Eugenol carbonate activity against Plasmodium falciparum, Leishmania braziliensis, and Trypanosoma cruzi.

Neglected tropical diseases are a major health problem throughout the world, and there are few effective and safe drugs. In this study, we report the design and synthesis of a novel series of carbonates of eugenol using different aliphatic alcohols and N,N-carbonyldiimidazole. Spectroscopic techniques, including 1 H nuclear magnetic resonance (NMR), 13 C NMR, Fourier transform infrared, and high-resolution mass spectrometry, were used to confirm the structures of the synthesized compounds. In vitro and in silico studies of prodrugs of eugenol were performed to determine their antiplasmodial, trypanocidal, and leishmanicidal activities, and also their cytotoxicity. Compounds were highly active against Leishmania braziliensis and Plasmodium falciparum, whereas the activity shown for Trypanosoma cruzi was moderate. Molecular docking was used to determine a possible mode of action of eugenol against the dihydroorotate dehydrogenase of the three parasites (TcDHODH, LbDHODH, and PfDHODH). Notably, the docking results showed that eugenol not only has binding energy similar to that of the natural substrate (-7.2 and -7.1, respectively) but also has interactions with relevant biological residues of PfDHODH. This result indicates that eugenol could act as a substrate for PfDHODH in the pyrimidine biosynthesis pathway of P. falciparum. In conclusion, the combination of certain aliphatic alcohols and eugenol through a carbonate bond could significantly increase the antiparasitic activity of this class of compounds, which merits further studies.

Curcumin Inhibits In Vitro SARS-CoV-2 Infection In Vero E6 Cells through Multiple Antiviral Mechanisms.

Due to the scarcity of therapeutic approaches for COVID-19, we investigated the antiviral and anti-inflammatory properties of curcumin against SARS-CoV-2 using in vitro models. The cytotoxicity of curcumin was evaluated using MTT assay in Vero E6 cells. The antiviral activity of this compound against SARS-CoV-2 was evaluated using four treatment strategies (i. pre-post infection treatment, ii. co-treatment, iii. pre-infection, and iv. post-infection). The D614G strain and Delta variant of SARS-CoV-2 were used, and the viral titer was quantified by plaque assay. The anti-inflammatory effect was evaluated in peripheral blood mononuclear cells (PBMCs) using qPCR and ELISA. By pre-post infection treatment, Curcumin (10 µg/mL) exhibited antiviral effect of 99% and 99.8% against DG614 strain and Delta variant, respectively. Curcumin also inhibited D614G strain by pre-infection and post-infection treatment. In addition, curcumin showed a virucidal effect against D614G strain and Delta variant. Finally, the pro-inflammatory cytokines (IL-1ß, IL-6, and IL-8) released by PBMCs triggered by SARS-CoV-2 were decreased after treatment with curcumin. Our results suggest that curcumin affects the SARS-CoV-2 replicative cycle and exhibits virucidal effect with a variant/strain independent antiviral effect and immune-modulatory properties. This is the first study that showed a combined (antiviral/anti-inflammatory) effect of curcumin during SARS-CoV-2 infection. However, additional studies are required to define its use as a treatment for the COVID-19.

New thiazolyl-pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents.

A new series of N-substituted pyrazoline derivatives 6a-g, 7a-g, 8a-g, and 9a-g was synthetized by reaction of hydrazine derivatives and chalcone-thiazole hybrids bearing nitrogen mustard 5a-g. The chalcones 5a-g were obtained by Claisen-Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a-g. These new compounds 6/7/8/9a-g were screened for their antifungal activity against Cryptococcus neoformans, with IC50 values of 3.9-7.8 µg/ml for the N-3,5-dichlorophenyl pyrazolines 9e-g. Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl (6a,b) and N-formyl pyrazolines (7a, 7b, 7c, and 7g) showed inhibitory activity against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-intermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g, 8f, and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC50 values of 11.80, 6.46, and 4.98 µM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent.

Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum.

In low-income populations, neglected diseases are the principal cause of mortality. Of these, leishmaniasis and malaria, being parasitic, protozoan infections, affect millions of people worldwide and are creating a public health problem. The present work evaluates the leishmanicidal and antiplasmodial action of a series of twelve p-coumaric acid derivatives. Of the tested derivatives, eight presented antiparasitic activities 1-3, 8-12. The hexyl p-coumarate derivative (9) (4.14 ± 0.55 µg/mL; selectivity index (SI) = 2.72) showed the highest leishmanicidal potency against the Leishmania braziliensis amastigote form. The results of the molecular docking study suggest that this compound inhibits aldehyde dehydrogenase (ALDH), mitogen-activated kinase protein (MPK4), and DNA topoisomerase 2 (TOP2), all of which are key enzymes in the development of Leishmania braziliensis. The data indicate that these enzymes interact via Van der Waals bonds, hydrophobic interactions, and hydrogen bonds with phenolic and aliphatic parts of this same compound. Of the other compounds analyzed, methyl p-coumarate (64.59 ± 2.89 µg/mL; IS = 0.1) demonstrated bioactivity against Plasmodium falciparum. The study reveals that esters presenting a p-coumarate substructure are promising for use in synthesis of derivatives with good antiparasitic profiles.

Synthesis and evaluation of the in vitro and in vivo antitrypanosomal activity of 2-styrylquinolines.

In this study, we report the synthesis and evaluation of in vitro and in vivo antitrypanosomal activity of styrylquinoline-like compounds (SQ) 3a-h. Synthesis was carried out by using quinaldine and 8- hydroxyquinaldine with a variety of aromatic aldehydes. The structure of SQs was corroborated by one and two-dimension NMR spectroscopy. In vitro antitrypanosomal activity on T. cruzi Talahuen strain was evaluated using ß-galactosidase enzymatic method; cytotoxicity on U-937 cells was assessed by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method. On the other hand, in vivo therapeutical response to 3a-f compounds was evaluated in BALB/c mice (Mus musculus) experimentally infected with T. cruzi blood trypomastigotes and then orally administered with 100 mg/kg weight day for 20 days. All of the compounds showed in vitro activity with EC50 values ranging between 4.6 ± 0.1 µg/mL (14.4 µM) and 36.6 ± 6.1 µg/mL (91 µM). Furthermore, treatment with 3a-f compounds for 20 days resulted in improvement in all of the mice, with a 83-96% decrease in parasitic load at day 90 post-treatment. Treatment with benznidazol (BZ) managed to cure 100% of the mice at the end of treatment. None of the treatments affected the weight of the animals or alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine levels in serum. These results suggest a therapeutic potential of 3a-f compounds as treatment for the infection.

The Hydroalcoholic Extract of Uncaria tomentosa (Cat's Claw) Inhibits the Infection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) In Vitro.

The coronavirus disease 2019 (COVID-19) has become a serious problem for public health since it was identified in the province of Wuhan (China) and spread around the world producing high mortality rates and economic losses. Nowadays, the WHO recognizes traditional, complementary, and alternative medicine for treating COVID-19 symptoms. Therefore, we investigated the antiviral potential of the hydroalcoholic extract of Uncaria tomentosa stem bark from Peru against SARS-CoV-2 in vitro. The antiviral activity of U. tomentosa against SARS-CoV-2 in vitro was assessed in Vero E6 cells using cytopathic effect (CPE) and plaque reduction assay. After 48 h of treatment, U. tomentosa showed an inhibition of 92.7% of SARS-CoV-2 at 25.0 µg/mL (p < 0.0001) by plaque reduction assay on Vero E6 cells. In addition, U. tomentosa induced a reduction of 98.6% (p=0.02) and 92.7% (p=0.03) in the CPE caused by SARS-CoV-2 on Vero E6 cells at 25 µg/mL and 12.5 µg/mL, respectively. The EC50 calculated for the U. tomentosa extract by plaque reduction assay was 6.6 µg/mL (4.89-8.85 µg/mL) for a selectivity index of 4.1. The EC50 calculated for the U. tomentosa extract by TCID50 assay was 2.57 µg/mL (1.05-3.75 µg/mL) for a selectivity index of 10.54. These results showed that U. tomentosa, known as cat's claw, has an antiviral effect against SARS-CoV-2, which was observed as a reduction in the viral titer and CPE after 48 h of treatment on Vero E6 cells. Therefore, we hypothesized that U. tomentosa stem bark could be promising in the development of new therapeutic strategies against SARS-CoV-2.

