Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs

Author Posting. © The Author(s), 2012. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Bioorganic & Medicinal Chemistry Letters 22 (2012): 2579-2581, doi:10.1016/j.bmcl.2012.01.119.Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.This work was supported by the National Institutes of Health (R01AI082577), Boston University and Northeastern University

Chemically modified dsRNA induces RNAi effects in insects in vitro and in vivo: a potential new tool for improving RNA-based plant protection

Global agriculture loses over $100 billion of produce annually to crop pests such as insects. Many of these crop pests either are not currently controlled by artificial means or have developed resistance against chemical pesticides. Long dsRNAs are capable of inducing RNAi in insects and are emerging as novel, highly selective alternatives for sustainable insect management strategies. However, there are significant challenges associated with RNAi efficacy in insects. In this study, we synthesized a range of chemically modified long dsRNAs in an approach to improve nuclease resistance and RNAi efficacy in insects. Our results showed that dsRNAs containing phosphorothioate modifications demonstrated increased resistance to southern green stink bug saliva nucleases. Phosphorothioate-modified and 2′-fluoro-modified dsRNA also demonstrated increased resistance to degradation by soil nucleases and increased RNAi efficacy in Drosophila melanogaster cell cultures. In live insects, we found chemically modified long dsRNAs successfully resulted in mortality in both stink bug and corn rootworm. These results provide further mechanistic insight into the dependence of RNAi efficacy on nucleotide modifications in the sense or antisense strand of the dsRNA in insects and demonstrate for the first time that RNAi can successfully be triggered by chemically modified long dsRNAs in insect cells or live insects

Selective Inhibitors of Protozoan Protein N-myristoyltransferases as Starting Points for Tropical Disease Medicinal Chemistry Programs

Inhibition of N-myristoyltransferase has been validated pre-clinically as a target for the treatment of fungal and trypanosome infections, using species-specific inhibitors. In order to identify inhibitors of protozoan NMTs, we chose to screen a diverse subset of the Pfizer corporate collection against Plasmodium falciparum and Leishmania donovani NMTs. Primary screening hits against either enzyme were tested for selectivity over both human NMT isoforms (Hs1 and Hs2) and for broad-spectrum anti-protozoan activity against the NMT from Trypanosoma brucei. Analysis of the screening results has shown that structure-activity relationships (SAR) for Leishmania NMT are divergent from all other NMTs tested, a finding not predicted by sequence similarity calculations, resulting in the identification of four novel series of Leishmania-selective NMT inhibitors. We found a strong overlap between the SARs for Plasmodium NMT and both human NMTs, suggesting that achieving an appropriate selectivity profile will be more challenging. However, we did discover two novel series with selectivity for Plasmodium NMT over the other NMT orthologues in this study, and an additional two structurally distinct series with selectivity over Leishmania NMT. We believe that release of results from this study into the public domain will accelerate the discovery of NMT inhibitors to treat malaria and leishmaniasis. Our screening initiative is another example of how a tripartite partnership involving pharmaceutical industries, academic institutions and governmental/non-governmental organisations such as Medical Research Council and Wellcome Trust can stimulate research for neglected diseases

La "tisanerie" réunionnaise (conséquences sur la végétation endémique des Mascareignes)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Découverte de composés à activité antiplasmodiale (nouvelle approche)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Activité antiplasmodiale de nouvelles tétrahydro-b-carbolines chirales (découverte et optimisation)

Chaque année, des millions de personnes sont infectées par Plasmodium, le parasite responsable du Paludisme. Les résistances nombreuses aux antipaludiques classiques ont créé un réel besoin de nouveaux traitements. Il est aujourd'hui essentiel de découvrir des molécules actives sur de nouvelles cibles antiparasitaires. Nous avons utilisé une stratégie peu courante consistant à s'inspirer de toutes les connaissances acquises sur une cible humaine pour concevoir des composés actifs sur une cible orthologue plasmodiale. Les phosphodiestérase (PDE) sont des enzymes responsables de l'hydrolyse des nucléotides cycliques AMPc et GMPc, seconds messagers impliqués dans l'homéostasie cellulaire. Ces enzymes sont exprimées chez tous les mammifères, mais aussi chez des organismes inférieurs comme Plasmodium. Nous avons conçu et synthétisé des inhibiteurs de phosphodiestérase dérivés du tadalafil, médicament inhibiteur de la PDE5 humaine, possédant un noyau tétrahydro- -carboline. Nous avons évalué leur activité antiplasmodiale et avons identifié des composés actifs in vitro et in vivo sur le parasite. Une étape d'optimisation des composés a été entreprise pour répondre aux exigences scientifiques et techniques d'un projet de développement d'un médicament antiparasitaire.LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF