycle analysis. Modulation of clonogenic efficiency and migratory capacity by N4 -TSCs were also evaluated. We further investigated the effects of N4 -TSCs on ROS level and Ribonucleotide Reductase (RR) activity. We analyzed the action of these compounds on cellular mammosphere-forming capacity. We found that T1 and T2 had specific anti-tumor effect on all breast cancer cell lines based on their pro-apoptotic action and inhibitory effect on clonogenic efficiency and cell migration capacity. We also showed that both compounds increased ROS level and inhibited RR activity. Finally, we found that all N4 -TSCs diminished mammospehere-forming capacity of MCF-7 and BT 474 cells. N4 -TSCs showed specific anti-tumor action on human breast cancer cells independently their biomarkers expression pattern. Our results place these compounds as promising novel anti-tumor drugs with potential therapeutic application against different types of breast cancer.