Development of peptoid-based heteroaryl-decorated histone deacetylase (HDAC) inhibitors with dual-stage antiplasmodial activity.

Dynamics of epigenetic modifications such as acetylation and deacetylation of histone proteins have been shown to be crucial for the life cycle development and survival of Plasmodium falciparum, the deadliest malaria parasite. In this study, we present a novel series of peptoid-based histone deacetylase (HDAC) inhibitors incorporating nitrogen-containing bicyclic heteroaryl residues as a new generation of antiplasmodial peptoid-based HDAC inhibitors. We synthesized the HDAC inhibitors by an efficient multicomponent protocol based on the Ugi four-component reaction. The subsequent screening of 16 compounds from our mini-library identified 6i as the most promising candidate, demonstrating potent activity against asexual blood-stage parasites (IC50Pf3D7 = 30 nM; IC50PfDd2 = 98 nM), low submicromolar activity against liver-stage parasites (IC50PbEEF = 0.25 µM), excellent microsomal stability (t1/2 > 60 min), and low cytotoxicity to HEK293 cells (IC50 = 136 µM).

Evolution over the last 40 years of the assisted reproduction technologies in cattle - the Brazilian perspective I - timed artificial insemination.

The reproductive efficiency of the herd is correlated with higher productivity in livestock. Reproduction biotechniques, such as ovulation synchronization protocols, are important to optimize production and accelerate genetic profit in beef and dairy herds. The objective of this review is to describe the evolution over the last 40 years of the artificial insemination (AI) and the timed-AI (TAI) protocols in cattle from a Brazilian perspective. TAI protocols are based on synchronizing emergence of the wave of follicular growth, controlling circulating progesterone (P4) concentrations, stimulating the final growth of the follicle and inducing a synchronized ovulation. Hormonal alternatives that optimize the response at the end of the protocol and strategies to induce final follicle growth and ovulation in categories of females with low expression of estrus are described. Furthermore, the potential positive effect of previous exposure to injectable P4 on fertility of Bos indicus and Bos taurus cows is also discussed.

Design, Synthesis, Antitumor, and Antiplasmodial Evaluation of New 7-Chloroquinoline-Benzimidazole Hybrids.

Newly synthesized 7-chloro-4-aminoquinoline-benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC50 value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure-activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R2 = 0.886; Rext2 = 0.937; F = 41.589) and Dd2 strain (R2 = 0.859; Rext2 = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities.

Biochemical profile and oocyte quality of primiparous Bos indicus cows submitted to a timed artificial insemination protocol.

The objective of this study was to verify the causes of the lower response of primiparous Bos indicus cows to the ovulation synchronization protocol. Two experiments were performed to evaluate the biochemical profile, oocyte and follicular cell quality (Experiment 1) and pregnancy (Experiment 2). In Experiment 1, suckled primiparous (n = 24) and multiparous cows (n = 24) were submitted to ovum pick up (OPU). On Day 0 (D0), all cows received 2 mg of estradiol benzoate (EB) and an intravaginal progesterone insert (P4). Five days (D5) after the first hormonal administration (EB + P4), all follicles larger than 3 mm were counted on each ovary, and ovum pick-up (OPU) was performed. On day 12 (D12), the intravaginal progesterone insert was removed, and measurement and aspiration of the largest follicle were performed. Blood samples were collected on D5 and D12 to evaluate the concentrations of glucose, cholesterol, NEFA, IGF-1 and insulin. In Experiment 2, suckled primiparous (n = 50) and multiparous (n = 50) cows were subjected to an ovulation synchronization protocol based on E2/P4 (D0: 2 mg EB plus P4 intravaginal insert; D8: 500 µg of cloprostenol, 1 mg cypionate estradiol and 300UI of eCG; D10: artificial insemination). In addition, blood samples were collected on D10 for evaluation of the same hormones and metabolites described in Experiment 1. In all studies, calves remained with the cows during the experimental period. In experiment 1, the number of oocytes grade 1 (P = 0.83), grade 2 (P = 0.23) and grade 3 (P = 0.51), total number of retrieved oocytes (P = 0.14), oocyte quality index (P = 0.93) and total viable oocytes (P = 0.38) did not differ between primiparous and multiparous cows. The number of follicles at the time of follicular aspiration (20.7 ± 1.5 vs. 18.0 ± 1.9; P = 0.05) and the diameter of the largest follicle on D12 (13.5 ± 0.6 vs. 11.4 ± 0.6; P = 0.04) were greater in multiparous cows, and the number of degenerated oocytes was greater in primiparous cows (1.9 ± 0.7 vs. 1.2 ± 0.3; P = 0.05). On D5, the concentrations of IGF-1 (P = 0.47), insulin (P = 0.08), total cholesterol (P = 0.47), NEFA (P = 0.77) and glucose (P = 0.55) in the blood and IGF-1 (P = 0.97) and insulin (P = 0.11) in the follicular fluid did not differ between parity groups. On D12, there was no difference in the concentrations of IGF-1 (P = 0.26), total cholesterol (P = 0.32), NEFAs (P = 0.31) and glucose (P = 0.93) in the blood between primiparous and multiparous cows, however, the serum insulin concentration (P = 0.04) was higher in primiparous cows. There was no correlation between serum and follicular fluid insulin concentrations (r = 0.17; P = 0.31), however, there was a low correlation between serum and follicular fluid IGF-1 concentrations (r = 0.47; P = 0.002). Quantification of transcripts did not differ between parity groups. In experiment 2, concentrations of NEFA (P = 0.12) and insulin (P = 0.16) in the blood and P/AI (P = 0.93) did not differ between parity [60 % (30/50) primiparous vs. 60 % (30/50) multiparous]. In contrast, blood concentrations of IGF-1 (P = 0.0001), total cholesterol (P = 0.005) and glucose (P = 0.01) were greater in primiparous cows. It was concluded that the oocyte quality and expression of the genes evaluated in the granulosa cells were not different between primiparous and multiparous cows. Unexpectedly, the pregnancy rate did not differ between parity. Nevertheless, the blood concentrations of IGF-1, total cholesterol and glucose were greater in primiparous cows.

Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds.

Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the ß-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.

Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR).

Reverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum. Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar PfDXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the N-phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N-terminal domain. As shown for reverse carba and thia analogs, PfDXR selectively binds the S-enantiomer of the new lead compound. In addition, some representatives of the novel inhibitor subclass are nanomolar Escherichia coli DXR inhibitors, whereas the inhibition of Mycobacterium tuberculosis DXR is considerably weaker.

Functionalization of Chlorotonils: Dehalogenil as Promising Lead Compound for In Vivo Application.

The natural product chlorotonil displays high potency against multidrug-resistant Gram-positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late-stage functionalization, we aimed to further optimize the molecule. Previously unknown reactions including a sulfur-mediated dehalogenation were revealed. Dehalogenil, the product of this reaction, was identified as the most promising compound so far, as this new derivative displayed improved solubility and in vivo efficacy while retaining excellent antimicrobial activity. We confirmed superb activity against multidrug-resistant clinical isolates of Staphylococcus aureus and Enterococcus spp. and mature transmission stages of Plasmodium falciparum. We also demonstrated favorable in vivo toxicity, pharmacokinetics and efficacy in infection models with S. aureus. Taken together, these results identify dehalogenil as an advanced lead molecule.

High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum.

In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure-activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated.

Genetic Identification and Technological Potential of Indigenous Lactic Acid Bacteria Isolated from Alheira, a Traditional Portuguese Sausage.

Alheira is a naturally fermented meat sausage traditionally made in the Portuguese region of Trás-os-Montes. Lactic acid bacteria (LAB) are the dominant microorganisms in alheira and can endow it with various technological properties. This study aimed (1) to characterize technological features and in vitro antimicrobial activity of LAB isolated from alheira, and (2) to reveal associations between such phenotypic characteristics and the isolates species identified through amplification and sequencing of the 16S ribosomal gene. Sixty-two LAB isolates were identified and Enterococcus (E.) faecium corresponded to 32.3% of isolates, followed by Leuconostoc (L.) mesenteroides (19.4%) and Latilactobacillus (Lb.) sakei (17.7%), aligning with previous research on traditional Portuguese fermented meat sausages. The phenotypic analysis of LAB isolates indicated diverse acidification capacities, proteolytic activities, and inhibitory effects against foodborne pathogens Listeria (L.) monocytogenes, Salmonella (S.) Typhimurium and Staphylococcus (S.) aureus. Overall, lactobacilli displayed high inhibition activity against the pathogens S. aureus, L. monocytogenes, and S. Typhimurium. Although the mechanisms for the inhibition of pathogen growth need to be further elucidated, these findings enhance our understanding of LAB diversity and functionality in alheira sausages, contributing to product safety and quality.

Is estradiol valerate an alternative to estradiol benzoate in promoting the synchronization of ovulation and timed artificial insemination in suckled Bos indicus beef cows?

The objective of the present study was to evaluate the effect of estradiol valerate administered at the beginning of the ovulation synchronization protocol on the pregnancy rate of Bos indicus cows. In the experiments, the following products from MSD, Sao Paulo, Brazil were used: estradiol valerate (EV), estradiol benzoate (EB), intravaginal progesterone device (P4), estradiol cypionate (EC), equine chorionic gonadotropin (eCG) and cloprostenol (PGF). In Experiment 1, Bos indicus cows (n=899) with a body condition score (BCS) of 2.76 ± 0.01 were included in a 3 (device) × 2 (protocol: 5 mg of EV or 2 mg of EB) factorial design. There were three types of P4 devices: a new device (New), a device previously used for 9 days (1×), and a device previously used for 18 days (2×). Nine days later (D9), the P4 device was removed, and cows received 300 IU of eCG. In addition, cows in the EB group received 1 mg of EC and 265 µg of PGF. Timed artificial insemination (TAI) was performed 48 h after P4 device removal in the EB group (TAI48) and 54 h after P4 device removal in the EV group (TAI54). In Experiment 2, Bos indicus cows (n=434) with a BCS of 2.62 ± 0.01 received a new P4 device or one previously used for 9 days and 5 mg of EV. On D9, all cows received 300 IU of eCG, and the P4 devices were removed and distributed in TAI48 and TAI54 cows. In Experiment 3, Bos indicus cows (n=429) with a BCS of 2.80 ± 0.01 were divided into the control and EV/EC groups. All cows received a P4 device. In addition, cows in the control group received 2 mg of EB, and cows in the EV/EC group received 5 mg of EV on D0. On D9, all cows received 1 mg of EC and 300 IU of eCG, and the P4 devices were removed. Cows in the control group also received 265 µg of PGF. All cows were inseminated 48 h after the removal of the P4 device. In Experiment 1, there was no effect of the interaction between protocol and P4 device on the occurrence of estrus (P=0.45) or on the pregnancy per artificial insemination ratio (P/AI; P=0.30). In addition, the occurrence of estrus and P/AI were not different between in the two estradiol groups (P=0.12 and P=0.82) and across the types of intravaginal P4 device (P=0.91 and P=0.47). In Experiment 2, the pregnancy rate was lower (tendency) in TAI48 cows (P=0.07). In Experiment 3, the estrus rate (P=0.12) and P/AI (P=0.56) were similar between the experimental groups. In summary, protocols using estradiol valerate without exogenous ovulation induction require adjustments in the timing of AI from 48 to 54 h after P4 device removal. However, a combination of estradiol valerate at the beginning of the protocol and estradiol cypionate nine days later successfully induced ovulation in Bos indicus cows inseminated 48 h after P4 device removal.