Transforming Growth Factor Beta (TGFß1) and Epidermal Growth Factor (EGF) as Biomarkers of Leishmania (V) braziliensis Infection and Early Therapeutic Response in Cutaneous Leishmaniasis: Studies in Hamsters.

Introduction: In cutaneous leishmaniasis, the host immune response is responsible for the development of skin injuries but also for resolution of the disease especially after antileishmanial therapy. The immune factors that participate in the regulation of inflammation, remodeling of the extracellular matrix, cell proliferation and differentiation may constitute biomarkers of diseases or response to treatment. In this work, we analyzed the production of the growth factors EGF, TGFß1, PDGF, and FGF during the infection by Leishmania parasites, the development of the injuries and the early response to treatment. Methodology: Golden hamsters were infected with L. (V) braziliensis. The growth factors were detected in skin scrapings and biopsies every 2 weeks after infected and then at day 7 of treatment with different drug candidates by RT-qPCR. The parasitic load was also quantified by RT-qPCR in skin biopsies sampled at the end of the study. Results: The infection by L. (V) braziliensis induced the expression of all the growth factors at day 15 of infection. One month after infection, EGF and TGFß1 were expressed in all hamsters with inverse ratio. While the EGF and FGF levels decreased between day 15 and 30 of infection, the TGFß1 increased and the PGDF levels did not change. The relative expression of EGF and TGFß1 increased notably after treatment. However, the increase of EGF was associated with clinical cure while the increase of TGFß1 was associated with failure to treatment. The amount of parasites in the cutaneous lesion at the end of the study decreased according to the clinical outcome, being lower in the group of cured hamsters and higher in the group of hamsters that had a failure to the treatment. Conclusions: A differential profile of growth factor expression occurred during the infection and response to treatment. Higher induction of TGFß1 was associated with active disease while the higher levels of EGF are associated with adequate response to treatment. The inversely EGF/TGFß1 ratio may be an effective biomarker to identify establishment of Leishmania infection and early therapeutic response, respectively. However, further studies are needed to validate the utility of the proposed biomarkers in field conditions.

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities.

The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18-23, 26 and 30) and eight of them against T. cruzi (19-22, 24 and 28-30) with EC50 values lower than 40 µM. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 µM and 8.25 and 8.69 µM, respectively. Compounds 19-22, 24 and 28-30 showed higher activities than benznidazole (BNZ). Most of the compounds showed antiprotozoal activity and with exception of 18, 26 and 28, the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19, bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity.

Concordancia entre el peso directo de porciones de alimentos ingeridas y la estimación de pesos con ayuda de figuras geométricas y la técnica de pesos memorizados por el entrevistador, en niños de 5-9 años / Concordance between direct weigh of food portions consumed by children 5 to 9 years old, using tridimensional geometrical figures and interviewer memorization weightÆs technique

