A Replicative In Vitro Assay for Drug Discovery against Leishmania donovani.

The protozoan parasite Leishmania donovani is the causative agent of visceral leishmaniasis, a disease potentially fatal if not treated. Current available treatments have major limitations, and new and safer drugs are urgently needed. In recent years, advances in high-throughput screening technologies have enabled the screening of millions of compounds to identify new antileishmanial agents. However, most of the compounds identified in vitro did not translate their activities when tested in in vivo models, highlighting the need to develop more predictive in vitro assays. In the present work, we describe the development of a robust replicative, high-content, in vitro intracellular L. donovani assay. Horse serum was included in the assay media to replace standard fetal bovine serum, to completely eliminate the extracellular parasites derived from the infection process. A novel phenotypic in vitro infection model has been developed, complemented with the identification of the proliferation of intracellular amastigotes measured by EdU incorporation. In vitro and in vivo results for miltefosine, amphotericin B, and the selected compound 1 have been included to validate the assay

Effectiveness of a Virtual Exercise Program During COVID-19 Confinement on Blood Pressure Control in Healthy Pregnant Women

Background: The situation caused by COVID-19 has led to movement restrictions for the majority of the population due to the confinement established by the health authorities. This new situation has changed people’s habits and significantly affected the pregnant population. Decreased exercise and increased psychophysical stress are associated with excessive weight gain, diabetes, and gestational cardiovascular complications that affect the mother, fetus, and newborn. Recent research shows that the dynamics of maternal blood pressure is one of the most important control factors during pregnancy. Thus, prevention of these type of pathologies through interventions without maternal-fetal risks is important. Objectives: To examine the influence of a virtual exercise program on maternal blood pressure during pregnancy. Materials and Methods: A randomized clinical trial design was used (NCT04563065). Data from 72 pregnant women without obstetric contraindications under confinement conditions in the Madrid area were collected. Women were randomly assigned to the intervention (IG) or control group (CG). They previously signed informed consent forms. A moderate exercise program was performed as an intervention from 8–10 to 38–39 weeks of pregnancy. Systolic (SBP) and diastolic (DBP) maternal blood pressure were measured during the first, second and third trimesters of pregnancy, as well as before and immediately after delivery in both study groups. Results: No differences in systolic and diastolic blood pressure during the first, second and third trimesters were found between groups. Significant differences in SBP were found immediately before delivery (IG = 119.83 ± 10.16 vs. CG = 125.6 ± 10.91; p = 0.047) and immediately after delivery (IG = 115.00 ± 11.18 vs. CG = 122.24 ± 15.71; p = 0.045). Conclusions: Results show lower SBP values for the IG during delivery than CG. A virtual exercise program throughout pregnancy during COVID-19 confinement can help to control systolic blood pressure before and immediately after delivery in healthy pregnant women

Tetrahydro-2-naphthyl and 2‑Indanyl Triazolopyrimidines Targeting <i>Plasmodium falciparum</i> Dihydroorotate Dehydrogenase Display Potent and Selective Antimalarial Activity

Malaria persists as one of the most devastating global infectious diseases. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) has been identified as a new malaria drug target, and a triazolopyrimidine-based DHODH inhibitor <b>1</b> (DSM265) is in clinical development. We sought to identify compounds with higher potency against <i>Plasmodium</i> DHODH while showing greater selectivity toward animal DHODHs. Herein we describe a series of novel triazolopyrimidines wherein the <i>p</i>-SF₅-aniline was replaced with substituted 1,2,3,4-tetrahydro-2-naphthyl or 2-indanyl amines. These compounds showed strong species selectivity, and several highly potent tetrahydro-2-naphthyl derivatives were identified. Compounds with halogen substitutions displayed sustained plasma levels after oral dosing in rodents leading to efficacy in the <i>P. falciparum</i> SCID mouse malaria model. These data suggest that tetrahydro-2-naphthyl derivatives have the potential to be efficacious for the treatment of malaria, but due to higher metabolic clearance than <b>1</b>, they most likely would need to be part of a multidose regimen