The problem of antimalarial resistance and its implications for drug discovery.

INTRODUCTION: Malaria remains a devastating infectious disease with hundreds of thousands of casualties each year. Antimalarial drug resistance has been a threat to malaria control and elimination for many decades and is still of concern today. Despite the continued effectiveness of current first-line treatments, namely artemisinin-based combination therapies, the emergence of drug-resistant parasites in Southeast Asia and even more alarmingly the occurrence of resistance mutations in Africa is of great concern and requires immediate attention. AREAS COVERED: A comprehensive overview of the mechanisms underlying the acquisition of drug resistance in Plasmodium falciparum is given. Understanding these processes provides valuable insights that can be harnessed for the development and selection of novel antimalarials with reduced resistance potential. Additionally, strategies to mitigate resistance to antimalarial compounds on the short term by using approved drugs are discussed. EXPERT OPINION: While employing strategies that utilize already approved drugs may offer a prompt and cost-effective approach to counter antimalarial drug resistance, it is crucial to recognize that only continuous efforts into the development of novel antimalarial drugs can ensure the successful treatment of malaria in the future. Incorporating resistance propensity assessment during this developmental process will increase the likelihood of effective and enduring malaria treatments.

Lactic acid bacteria from artisanal raw goat milk cheeses: technological properties and antimicrobial potential.

In cheese-making, a starter culture composed of adequately chosen lactic acid bacteria (LAB) may be suitable to ensure the rapid acidification of milk, improve textural and sensory characteristics, and avoid pathogen proliferation. In this work, 232 LAB isolates collected from artisanal goat's raw milk cheeses produced in Portugal were evaluated for their antimicrobial capacity (at 10 and 37°C), as well as their acidifying and proteolytic properties. Among the 232 isolates, at least 98% of those isolated in De Man- Rogosa-Sharpe (MRS) agar presented antagonism against Listeria monocytogenes, Salmonella Typhimurium, or Staphylococcus aureus, whereas less than 28.1% of M17-isolated LAB showed antagonism against these pathogens. M17-isolated LAB displayed better results than MRS ones in terms of acidifying capacity. As for the proteolytic assay, only 2 MRS isolates showed casein hydrolysis capacity. Principal component analyses and molecular characterization of a subset of selected isolates were conducted to identify those with promising capacities and to correlate the identified LAB genera and species with their antimicrobial, acidifying, and/or proteolytic properties. Lactococcus strains were associated with the highest acidifying capacity, whereas Leuconostoc and Lacticaseibacillus strains were more related to antimicrobial capacities. Leuconostoc mesenteroides, Lactococcus lactis, and Lacticaseibacillus paracasei were the predominant organisms found. The results of this work highlight various strains with pathogen inhibition capacity and suitable technological properties to be included in a customized starter culture. In future work, it is necessary to appropriately define the starter culture and implement it in the cheese-making process to evaluate if the in-vitro capacities are observable in a real food system.

Synthesis, antiproliferative and antiplasmodial evaluation of new chloroquine and mefloquine-based harmiquins.

Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and ß-carboline alkaloid harmine against cancer cell lines and Plasmodium falciparum. The hybrids were prepared from the corresponding amines by 1,1'-carbonyldiimidazole (CDI)-mediated synthesis. In vitro evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine 16 as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 (IC 50 = 5.48 ± 3.35 µmol L-1). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the Plasmodium life cycle identified CQ-based UT harmiquine 12 as a novel antiplasmodial hit because it displayed low IC 50 values in the submicromolar range against CQ-sensitive and resistant strains (IC 50 0.06 ± 0.01, and 0.19 ± 0.02 µmol L-1, respectively), and exhibited high selectivity against Plasmodium, compared to mammalian cells (SI = 92).

Unveiling Microbial Chemical Interactions Based on Metabolomics Approaches.