Objetivo: Evaluar la concordancia entre el peso directo de porciones de alimentos ingeridas y la estimación de pesos con ayuda de figuras tridimensionales y la técnica de pesos memorizados por el entrevistador, en ni±os entre 5 y 9 años. Metodología: Se realizó un estudio descriptivo transversal, con una muestra a conveniencia conformada por 21 niñas y 9 niños con edades entre los 5 y 9 años, pertenecientes a preescolar y los grados primero, segundo y tercero de primaria. Para la selección de la muestra, se tomaron como criterios de inclusión: que consumieran el almuerzo o la comida completa en el hogar y que no padecieran enfermedades que modificaran su alimentación. Para la recolección de la información, se realizaron dos visitas domiciliarias con previo consentimiento informado de las madres sobre el objetivo del proyecto y la metodología que se emplearía. Resultados: Del total de alimentos incluidos en esta investigación (29 alimentos), se encontró que solo 14 de ellos fueron consumidos en el almuerzo o la cena de los niños evaluados, entre los más frecuentes estuvieron el arroz, las tajadas de plátano maduro y la carne, alimentos característicos de la región; sin embargo se encontraron alimentos consumidos por los ni±os, que durante el proceso de capacitación no fueron estandarizados. Conclusiones: Entre los hallazgos se destaca que aunque las diferencias fueron significativas sólo para algunos alimentos, hubo mayor concordancia entre el peso directo y el peso estimado con figuras tridimensionales, que con el peso estimado bajo la técnica de peso memorizado por el entrevistador, sugiriendo que el uso de figuras tridimensionales permite una aproximación mayor al peso de los alimentos ingeridos.

Objective: To evaluate the concordance between direct weigh of food portionsconsumed with weight’s estimation using tridimensional geometrical figuresand interviewer memorization weight’s technique. Methods a cross–sectionalstudy including Children (21 women, 9 men), aged 5-9 years, recruited from the school Jesús Rey, Medellín-Colombia. Two home visits were realized. At the first visit a direct weigh of food consumed by children was realized, in the second one, two assessments were obtained, one for each weight’s estimation techniques. Results: Significant differences were found only for some aliments. A better concordance between direct weight and geometrical figures was found, suggesting that this technique shows a good approximation to thereal weight’s portions consumed. The interviewer memorization’s weight technique showed only a small concordance with direct weight food’s technique. Conclusions: using tridimensional geometrical figures of aliments is a good technique to get the real weight’s portions of food consumed by children.

Factores nutricionales, sociales, psicoafectivos y de salud de los adultos mayores / Nutritional, social and health factors of elderly people

El envejecimiento es un proceso dinámico, progresivo e irreversible en el que intervienen múltiples factores biológicos, psíquicos y sociales; una alta proporción de la sociedad ve en el envejecimiento, un proceso en el que las personas pierden su autonomía, independencia, la capacidad laboral e intelectual; convirtiéndose el adulto mayor en una carga para sus familias y la sociedad. En los últimos años este concepto está cambiando favorablemente, en parte por el deseo de las personas adultas y de los adultos mayores de tener un envejecimiento exitoso o activo como lo define la Organización Mundial de la Salud (OMS), en el cual convergen las oportunidades de bienestar físico, social y mental que se han tenido durante toda la vida, y la aceptación del envejecimiento como una etapa más del proceso vital en la que debe tenerse una adecuada nutrición y actividad física, aspectos que general-mente son descuidados en esta etapa. El proceso de envejecimiento lo enfrentan todos los países del mundo, algunos con índices más elevados; aunque Colombia no presenta tales índices, se deben establecer estrategias que redunden en una buena calidad de vida de los adultos mayores.

The aging is a dynamic, progressive and irreversible process influenced bymany biological, physical and social factors. High proportion of the societysees in aging, a process in which people lose their autonomy, independence,and intellectual capacity, consequently elderly people become a burden fortheir families and for the society. During last years, this concept has beenchanging favorably in part because of desire of adults and elderly people ofhaving a successful and active aging as defined by the Word Health organization.This definition consist of physical, social and mental well-being opportunitiesof elderly stage as part of the vital process, with adequate nutritionand physical activity, aspects, that are usually neglected. This process is experienced by all countries in the world, some of them with higher rates. Although Colombia does not have those rates, strategies need be established inorder to improve the quality of life of this population.