Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments

From punishment to positive parenting : a review of parental support programs

Resumen: En Uruguay existe desde 2007 la Ley 18214 que prohíbe la utilización del castigo físico, tanto a padres como a responsables de la educación de niños y niñas. A pesar que la ley propone la realización de programas de sensibilización y educación que promuevan alternativas al castigo físico como forma de disciplinamiento, no existen aún propuestas que aborden la temática. En tanto, surgen datos inquietantes sobre la prevalencia de castigo físico en la infancia. El artículo presenta programas de apoyo parental basados en la parentalidad positiva, que previenen dificultades en el ejercicio de la crianza y promueven el desarrollo de los integrantes de las familias. Se destacan aquellos que cuentan con evidencia científica en cuanto al logro de sus objetivos.Abstract: In Uruguay, since 2007 Law 18214 prohibits parents and adults responsible for the education of a child, to use of physical punishment. Although the law also proposes the realization of sensitization programs and education to promote alternatives to physical punishment as a disciplinary strategy, there have not yet been proposals that address the issue. Meanwhile, there are disturbing data on the prevalence of physical punishment in childhood. This article presents parental programmes inspired in positive parenting, aiming to prevent difficulties in child rearing and promote development of all family members involved. Special attentionis paid to those that count with scientific evidence with refence to the goals achieved

Antiparasitic Meroterpenoids Isolated from Memnoniella dichroa CF-080171

Memnoniella is a fungal genus from which a wide range of diverse biologically active compounds have been isolated. A Memnoniella dichroa CF-080171 extract was identified to exhibit potent activity against Plasmodium falciparum 3D7 and Trypanosoma cruzi Tulahuen whole parasites in a high-throughput screening (HTS) campaign of microbial extracts from the Fundación MEDINA’s collection. Bioassay-guided isolation of the active metabolites from this extract afforded eight new meroterpenoids of varying potencies, namely, memnobotrins C-E (1–3), a glycosylated isobenzofuranone (4), a tricyclic isobenzofuranone (5), a tetracyclic benzopyrane (6), a tetracyclic isobenzofuranone (7), and a pentacyclic isobenzofuranone (8). The structures of the isolated compounds were established by (+)-ESI-TOF high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Compounds 1, 2, and 4 exhibited potent antiparasitic activity against P. falciparum 3D7 (EC50 0.04–0.243 μM) and T. cruzi Tulahuen (EC50 0.266–1.37 μM) parasites, as well as cytotoxic activity against HepG2 tumoral liver cells (EC50 1.20–4.84 μM). The remaining compounds (3, 5–8) showed moderate or no activity against the above-mentioned parasites and cells

Antiparasitic Meroterpenoids Isolated from <i>Memnoniella dichroa</i> CF-080171

Memnoniella is a fungal genus from which a wide range of diverse biologically active compounds have been isolated. A Memnoniella dichroa CF-080171 extract was identified to exhibit potent activity against Plasmodium falciparum 3D7 and Trypanosoma cruzi Tulahuen whole parasites in a high-throughput screening (HTS) campaign of microbial extracts from the Fundación MEDINA’s collection. Bioassay-guided isolation of the active metabolites from this extract afforded eight new meroterpenoids of varying potencies, namely, memnobotrins C-E (1–3), a glycosylated isobenzofuranone (4), a tricyclic isobenzofuranone (5), a tetracyclic benzopyrane (6), a tetracyclic isobenzofuranone (7), and a pentacyclic isobenzofuranone (8). The structures of the isolated compounds were established by (+)-ESI-TOF high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Compounds 1, 2, and 4 exhibited potent antiparasitic activity against P. falciparum 3D7 (EC50 0.04–0.243 μM) and T. cruzi Tulahuen (EC50 0.266–1.37 μM) parasites, as well as cytotoxic activity against HepG2 tumoral liver cells (EC50 1.20–4.84 μM). The remaining compounds (3, 5–8) showed moderate or no activity against the above-mentioned parasites and cells

A complete toolset for the study of Ustilago bromivora and Brachypodium sp. as a fungal-temperate grass pathosystem.

Due to their economic relevance, the study of plant pathogen interactions is of importance. However, elucidating these interactions and their underlying molecular mechanisms remains challenging since both host and pathogen need to be fully genetically accessible organisms. Here we present milestones in the establishment of a new biotrophic model pathosystem: Ustilago bromivora and Brachypodium sp. We provide a complete toolset, including an annotated fungal genome and methods for genetic manipulation of the fungus and its host plant. This toolset will enable researchers to easily study biotrophic interactions at the molecular level on both the pathogen and the host side. Moreover, our research on the fungal life cycle revealed a mating type bias phenomenon. U. bromivora harbors a haplo-lethal allele that is linked to one mating type region. As a result, the identified mating type bias strongly promotes inbreeding, which we consider to be a potential speciation driver

A complete toolset for the study of Ustilago bromivora and Brachypodium sp as a fungal-temperate grass pathosystem

Due to their economic relevance, the study of plant pathogen interactions is of importance. However, elucidating these interactions and their underlying molecular mechanisms remains challenging since both host and pathogen need to be fully genetically accessible organisms. Here we present milestones in the establishment of a new biotrophic model pathosystem: Ustilago bromivora and Brachypodium sp. We provide a complete toolset, including an annotated fungal genome and methods for genetic manipulation of the fungus and its host plant. This toolset will enable researchers to easily study biotrophic interactions at the molecular level on both the pathogen and the host side. Moreover, our research on the fungal life cycle revealed a mating type bias phenomenon. U. bromivora harbors a haplo-lethal allele that is linked to one mating type region. As a result, the identified mating type bias strongly promotes inbreeding, which we consider to be a potential speciation driver