Microorganisms are ubiquitous in diverse habitats and studying their chemical interactions with the environment and comprehend its complex relations with both hosts and environment, are crucial for the development of strategies to control microbial diseases. This chapter discusses the importance of studying microorganisms with agricultural benefits, using specialized metabolites as examples. Herein we highlight the challenges and opportunities in utilizing microorganisms as alternatives to synthetic pesticides and fertilizers in agriculture. Genome-guided investigations and improved analytical methodologies are necessary to characterize diverse and complex biomolecules produced by microorganisms. Predicting and isolating bioproducts based on genetic information have become a focus for researchers, aided by tools like antiSMASH, BiG-SCAPE, PRISM, and others. However, translating genomic data into practical applications can be complex. Therefore, integrating genomics, transcriptomics, and metabolomics enhances chemical characterization, aiding in discovering new metabolic pathways and specialized metabolites. Additionally, elicitation is one promising strategy to enhance beneficial metabolite production. Finally, identify and characterize microbial secondary metabolites remain challenging due to their low production, complex chemical structure characterization and different environmental factors necessary for metabolite in vitro production.

Lost to follow-up of patients who received intravitreal anti-vascular endothelial growth factor therapy to treat four different retina disorders in an individual center in Brazil.

Objectives: To identify risk factors for loss to follow-up in periodic intravitreal anti-vascular endothelial growth factor injections for the treatment patients with diabetic macular edema, subretinal neovascularization, age-related macular degeneration, and retinal vein occlusion in a single eye center in São Paulo, Brazil. Methods: This was a retrospective longitudinal study that gathered information from 992 patients who required intravitreal anti-vascular endothelial growth factor drugs over 6 months. The authors included age, eye disease, laterality, monthly income, distance, and payment mode as risk factors. Results: Two hundred and seventy patients (29.93%) were lost to follow-up. Multivariate analysis showed age, monthly income, eye involvement, and type of medical assistance independently associated with loss to follow-up. The odds of loss to follow-up were greater among older patients than those less than 50 years (reference), p < 0.001. The odds of loss to follow-up were greater among patients who received unilateral treatment than those who received bilateral injections (p = 0.013). Concerning gross monthly income, there were no differences in the odds of the four salary strata; the data also indicate an absence of difference in the three strata of patients' distance to the clinic. Considering the diagnosis, only age-related macular degeneration showed greater odds of loss to follow-up (p = 0.016). Finally, the data suggest greater odds of loss to follow-up in private patients than in those on a health care plan (p < 0.001). Conclusion: Loss to follow-up is paramount because many patients may remain unassisted concerning their eye diseases. Identifying the risk factors is crucial to enforcing measures to increase adherence and the long-term success of the treatment.

Efficacy and safety of ivermectin for the treatment of Plasmodium falciparum infections in asymptomatic male and female Gabonese adults - a pilot randomized, double-blind, placebo-controlled single-centre phase Ib/IIa clinical trial.

BACKGROUND: Ivermectin's mosquitocidal effect and in vitro activity against Plasmodium falciparum asexual stages are known. Its in vivo blood-schizonticidal efficacy is unknown. Ivermectin's tolerability and efficacy against P. falciparum infections in Gabonese adults were assessed. METHODS: The study consisted of a multiple dose stage and a randomized, double-blind, placebo-controlled stage. Adults with asymptomatic P. falciparum parasitaemia (200-5000 parasites/µl) were enrolled. First, three groups of five participants received 200 µg/kg ivermectin once daily for one, two, and three days, respectively, and then 34 participants were randomized to 300 µg/kg ivermectin or placebo once daily for 3 days. Primary efficacy outcome was time to 90% parasite reduction. Primary safety outcomes were drug-related serious and severe adverse events (Trial registration: PACTR201908520097051). FINDINGS: Between June 2019 and October 2020, 49 participants were enrolled. Out of the 34 randomized participants, 29 (85%) completed the trial as per protocol. No severe or serious adverse events were observed. The median time to 90% parasite reduction was 24.1 vs. 32.0 h in the ivermectin and placebo groups, respectively (HR 1.38 [95% CI 0.64 to 2.97]). INTERPRETATION: Ivermectin was well tolerated in doses up to 300 µg/kg once daily for three days and asymptomatic P. falciparum asexual parasitaemia was reduced similarly with this dose of ivermectin compared to placebo. Further studies are needed to evaluate plasmodicidal effect of ivermectin at higher doses and in larger samples. FUNDING: This study was funded by the Centre de Recherches Médicales de Lambaréné and the Centre for Tropical Medicine of the Bernhard Nocht Institute for Tropical Medicine.

Design, synthesis and antiplasmodial evaluation of new amide-, carbamate-, and ureido-type harmicines.

Malaria, one of the oldest parasitic diseases, remains a global health threat, and the increasing resistance of the malaria parasite to current antimalarials is forcing the discovery of new, effective drugs. Harmicines, hybrid compounds in which harmine/ß-carboline alkaloids and cinnamic acid derivatives are linked via an amide bond or a triazole ring, represent new antiplasmodial agents. In this work, we used a multiple linear regression technique to build a linear quantitative structure-activity relationship (QSAR) model, based on a group of 40 previously prepared amide-type (AT) harmicines and their antiplasmodial activities against erythrocytic stage of chloroquine-sensitive strain of P. falciparum (Pf3D7). After analysing the QSAR model, new harmicines were designed and synthesized: six amide-type, eleven carbamate-type and two ureido-type harmicines at the N-9 position of the ß-carboline core. Subsequently, we evaluated the antiplasmodial activity of the new harmicines against the erythrocytic and hepatic stages of the Plasmodium life cycle in vitro and their antiproliferative activity against HepG2 cells. UT harmicine (E)-1-(2-(7-methoxy-1-methyl-9H-pyrido[3,4-b]indol-9-yl)ethyl)-3-(3-(3-(trifluoromethyl)phenyl)allyl)urea at the N-9 position of the ß-carboline ring exhibited pronounced antiplasmodial activity against both the erythrocytic and the hepatic stages of the Plasmodium life cycle, accompanied by good selectivity towards Plasmodium.

Quantification of Plasmodium falciparum HRP-2 as an alternative method to [3H]hypoxanthine incorporation to measure the parasite reduction ratio in vitro.

In the absence of a highly efficacious vaccine, chemotherapy remains the cornerstone to control malaria morbidity and mortality. The threat of the emergence of parasites resistant to artemisinin-based combination therapies highlights the need for new antimalarial drugs ideally with superior properties. The killing rate reflects the speed of action of antimalarial drugs, which can be measured in vitro through the parasite reduction ratio (PRR) assay to shortlist interesting candidates. As a standard, the in vitro PRR assay is performed by measuring [3H]hypoxanthine incorporation of Plasmodium falciparum. This methodology is restricted to specialised laboratories owing to the handling of radioactive material. In this work, we describe a sandwich enzyme-linked immunosorbent assay to detect P. falciparum histidine-rich protein 2 (HRP-2) as an alternative methodology to assess the PRR. We first validated the methodology with established antimalarial drugs (artesunate, chloroquine, pyrimethamine and atovaquone) by comparing our results with previous results of the [3H]hypoxanthine incorporation readout provided by an expert laboratory, and subsequently assessed the speed of action of four new antimalarial candidates (compound 22, chlorotonil A, boromycin and ivermectin). The HRP-2 PRR assay achieved comparable results to the [3H]hypoxanthine incorporation readout in terms of parasite growth rate over time, lag phase and parasite clearance time. In addition, parasite growth following drug exposure was quantified after 7, 14, 21 and 28 days of recovery time. In conclusion, the PRR assay based on HRP-2 is similar to [3H]hypoxanthine in determining a drug's parasite killing rate and can be widely used in all research laboratories.

Technologies Applied to the Mental Health Care of Pregnant Women: A Systematic Literature Review.

OBJECTIVE: This article aims to review the literature regarding the use of technologies to promote mental health for pregnant women. We seek to: understand the strategies that pregnant women use for mental health care. Also, we investigate the existence of scientific evidence that validates such practices. METHODS: This study follows the PRISMA guidelines for systematic reviews. We analyze 27 studies published between 2012 and 2019. We include publications in Portuguese, English, and Spanish. RESULTS: The results revealed several different possibilities to use technology, including the use of text messages and mobile applications on smartphones. Mobile applications are the most commonly used approaches (22.5%). Regarding the strategies used, cognitive-behavioral approaches, including mood checks, relaxation exercises, and psychoeducation comprised 44.12% of the content. CONCLUSION: There is a need for further investigation and research and development efforts in this field to better understand the possibilities of intervention in mental health in the digital age.

OBJETIVO: Este artigo objetiva revisar a literatura quanto ao uso das tecnologias como promotoras de saúde mental de gestantes. Desta forma, compreender quais são as estratégias utilizadas no cuidado da saúde mental dessas mulheres, assim como verificar se há evidências científicas que justifiquem a implementação dessas práticas. MéTODOS:: Este estudo segue o protocolo PRISMA para revisões sistemáticas de 27 estudos publicados em 2012-2019, incluindo publicações em português, inglês e espanhol. RESULTADOS: Os resultados revelaram diferentes possibilidades de utilização da tecnologia, sendo o uso de mensagens de texto e de aplicativos em smartphones mais os utilizados (22,5%). No que se refere às ferramentas utilizadas, estratégias cognitivo-comportamentais, tais como verificação do humor, exercícios de relaxamento e psicoeducação compreenderam 44,12% do conteúdo. CONCLUSãO:: Verifica-se a necessidade de mais investimentos nessa área para que se possa compreender as possibilidades de intervenção em saúde mental na era digital.

Technologies Applied to the Mental Health Care of Pregnant Women: A Systematic Literature Review / Tecnologias aplicadas aos cuidados em saúde mental de grávidas: revisão sistemática da literatura

Abstract Objective: This article aims to review the literature regarding the use of technologies to promote mental health for pregnant women. We seek to: understand the strategies that pregnant women use for mental health care. Also, we investigate the existence of scientific evidence that validates such practices. Methods: This study follows the PRISMA guidelines for systematic reviews. We analyze 27 studies published between 2012 and 2019. We include publications in Portuguese, English, and Spanish. Results: The results revealed several different possibilities to use technology, including the use of text messages and mobile applications on smartphones. Mobile applications are the most commonly used approaches (22.5%). Regarding the strategies used, cognitive-behavioral approaches, including mood checks, relaxation exercises, and psychoeducation comprised 44.12% of the content. Conclusion: There is a need for further investigation and research and development efforts in this field to better understand the possibilities of intervention in mental health in the digital age.

Resumo Objetivo: Este artigo objetiva revisar a literatura quanto ao uso das tecnologias como promotoras de saúde mental de gestantes. Desta forma, compreender quais são as estratégias utilizadas no cuidado da saúde mental dessas mulheres, assim como verificar se há evidências científicas que justifiquem a implementação dessas práticas. Métodos: Este estudo segue o protocolo PRISMA para revisões sistemáticas de 27 estudos publicados em 2012-2019, incluindo publicações em português, inglês e espanhol. Resultados: Os resultados revelaram diferentes possibilidades de utilização da tecnologia, sendo o uso de mensagens de texto e de aplicativos em smartphones mais os utilizados (22,5%). No que se refere às ferramentas utilizadas, estratégias cognitivo-comportamentais, tais como verificação do humor, exercícios de relaxamento e psicoeducação compreenderam 44,12% do conteúdo. Conclusão: Verifica-se a necessidade de mais investimentos nessa área para que se possa compreender as possibilidades de intervenção em saúde mental na era digital.